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THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™ NOVEMBER/DECEMBER 2008

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EDITORIAL

e-Prescribing: A Move Toward Appropriate Medication Use Jack E. Fincham, PhD, RPh REGULATORY

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NOVEMBER/DECEMBER 2008

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EDITORIAL

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Publisher Nicholas Englezos nick@engagehc.com 732-992-1884

e-Prescribing: A Move Toward Appropriate Medication Use Jack E. Fincham, PhD, RPh

Associate Publisher Maurice Nogueira maurice@engagehc.com 732-992-1895

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Erythropoiesis-Stimulating Agents in a Meta-Stable State: Guidelines, Economics, and Policy in Flux Interview (Part 2) with Samuel M. Silver, MD, PhD Stakeholder Perspective by F. Randy Vogenberg, RPh, PhD

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Role for Automated Communication Strategies in Medication Adherence Management

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An Overview of Cholesterol Management Robyn A. Burns Schaiff, PharmD, BCPS; Richard M. Moe, MD, PhD; Daniel W. Krichbaum, PharmD Stakeholder Perspective: JUPITER by Wayne Kuznar Stakeholder Perspective by Thomas McCarter, MD, FACP

Editor-in-Chief Robert E. Henry rhenry@AHDBonline.com 732-992-1885

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GENERIC DRUG TRENDS Focus on Lowest Net Cost Drug Reduces Costs for Patients, Plan Sponsors Dana H. Felthouse, MBA

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FDA WATCH The Obama Administration and the FDA Mark Senak, JD

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Continued DEPARTMENTS

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AHA MEETING HIGHLIGHTS The Antiplatelet Drug Pipeline: Some Promising Candidates

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MEDICAL TOURISM Promotion of Medical Tourism in the Media Creates a Trend J. Warren Salmon, PhD

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American Health & Drug Benefits, ISSN 1942-2962 (print); ISSN 1942-2970 (online), is published 9 times a year by Engage Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205B, Monroe Township, NJ 08831. Copyright © 2008 by Engage Healthcare Communications, LLC. All rights reserved. American Health & Drug Benefits and The Peer-Reviewed Forum for Evidence in Benefit Design are trademarks of Engage Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher. Printed in the United States of America. Address all editorial correspondence to: editorial@AHDBonline.com, Telephone: 732-992-1889. Fax: 732-992-1881. American Health & Drug Benefits, 241 Forsgate Drive, Suite 205A, Monroe Township, NJ 08831.

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Managed Markets Marketing Jeffrey A. Bourret, MS, RPh, FASHP Charles E. Collins, Jr, MS, MBA Outcomes Research Gordon M. Cummins, MS Timothy S. Regan, BPharm, RPh Patient Advocacy William E. Fassett, PhD, RPh, MBA Pharmacoeconomics Jeff Jianfei Guo, BPharm, MS, PhD Pharmacy Benefit Design Jan E. Berger, MD, MJ Joel V. Brill, MD Paul A. Polansky, BSPharm, MBA Scott R. Taylor, RPh, MBA Pharmacy & Specialty Products James T. Kenney, RPh, MBA Policy & Public Health Joseph R. Antos, PhD Alex A. Hathaway, MD, MPH, FACPM Jack E. Fincham, PhD, RPh Reimbursement Policy Michael Schaffer, PharmD, MBA Grant D. Lawless, MD, BSPharm, FACP Research & Development Michael F. Murphy, MD, PhD Wayne A. Rosenkrans, Jr, PhD

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EDITORIAL

e-Prescribing: A Move Toward Appropriate Medication Use Jack E. Fincham, PhD, RPh

T

he way physicians order medications for patients has not changed for more than a century. New technologies, including electronic prescribing (e-prescribing), make the handwritten prescription seem like an archaic link to the past. e-Prescribing has been defined as the use of computing devices to enter, modify, review, and output or communicate drug prescriptions.1 The earliest application of physicians ordering medications and other therapies by computer was in hospitals in the 1970s; it became more prominent when the US Institute of Medicine endorsed its use as a way to reduce the 98,000 annual deaths from medication errors among hospitalized patients.2 Now we see the promotion of e-prescribing from varying parties. Current physician use of e-prescribing is estimated to be between 3% and 18%, depending on the definition used.

The need to change how drugs are ordered stems from the tremendous duplication, waste, and inefficiency in the current prescribing of medications. One of the earliest mentions of e-prescribing in the medical literature was in the early 1990s in a study conducted in Wales, which profiled the use of computers for refill prescription prescribing (ie, repeat prescribing).3 A small percentage (11%) of the Welsh physicians used computers for this purpose.3 The authors concluded the article with an exhortation that, “Mechanisms to encourage greater and more sophisticated use of computers and information technology need to be explored.”3 In the United States, e-prescribing was touted in the mid-1990s as a means to more accurately transmit physicians’ orders.4 Others suggested that it would lead to enhanced medication use in hospitals and beyond.5 Medicare has begun a process of incentivizing physicians who successfully use e-prescribing over a 4-year period. These payments amount to a 2%

Dr Fincham is Professor of Pharmacy Practice and Administration, University of Missouri School of Pharmacy, Kansas City, MO. His new book, e-Prescribing: The Electronic Transformation of Medicine, will be published in 2009. Some material from the book is presented in this editorial.

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incentive in 2009 and 2010, 1% in 2011 and 2012, and 0.5% in 2013.6 Alaska became the last of the 50 US states to enable e-prescribing in mid-August 2007. Varying estimates have suggested that 21% of physicians have access to information technology with e-prescribing systems in place.7 A recent survey showed that although a vast majority of the physicians surveyed (85%) think e-prescribing is a “good idea,” only 7% use the technology at present.8 Several observations are important. Small, independent pharmacies have been slow to upgrade their pharmacy management systems to accept e-prescriptions because of large fees charged by software vendors.

Large chain pharmacies embrace e-prescribing at the corporate level, but local store support is low, and there is inadequate training of pharmacy staff.9

The Limits of e-Prescribing A number of problems related to the prescribing, dispensing, and drug-use process will not be influenced by e-prescribing. Some of these are drug-specific, patient-specific, or system-specific. Patient medication noncompliance and persistence, over the counter (OTC) drug misuse, adverse drug reactions, prescribing errors, and/or dispensing errors are commonplace. No systems yet devised or planned can totally eliminate these problems from negatively influencing appropriate drug use in the US healthcare system.

There are fundamental flaws in the drug-use process in the United States. Medication compliance hovers around 50%, and prescription drug misuse is rampant.

OTC medications are misused. Adverse drug events (often preventable) occur because of inadequate information available. Antibiotic misuse and overuse has led to many drug-resistant strains. Despite recent changes to Medicare with the Part D program, many patients remain uninsured for prescription medications. e-Prescribing will not by itself affect these and other systemic medication-related error-producing system segments.

Despite elaborate and sophisticated health information technology (HIT)-enabled e-prescribing, errors will continue to be made. Physicians have the potential

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e-Prescribing

to make errors in prescribing (wrong patient; right patient wrong drug; wrong dose and/or wrong duration of therapy). Pharmacists also commit errors in dispensing, labeling, misreading orders, and/or dispensing to the wrong patient. Patients are also able to underdose, overdose, use the wrong drugs for the wrong length of time, and/or use the right drug for the wrong period of time.

A startling 15% of diagnoses are estimated to be made in error.10 Groopman further suggests that 80% of these errors are predictable, based on the compressed and hurried fashion in which physicians now diagnose patients’ maladies.10 e-Prescribing will not reverse this rate of inaccuracy. If the right drug is prescribed for the wrong diagnosis, the patient will always suffer.

The Benefits of e-Prescribing e-Prescribing provides enhanced decision support for the selection of prescription products, information about formularies, dosing and frequency of such formularies, checking for allergies to particular medications, drug interactions, avoidance of therapeutic duplication, and maximum or minimum doses. Many have noted that e-prescribing can provide computer-based support for creation, transmission, dispensing, and monitoring of drug therapies. Clinical decision support and computerized physician order entry have made impacts on medication errors and have been promoted as providing a major opportunity to make huge inroads on medication errors.11 e-Prescribing has been suggested to reduce clinical risk management and provide operational efficiency as well as access to electronic patient records. Enabling clinical risk management and enhanced communication can reduce the incidence of adverse drug events. e-Prescribing can provide a more accurate detailing of prescriptions and associated records.

Reduced Drug Spending Spending on drugs as a percentage of the total US healthcare spending increased slightly between 2006 and 2007, from 10.07% to 10.14%.12 Drivers for the significant costs of medications include increased technologies available, increasing numbers of patients and prescriptions per patient, and the number of seniors taking advantage of the Medicare Part D drug benefit.

Generic drug use accounts for more than 63% of prescriptions filled in the United States, but it remains only 20% of the total drug expenditures.13 One of the tangible benefits of e-prescribing in third-party programs is the potential to reduce excess spending on

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drugs that are not on plan formularies and to reduce spending on drugs for which generic substitutes are available and for drugs prescribed inappropriately.

Third-party plans include prescription drug plans, Medicare Advantage plans, and Medicaid plans that have formulary and generic option warnings that indicate to the prescriber and/or to the dispenser that a certain drug prescribed may not be appropriate. As more widespread adoption of e-prescribing by physicians occurs, rates of formulary compliance and generic drug utilization undoubtedly will increase.

Improved Drug-Use Process It is difficult to predict what issues will be addressed when in the new Congress. Attempts will undoubtedly be made to streamline the drug-use process from many angles and to reduce the rate of increase in drug expenditures. The compliance of prescribers and pharmacists with formulary guidelines will be enhanced by e-prescribing, and incorporating e-prescribing as a part of a greater emphasis on HIT applications will no doubt be front and center of proposals seeking to enable more efficient drug prescribing and therapeutic use.

Several segments of e-prescribing systems will enable drugs to be used more appropriately and thus less expensively. Physicians will have alerts about formulary acceptability or lack thereof when entering a specific drug for patients; in addition, pharmacists will have computer prompts that will serve as “gate keeper” warnings for nonformulary, expensive, and inappropriately prescribed drugs.

Practical Considerations • With hundreds of thousands of physicians’ offices still to be electronically equipped to transfer prescriptions, there will be a major shift in how prescriptions are transmitted. Drug-use records will need to be converted to digital access—how this will be paid for is a concern. The Centers for Medicare & Medicaid Services has and will continue to offer incentives for e-prescribing to encourage use.

• Physicians have lagged behind other professions in utilizing electronic communication. Studies have shown that only 17% of physicians communicate with their patients via e-mail.14 This percentage will increase once electronic medical records, HIT, and policy influences are better accepted by the medical community.

• As with any computer-associated programs, appropriate care will need to be taken in the training of physicians on how to use the program. e-Prescribing

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EDITORIAL

in and of itself will not solve all drug-related errors.

Some have suggested that e-prescribing will enhance patient compliance with medications. Data from European studies do not necessarily bear this out.15 e-Prescribing has been in place elsewhere in the world where we see national health insurance schemes and programs. This new technology will be effective only as far as it directly improves patient care and patient outcomes and does so in an economically sound fashion.

• e-Prescribing has unlimited potential to enhance the drug-use process from prescribing to the point of patient delivery of medications. Error reduction, precise dosing, help in choosing the appropriate drug, and enhancement of quality of care are but a few of the potential and very real consequences of eprescribing. As is often the case, the recognition of the many potential benefits and a thorough assessment of the issues that e-prescribing can and cannot address will bode well for all involved in the druguse process. For optimal effect, e-prescribing must be part of a comprehensive revamping of how information is gathered, stored, and shared in the healthcare delivery system. ■ References 1. Teich JM, Marchibroda JM. Electronic prescribing: toward maximum value and rapid adoption. A report of the Electronic Prescribing Initiative. Washington, DC: eHealth Initiative; April 14, 2004. http://ehr.medigent.com/assets/collaborate/2004/04/14/eHealth%20 Initiative%20Electronic%20Prescribing%20Report%2004.14.04%20

Executive%20Summary.pdf. Accessed October 28, 2008.

2. Institute of Medicine. To Err Is Human: Building a Safer Health System.

November 1999. http://www.iom.edu/Object.File/Master/4/117/ToErr 8pager.pdf. Accessed October 27, 2008.

3. Goves JR, Davies T, Reilly T. Computerisation of primary care in Wales. BMJ. 1991;303:93-94.

4. Siwicki B. Electronic prescriptions: just what the doctor ordered.

Health Data Manag. 1995;3:62-68.

5. Schiff GD, Rucker TD. Computerized prescribing: building the electronic infrastructure for better medication usage. JAMA. 1998;280:516-517.

6. US Department of Health & Human Services. HHS takes new steps to accelerate adoption of electronic prescribing. HHS.gov. July 21, 2008. http://www.hhs.gov/news/facts/eprescribing. html. Accessed October 28, 2008.

7. Grossman JM, Gerland A, Reed MC, Fahlman C. Physicians’ experiences using commercial e-prescribing systems. Health Aff (Millwood).

2007;26:w393-w404.

8. Glendinning D. Pharmacy benefit managers push Medicare e-prescribing. Am Med News. August 13, 2007. http://www.ama-assn.org/amed news/2007/08/13/gvsd0813.htm. Accessed August 17, 2007.

9. Mohr R, Islam S, Proctor K, et al. Readers’ perspectives: pharmacy benefit plans and pharmacies are moving expeditiously to support electronic prescriptions. Health Data Manag. 2005;13:88.

10. Groopman J. How Doctors Think. New York, NY: Houghton Mifflin; 2007:24.

11. Teich JM, Osheroff JA, Pifer EA, et al. The CDS Expert Review Panel. Clinical decision support in electronic prescribing: recommendations and an action plan. J Am Med Inform Assoc. 2005;12:365-376.

12. Poisal JA, Truffer C, Smith S, et al. Health spending projections through 2016: modest changes obscure Part D’s impact. Health Aff (Millwood). 2007;26:w242-w253.

13. The Henry J. Kaiser Family Foundation. Prescription Drug Trends.

May 2007. Fact Sheet (#3057-06). http://www.kff.org/rxdrugs/upload/ 3057_06.pdf. Accessed October 9, 2008.

14. Brooks RG, Menachemi N. Physicians’ use of email with patients: factors influencing electronic communication and adherence to best practices. J Med Internet Res. 2006;8:e2.

15. Chhanabhai PN, Holt A, Benwell G. Sustainable health systems: addressing three key areas. Stud Health Technol Inform. 2007;129:1139-1143.

CAPTION CONTEST Winners Receive $50

Submit your caption at www.AHDBonline.com Submission deadline: January 5, 2009 Winners’ names posted: January 7, 2009

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Eisai is proud to be joined in this new initiative by the North American Thrombosis Forum (NATF),*

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GENERIC DRUG TRENDS

Focus on Lowest Net Cost Drug Reduces Costs for Patients, Plan Sponsors Dana H. Felthouse, MBA

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he use of generic drugs is one of the key drivers of value in the pharmacy benefit today. Both drug benefit plan sponsors and beneficiaries realize cost-savings by increasing the use of generic drugs when medically appropriate. On average, generic drugs cost 30% to 80% less than their brand-name counterparts.1 It is important for plan sponsors and plan beneficiaries to understand the safety and efficacy of generic drugs, as well as the potential cost-savings.

Therapeutic Scope of Generics The increasing availability of generic drug therapies is slowing the rate of growth in prescription drug expenditures. For the first time since the mid-1980s, the growth in per-capita spending on prescription drugs has dropped below the percentage of growth in the US healthcare expenditures.2 The average rate of increase for drug expenditures for US employers in 2008 was 4.86%,3 according to findings from the 2008 Pharmacy Benefit Management Institute (PBMI)’s annual drug benefit plan design survey of US employers.3 This growth rate represents the lowest cost increase since PBMI began conducting its annual survey in 1995. This new survey, conducted in May and June 2008, was completed by 223 employers, representing 15,137,168 members. The increasing use of generic drugs contributes to this single-digit growth in expenditures.

When purchasers and consultants discuss generic drugs, they refer to 2 different rates or metrics—genericdispensing rate and generic substitution rate (Table 1).

Generic-dispensing rate is a clear metric for tracking progress in the use of lower-cost prescription drugs. In most cases, the generic-dispensing rate is the most Ms Felthouse is President, Pharmacy Benefit Management Institute (PBMI), Scottsdale, AZ. She has been the lead author of PBMI’s annual Prescription Drug Benefit Cost and Plan Design Report and PBM Customer Satisfaction Report since 2001. She can be reached at dfelthouse@pbmi. com. The annual reports can be accessed at www.pbmi.com.

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actionable metric to monitor improvement in generic use and the associated savings. PBMI’s 2008 study also documents continued increases in average generic-dispensing rates for US employers in retail and in mail dispensing since 2002 (Table 2).3 Generic-dispensing rates will continue to increase as more brand-name drugs used by ambulatory populations become available as generics.

The creation of incentives for plan members to use generic drugs is essential for a high-performing drug benefit program. Generic incentives are of increasing importance in 2008 as more branded drugs come off patent.

The result is a growing range of generic drug options to treat allergies, arthritis, asthma, depression, elevated cholesterol levels, hypertension, and chronic pain.

Education Tools for Plan Members Drug companies are spending billions of dollars to encourage consumers to request high-cost, brand-name drugs from their physicians. Consumers and drug benefit plan sponsors will realize reduced prescription drug costs if consumers make the choice to purchase the lowest-cost drug that is medically appropriate for their needs. Empowering consumers to make that choice is a challenge.

Complex benefit designs make it difficult for consumers to keep track of their plans’ preferred drugs and beneficiary cost-sharing, and discuss this information with their prescribing physicians. Consumers need access to up-to-the-minute information on their plans’ copayments and prescription costs to make educated, cost-effective decisions.

Repetition Research has shown that people often need to see or hear a message multiple times (as many as 7) before it makes an impression. Repetition is good, as is using a variety of ways to communicate because people have different learning styles. Organizations should leverage every available opportunity to deliver messages that increase confidence in and encourage the use of generics. Messaging opportunities include: • Direct mail targeted to high utilizers of prescription drugs

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Table 1 Must-Know Generic Terms

Tracking Availability and Price of Generic Drugs

• Generic-Dispensing Rate: Percentage of total prescriptions filled with a generic drug • Generic Substitution Rate: Percentage of total prescriptions that could be filled with a generic drug that actually are filled with a generic Source: Pharmacy Benefit Management Institute.

The ABCs of Generic Drugs. White Paper Series. 2008. http://www.pbmi.com/pbm101white paperseries.asp.

Table 2 Trends in Average Generic-Dispensing Rates Year

Average retail generic-dispensing rate, %

Average mail generic-dispensing rate, %

2002 2003 2004 2005-2006 2007 2008

42.0 44.0 47.0 51.0 54.5 60.4

32.0 34.0 38.0 39.0 41.7 49.3

Source: Pharmacy Benefit Management Institute. Prescription Drug Benefit Cost and Plan Design Report, 2008-2009 Edition. 2008. www. pbmi.com/2008_report/index.html.

• Employee meetings • Employee/retiree/member publications, both print and electronic • Employee/member intranet • Online tools for comparing brand and generic alternatives • Payroll envelopes and electronic funds transfer notifications • Podcasts • Posters in break rooms and high-traffic areas • Retiree association events.

Consumer Resources The following consumer-focused resources can supplement plan benefits communication efforts: • Consumer Reports Best Buy Drugs is an independent, online resource that helps beneficiaries learn about generic alternatives and empowers them to discuss cost-effective options with their physicians.

Beneficiaries can obtain free reports that compare the safety, efficacy, and cost of brand-name and generic drug options for 16 different medical conditions (www.crbestbuydrugs.org).

• The Generic Pharmaceutical Association offers consumer education on generics, including a frequently asked question-and-answer section and downloadable brochures (www.gphaonline.org/AM/ Template.cfm?Section=About_Generics).

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Using generic drugs to save money is a winning strategy for every drug benefit program. The savings begin when a brandname drug goes off patent. Here is a list of tools to help track the availability and price of generic drugs.

• Trends in Manufacturer Prices of Prescription Drugs Used by Medicare Beneficiaries: The AARP’s Public Policy Institute’s annual report on changes in manufacturer list prices for brand-name and generic drugs. Includes average annual percent change in manufacturer prices for the top 25 generic prescription drugs. Shows price changes by manufacturer and therapeutic category for the most widely used generic drugs. www.aarp.org/research/health/drugs/rx_ watchdog.html.

• Drug Patent Watch: Information on drugs and their patent expirations. Subscribe to free bulletins on imminent patent expirations. www.drugpatentwatch.com/.

• Drugs@FDA: Monthly drug approval reports. Searchable database of FDA-approved drugs. Search by brand name or active ingredient for availability of generic alternatives. www. accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm.

• FDA Electronic Orange Book: Searchable database of all FDAapproved prescription drugs—brand-name and generic drugs, with therapeutic equivalence evaluations. Daily updates for new generic approvals. www.fda.gov/cder/ob/.

• FDA Generic Drug Approvals: Monthly reports on first-time generic drug approvals. www.fda.gov/cder/ogd/approvals/ default.htm.

• Generic Pharmaceutical Association: Statistics and resources for consumers and researchers. Includes list of generic prescription medications recently approved by the FDA and guidelines for navigating the Drugs@FDA website. www.gphaonline.org/AM/Template.cfm?Section=Home.

• The US Food and Drug Administration (FDA) offers consumer education materials that can be downloaded, ordered in quantities, or used as resources for developing employer-specific materials.

Resources available in multiple languages include print brochures, posters, articles, PowerPoint presentations, audio presentations and handouts (www.fda. gov/cder/consumerinfo/generic_all_re sources.htm).

Aligning your drug benefit plan to encourage the utilization of the lowest net cost drug that is medically appropriate for a patient will enhance the clinical and economic returns of your investment in prescription drugs. ■

References 1. Generic Pharmaceutical Association. About generics: same medicine, same results, lower cost. http://www.gphaonline.org/AM/Template.cfm?

Section=About_Generics. Accessed November 10, 2008.

2. PricewaterhouseCoopers Health Research Institute. Behind the Numbers: Healthcare Cost Trends for 2008. 2008. www.pwc.com/extweb/ pwcpublications.nsf/docid/88FF5DC2E5E1143085257300006C68B1.

Accessed November 10, 2008.

3. Pharmacy Benefit Management Institute. Prescription Drug Benefit Cost and Plan Design Report, 2008-2009 Edition. 2008. www.pbmi. com/2008_report/index.html. Accessed November 10, 2008.

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“We either do it right or we don’t do it at all.” ©2008 Mylan Pharmaceuticals Inc.

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He’s kept his word for 47 Years.

In 1961, two U.S. Army buddies, Milan (Mike) Puskar and Don Panoz, founded a pharmaceutical company with a handful of employees in a small town in West Virginia. From the beginning, the founders were determined to build a company based on quality and integrity and to follow Mike’s philosophy—

“We either do it right or we don't do it at all.”

Over the past 47 years, that company, Mylan Pharmaceuticals, has grown to become the largest U.S.-based manufacturer of generic pharmaceuticals by total prescriptions*. . . and Mike Puskar is still Chairman of the Board. His no-compromise attitude continues to guide all aspects of company business, from research and development, to manufacturing and distribution.

Today, every employee in the Mylan family is always ready to take the extra step necessary to ensure that Mylan Products deliver the high quality that patients expect and deserve. This unwavering commitment assures that products from Mylan will always offer quality and affordability for the patients who need them and peace of mind for the pharmacists who dispense them.

*IMS National Prescription Audit. Total Prescriptions: June 2007 - June 2008.

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Erythropoiesis-Stimulating Agents in a Meta-Stable State: Guidelines, Economics, and Policy in Flux Interview (Part 2) with Samuel M. Silver, MD, PhD Medicare coverage of erythropoiesis-stimulating agents is a complex issue with implications for a variety of healthcare stakeholders. In the first part of the interview (see AHDB, May 2008), Samuel M. Silver, MD, PhD, examined the evolution and clinical implications of the Medicare coverage decisions and the eventual shift in clinical practice away from the approved indication to situations involving quality-of-life issues. In this second part, Dr Silver discusses with F. Randy Vogenberg, RPh, PhD, the clinical implications of the Medicare coverage decision regarding erythropoiesis-stimulating agents, pointing out the noneconomic reasons why transfusions can be risky to cancer patients, and how such policy decisions can have profound implications for patients. Dr Silver calls for new studies to be initiated, which would be funded by the 2 major manufacturers of these drugs, to investigate the concerns regarding tumor progression and thromboembolic events that are potentially associated with these expensive and potentially toxic medications. The discussion resumes where Dr Silver explains why it would be good to compare claims data of cancer patients who are receiving these medications and their transfusion requirements. [ADHB. 2008;1(9):14-18.]

F. Randy Vogenberg: There have been attempts to look at large claim databases (eg, WellPoint’s) of patients receiving erythropoiesis-stimulating agents (ESAs). News about the cutback on ESA use was accompanied by reports about the rise in the number of transfusions. At the same time, articles published in pharmacy and hospital journals were advocating the use of ESAs to avoid transfusions. So, the message is mixed. What people are doing in an inventory environment is not the same as what they are doing in an institutional inpatient environment. And hospitals may continue to use ESAs to avoid the more costly transfusion, a purely cost consideration. Is this how you see it?

Samuel Silver: I think this may be true. But the issue of transfusion is beyond cost, especially in the outpatient setting today, where 85% of cancer patient care occurs in the community and not in academic medical centers.

The first issue is that giving transfusions at centers such as the University of Michigan is relatively simple, and our facilities are well prepared to administer them.

Dr Silver is Professor of Internal Medicine, Director, Cancer Center Network, Division of Hematology/Oncology, and Assistant Dean for Research, University of Michigan Health Systems, Ann Arbor, MI.

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We have a good blood bank on site and plenty of chairs for transfusions, so we can get people set up, and we have blood irradiators (see below). But in the community, physicians by and large don’t give transfusions in their offices because of the administrative and procedural hassle. Rather, they send patients to their hospital outpatient infusion area, which is usually very small, where they can run out of transfusion chairs relatively rapidly, so that we now have a group of patients either requiring admission for transfusion or experiencing a significant delay waiting for an outpatient chair. And these are not patients with shortness of breath who require admission but rather it’s a quality-of-life (QOL) matter, because of the requirement of an inpatient stay.

The second issue is that the typical Medicare beneficiary has many comorbid conditions (eg, heart failure) in addition to cancer. Thus, we are no longer talking only about potential infectious complications of transfusion but also about issues of fluid overload that would not occur when using an ESA. The third concern is that many patients receiving chemotherapy, especially those with hematologic malignancies, are immunosuppressed. They require irradiated blood products to avoid transfusion-associated graft-versus-host disease. Irradiating blood is very easy; any university blood bank will have a blood irra-

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diator. It does not require much time, but it will add some expense. Nonetheless, it is well worth it.

However, if the patient is in a suburban or rural community, that patient may not have immediate access to irradiated blood and will have to wait a day or two to get it. So, all of a sudden something that would be simple for me at the University of Michigan becomes a process that takes several days for a patient that receives chemotherapy in a suburban or rural facility.

These are some of the noneconomic, procedural issues that are involved in giving transfusions.

Vogenberg: The other side of this issue concerns younger populations. The 50- to 60-year-old patient may still have a commercial insurance and not Medicare. Thus, there are also direct economic costs to consider, such as absence from work, particularly when the patient may be tied up for a day or two, as you said. There are many repercussions for Medicare, which is the focus for the Centers for Medicare & Medicaid Services (CMS), and for commercial insurers and employers, who are paying the bills. This is not well understood; the tendency is to just look at the drug cost and the drug companies, and this is more emotional than rational.

KEY POINTS ▲ Despite the high costs of the ESAs, the issue of transfusions

in cancer patients is beyond economics. ▲ The noneconomic issues surrounding transfusions that trans-

late to unnecessary risks for patients are: 1. Inadequate facilities that mean long waiting periods 2. Many patients are Medicare beneficiaries and thus often have multiple comorbidities 3. These patients are often immunosuppressed, requiring irradiated blood products, which could be a problem in nonacademic centers. ▲ Although Medicare is not supposed to consider costs in its

decisions, cost is an underlying context for Medicare coverage for these very expensive medications, which, nevertheless, may reduce hospitalization for transfusions.

Silver: In the meantime, Representatives Peter Stark and Henry Waxman are saying they are protecting the patients from this “miracle grow for tumors.”

And because we have no quality-of-life (QOL) data, there are no improvements in QOL issues. Now what do we do? We definitely require more data.

Silver: True. And the next thing we know, we are talking about Medicare Part B, and we begin to reach out to Medicare Part A, when we start admitting people to the hospital. Apparently those involved in Medicare Part B decisions don’t see this, but we certainly see this as citizens and on the private side. And the employers see this. So the US Food and Drug Administration (FDA) has issued new warnings, which essentially reflect the concerns about potential tumor progression, venous thromboembolism, and keeping the hemoglobin level at <12 g/dL (although this cut-off measure was dropped by the FDA from the most recent ESA labeling).

The FDA reiterated this in its most recent statement. That is where we are from the point of view of the FDA and CMS. And the Senate passed a nonbinding resolution about it, since the Senate has a sense that the National Coverage Decision (NCD) has no weight and should be changed.

Silver: CMS is not transparent at all. When you read the NCD, their background materials have been tightened up a bit. But the intellectual basis to bridge between the final coverage decision background material and the rules is missing.

Vogenberg: This NCD issue probably comes at a good time for CMS, because the current Congress is deadlocked on many issues. So nothing is going to happen. There are no repercussions against CMS’s decision about ESAs, and it can come back and say it has saved a lot of money, while preventing further harm to their beneficiaries. It is really almost a neutral situation from a public policy perspective.

Vogenberg: This is very typical of what you would see in almost any insurance company. You get caught up in this dynamic of economics and cost, and you are trying to provide just enough access so that people are happy, but at the same time less attention is paid to QOL than to the science, so it really is about economics. For CMS, it appears to be about money. They had to stay within a budget, and they

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The next thing we know, we are talking about Medicare Part B, and we begin to reach out to Medicare Part A, when we start admitting people to the hospital.

Vogenberg: How transparent is CMS regarding its data?

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knew the ESA coverage was a budget buster and a highexpenditure category, as it is for any employer. This is the perfect moment to come up with a Solomon-like decision.

CMS is not required to disclose as much as the FDA. This makes it easier for the commercial carriers to follow suit.

Medicare is not supposed to talk about costs or to consider it in its decisions, but of course it is the underlying context.

Silver: In addition, CMS will identify 10 more questions that should be answered, as they did 1 year ago, even though many of these questions are unanswerable, because the data don’t exist, and CMS knows it; a true Catch-22.

Vogenberg: This points to an interesting dichotomy between what the Agency for Healthcare Research and Quality is doing and Medicare Part D initiatives and the general Medicare initiatives about quality issues in hospitals, such as pay-for-performance. On one hand, CMS is saying it is going to pay for improved performance and outcomes in the hospitals, which, based on the current literature, suggests they would be using ESAs; these drugs lead to better results and reduce complications and readmissions, which are the criteria for quality. But on the other hand, Medicare coverage decision, which was based on an outpatient basis, prevents clinicians from using these drugs.

Silver: That brings up an interesting point. In CMS’s Physicians’ Quality Reporting Initiative, one of the early reporting initiatives dealt with the use of ESAs in myelodysplastic syndrome (MDS). It was necessary to make sure patients had sufficient iron stores, which was a quality point. Yet, the payment for MDS associated with ESAs was denied at that time, as we discussed in the first part of this interview (AHDB. May 2008;1[4]:46-50).

Vogenberg: And then it could be argued that the cost of these medications is too high?

Silver: Actually, Medicare is not supposed to talk about costs or to consider it in its decisions, but of course it is the underlying context.

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Vogenberg: And what is the Veterans Administration (VA) doing with the coverage?

Silver: I do not have the answer to that. The VA has an excellent electronic medical records system; however, in the past few months the VA was unable to use any of their data for Health Services Research purposes because of confidentiality and HIPAA (Health Insurance Portability and Accountability Act) issues.

Vogenberg: There must have been some kind of analyses done within the VA military review structure when all this was transpiring, because they are so cost and quality conscious. I wonder what the VA system is doing about TRICARE and the active military, which represents a large population?

Silver: This is a very important issue. The FDA has asked the American Society of Clinical Oncology (ASCO) and the American Society of Hematology (ASH) to determine what studies should be done in the future. ASH has asked the American Association of Cancer Research (AACR) to participate in this initiative. We are trying to convene a meeting with representatives from the FDA, CMS, ASH, ASCO, and AACR to determine what trials are needed and who should be running them.

Vogenberg: Would they be doing a corresponding health economics analysis with clinical studies parameters?

Silver: That would be an important thing to look at as well, but the executive committee of ASH believes that the National Institutes of Health (NIH) should not be paying for such studies to help determine the best hemoglobin range for ESA use. The Executive Committee is concerned that this type of study costs a lot of money. And diverting NIH money for this clinical question would leave less money for important basic science research.

Vogenberg: That is a good point.

Silver: It would be important to engage both Johnson & Johnson and Amgen to design an open study that would be funded by an unrestricted grant from both drug manufacturers to examine the pathophysiology of ESA-associated thromboembolism. And maybe we should involve the NIH and the National Cancer Institute or the National Institute of Diabetes and Kidney Disease to address issues surrounding end-

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stage renal disease (ESRD). So we need to focus on 3 aspects of the drugs—tumor promotion, the biology of venous thromboembolism, and the relationship to ESRD, which can teach us a lot. And these 3 things should happen in parallel, along with the economic issues that are related to these clinical considerations.

Vogenberg: Clinically speaking, where would you want the focus of these studies to remain?

Silver: Future studies should somehow focus on QOL in a meaningful way. Combining the efforts of Johnson & Johnson and Amgen may be effective. In that way, individual marketing agendas could be put aside. For at least the moment, private payers have been using the ASH/ASCO guidelines as opposed to Medicare guidelines. This, of course, could change tomorrow. When I spoke with Dr Lee Newcomer of UnitedHealthcare a while back, he made no promises. He seemed to think it was very reasonable to use the ASH/ASCO guidelines, using an initial hemoglobin level of <10 g/dL, and then maintaining patients at hemoglobin levels between 10 g/dL and 12 g/dL. As I mentioned in the previous article in this journal (May 2008), oncologists have come to view this issue with concern; we are generally maintaining patients at or below hemoglobin levels of 12 g/dL. Vogenberg: Are physicians still providing ESAs as freely as they had before the new Medicare coverage ruling was announced?

Silver: No. In fact, the number of those using ESAs has declined significantly. This may have been associated with the FDA issuing the black box warnings in March 2007. I think the bottom line is that most physicians want to use drugs in a reasonable way, and perhaps they overcompensate when they hear the cynical perspective about perverse physician incentives. So when the black box warning was issued, there was a great deal of self-correction.

Vogenberg: Carriers will be more willing to take the soft approach UnitedHealthcare has taken, unlike that taken by Medicare. They will seek the benefit of the reduced expenditures by informing their provider networks and offering them the opportunity to avoid potential complications and to be in compliance with the guidelines. This could be a winwin situation for everybody.

Silver: Possibly. But it is a complicated issue. Pa-

tients getting chemotherapy are receiving toxic agents with therapeutic ratios that are some of the most difficult in medicine. Many of the patients, especially those in the Medicare population, have incurable cancers; they are receiving chemotherapy mainly for palliation.

The goal is to give them as high a QOL as possible. If they are receiving chemotherapy and spend the last 2 months of their lives in the hospital, we are not doing the right thing.

Debilitating patients for the majority of their remaining time to shrink a tumor is not good care. A Pyrrhic victory in this scenario is no victory at all. And using a drug that potentially can cause thromboembolic events only complicates this picture.

I was called to an FDA meeting in which a patient representative was anxiously going on about tumor growth associated with ESAs that patient was receiving. This is a difficult thing to say, but having progression of an incurable cancer is not always the worst thing that can happen. Chemotherapy is rarely provided with curative intent in this population. Appropriate palliation may include chemotherapy along with adjunctive therapies, such as ESAs, that may cause a small risk of tumor growth.

We need to focus on 3 aspects of the drugs—tumor promotion, the biology of venous thromboembolism, and the relationship to ESRD, which can teach us a lot.

Vogenberg: This is a valid point that many people forget. Patients who are seriously ill often lose sight of reality or don’t want to face it.

Silver: Right. Sometimes we need to reach deeper into the bag for more information.

As I have said, finding this would be tantamount to finding the Holy Grail, and unfortunately, you cannot infallibly predict outcomes. ■ Disclosure Statement Dr Silver is a consultant to Bear Stearns, Lehman Brothers, and the Gerson Lehrman Group, and receives grant/research support from Blue Cross Blue Shield of MI.

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Stakeholder Perspective The Clinical and Economic Complexity of Biologics PAYERS/PATIENTS: The inability to predict outcomes with erythropoiesis-stimulating agents (ESAs) or with other biologic agents is emerging as a key concern. Whether in rheumatoid arthritis, multiple sclerosis, or erythropoiesis, unintended or unknown effects from these new biologic medication technologies are gradually better detected and better understood, helping to determine the most appropriate uses. From the perspective of economic decision makersâ&#x20AC;&#x201D;patients, health plans, or employersâ&#x20AC;&#x201D;the easy clinical decision to use biologic medications has become muddier, while these same (typically elderly) patients are rethinking their need for a wider variety of end-of-life therapies that have focused more on quality-of-life issues than on changing the lifespan.

ESAs provide an interesting insight into the complexity of clinical use of biologics and their economic impacts on all payers, as well as the types of clinical service providers. Given that many patients who are using biologics are covered under a Medicare drug plan but also have multiple comorbidities, this further illustrates the dilemma of finding a technological advancement end point where costs become more predictable. As Dr Silver points out in the interview, several concerns involving patients who receive ESA therapy go beyond a single decision point.

Because of the paucity of data to clearly guide the multipoint clinical and coverage decisions, the Centers for Medicare & Medicaid Services (CMS) and private insurers are erring on the side of limited coverage, following the evidence-based medicine (EBM) model. Although in itself not siding with any coverage position, EBM can conveniently be used for any stakeholderâ&#x20AC;&#x2122;s position, whether economic or clinical. In the case of ESAs, there seems to be a clinical and an economic dilemma forebod-

ing of the bigger and more expansive decisions our society faces through the lens of healthcare insurance coverage for the growing pipeline of biologicbased technologies.

The role of regulators (CMS, US Food and Drug Administration) and system researchers (Association for Healthcare Research and Quality, quality improvement organizations) should be determined by Congress to better align incentives, along with a clearer direction for the use of new technologies (diagnostic or therapeutic). Mixed messages and misalignment of incentives has long been an albatross around the US healthcare system that has fed many debates and articles arguing the myriad of issues relevant to each of the stakeholders.

This has been good for academics, consultants, and special interest lobbyists, but not for frontline patients and healthcare professionals, or those paying the bills for care.

Based on reports from the recent presidential campaign and from groups such as the Kaiser Foundation or the Wall Street Journal, neither party nor either of the candidates has had the single obvious solution to our looming healthcare crisis in the next decade. Perhaps our economic distress will aid patients, as reflective of our society, in establishing new parameters around life-and-death decisions that will help our healthcare system seek a new balance in harnessing technologies for the most appropriate use, which will then determine its hierarchical cost in our economy.

F. Randy Vogenberg, RPh, PhD Chief Strategy Officer Employer-based Pharmaceutical Strategies, LLC Senior Scholar, Department of Health Policy Thomas Jefferson University, Jefferson Medical School

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Early and intensive treatment can help patients reach their A1C goal Are your plan members not taking their type 2 diabetes medications? s Many patients are not reaching the ADA A1C target goal of <7%, and many are stopping their medications.1,2

Recent data show a drop in the use of oral antidiabetic medications3 2,500

TRx (000s)

2,400 2,300 2,200

OAD TRx 4 week moving avg

Trend (Pre-NEJM)

2,100 2,000 3/16/2007

Days

6/6/2008

The need for early treatment s Because many patients already have chronic complications at the time of diagnosis, treatment plans must be aggressive from the start to optimally manage type 2 diabetes.4 s Long-term benefits of diabetes medications can only be realized if patients adhere to their treatment regimen.2

“Early, intensive intervention has the potential to get patients to glycaemic goals more quickly and be more effective at keeping them at goal...” 5

References: 1. Hoerger TJ, Segel JE, Gregg EW, Saaddine JB. Is glycemic control improving in U.S. adults? Diabetes Care. 2008;31:81-86. 2. Rodgers K. Ensuring compliance in patients with diabetes. In: Diabetes: Disease Management Guide. 4th ed. Montvale, NJ: Thomson PDR; 2004:501-505.

3. Data on file, Takeda Pharmaceuticals North America, Inc. 4. Cornell SA. Clinical case study: achieving long-term control of insulin resistance. J Manag Care Pharm. 2007;13(suppl B):S11-S15. 5. Goldstein BJ, Gomis R, Lee H-K, Leiter LA, on behalf of the Global Partnership for Effective Diabetes Management. Type 2 diabetes—treat early, treat intensively. Int J Clin Pract. 2007;61(suppl 157):16-21. ©2008 Takeda Pharmaceuticals North America, Inc.

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Role for Automated Communication Strategies in Medication Adherence Management S. Michael Ross, MD, MHA Lack of medication adherence is a prevalent problem that causes a broad range of healthand health-economics–related issues. Adherence management is therefore an important strategy, but it also presents its own set of challenges. Interventional communication from care support teams at managed care organizations and disease management and wellness programs has proved effective at modifying patients’ medication adherence and reporting behaviors. However, these communications do not work well from an economic standpoint.

It is not economically feasible to scale call centers and the numbers of clinical and professional staff to communicate with the increasing number of patients with chronic diseases who require ongoing medication use. Using communication automation to augment traditional call center outreach can help to mediate patient medication-taking behaviors. Specific design criteria for the automation of this interaction are discussed in this article, offering supporting data from a recent trial of 304 elderly patients with hypertension, and showing the benefits of using such a system for effective blood pressure monitoring, at reduced costs. [AHDB. 2008;1(9):20-27.]

“Drugs don’t work in patients who don’t take them.” —C. Everett Koop, former US Surgeon General

A

dherence to medications is essential for patients with chronic disease for optimizing clinical outcomes. When used appropriately, medication is a very cost-effective method for treatment and prevention of disease. Patients who fail to take their medications as prescribed do not get the full benefit from the drugs, and they may also end up with unnecessary hospitalizations, emergency department visits, and nursing home admissions. Cost-effective, scalable interventions are essential to reduce nonadherence. In this article, we examine the use of automated phone-based patient communication to support outreach efforts, as well as the impact this type of intervention can have on clinical outcomes and costs.

In their 2005 study of medication-taking behaviors, Osterberg and Blaschke observed that, “Common barriers to adherence are under the patient’s control, so attention to them is a necessary and important step in improving adherence.”1 In that study, the following reasons were cited by patients for not adhering to their

Dr Ross is Vice President of Healthcare, Varolii Corporation, Seattle, WA.

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medication regimens1: • Forgetfulness—30% • No reason—27% • Other priorities—16% • Decision to omit doses—11% • Lack of information—9% • Emotional factors—7%.

Lack of information and forgetfulness combined comprise 39% of the reasons cited in this study for poor medication ahderence.1 These 2 areas can be positively affected by improved communications between the care provider and the patient that, in turn, can improve medication adherence.

One other common and well-documented reason for poor adherence is side effects.2,3 Patients who experience unpleasant or unexpected side effects may stop taking their medications, often without informing their physicians or other care providers.2,3 In their study, Osterberg and Blaschke further observe that there are 4 general methods to help improve patient adherence1: 1. Patient education 2. Revised dosing schedules

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3. Expanded hours when the clinic is open, including evening hours 4. Shorter wait times and improved communication between physicians and patients.

Although not all of these general methods are relevant to our topic, patient education and communication between physicians and patients are 2 areas that can be affected by effective communications.

Illustrative Case Tom’s blood pressure (BP) was elevated during his past 2 visits to his physician. At the most recent visit, his doctor suggests an antihypertensive regimen and prescribes lisinopril. Tom fills the prescription order for lisinopril at the local pharmacy and takes it home. As part of his routine care, Tom schedules a follow-up examination. After a period of time, we may expect a reduction in Tom’s BP level. But instead, at his follow-up visit, Tom’s BP is still elevated. Was lisinopril ineffective in Tom’s case? Not necessarily. In fact, the medication might well have proved effective if Tom had remembered to take it. But Tom took the first day’s dosage, put the bottle in his medicine chest, and then promptly forgot about it. He also was not reminded to take the medication.

The Challenge: Improving Care for 10 Million “Toms” Tom is not alone. Findings from Osterberg and Blaschke’s study show that, “Of all medication-related hospital admissions in the United States, 33% to 69% are due to poor medication adherence, with a resultant cost of approximately $100 billion a year.”1 In addition, according to well-documented surveys, failure to adhere to treatment, also known as noncompliance, is a large-scale problem.4,5 The 2006 Case Management Adherence Guidelines, issued by the Case Management Society of America, offer insight into the magnitude of the issue, noting that “the number one problem in treating illness today is patients’ failure to take prescription medications correctly, regardless of patient age.”4 In a 2003 study, the World Health Organization found that approximately 50% of the 1.8 billion prescription medications dispensed annually in the United States are not taken correctly by patients.5 It is reasonable to assume that at least some of these nonadherent patients are not receiving the full benefits of the prescribed medication. In 1998, nonadherence to heart disease medication regimens alone was reported to be the cause of 125,000 preventable deaths each year in the United States.6 This places medication nonadherence among the major causes of health-related deaths in the

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KEY POINTS ▲ Medication nonadherence is a major cause of morbidity and

mortality, and is a large contributor to escalating healthrelated economic costs. ▲ Lack of information and forgetfulness are 2 main reasons for

nonadherence that can be positively affected by improved patient–provider communication. ▲ With chronic diseases estimated to involve hundreds of

millions of patients, the scale of disease management enrollment is too great to be cost-effective using traditional outreach methods. ▲ The challenge is to scale outreach programs efficiently, with-

out losing the personal touch necessary to help change behavior. ▲ In a new study of automated telephony for blood pressure

monitoring, this technology reduced the cost of blood pressure reading by 95% compared with supportive care reading. ▲ The study results suggest that efficient, effective automated

communications with patients can produce positive clinical outcomes at reduced costs.

Table

Medication Nonadherence Major Cause of Death in the United States Condition Annual deaths, N 1. Heart disease 652,091 2. Cancer 559,312 3. Stroke 143,579 4. Chronic lower respiratory diseases 130,933 5. Medication nonadherence 125,000* 6. Diabetes 75,119 7. Alzheimer’s disease 71,599

* This number refers to medication nonadherence deaths from heart disease alone; the number for all deaths from medication nonadherence could therefore be higher. Source: McCarthy R. The price you pay for the drug not taken.

Bus Health. 1998;16:27-33.

Source: Kung HC, Hoyert DL, Xu JQ, Murphy SL. Deaths: final data for 2005.

Natl Vital Stat Rep. 2008;56:1-120.

United States, after heart disease, cancer, stroke, and chronic lower respiratory diseases, according to the 2005 National Vital Statistics Reports (Table).7 In reality, deaths from all medication nonadherence could be much larger than the 125,000 deaths for heart disease only.

Patients who stop taking medication as a result of forgetfulness, lack of information, or side effects can often be helped by effective outreach from their physician or clinical care professionals to remind patients to take their medications, elicit information about side effects and their impact on noncompliance, offer encouragement, and even connect them with their

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Figure 1 Average Annual Prescriptions Filled by Noninstitutionalized Medicare Enrollees, ≥65 y Prescriptions filled, % 60

57

50 42

40

32

30

30 23 20

23

24

18 10

10 0

1992 1996 2000 Year

0 1-2 3-4 5+ Chronic conditions (N), 2000

Yes No Rx coverage, 2000

Source: Cherry DK, Woodwell DA, Rechtsteiner EA. National Ambulatory Medical Care Survey: 2005 summary. Adv Data. 2007;(387):1-39.

clinical care team, if needed. This, in fact, is one of the key premises around which managed care organizations (MCOs) and wellness programs are organized: by offering regular, relevant “interventional” communications in a structured program, these organizations can positively affect medication-taking behaviors of their program members.

Health Economics: The Costs of Noncompliance Adherence is critical to everyone involved in healthcare: from patients and payers (insurance, government, employers) to retail pharmacies and pharmaceutical manufacturers. And it is the sheer number of these patients that forms the heart of the adherence challenge. For patients, adherence is an important factor in improving clinical outcomes; this issue has been well documented in the literature.1 Indeed, the Case Management Society of America observes, “Nonadherence to medications is a common factor that prevents patients from achieving the full therapeutic benefit of their therapies.”4 For organizations, improved patient adherence means the ability to deliver better care while reducing medical expense ratios driven by unnecessary hospitalizations, emergency department visits, nursing home admissions, and excess consumption of interventional treatments.5 For manufacturers and retail pharmacies, whose nonadherent patients do not fill prescriptions as indicated, or who have poor medication possession ratios, improving patient adherence is not only important to

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patient health but can also affect bottom-line revenues.

Let’s return briefly to our hypertensive patient, Tom. During the follow-up appointment, Tom’s doctor asks if he is taking his medication as prescribed. Tom sheepishly admits he has forgotten. Tom’s doctor reminds him of the importance of taking medications as prescribed, and provides information about hypertension, the associated health risks of stroke and heart attack, and strongly encourages him to “stick” with the medication regimen. Concerned about his health and encouraged by his healthcare provider, Tom signs up for a wellness program through his employer. A care representative from the wellness program contacts Tom, enrolls him in the program, and begins to provide him with information, tips, and additional encouragement.

The outcome? Tom’s BP is much better managed now, and he will likely have an improved clinical outcome as a result.

Of course, Tom is a hypothetical patient, but this is a common story for millions of real patients with hypertension. Illustrative of the scale of this particular condition, the 2005 National Ambulatory Medical Care Survey revealed that there were 44 million visits to office-based physicians with hypertension as a primary diagnosis.8 Further complicating the issue is the fact that many of these patients may be older and may take more than 1 medication regularly.4 We live in a society experiencing a “graying” of its population, as the baby boom generation begins to mature past the age of 65 years.

Many boomers, as well as millions of others, will be prescribed multiple medications (Figure 1) for chronic conditions, such as hypertension, high cholesterol, depression, and diabetes.8 The Centers for Disease Control and Prevention’s (CDC) Health, United States, 2007, survey shows that slightly more than 30% of all individuals between the ages of 45 and 64 had taken 3 or more prescription medications in the past month.9

Provider Communication It is well-documented that clear, consistent provider communication can have a positive impact on patient well-being. In an article on literature searches for physician–patient relations, Stewart notes that “Most of the studies reviewed demonstrated a correlation between effective physician–patient communication and improved patient health outcomes.”10 Thus, it is not surprising that regular, consistent communications from care support teams, such as those in wellness organizations, can have the same

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effect. If it were just 1 doctor effectively communicating to 1 patient the importance of consistently taking medication as prescribed, it might be easier to resolve the adherence problem. But, as we have noted, there are tens of millions of “Toms” with a variety of chronic conditions who require this type of outreach. The CDC notes in its Health, United States, 2007, that in 2005, the percentage of adults with 3 or more chronic conditions increased with age from 7% of adults aged 45 to 54 years to 37% of adults aged 75 years and older.9 Although managing chronic conditions is a problem of scale, the real challenge lies in scaling efficiently, without losing the personal touch necessary to help change behavior.

tive (and often is with small populations). For the organizations paying for these programs, cost benefits are largely dependent on the ability to reach large numbers of patients, enroll them, and provide ongoing health and wellness support. Considering that the number of individuals with chronic diseases is estimated to be in the hundreds of millions, the scale of enrollment is too great to manage cost-effectively with traditional outreach methods.

For organizations, improved patient adherence means the ability to deliver better care while reducing medical expense ratios driven by unnecessary hospitalizations and excess interventions.

The Economics of Outreach: Scaling Clinical Call Centers Is Expensive Clinical outreach centers typically employ a blend of trained care professionals and clinical care professionals, such as registered nurses and pharmacists. The fully loaded hourly wage of these individuals can exceed $50, which means the cost of even a relatively brief (15-20 minute) phone call can approach $20. This figure is conservative, given that the industry-standard cost for a call for technical support centers ranges between $20 and $40,11 using significantly less costly staff. This cost does not decrease with increased call center staff or with larger numbers of patients to call, so organizations’ abilities to scale outreach programs using care representatives are significantly limited.

Today, health plans and disease management programs are evolving new strategies and solutions to help their patient populations adhere to treatment plans.

We suggest that any strategy must meet 2 primary tests: 1. Is it efficient? Efficient solutions scale well and offer a low marginal cost of operation.

2. Is it effective? Effective solutions deliver similar response rates and engagement rates as the current gold standard—human outreach by care support representatives.

Communication Works, but Not Cost-Effective In the Medicare Health Support phase 1 study, the Centers for Medicare & Medicaid Services determined that the value delivered by these programs does not overcome program costs.12 It was simply not cost-efficient (nor economically feasible) for clinical staff or care support specialists to communicate with even moderately large at-risk populations. And yet, the same study found that this type of interventional communication had a clear beneficial impact on participants.

“Participating beneficiaries tend to be a healthier and less-costly subset of the intervention group. Thus, high participation rates will likely be a factor in the ability of the [Medicare Health Support organizations] to impact their assigned intervention populations.”12 And although human communication is certainly the benchmark for clinical results, automating communication shows some positive results. Properly implemented, this form of communication may deliver similar clinical results at a far lower marginal cost.

What Needs to Be Done Today and Tomorrow Traditionally, MCOs and disease management programs use a broad range of outreach methods, including nurses or other specialty practitioners to contact participants, review program benefits, respond to questions, and ultimately, enroll members. Once enrolled, these same specialists may contact members for surveys, health status updates, medication reminders, and other communications designed to foster compliance.

In principle, this form of operation should be effec-

Communications Automation: Scalable Interaction for Large Populations As noted earlier, any type of automated communication must be able to connect efficiently with large numbers of patients or members. Automated communication must also connect effectively, by delivering an experience that resembles an actual clinician–patient interaction. Modern communications systems can be modeled against good examples of productive clinical interactions (eg, a system could emulate the voice and

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persona of an experienced call center representative or an outreach nurse).

Effective interventional dialogue with patients involves understanding the patient’s specific concerns and health beliefs, embracing that information, and then using it to tailor interventions specific to their needs. When insights such as these are applied to the treatment regimen, adherence improves dramatically.13 And as discussed before, improved adherence can provide a positive boost to health outcomes, both proximal and for the long-term.

Automated patient communication offers additional potential benefits. With the majority of contacts managed through an automated system, organizations can optimize the use of live agent care support resources by triaging those patients most in need, thereby responding more efficiently to critical patient care questions (see below).

The ability to deliver automated patient communication programs efficiently and effectively may offer additional distinct advantages, including increased scope and improved health economics.

The ability to deliver automated patient communication programs efficiently (at a low unit cost) and effectively (with a positive result across the majority of respondents) may offer additional distinct advantages, including increased scope (the lowered unit cost improves the provider’s ability to reach out to more patients or members) and improved health economics (improved individual outcomes across a broad segment of the at-risk population that contributes to improvement in the aggregate outcome profile).

Key Criteria for Successful Automation of Patient Outreach Communications Varolii Corporation’s healthcare division has been communicating with tens of millions of patients on a monthly basis on a variety of healthcare-related areas.

Based on the experience of delivering these automated calls, and on Varolii’s general experience in delivering billions of automated notifications over the past several years in a variety of industries, we believe that 5 key criteria can determine whether automated communica-

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tions will serve as a useful adjunct to patient outreach.

These criteria revolve around the concepts of efficiency and effectiveness discussed earlier: 1. Scalability. If you cannot reach large populations cost-effectively, then any other enabling criteria will not matter.

2. Clarity. Most people, particularly older or at-risk individuals, find artificial voices, varying intonations, pace, and variable volume levels not only annoying, but difficult to understand.14 3. Personalization and Interactivity. “Personalization,” or tailoring the message to specifically address individual concerns, enables automated communications to more closely match the experience of conversing with a clinician or specialty representative.

Results of Datamonitor’s Patient Compliance Survey, 2004, authored by Adele Schulz, “support the idea that personalized communication with patients is an important tool in compliance initiatives.”15 “Interactivity” is the ability to accept patient responses either through keypad presses or voice response, and deliver the next question or information based on the previous response. Interactivity can help ensure regulatory compliance by enabling appropriate authentication. As an example, HIPAA (Health Insurance Portability and Accountability Act) compliance through authentication, sometimes known as right party contact, could be managed as follows: • Before giving any personalized information, an automated system could ask the individual to confirm that he/she is the correct party • If further authentication is required, the system could ask for appropriate credentials.

This type of interactivity can also be used to collect survey data and patient feedback through survey questions.

4. Reporting Visibility. Reporting is important both to understand aggregate behaviors and make useful program changes, as well as to provide substantiated, auditable performance data. Automation offers significant advantages in data collection and speed of analysis. Reporting can help organizations measure the results of their outreach efforts more effectively.

Demonstration of results against required objectives, such as the Health Effectiveness Data and Information Set and other programs from accrediting and regulatory bodies, may enable organizations to satisfy these requirements more efficiently with a better outcome.

5. Analytics. Analytics underlies useful personalization. Applying a detailed scoring model helps the

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evaluation of several key factors, Figure 2 Survey Call Flow such as which patients are most likely to take action, and whether Greeting call they are being contacted too litDynamic prompts Auth tle, too much, or the right amount using the best method. At a deep“Did you check your er level, analytics also provides Answering blood pressure?”

Yes No insight on the best approach for machine Message contacting patients, evaluating 3rd party retrieval with PIN “What such treatment strategies as the “What were prevented you from best calling windows, media the results?” checking it?”

Within (voice, e-mail, text message, or a Out of limits limits combination of these), persona, “Did you take your retry strategy, among near-infinite medication?” combinations of these.

The impact of automated comNo Yes Immediate “Thank you” “Why not?” munication is further enhanced transfer to care specialist by tailoring interventional strategies on a per-patient basis, combining analysis of historical patient clinical data along with My doctor I didn’t I didn’t think I forgot discontinued Rx feel well it was working actual patient response data. For example, an analytics-enabled solution may initially help deter“Thank you” mine which patients should be contacted first, based on drug and Source: Montijo M, Ross M. Use of automated telephony to optimize blood pressure and medication therapeutic categories, number of management of hypertensive frail elderly patients. Presented at the Disease Management Association maintenance medications, comof America 9th Annual Disease Management Leadership Forum and Integrated Case Summit; September 16, 2007; Las Vegas, NV. plexity of medication regimen, or patient demographics. lower is better. The TTT also bases optimal target By looking at the history of patient refill behaviors, ranges on specific patient diagnoses, such as BP the system can determine whether, when, and how fre<140/90 mm Hg for patients with heart failure (HF) quently to communicate with the individual patient. but BP <130/80 mm Hg for patients with diabetes.

Over time, the system can become increasingly “intelFor the present trial, a cohort of approximately 800 ligent” and better capable of determining the profile of patients was selected from the MHS pilot population, the most receptive patients. based on a primary diagnosis of HF or diabetes and Results from automated systems capable of decisionrecently reported BP readings above the established tarmaking can support effective personalized communicaget range.16 Of these, 318 agreed to participate in a trial tions with many patients on an individualized basis. This of an automated telephony system and home BP moniprocess is sometimes referred to as “mass personalization.” toring. A matched cohort of 304 hypertensive beneficiAutomated Communication Improves BP Monitoring aries continued to receive the usual nurse-based disease in Frail Elderly: New Study Results management services of the MHS program as a comparThe following study was developed to address ison group. The study examined whether frail, elderly uncontrolled hypertension and the use of automated (median age, 75 years) patients with hypertension were communication in a patient cohort from the Medicare willing and able to listen and respond to weekly autoHealth Support (MHS) pilot program in Maryland and mated phone calls that provided support for therapeutic the District of Columbia during a 2-month period and medication regimens, while offering care support (March 19, 2007-May 24, 2007).16 personnel with weekly reporting on the results. The The Treat to Target (TTT) initiative approaches study covered 2 areas—patient BP and patient adheruncontrolled hypertension by the simple principle that ence to specific antihypertensive regimens. The objec-

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tives were to improve quality of care and lower care support personnel utilization.

The study posed a series of questions using branching logic to generate targeted questioning of yes/no and multiple choice questions. Figure 2 depicts the format of the survey, showing the nature of the logic, the location of the transfers to human clinical support, and

Perhaps the most important outcome of this study was that 174 patients (54% of the study group) had their antihypertensive regimens altered. the types of questions asked. The main results of this survey were16: • 245 patients (87.5%) achieved systolic BP within target or had marked improvement from baseline >160 mm Hg • 302 patients (96.8%) achieved diastolic BP within target or significantly improved from baseline >100 mm Hg • 66% of the contacts validated as a “live answer” (ie, the patient answered the call, or someone else in the household handed the phone to the patient, after which the patient validated) • Of those responding, 581 (33%) completed the entire survey, and 33% were transferred to a care support specialist for additional assistance • No difference was seen between the automatedtelephony and nurse-contacted cohorts in percent achieving targeted systolic and diastolic BP or percent receiving antihypertensive medication adjustment • Cost of automated telephony for a BP reading was 95% lower than using a care support representative to retrieve the reading.

Perhaps the most important outcome of this study was that 174 patients (54% of the study group) had their antihypertensive regimens altered based on survey responses.16 The clear inference is that frequent reporting on patient BP and medication-taking behaviors, along with the ability to efficiently gather and analyze that information, offers clinicians significant insights on ongoing titration of medication or other elements of a therapeutic regimen.

Better Health and Health Economics Results of this study show how applying certain forms of automated communication to treatment adherence programs may potentially offer distinct

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advantages to patients and organizations.16 In addition to the improvements in clinical outcomes delivered by regular communications, automating outreach programs may enable MCOs and disease management/ wellness programs to: • Reach out to more patients cost-effectively • Target and reach substantially more patients, and enroll more patients overall into existing programs for improved return on investment • Consistently manage patient adherence across large populations • Gain potential insights into patient medication-taking and other relevant behaviors for further analysis • Empower existing care support staff by driving inbound, interested patients into the call center and by triaging the more acute or at-risk individuals.

Conclusions It is well understood that regular, consistent communications from care teams can mediate medication-taking behaviors in many patients with chronic diseases and, in many cases, the health outcomes are dependent on those behaviors. These communications comprise a focus area in healthcare that can be extended by using modern automated communications to augment other outreach strategies. Although all the data from the new study cited here are not in yet, automated communications satisfying the criteria outlined in this article are demonstrating some ability to connect with, and mediate behavior in, large populations of chronically ill patients. Our hope is that in the future, automated communications systems will enable organizations to provide communications at a scale that will improve health outcomes, both proximal and longer-term, for the millions of “Toms” with chronic conditions. ■ References 1. Osterberg L, Blaschke T. Adherence to medication. N Engl J Med. 2005;353:487-497.

2. Pharmaceutical Safety Institute. Pharmaceutical Safety Institute and Harris Interactive Consumer Drug Safety Perception Survey Results. http://www.psisafety.org/images/InstituteHarrisSurvey.pdf. Accessed September 12, 2008.

3. Sud A, Kline-Rogers E, Fang J, et al. Reasons for non-adherence to cardiac medications in patients discharged with acute coronary symptoms. Presented at the American College of Cardiology Annual Scientific Session; March 7-10, 2004; New Orleans, LA. 4. Case Management Society of America. Case Management Adherence Guidelines, Version 2.0. http://www.cmsa.org/portals/0/pdf/CMAG2.pdf.

Accessed June 7, 2008.

5. Sabaté E, ed. Adherence to long-term therapies: evidence for action [monograph online]. World Health Organization; 2003. http://whqlibdoc. who.int/publications/2003/9241545992.pdf. Accessed June 9, 2008.

6. McCarthy R. The price you pay for the drug not taken. Bus Health.

1998;16:27-33. http://findarticles.com/p/articles/mi_m0903/is_n10_v16/ ai_n27541886/pg_1?tag=artBody;col1. Accessed October 22, 2008.

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7. Kung HC, Hoyert DL, Xu JQ, Murphy SL. Deaths: final data for 2005.

Natl Vital Stat Rep. 2008;56:1-120.

8. Cherry DK, Woodwell DA, Rechtsteiner EA. National Ambulatory Medical Care Survey: 2005 summary. Adv Data. 2007;387:1-39.

9. Centers for Disease Control and Prevention. National Center for Health Statistics. Health, United States, 2007. Hyattsville, MD: US Department of Health and Human Services; 2007. http://www.cdc. gov/nchs/data/hus/hus07.pdf. Accessed June 8, 2008.

10. Stewart MA. Effective physician-patient communication and health outcomes: a review. Can Med Assoc J [serial online]. 1995;152:1423-1433. http://www.cmaj.ca/cgi/content/abstract/152/9/1423. Accessed June 7, 2008.

11. HDI Advisory Services. Advisory Services Q&A page. http:// www.thinkhdi.com/library/deliverfile.aspx?filecontentid=350. Accessed June 12, 2008.

12. McCall N, Cromwell J, Bernard S. Evaluation of Phase I of Medicare Health Support (Formerly Voluntary Chronic Care Improvement) Pilot Program Under Traditional Fee-for-Service Medicare. Baltimore, MD: RTI

International; June 2007. Project No: 0207960.002. Contract No: 50000-0022. Sponsored by Centers for Medicare & Medicaid Services.

13. Friedman RH, Kazis LE, Jette A, et al. A telecommunications system for monitoring and counseling patients with hypertension: impact on medication adherence and blood pressure control. Am J Hypertens.

1996;9:285-292.

14. Boehm E, for Forrester Research Inc. Designing interactions for an aging population. July 2007. http://www.forrester.com/Research/PDF/ 0,5110,42827,00.pdf. Accessed November 6, 2008.

15. Non-compliance costs drug industry dear. September 6, 2004. http://www.in-pharmatechnologist.com/layout/set/print/content/view/ print/183261. Accessed October 22, 2008.

16. Montijo M, Ross M. Use of automated telephony to optimize blood pressure and medication management of hypertensive frail elderly patients. Presented at the Disease Management Association of America 9th Annual Disease Management Leadership Forum and Integrated Case Summit; September 16, 2007; Las Vegas, NV.

Stakeholder Perspective Efficient Automated Call System Improves Adherence, but What about Net Costs?

PAYERS/FINANCIAL OFFICERS: Managed care organizations (MCOs) strive to deliver the highest level of value for each healthcare dollar that the organization must spend. An MCO incurs an expense to buy pharmaceuticals for its members and, in turn, those medications should improve the health of the member/patient. The MCO, in return, wants its members to improve their health, maintain their current health, or avoid catastrophic health problems because of their member’s adherence to a prescribed medication regimen. Dr Ross describes an outgoing automated phone calling system that he reports improves adherence for patients in following their prescribed antihypertensive medication regimen. He reports results of his recent study that follows 304 elderly patients with hypertension who are matched to another 304 control patients.

An automated phone system makes outbound calls to these patients. Dr Ross reports this automated calling system as having variable costs that are less expensive than those calls initiated from the clinical outreach call centers of disease management companies. It is appropriate to note that Dr Ross is Vice President of Healthcare for Varolii Corporation, which provides such automated calling systems.

At MCOs, the chief medical officers, medical directors, directors of pharmacy, directors of utiliza-

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tion management, and directors of quality management are all interested in methods that improve patient compliance, improve outcomes for patients, or improve the documentation of that compliance.

The chief financial officers of these organizations, however, want to know if these programs that improve medication adherence will also save the MCO money. The present article clearly addresses the first issue by proposing a method where an MCO can efficiently improve pharmacy compliance. In that, this article is useful for those involved in medication compliance.

The article, however, does not address the chief financial officer’s usual question, “How does efficiently increasing medication adherence save the MCO money in the long run?” That question is important and is worthy of further research, by Dr Ross or by others. It could be reframed as, “Will the cash outflows spent to operate an automated call center yield a positive net present value when measured against the future savings (ie, decreased cash outflows) in medical expenses on those same targeted patients?”

Geoffrey P. Cole, MD, MBA Chief Medical Officer Health Plan Select Athens, Georgia

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For Anemic Cancer Patients With Metastatic, Non-myeloid Malignancies Receiving Chemotherapy…

CONTROL THE RESPONSE MANAGE HEMOGLOBIN AND REDUCE TRANSFUSIONS When Treating Your Patients: • Evaluate for other treatable etiologies of anemia (iron, folate, or B12 deficiency, hemolysis, or bleeding) to treat appropriately • PROCRIT therapy should not be initiated at hemoglobin (Hb) levels 10 g/dL • The dose of PROCRIT should be titrated for each patient to achieve and maintain the lowest Hb level sufficient to avoid the need for red blood cell (RBC) transfusion • The rate of Hb increase should not exceed 1 g/dL in any 2-week period • Monitor Hb weekly until stable, and then regularly during therapy

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Additional Important Safety Information

PROCRIT is indicated for the treatment of anemia due to the effect of concomitantly administered chemotherapy based on studies that have shown a reduction in the need for RBC transfusions in patients with metastatic, non-myeloid malignancies receiving chemotherapy for a minimum of 2 months. Studies to determine whether PROCRIT increases mortality or decreases progression-free/recurrence-free survival are ongoing.

• PROCRIT is not indicated for use in patients receiving hormonal agents, therapeutic biologic products, or radiotherapy unless receiving concomitant myelosuppressive chemotherapy.

• PROCRIT is not indicated for patients receiving myelosuppressive therapy when the anticipated outcome is cure due to the absence of studies that adequately characterize the impact of PROCRIT on progression-free and overall survival (see WARNINGS: Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence).

• PROCRIT is not indicated for the treatment of anemia in cancer patients due to other factors such as iron or folate deficiencies, hemolysis, or gastrointestinal bleeding (see PRECAUTIONS: Lack or Loss of Response).

• PROCRIT use has not been demonstrated in controlled clinical trials to improve symptoms of anemia, quality of life, fatigue, or patient well-being.

• Patients with chronic renal failure experienced greater risks for death and serious cardiovascular events (including myocardial infarction, stroke, congestive heart failure, and hemodialysis vascular access thrombosis) when administered ESAs to target higher versus lower hemoglobin levels (13.5 vs.11.3 g/dL; 14 vs. 10 g/dL) in two clinical studies; these risks also increased in controlled clinical trials of patients with cancer. A rate of hemoglobin rise of >1 g/dL over 2 weeks may contribute to these risks.

• PROCRIT therapy should not be initiated at hemoglobin levels 10 g/dL. • The dose of PROCRIT should be titrated for each patient to achieve and maintain the lowest hemoglobin level sufficient to avoid the need for blood transfusion.

• When the hemoglobin reaches a level needed to avoid transfusion or, increases by more than 1 g/dL in a 2-week period, the PROCRIT dose should be reduced by 25%. Withhold the dose of PROCRIT if the hemoglobin exceeds a level needed to avoid transfusion. Restart dose at 25% below the previous dose when the hemoglobin approaches a level where transfusions may be required. Discontinue if after 8 weeks of therapy there is no response as measured by hemoglobin levels or if transfusions are still required.

• Monitor hemoglobin regularly during therapy, weekly until hemoglobin becomes stable.

• Cases of pure red cell aplasia (PRCA) and of severe anemia, with or without other cytopenias, associated with neutralizing antibodies to erythropoietin have been reported in patients treated with PROCRIT; predominantly in patients with chronic renal failure receiving PROCRIT by subcutaneous administration. If any patient develops a sudden loss of response to PROCRIT, accompanied by severe anemia and low reticulocyte count, and anti-erythropoietin antibody-associated anemia is suspected, withhold PROCRIT and other erythropoietic proteins.

Contact ORTHO BIOTECH (1-888-2ASKOBI or 1-888-227-5624) to perform assays for binding and neutralizing antibodies. If erythropoietin antibody-mediated anemia is confirmed, PROCRIT should be permanently discontinued and patients should not be switched to other erythropoietic proteins.

• The safety and efficacy of PROCRIT therapy have not been established in patients with a known history of a seizure disorder or underlying hematologic disease (e.g., sickle cell anemia, myelodysplastic syndromes, or hypercoagulable disorders).

• In some female patients, menses have resumed following PROCRIT therapy; the possibility of pregnancy should be discussed and the need for contraception evaluated.

• Prior to and regularly during PROCRIT therapy monitor iron status; transferrin saturation should be 20% and ferritin should be 100 ng/mL. During therapy absolute or functional iron deficiency may develop and all patients will eventually require supplemental iron to adequately support erythropoiesis stimulated by PROCRIT. • Treatment of patients with grossly elevated serum erythropoietin levels (e.g., >200 mUnits/mL) is not recommended.

• During PROCRIT therapy, blood pressure should be monitored carefully and aggressively managed, particularly in patients with an underlying history of hypertension or cardiovascular disease.

• Seizures in PROCRIT-treated patients have been reported in the context of a significant increase in hemoglobin from baseline; increases in blood pressure were not always observed; and patients may have had other underlying central nervous system pathology.

• The most commonly reported side effects (>10%) for PROCRIT in clinical trials were pyrexia, diarrhea, nausea, vomiting, edema, asthenia, fatigue, shortness of breath, paresthesia, and upper respiratory infection.

Important Safety Information WARNINGS: INCREASED MORTALITY, SERIOUS CARDIOVASCULAR and THROMBOEMBOLIC EVENTS, and INCREASED RISK OF TUMOR PROGRESSION OR RECURRENCE Renal failure: Patients experienced greater risks for death and serious cardiovascular events when administered erythropoiesis-stimulating agents (ESAs) to target higher versus lower hemoglobin levels (13.5 vs. 11.3 g/dL; 14 vs. 10 g/dL) in two clinical studies. Individualize dosing to achieve and maintain hemoglobin levels within the range of 10 to 12 g/dL. Cancer: • ESAs shortened overall survival and/or increased the risk of tumor progression or recurrence in some clinical studies in patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers (see WARNINGS: Table 1).

• To decrease these risks, as well as the risk of serious cardio- and thrombovascular events, use the lowest dose needed to avoid red blood cell transfusion.

• Use ESAs only for treatment of anemia due to concomitant myelosuppressive chemotherapy.

• ESAs are not indicated for patients receiving myelosuppressive therapy when the anticipated outcome is cure.

• Discontinue following the completion of a chemotherapy course.

Perisurgery: PROCRIT® (Epoetin alfa) increased the rate of deep venous thromboses in patients not receiving prophylactic anticoagulation. Consider deep venous thrombosis prophylaxis.

Contraindications • PROCRIT is contraindicated in patients with uncontrolled hypertension or with known hypersensitivity to albumin (human) or mammalian cell-derived products.

Please see Brief Summary of Prescribing Information, including Boxed WARNINGS, on adjacent page.

Manufactured by: Amgen Inc., Thousand Oaks, California 91320-1789 Distributed by: Ortho Biotech Products, L.P., Bridgewater, New Jersey 08807-0914 © Ortho Biotech Products, L.P. 2008 11/08 08PCTC2487 308470

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BRIEF SUMMARY OF PROCRIT® PRESCRIBING INFORMATION FOR THE TREATMENT OF ANEMIA IN CANCER PATIENTS ON CHEMOTHERAPY PROCRIT® (Epoetin alfa) FOR INJECTION FOR FULL PRESCRIBING INFORMATION FOR ALL INDICATIONS, REFER TO THE PHYSICIANS’ DESK REFERENCE® WARNINGS: INCREASED MORTALITY, SERIOUS CARDIOVASCULAR and THROMBOEMBOLIC EVENTS, and INCREASED RISK OF TUMOR PROGRESSION OR RECURRENCE Renal failure: Patients experienced greater risks for death and serious cardiovascular events when administered erythropoiesis-stimulating agents (ESAs) to target higher versus lower hemoglobin levels (13.5 vs. 11.3 g/dL; 14 vs. 10 g/dL) in two clinical studies. Individualize dosing to achieve and maintain hemoglobin levels within the range of 10 to 12 g/dL. Cancer: • ESAs shortened overall survival and/or increased the risk of tumor progression or recurrence in some clinical studies in patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers (see WARNINGS: Table 1).

• To decrease these risks, as well as the risk of serious cardio- and thrombovascular events, use the lowest dose needed to avoid red blood cell transfusion.

• Use ESAs only for treatment of anemia due to concomitant myelosuppressive chemotherapy.

• ESAs are not indicated for patients receiving myelosuppressive therapy when the anticipated outcome is cure.

• Discontinue following the completion of a chemotherapy course.

Perisurgery: PROCRIT® increased the rate of deep venous thromboses in patients not receiving prophylactic anticoagulation. Consider deep venous thrombosis prophylaxis.

(See WARNINGS: Increased Mortality, Serious Cardiovascular and Thromboembolic Events, WARNINGS: Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence, INDICATIONS AND USAGE, and DOSAGE AND ADMINISTRATION in full Prescribing Information.)

INDICATIONS AND USAGE PROCRIT® is indicated for the treatment of anemia due to the effect of concomitantly administered chemotherapy based on studies that have shown a reduction in the need for RBC transfusions in patients with metastatic, non-myeloid malignancies receiving chemotherapy for a minimum of 2 months. Studies to determine whether PROCRIT® increases mortality or decreases progression-free/recurrence-free survival are ongoing.

• PROCRIT® is not indicated for use in patients receiving hormonal agents, therapeutic biologic products, or radiotherapy unless receiving concomitant myelosuppressive chemotherapy.

• PROCRIT® is not indicated for patients receiving myelosuppressive therapy when the anticipated outcome is cure due to the absence of studies that adequately characterize the impact of PROCRIT® on progressionfree and overall survival (see WARNINGS: Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence).

• PROCRIT ® is not indicated for the treatment of anemia in cancer patients due to other factors such as iron or folate deficiencies, hemolysis, or gastrointestinal bleeding (see PRECAUTIONS: Lack or Loss of Response).

• PROCRIT ® use has not been demonstrated in controlled clinical trials to improve symptoms of anemia, quality of life, fatigue, or patient well-being.

CONTRAINDICATIONS PROCRIT® is contraindicated in patients with: 1. Uncontrolled hypertension. 2. Known hypersensitivity to mammalian cell-derived products. 3. Known hypersensitivity to Albumin (Human).

WARNINGS Pediatrics Risk in Premature Infants The multidose preserved formulation contains benzyl alcohol. Benzyl alcohol has been reported to be associated with an increased incidence of neurological and other complications in premature infants which are sometimes fatal.

Adults Increased Mortality, Serious Cardiovascular and Thromboembolic Events Patients with chronic renal failure experienced greater risks for death and serious cardiovascular events when administered erythropoiesis-stimulating agents (ESAs) to target higher versus lower hemoglobin levels (13.5 vs. 11.3 g/dL; 14 vs. 10 g/dL) in two clinical studies. Patients with chronic renal failure and an insufficient hemoglobin response to ESA therapy may be at even greater risk for cardiovascular events and mortality than other patients. PROCRIT® and other ESAs increased the risks for death and serious cardiovascular events in controlled clinical trials of patients with cancer. These events included myocardial infarction, stroke, congestive heart failure, and hemodialysis vascular access thrombosis. A rate of hemoglobin rise of > 1 g/dL over 2 weeks may contribute to these risks.

In a randomized prospective trial, 1432 anemic chronic renal failure patients who were not undergoing dialysis were assigned to Epoetin alfa (rHuEPO) treatment targeting a maintenance hemoglobin concentration of 13.5 g/dL or 11.3 g/dL. A major cardiovascular event (death, myocardial infarction, stroke, or hospitalization for congestive heart failure) occurred among 125 (18%) of the 715 patients in the higher hemoglobin group compared to 97 (14%) among the 717 patients in the lower hemoglobin group (HR 1.3, 95% CI: 1.0, 1.7, p = 0.03).

Increased risk for serious cardiovascular events was also reported from a randomized, prospective trial of 1265 hemodialysis patients with clinically evident cardiac disease (ischemic heart disease or congestive heart failure). In this trial, patients were assigned to PROCRIT® treatment targeted to a maintenance hematocrit of either 42 ± 3% or 30 ± 3%. Increased mortality was observed in 634 patients randomized to a target hematocrit of 42% [221 deaths (35% mortality)] compared to 631 patients targeted to remain at a hematocrit of 30% [185 deaths (29% mortality)]. The reason for the increased mortality observed in this study is unknown, however, the incidence of non-fatal myocardial infarctions (3.1% vs. 2.3%), vascular access thromboses (39% vs. 29%), and all other thrombotic events (22% vs. 18%) were also higher in the group randomized to achieve a hematocrit of 42%. An increased incidence of thrombotic events has also been observed in patients with cancer treated with erythropoietic agents.

In a randomized controlled study (referred to as Cancer Study 1 - the ‘BEST’ study) with another ESA in 939 women with metastatic breast cancer receiving chemotherapy, patients received either weekly Epoetin alfa or placebo for up to a year. This study was designed to show that survival was superior when an ESA was administered to prevent anemia (maintain hemoglobin levels between 12 and 14 g/dL or hematocrit between 36% and 42%). The study was terminated prematurely when interim results demonstrated that a higher mortality at 4 months (8.7% vs. 3.4%) and a higher rate of fatal thrombotic events (1.1% vs. 0.2%) in the first 4 months of the study were observed among patients treated with Epoetin alfa. Based on Kaplan-Meier estimates, at the time of study termination, the 12-month survival was lower in the Epoetin alfa group than in the placebo group (70% vs. 76%; HR 1.37, 95% CI: 1.07, 1.75; p = 0.012).

A systematic review of 57 randomized controlled trials (including Cancer Studies 1 and 5 - the ‘BEST’ and ‘ENHANCE’ studies) evaluating 9353 patients with cancer compared ESAs plus red blood cell transfusion with red blood cell transfusion alone for prophylaxis or treatment of anemia in cancer patients with or without concurrent antineoplastic therapy. An increased relative risk of thromboembolic events (RR 1.67, 95% CI: 1.35, 2.06; 35 trials and 6769 patients) was observed in ESA-treated patients. An overall survival hazard ratio of 1.08 (95% CI: 0.99, 1.18; 42 trials and 8167 patients) was observed in ESA-treated patients.

An increased incidence of deep vein thrombosis (DVT) in patients receiving Epoetin alfa undergoing surgical orthopedic procedures has been observed (see ADVERSE REACTIONS, Surgery Patients: Thrombotic/Vascular Events in full Prescribing Information). In a randomized controlled study (referred to as the ‘SPINE’ study), 681 adult patients, not receiving prophylactic anticoagulation and undergoing spinal surgery, received either 4 doses of 600 U/kg Epoetin alfa (7, 14, and 21 days before surgery, and the day of surgery) and standard of care (SOC) treatment, or SOC treatment alone. Preliminary analysis showed a higher incidence of DVT,

determined by either Color Flow Duplex Imaging or by clinical symptoms, in the Epoetin alfa group [16 patients (4.7%)] compared to the SOC group [7 patients (2.1%)]. In addition, 12 patients in the Epoetin alfa group and 7 patients in the SOC group had other thrombotic vascular events. Deep venous thrombosis prophylaxis should be strongly considered when ESAs are used for the reduction of allogeneic RBC transfusions in surgical patients (see BOXED WARNINGS and DOSAGE AND ADMINISTRATION in full Prescribing Information).

Increased mortality was also observed in a randomized placebo-controlled study of PROCRIT® in adult patients who were undergoing coronary artery bypass surgery (7 deaths in 126 patients randomized to PROCRIT® versus no deaths among 56 patients receiving placebo). Four of these deaths occurred during the period of study drug administration and all four deaths were associated with thrombotic events. ESAs are not approved for reduction of allogeneic red blood cell transfusions in patients scheduled for cardiac surgery.

Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence Erythropoiesis-stimulating agents resulted in decreased locoregional control/progression-free survival and/or overall survival (see Table 1). These findings were observed in studies of patients with advanced head and neck cancer receiving radiation therapy (Cancer Studies 5 and 6), in patients receiving chemotherapy for metastatic breast cancer (Cancer Study 1) or lymphoid malignancy (Cancer Study 2), and in patients with non-small cell lung cancer or various malignancies who were not receiving chemotherapy or radiotherapy (Cancer Studies 7 and 8).

Table 1: Randomized, Controlled Trials with Decreased Survival and/or Decreased Locoregional Control Adverse Achieved Outcome for Hemoglobin Hemoglobin Primary ESA-containing Study / Tumor / (n) Target (Median Q1,Q3) Endpoint Arm Chemotherapy Cancer Study 1 Metastatic breast 12-14 g/dL 12.9 g/dL 12-month overall Decreased 12-month cancer (n=939) 12.2, 13.3 g/dL survival survival Cancer Study 2 Lymphoid 13-15 g/dL (M) 11.0 g/dL Proportion of Decreased overall malignancy (n=344) 13-14 g/dL (F) 9.8, 12.1 g/dL patients achieving survival a hemoglobin response Cancer Study 3 Early breast 12.5-13 g/dL 13.1 g/dL Relapse-free and Decreased 3 yr. cancer (n=733) 12.5, 13.7 g/dL overall survival relapse-free and overall survival Cancer Study 4 Cervical Cancer 12-14 g/dL 12.7 g/dL Progression-free Decreased 3 yr. (n=114) 12.1, 13.3 g/dL and overall survival progression-free and locoregional and overall survival control and locoregional control Radiotherapy Alone Cancer Study 5 Head and neck ≥15 g/dL (M) Not available Locoregional Decreased 5-year cancer (n=351) ≥14 g/dL (F) progression-free locoregional survival progression-free survival Decreased overall survival Cancer Study 6 Head and neck 14-15.5 g/dL Not available Locoregional Decreased cancer (n=522) disease control locoregional disease control No Chemotherapy or Radiotherapy Cancer Study 7 Non-small cell 12-14 g/dL Not available Quality of life Decreased overall lung cancer (n=70) survival Cancer Study 8 Non-myeloid 12-13 g/dL 10.6 g/dL RBC transfusions Decreased overall malignancy (n=989) 9.4, 11.8 g/dL survival

Decreased overall survival: Cancer Study 1 (the ‘BEST’ study) was previously described (see WARNINGS: Increased Mortality, Serious Cardiovascular and Thromboembolic Events). Mortality at 4 months (8.7% vs. 3.4%) was significantly higher in the Epoetin alfa arm. The most common investigator-attributed cause of death within the first 4 months was disease progression; 28 of 41 deaths in the Epoetin alfa arm and 13 of 16 deaths in the placebo arm were attributed to disease progression. Investigator assessed time to tumor progression was not different between the two groups. Survival at 12 months was significantly lower in the Epoetin alfa arm (70% vs. 76%, HR 1.37, 95% CI: 1.07, 1.75; p = 0.012).

Cancer Study 2 was a Phase 3, double-blind, randomized (darbepoetin alfa vs. placebo) study conducted in 344 anemic patients with lymphoid malignancy receiving chemotherapy. With a median follow-up of 29 months, overall mortality rates were significantly higher among patients randomized to darbepoetin alfa as compared to placebo (HR 1.36, 95% CI: 1.02, 1.82).

Cancer Study 7 was a Phase 3, multicenter, randomized (Epoetin alfa vs. placebo), double-blind study, in which patients with advanced non-small cell lung cancer receiving only palliative radiotherapy or no active therapy were treated with Epoetin alfa to achieve and maintain hemoglobin levels between 12 and 14 g/dL. Following an interim analysis of 70 of 300 patients planned, a significant difference in survival in favor of the patients on the placebo arm of the trial was observed (median survival 63 vs. 129 days; HR 1.84; p = 0.04).

Cancer Study 8 was a Phase 3, double-blind, randomized (darbepoetin alfa vs. placebo), 16-week study in 989 anemic patients with active malignant disease, neither receiving nor planning to receive chemotherapy or radiation therapy. There was no evidence of a statistically significant reduction in proportion of patients receiving RBC transfusions. The median survival was shorter in the darbepoetin alfa treatment group (8 months) compared with the placebo group (10.8 months); HR 1.30, 95% CI: 1.07, 1.57.

Decreased progression-free survival and overall survival: Cancer Study 3 (the ‘PREPARE’ study) was a randomized controlled study in which darbepoetin alfa was administered to prevent anemia conducted in 733 women receiving neo-adjuvant breast cancer treatment.

After a median follow-up of approximately 3 years, the survival rate (86% vs. 90%, HR 1.42, 95% CI: 0.93, 2.18) and relapse-free survival rate (72% vs. 78%, HR 1.33, 95% CI: 0.99, 1.79) were lower in the darbepoetin alfatreated arm compared to the control arm.

Cancer Study 4 (protocol GOG 191) was a randomized controlled study that enrolled 114 of a planned 460 cervical cancer patients receiving chemotherapy and radiotherapy. Patients were randomized to receive Epoetin alfa to maintain hemoglobin between 12 and 14 g/dL or to transfusion support as needed. The study was terminated prematurely due to an increase in thromboembolic events in Epoetin alfa-treated patients compared to control (19% vs. 9%). Both local recurrence (21% vs. 20%) and distant recurrence (12% vs. 7%) were more frequent in Epoetin alfa-treated patients compared to control. Progression-free survival at 3 years was lower in the Epoetin alfa-treated group compared to control (59% vs. 62%, HR 1.06, 95% CI: 0.58, 1.91).

Overall survival at 3 years was lower in the Epoetin alfa-treated group compared to control (61% vs. 71%, HR 1.28, 95% CI: 0.68, 2.42).

Cancer Study 5 (the ‘ENHANCE’ study) was a randomized controlled study in 351 head and neck cancer patients where Epoetin beta or placebo was administered to achieve target hemoglobin of 14 and 15 g/dL for women and men, respectively. Locoregional progression-free survival was significantly shorter in patients receiving Epoetin beta (HR 1.62, 95% CI: 1.22, 2.14; p = 0.0008) with a median of 406 days Epoetin beta vs. 745 days placebo. Overall survival was significantly shorter in patients receiving Epoetin beta (HR 1.39, 95% CI: 1.05, 1.84; p = 0.02).

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Decreased locoregional control: Cancer Study 6 (DAHANCA 10) was conducted in 522 patients with primary squamous cell carcinoma of the head and neck receiving radiation therapy randomized to darbepoetin alfa with radiotherapy or radiotherapy alone. An interim analysis on 484 patients demonstrated that locoregional control at 5 years was significantly shorter in patients receiving darbepoetin alfa (RR 1.44, 95% CI: 1.06, 1.96; p = 0.02). Overall survival was shorter in patients receiving darbepoetin alfa (RR 1.28, 95% CI: 0.98, 1.68; p = 0.08).

Pure Red Cell Aplasia Cases of pure red cell aplasia (PRCA) and of severe anemia, with or without other cytopenias, associated with neutralizing antibodies to erythropoietin have been reported in patients treated with PROCRIT®. This has been reported predominantly in patients with chronic renal failure (CRF) receiving PROCRIT® by subcutaneous administration. Any patient who develops a sudden loss of response to PROCRIT®, accompanied by severe anemia and low reticulocyte count, should be evaluated for the etiology of loss of effect, including the presence of neutralizing antibodies to erythropoietin (see PRECAUTIONS: Lack or Loss of Response). If anti-erythropoietin antibody-associated anemia is suspected, withhold PROCRIT® and other erythropoietic proteins. Contact ORTHO BIOTECH at 1 888 2ASK OBI (1-888-227-5624) to perform assays for binding and neutralizing antibodies.

PROCRIT® should be permanently discontinued in patients with antibody-mediated anemia. Patients should not be switched to other erythropoietic proteins as antibodies may cross-react (see ADVERSE REACTIONS: Immunogenicity).

Albumin (Human) PROCRIT® contains albumin, a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin.

PRECAUTIONS The parenteral administration of any biologic product should be attended by appropriate precautions in case allergic or other untoward reactions occur (see CONTRAINDICATIONS). In clinical trials, while transient rashes were occasionally observed concurrently with PROCRIT® therapy, no serious allergic or anaphylactic reactions were reported (see ADVERSE REACTIONS in full Prescribing Information for more information regarding allergic reactions).

The safety and efficacy of PROCRIT® therapy have not been established in patients with a known history of a seizure disorder or underlying hematologic disease (eg, sickle cell anemia, myelodysplastic syndromes, or hypercoagulable disorders).

In some female patients, menses have resumed following PROCRIT® therapy; the possibility of pregnancy should be discussed and the need for contraception evaluated.

Hematology: Exacerbation of porphyria has been observed rarely in patients with CRF treated with PROCRIT®.

However, PROCRIT® has not caused increased urinary excretion of porphyrin metabolites in normal volunteers, even in the presence of a rapid erythropoietic response. Nevertheless, PROCRIT® should be used with caution in patients with known porphyria.

In preclinical studies in dogs and rats, but not in monkeys, PROCRIT® therapy was associated with subclinical bone marrow fibrosis. Bone marrow fibrosis is a known complication of CRF in humans and may be related to secondary hyperparathyroidism or unknown factors. The incidence of bone marrow fibrosis was not increased in a study of adult patients on dialysis who were treated with PROCRIT® for 12 to 19 months, compared to the incidence of bone marrow fibrosis in a matched group of patients who had not been treated with PROCRIT®.

Cancer patients should have hemoglobin measured once a week until hemoglobin has been stabilized, and measured periodically thereafter.

Lack or Loss of Response: If the patient fails to respond or to maintain a response to doses within the recommended dosing range, the following etiologies should be considered and evaluated: 1. Iron deficiency: Virtually all patients will eventually require supplemental iron therapy (see IRON EVALUATION); 2. Underlying infectious, inflammatory, or malignant processes; 3. Occult blood loss; 4. Underlying hematologic diseases (ie, thalassemia, refractory anemia, or other myelodysplastic disorders); 5. Vitamin deficiencies: Folic acid or vitamin B12; 6. Hemolysis; 7. Aluminum intoxication; 8. Osteitis fibrosa cystica; 9. Pure Red Cell Aplasia (PRCA) or anti-erythropoietin antibody-associated anemia: In the absence of another etiology, the patient should be evaluated for evidence of PRCA and sera should be tested for the presence of antibodies to erythropoietin (see WARNINGS: Pure Red Cell Aplasia).

Iron Evaluation: During PROCRIT® therapy, absolute or functional iron deficiency may develop. Functional iron deficiency, with normal ferritin levels but low transferrin saturation, is presumably due to the inability to mobilize iron stores rapidly enough to support increased erythropoiesis. Transferrin saturation should be at least 20% and ferritin should be at least 100 ng/mL. Prior to and during PROCRIT® therapy, the patient’s iron status, including transferrin saturation (serum iron divided by iron binding capacity) and serum ferritin, should be evaluated. Virtually all patients will eventually require supplemental iron to increase or maintain transferrin saturation to levels which will adequately support erythropoiesis stimulated by PROCRIT®.

Drug Interaction: No evidence of interaction of PROCRIT® with other drugs was observed in the course of clinical trials.

Carcinogenesis, Mutagenesis, and Impairment of Fertility: Carcinogenic potential of PROCRIT® has not been evaluated. PROCRIT® does not induce bacterial gene mutation (Ames Test), chromosomal aberrations in mammalian cells, micronuclei in mice, or gene mutation at the HGPRT locus. In female rats treated IV with PROCRIT®, there was a trend for slightly increased fetal wastage at doses of 100 and 500 Units/kg.

Pregnancy Category C: PROCRIT® has been shown to have adverse effects in rats when given in doses 5 times the human dose. There are no adequate and well-controlled studies in pregnant women. PROCRIT® should be used during pregnancy only if potential benefit justifies the potential risk to the fetus.

In studies in female rats, there were decreases in body weight gain, delays in appearance of abdominal hair, delayed eyelid opening, delayed ossification, and decreases in the number of caudal vertebrae in the F1 fetuses of the 500 Units/kg group. In female rats treated IV, there was a trend for slightly increased fetal wastage at doses of 100 and 500 Units/kg. PROCRIT® has not shown any adverse effect at doses as high as 500 Units/kg in pregnant rabbits (from day 6 to 18 of gestation).

Nursing Mothers: Postnatal observations of the live offspring (F1 generation) of female rats treated with PROCRIT® during gestation and lactation revealed no effect of PROCRIT® at doses of up to 500 Units/kg. There were, however, decreases in body weight gain, delays in appearance of abdominal hair, eyelid opening, and decreases in the number of caudal vertebrae in the F1 fetuses of the 500 Units/kg group. There were no PROCRIT®-related effects on the F2 generation fetuses.

It is not known whether PROCRIT® is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PROCRIT® is administered to a nursing woman.

Pediatric Use: See WARNINGS: Pediatrics Pediatric Cancer Patients on Chemotherapy: The safety and effectiveness of PROCRIT® were evaluated in a randomized, double-blind, placebo-controlled, multicenter study (see CLINICAL EXPERIENCE, Weekly (QW) Dosing, Pediatric Patients in full Prescribing Information).

Geriatric Use: Insufficient numbers of patients age 65 or older were enrolled in clinical studies of PROCRIT® for the treatment of anemia associated with pre-dialysis chronic renal failure, cancer chemotherapy, and Zidovudine-treatment of HIV infection to determine whether they respond differently from younger subjects.

Information for Patients Patients should be informed of the increased risks of mortality, serious cardiovascular events, thromboembolic events, and increased risk of tumor progression or recurrence (see WARNINGS). In those situations in which the physician determines that a patient or their caregiver can safely and effectively administer PROCRIT® at home,

instruction as to the proper dosage and administration should be provided. Patients should be instructed to read the PROCRIT® Medication Guide and Patient Instructions for Use and should be informed that the Medication Guide is not a disclosure of all possible side effects. Patients should be informed of the possible side effects of PROCRIT® and of the signs and symptoms of allergic drug reaction and advised of appropriate actions. If home use is prescribed for a patient, the patient should be thoroughly instructed in the importance of proper disposal and cautioned against the reuse of needles, syringes, or drug product. A puncture-resistant container should be available for the disposal of used syringes and needles, and guidance provided on disposal of the full container.

Hypertension: Hypertension, associated with a significant increase in hemoglobin, has been noted rarely in patients treated with PROCRIT®. Nevertheless, blood pressure in patients treated with PROCRIT® should be monitored carefully, particularly in patients with an underlying history of hypertension or cardiovascular disease.

Seizures: In double-blind, placebo-controlled trials, 3.2% (n = 2/63) of patients treated with PROCRIT® TIW and 2.9% (n = 2/68) of placebo-treated patients had seizures. Seizures in 1.6% (n = 1/63) of patients treated with PROCRIT® TIW occurred in the context of a significant increase in blood pressure and hematocrit from baseline values. However, both patients treated with PROCRIT® also had underlying CNS pathology which may have been related to seizure activity.

In a placebo-controlled, double-blind trial utilizing weekly dosing with PROCRIT®, 1.2% (n = 2/168) of safetyevaluable patients treated with PROCRIT® and 1% (n = 1/165) of placebo-treated patients had seizures.

Seizures in the patients treated with weekly PROCRIT® occurred in the context of a significant increase in hemoglobin from baseline values however significant increases in blood pressure were not seen. These patients may have had other CNS pathology.

Thrombotic Events: In double-blind, placebo-controlled trials, 3.2% (n = 2/63) of patients treated with PROCRIT® TIW and 11.8% (n = 8/68) of placebo-treated patients had thrombotic events (eg, pulmonary embolism, cerebrovascular accident), (see WARNINGS: Increased Mortality, Serious Cardiovascular and Thromboembolic Events).

In a placebo-controlled, double-blind trial utilizing weekly dosing with PROCRIT®, 6.0% (n = 10/168) of safetyevaluable patients treated with PROCRIT® and 3.6% (n = 6/165) (p = 0.444) of placebo-treated patients had clinically significant thrombotic events (deep vein thrombosis requiring anticoagulant therapy, embolic event including pulmonary embolism, myocardial infarction, cerebral ischemia, left ventricular failure and thrombotic microangiopathy). A definitive relationship between the rate of hemoglobin increase and the occurrence of clinically significant thrombotic events could not be evaluated due to the limited schedule of hemoglobin measurements in this study.

The safety and efficacy of PROCRIT® were evaluated in a randomized, double-blind, placebo-controlled, multicenter study that enrolled 222 anemic patients ages 5 to 18 receiving treatment for a variety of childhood malignancies. Due to the study design (small sample size and the heterogeneity of the underlying malignancies and of anti-neoplastic treatments employed), a determination of the effect of PROCRIT® on the incidence of thrombotic events could not be performed. In the PROCRIT® arm, the overall incidence of thrombotic events was 10.8% and the incidence of serious or life-threatening events was 7.2%.

ADVERSE REACTIONS Immunogenicity As with all therapeutic proteins, there is the potential for immunogenicity. Neutralizing antibodies to erythropoietin, in association with PRCA or severe anemia (with or without other cytopenias), have been reported in patients receiving PROCRIT® (see WARNINGS: Pure Red Cell Aplasia) during post-marketing experience.

There has been no systematic assessment of immune responses, i.e., the incidence of either binding or neutralizing antibodies to PROCRIT®, in controlled clinical trials.

Where reported, the incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies across products within this class (erythropoietic proteins) may be misleading.

Adverse Experiences Reported in Clinical Trials In double-blind, placebo-controlled studies of up to 3 months duration involving 131 cancer patients, adverse events with an incidence > 10% in either patients treated with PROCRIT® or placebo-treated patients were as indicated below: Percent of Patients Reporting Event

Event Pyrexia Diarrhea Nausea Vomiting Edema Asthenia Fatigue Shortness of Breath Parasthesia Upper Respiratory Infection Dizziness Trunk Pain * Statistically significant

Patients Treated With PROCRIT® (n = 63) 29% 21%* 17%* 17% 17%* 13% 13% 13% 11% 11% 5% 3%*

Placebo-treated Patients (n = 68) 19% 7% 32% 15% 1% 16% 15% 9% 6% 4% 12% 16%

Although some statistically significant differences between patients being treated with PROCRIT® and placebotreated patients were noted, the overall safety profile of PROCRIT® appeared to be consistent with the disease process of advanced cancer. During double-blind and subsequent open-label therapy in which patients (n = 72 for total exposure to PROCRIT®) were treated for up to 32 weeks with doses as high as 927 Units/kg, the adverse experience profile of PROCRIT® was consistent with the progression of advanced cancer.

Three hundred thirty-three (333) cancer patients enrolled in a placebo-controlled double-blind trial utilizing Weekly dosing with PROCRIT® for up to 4 months were evaluable for adverse events. The incidence of adverse events was similar in both the treatment and placebo arms.

OVERDOSAGE The expected manifestations of PROCRIT® overdosage include signs and symptoms associated with an excessive and/or rapid increase in hemoglobin concentration, including any of the cardiovascular events described in WARNINGS and listed in ADVERSE REACTIONS in full Prescribing Information. Patients receiving an overdosage of PROCRIT® should be monitored closely for cardiovascular events and hematologic abnormalities. Polycythemia should be managed acutely with phlebotomy, as clinically indicated. Following resolution of the effects due to PROCRIT® overdosage, reintroduction of PROCRIT® therapy should be accompanied by close monitoring for evidence of rapid increases in hemoglobin concentration (>1 gm/dL per 14 days). In patients with an excessive hematopoietic response, reduce the PROCRIT® dose in accordance with the recommendations described in DOSAGE AND ADMINISTRATION in full Prescribing Information.

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PROCRIT ® (Epoetin alfa) FOR INJECTION DOSAGE AND ADMINISTRATION IMPORTANT: See BOXED WARNINGS and WARNINGS: Increased Mortality, Serious Cardiovascular and Thromboembolic Events.

Prior to initiating treatment with PROCRIT® a hemoglobin should be obtained to establish that it is >10 to ≤ 13 g/dL. The recommended dose of PROCRIT® is 300 Units/kg/day subcutaneously for 10 days before surgery, on the day of surgery, and for 4 days after surgery.

An alternate dose schedule is 600 Units/kg PROCRIT® subcutaneously in once weekly doses (21, 14, and 7 days before surgery) plus a fourth dose on the day of surgery.

All patients should receive adequate iron supplementation. Iron supplementation should be initiated no later than the beginning of treatment with PROCRIT® and should continue throughout the course of therapy. Deep venous thrombosis prophylaxis should be strongly considered (see BOXED WARNINGS).

PREPARATION AND ADMINISTRATION OF PROCRIT® 1. Do not shake. It is not necessary to shake PROCRIT®. Prolonged vigorous shaking may denature any glycoprotein, rendering it biologically inactive.

2. Protect the solution from light. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use any vials exhibiting particulate matter or discoloration.

3. Using aseptic techniques, attach a sterile needle to a sterile syringe. Remove the flip top from the vial containing PROCRIT®, and wipe the septum with a disinfectant. Insert the needle into the vial, and withdraw into the syringe an appropriate volume of solution.

4. Single-dose: 1 mL vial contains no preservative. Use one dose per vial; do not re-enter the vial. Discard unused portions.

Multidose: 1 mL and 2 mL vials contain preservative. Store at 2° to 8°C after initial entry and between doses. Discard 21 days after initial entry.

5. Do not dilute or administer in conjunction with other drug solutions. However, at the time of SC administration, preservative-free PROCRIT® from single-use vials may be admixed in a syringe with bacteriostatic 0.9% sodium chloride injection, USP, with benzyl alcohol 0.9% (bacteriostatic saline) at a 1:1 ratio using aseptic technique. The benzyl alcohol in the bacteriostatic saline acts as a local anesthetic which may ameliorate SC injection site discomfort. Admixing is not necessary when using the multidose vials of PROCRIT® containing benzyl alcohol.

Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, CA 91320-1799 Distributed by: Ortho Biotech Products, L.P. Raritan, New Jersey 08869-0670 Revised 08/2008 © OBPLP 2000 10112802BC

The Obama Administration and the FDA Mark Senak, JD

T

alk is swirling around Washington as to who may replace Dr Andrew C. von Eschenbach at the helm of the US Food and Drug Administration (FDA). One well-known blogger has even begun a voting contest where readers can choose from several candidates for FDA Commissioner and cast a vote. There is little question that the policy environment is pregnant with change, but in most cases, it is quite possibly less important who is appointed rather than what the changes may entail.

This was obviously true with the presidential election. Given that both the McCain and Obama positions favored the import of prescription drugs, the ability of the government to negotiate prices under Medicare Part D, and the increasing uptake of generic drugs before the campaign, it is virtually certain that the outcome of the presidential contest mattered less to the pharmaceutical and biotechnology industries than the contests in Congress. Not only did the November 4 election decide that Democrats were to achieve solid majorities in both chambers, it has also paved the way for new congressional committee assignments and chairs.

This is the one area where “who” may matter, although only in a matter of degree. Consider the case of the chairmanship for the Committee on Energy and Commerce.

A clash of the titans emerged between 2 powerful and prominent members of Congress—Congressman John D. Dingell, the current chair, and Congressman Henry Waxman, who emerged the winner. This committee is key to the oversight of various aspects of the FDA and the regulation of pharmaceutical industry. The activity of this committee for October 2008 includes the following investigations, announcements, statements, and reports: • Dingell, Stupak to Investigate Melamine Contamination in Chinese Milk Products (10/2) • Dingell, Stupak Question FDA’s No-Bid Contract with a PR Firm (10/2) • Dingell, Stupak Question Whether FDA Knowingly Allowed Dangerous Drugs to be Sold to U.S. Consumers (10/8) • Dingell, Stupak Continue DTC Ad Investigation (10/14)

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• Dingell, Stupak Continue Investigation into FDA’s Questionable Handling of Bisphenol A (10/14) • Dingell, Stupak Request Interview with von Eschenbach on Bisphenol A (10/15) • GAO Report Finds FDA’s Foreign Drug Inspection Program Needs Significant Improvement (10/22).

Ironically, Congressman Dingell made the case that he is the preferable chair, because he is friendlier to industry with this 1-month track record. Now that Congressman Waxman has prevailed over Congressman Dingell for the chairmanship, one can expect a great deal more intensity in terms of the breadth and depth regarding scrutiny of the FDA and the pharmaceutical industry than was shown in October 2008.

However, for the balance of the change, “who” is not as important as “what” in terms of what must be accomplished.

There is also a great deal of unfinished business with respect to the FDA itself. Once a gold standard agency, the FDA has suffered tremendously during the past 8 years and will have a great deal to do to reclaim its position as a flagship agency overseeing one fourth of the nation’s economy.

The following qualities are the ones that PresidentElect Obama may seek for the individual who will take over the FDA. That person must: • Have a solid grasp of the pharmaceutical industry, without being directly associated with it. There are members in the Senate, particularly Senator Kennedy, who may insist that the individual have no ties to the pharmaceutical industry itself. Still, the designee must have a good understanding of clinical research and public health.

• Be able to balance the policymakers hunger for safety, while assuring that the pipeline produces to provide access. Although the public appetite is extremely risk averse, our slant to caution may bring a slowdown in new drug approvals. Longer approval time in the end means potentially higher drug prices, as patented drugs will have less time on the market to recoup research and development costs.

• Have the credibility and gravitas to tell policymakers on the Hill to stop using the agency as a political means, to gently remind members of Congress that it is a new administration, that there is a 1-party rule, and that most of them are in that very same party.

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• Possess solid visionary and have noteworthy communication skills. The agency is in trouble not only from a functional point of view, but it has also done very little to proactively address the descent of its image and to communicate and assure the public and policymakers that it has a vision. In fact, the agency does not seem to acknowledge much of a problem, much less to have a plan for solving it. The new commissioner will need to understand this, act on it, and seize leadership.

In addition to these qualities, the first order of priority should be to completely implement the Food and Drug Administration Amendment Act (FDAAA).

Right now the pipeline is getting clogged with Complete Response Letters and shifting the Prescription Drug User Fee Act dates, as the FDA tries to understand and implement the FDAAA. The FDA has been charged with implementing a fairly broad scope of reforms, but the longer it takes to identify and follow a roadmap for doing so, the more in the dark drug sponsors are going to be, which again contributes to a sluggish pipeline.

And as the policy and the communications environments undergo breathtaking changes, it is important that the agency enunciate some points of view about the uses of digital and social media by pharmaceutical companies in marketing. The potential uses for social and digital media are extraordinary, from public service announcements to patient education videos, to risk management tools; however, because regulatory cultures of most pharmaceuticals are generally conservative, most are waiting for the FDA to say something with regard to the use of such media.

The FDA appears nowhere near doing this, even though other industries have begun to embrace and strategically anticipate and respond to the migration into digital media. It is time for the FDA to be a leader, not continue to be a follower, and give companies some guidance. And that guidance should be the medium, not the message.

All this and more needs to be accomplished by an Obama-appointed FDA Commissioner, and in no short order, for the sake of the agency, public health, and the economy. ■ Mr Senak is Senior Vice President at Fleishman-Hillard in Washington, DC, and writes the Eye on FDA blog, www.eyeonfda.com.

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AHA MEETING HIGHLIGHTS

The Antiplatelet Drug Pipeline: Some Promising Candidates

By Wayne Kuznar

S

everal antithrombotic drugs in late-stage development were featured at the 2008 Scientific Sessions of the American Heart Association (AHA).

Prasugrel. A new analysis of the antiplatelet drug prasugrel, a direct-acting P2Y12 antagonist currently under US Food and Drug Administration review, questions this agent’s supposed superiority over the current standard in this class, clopidogrel (Plavix). Results of the pivotal phase 3 Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel (TRITON), which compared prasugrel and clopidogrel, were released in late 2007.

Among patients being considered for coronary stents, prasugrel prevented more future cardiac events than clopidogrel, but with excess bleeding. Despite this excess risk, the net benefit still favored prasugrel—23 fewer myocardial infarctions (MIs) per 1000 patients treated, at a cost of 6 extra bleeding events.

More recent analyses of TRITON have shown that much of the benefit of prasugrel in preventing ischemic events occurs early on, but the excess bleeding occurs after 30 days of use. New analyses have shown that prasugrel is better than clopidogrel at preventing stent thrombosis (blood clots forming in stents).

At the AHA, a team of investigators at CedarsSinai Medical Center in Los Angeles discussed its independent statistical analysis (using a Bayesian method), showing that the true superiority of prasugrel in TRITON was not as large. In their analysis, the probability of a 10% or more benefit with prasugrel over clopidogrel is less than 80%, and the chance that prasugrel is 20% better than clopidogrel in preventing cardiac events is less than 5%. If bleeding events are considered, the probability of a net benefit with prasugrel is even smaller, they argued.

Because of the risk-benefit ratio, Sanjay Kaul, MD, MPH, Director of the Vascular Physiology and Thrombosis Research Laboratory at the Burns and Allen Research Institute at Cedars-Sinai, and lead investigator of the reanalysis, proposed a strategy for using prasugrel. “One potential approach to optimizing

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the benefit-risk profile of prasugrel could involve giving it during the first 30 days as acute ‘induction’ therapy, followed by maintenance ‘consolidation’ therapy with a less potent antiplatelet agent, such as clopidogrel, in patients who receive stents,” he said.

Rivaroxaban. This oral drug factor Xa inhibitor—a new class of anticlotting agents—is entering a phase 3 trial (and will enroll 16,000 patients) after the release of phase 2 data at the AHA. The data showed that rivaroxaban could reduce MI and stroke risk, with an acceptable bleeding risk at its 2 lowest doses.

That study enrolled 3491 stable patients with a recent MI who were taking aspirin and clopidogrel (if necessary). Patients were randomized to placebo or 1 of 4 doses of rivaroxaban (2.5-10 mg twice daily) for 6 months, and were followed for 1 month after stopping therapy. As expected, higher doses of rivaroxaban increased the rate of clinically significant bleeding.

Rivaroxaban reduced the risk of ischemic events by 21% relative to placebo, but this difference was not definitive, given the small number of patients enrolled, reported C. Michael Gibson, MD, Chief of Clinical Research, Beth Israel Deaconess Medical Center, Boston. “We have decided to go forward to phase 3 with the 2 lower doses—2.5 mg and 5 mg twice daily,” he said. These doses reduced the risk of death, MI, and stroke by 46% compared with placebo (P = .08) and were associated with a major bleeding rate of 1.2%.

There was no drug-induced liver injury with rivaroxaban. The development of an oral direct thrombin inhibitor—ximelagatran—was derailed as a result of liver toxicity.

Other late-phase antithrombotic/antiplatelet drugs investigated for various thrombotic indications were discussed at the meeting, including: • Apixaban, another oral factor Xa inhibitor • Cangrelor, another direct-acting P2Y12 antagonist • Dabigatran, an oral direct thrombin inhibitor, which was recently approved in Europe (brand name, Pradaxa) • Idraparinux, a long-acting factor Xa inhibitor. ■

November/December 2008

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AMCP MEETING HIGHLIGHTS

Specialty Pipeline Dominated by Biologics

By Alice Goodman

A

number of new specialty products are in late stages of development, said Deborah B. Cooper, PharmD, Clinical Advisor, Pipeline Series, CVS/Caremark, at the 2008 educational conference of the Academy of Managed Care Pharmacy. Specialty products comprise 49% of new chemical compounds currently in phase 3 and 55% of the phase 3 ambulatory care agents. The 53 new specialty drugs slated for launch in 2008-2009 are for these categories (several products are included in more than 1 category): • Oncology—17 • Rare or orphan diseases—11 • Metabolic diseases—8 • Immunology—6 • Infectious diseases—5 • Neurologic disorders—5 • Cardiovascular disorders—3 • Respiratory disorders—3 • Dermatology—2 • Gastrointestinal disorders—2.

Key trends for the specialty pipeline include (1) increased numbers of drugs for rare/orphan diseases, (2) emergence of more drugs with Risk Evaluation and Mitigation Strategy (REMS) programs, (3) expansion of adjunctive/additive agents for multiple disease states, and (4) a shift from injectable to oral therapies.

Rheumatoid Arthritis Toxilizumab (Actemra), an anti-interleukin-6 receptor monoclonal antibody, is pending approval for rheumatoid arthritis (RA) and is expected to be launched with a REMS program. It is administered intravenously every 4 weeks. Adverse events reported include infections, hypersensitivity reactions, headache, nasopharyngitis, and pleurisy.

Golimumab is a humanized anti-tumor necrosis factor drug pending approval for RA, psoriatic arthritis, and ankylosing spondylitis. It is administered as a subcutaneous injection every 4 weeks. An intravenous (IV) formulation is in phase 2, to be administered every 12 weeks. Adverse events included headache and injection-site and allergic reactions.

Multiple Sclerosis Fampridine SR is a twice-daily oral agent in phase 3, for the symptomatic treatment of multiple sclerosis (MS), to be used in conjunction with other MS drugs.

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It blocks potassium channels on axons of nerves and increases walking speed and/or muscle strength. Adverse events reported include falls, insomnia, paresthesias, dizziness, urinary tract infections, and nausea. Seizures have been reported with high doses of the drug.

Fingolimod is a once-daily oral immunosuppressant in phase 3, which, if approved, will be the first oral disease-modifying agent for MS. It causes a dose-related reduction in the number of circulating lymphocytes, leading to a decrease in the number of activated T-cells in the blood and central nervous system. Adverse events include headache and dose-dependent upper respiratory tract infection.

Psoriasis Ustekinumab (Stelara) is a fully humanized monoclonal antibody that targets interleukin-12 and -23, which are thought to be proinflammatory cytokines.

Approval is pending for chronic moderate-to-severe psoriasis. The drug is administered subcutaneously every 12 weeks. Adverse reactions include headache, infections, injection-site reactions, and respiratory tract infections.

SLE Epratuzumab, a monoclonal antibody that targets the CD22 antigen on the surface of B cells, is in phase 3 for the treatment of moderate-to-severe systemic lupus erythematosus (SLE). The CD22 receptor is implicated in inflammation. Epratuzumab is administered as an IV infusion every other week. Adverse reactions in clinical trials include arthralgia, hypotension, nausea, and palpitations.

Belimumab (LymphoStat-B), also in phase 3 for SLE, is a fully human monoclonal antibody that inhibits the biologic activity of B-lymphocyte stimulator, which at high levels may contribute to the pathogenesis of autoimmune diseases (eg, SLE, RA). It is administered intravenously every 28 days. It has shown a significant reduction in SLE flares and disease activity.

Hepatitis C Two drugs in phase 3 trials for hepatitis C virus (HCV) show very promising results for those who failed therapy with pegylated interferon alfa and ribavirin: Zadaxin (thymalfasin), an immunomodulator that stimulates T-cells and decreases viral replication; telaprevir, the first protease inhibitor for HCV, to be used with current therapies.

Approval and launch are expected in 2009 or 2010. ■

November/December 2008

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AMCP MEETING HIGHLIGHTS

Real-World Data Better than RCTs for Formulary Decisions

By Alice Goodman

R

eal-world data on a new therapy and a userfriendly assessment tool to evaluate real-world studies facilitate formulary and reimbursement decisions, said Diana Brixner, PhD, RPh, Professor and Chair, Department of Pharmacotherapy, and Executive Director, Pharmacy Outcomes Research Center, University of Utah, at the 2008 educational conference of the Academy of Managed Care Pharmacy.

Payers need information beyond randomized controlled trials (RCTs) to make the best decisions about how to deploy limited budgets for large patient populations. RCTs are conducted in a select patient population, according to strict protocols, and the results are not generalizable to large patient populations.

Supplemental observational open-label trials and postmarketing surveillance provide data on the effect of new treatments that are more relevant for managed care organizations (MCOs), such as quality-adjusted life-years, productivity, and absenteeism.

Dr Brixner summarized the proceedings of 2 roundtables that addressed issues surrounding use of real-world data in managed care. A roundtable in July 2007 included 4 MCO directors and 4 economists. The panel tackled the quality of real-world evidence, the complexity of real-world research, the lack of consistency in quality assurance and assessment in decision-making, and the time delay between accrual of real-world data and product launch. Recommendations for further study include: • Analysis of tools for quality assessment of observational studies • Development of a consolidated instrument to measures the quality assurance of these data • Establishment of a process to support application of a comprehensive quality assessment tool • Development of training for producers and users of observational studies on the consolidated tool.

“Our healthcare system is fragmented. A consolidated tool would reduce the impact of fragmentation,” said Dr Brixner.

Developing a new tool for quality assurance to evaluate real-world studies is a daunting task, and is still ongoing, Dr Brixner explained. In analyzing existing checklists, participants found that none of them fulfilled the criteria for a simple-to-use, comprehensive

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checklist to evaluate published real-world studies.

Existing checklists were either too long or too academic to support decision-making.

A second roundtable, held in March 2008, discussed how to act on the recommendations of the first roundtable. Participants agreed on the need: • For quality and convenience in assessment of realworld data • To recognize that the process of implementation of a new tool is as important as the new tool itself • For peer validation of a new tool • To educate all constituents about the tool and its implementation.

A small survey of 4 MCOs found that although none of them currently uses a checklist to evaluate realworld studies, they would use a tool if it was short and concise, validated, and recommended by a national organization, Dr Brixner said. ■

Unmanaged Moment

“On the other hand, where would we be if not for our overmedicated society?”

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CLINICAL

An Overview of Cholesterol Management Robyn A. Burns Schaiff, PharmD, BCPS; Richard M. Moe, MD, PhD; Daniel W. Krichbaum, PharmD Cardiovascular disease is the leading cause of death worldwide. Elevated cholesterol (hypercholesterolemia) and abnormal lipid profiles (dyslipidemia) are important risk factors for the development of cardiovascular disease. This article discusses the role of cholesterol in the body and the relationship between different cholesterol fractions and the risk of cardiovascular disease. The guidelines for assessment and treatment of dyslipidemia from the National Cholesterol Education Program are outlined, and cholesterol targets and goals of therapy are discussed. The mechanism of action, place in therapy (eg, first-line, second-line, or add-on), and common side effects are also discussed for each of the available classes of drugs used in the treatment of dyslipidemia. [ADHB. 2008;1(9):39-48.]

C

ardiovascular (CV) disease (CVD) is the leading cause of mortality and one of the leading causes of disability worldwide.1 In the United States alone, more than 80 million adults have at least one type of CVD, with hypertension, coronary heart disease (CHD), stroke, and heart failure among the most common forms of the disease. Elevated levels of cholesterol (hypercholesterolemia) and abnormal lipid profiles (dyslipidemia) are important risk factors for CVD. The American Heart Association (AHA) estimates that more than 100 million Americans have elevated cholesterol levels (>200 mg/dL) and 34 million have cholesterol levels that necessitate treatment.2 Cholesterol is an essential component of cell membranes and steroid hormones. The body synthesizes most of its required cholesterol with the remainder coming from the diet. Since cholesterol is mostly insoluble in blood, it is packaged with proteins and phospholipids to form lipoprotein complexes that circulate in the bloodstream. The types of cholesterolcontaining lipoproteins are high-density lipoproteins (HDL-C), low-density lipoproteins (LDL-C), very lowdensity lipoproteins (VLDL-C), and chylomicrons.

High levels of LDL-C are associated with increased CV risk in epidemiologic studies. In addition, numerous clinical studies using a variety of therapies have demonstrated decreased CV events and mortality with LDL reduction. Therefore, the first goal of therapy is

Dr Burns Schaiff is Senior Director, Regional Medical & Research Specialist, Pfizer, Inc, New York, NY; Dr Moe is Clinical Associate Professor, University of Missouri-Kansas City, Kansas City, MO; Dr Krichbaum is Senior Director Team Leader, Regional Medical & Research Specialist, Pfizer, Inc, New York, NY.

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reduction of LDL-C levels for the most common forms of dyslipidemia. Conversely, high levels of HDL-C are associated with decreased risk of CV events. However, clinical trials assessing the morbidity and mortality benefits of drug therapies that raise HDL-C levels have had varied results. HDL-C–modifying trials with niacin have demonstrated CV event reduction.3,4 Conversely, other treatments that raise HDL-C, including hormone replacement therapy5 and torcetrapib,6 have not decreased CV events. Because of this, in the absence of large clinical outcome trials, therapies that elevate HDL cannot be assumed to produce clinical event reduction.

Approach to Patient Assessment, Treatment The National Cholesterol Education Program (NCEP) evaluates evidence and develops guidelines for lipid management. The approach to patient management provided here comes primarily from the guidelines published in 2001 and updated in 2004.7,8 Since the primary goal of lipid management is to decrease the risk of CV events and death, the first step in management is to assess the patient’s overall CV risk. To make this assessment, a fasting lipoprotein analysis should be obtained to determine the patient’s LDL-C. Optimal levels for LDL-C and total cholesterol are <100 mg/dL and <200 mg/dL, respectively. The NCEP guidelines recommend that a fasting lipid panel be drawn at least every 5 years in all adults older than 20 years.7 In addition to LDL-C levels, the presence or absence of CHD or CHD-equivalent conditions must be assessed. CHD-equivalent conditions listed by the NCEP include diabetes mellitus, peripheral vascular disease, abdominal aortic aneurysm, symptomatic carotid disease, and a 10-year CV risk of less than 20%

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KEY POINTS ▲ Cholesterol is an essential component of cell membranes

and steroid hormones. ▲ Hypercholesterolemia and dyslipidemia are important risk

factors for cardiovascular disease, which affects more than 80 million Americans. ▲ Evidence shows that high levels of LDL-C are associated

with increased cardiovascular risk; reducing LDL levels has been associated with significant reduction in mortality. ▲ The first goal of therapy in hypercholesterolemia is reduc-

tion of LDL-C levels. ▲ Statins are considered the most effective lipid-lowering

agents available, both in lowering LDL levels and in the prevention of cardiovascular events.

Table 1 Major Risk Factors (Exclusive of LDL-C) that Modify LDL Goals* Cigarette smoking Hypertension (blood pressure ≥140/90 mm Hg or on antihypertensive medication) Low HDL-C (<40 mg/dL)† Family history of premature CHD (CHD in male first-degree relative <55 y, CHD in female first-degree relative <55 y) Age (men ≥45 y; women ≥55 y) *

Diabetes is regarded a CHD risk equivalent.

HDL cholesterol ≥60 mg/dL counts as a negative risk factor; its presence removes 1 risk factor from the total count.

LDL-C indicates low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; CHD, coronary heart disease.

Reprinted with permission from Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497. †

calculated with the Framingham risk calculator.7 Although not addressed by the NCEP, the National Kidney Foundation also considers chronic kidney disease (glomerular filtration rate <60 mL/min) to be a high-risk state and recommends that this patient group be treated as having a CHD-equivalent disease.9 Likewise, the AHA and the American Stroke Association recommend the use of a statin with intensive lipid-lowering effects in patients with atherosclerotic stroke or transient ischemic attack, even in the absence of known CHD.10 In the absence of CHD or CHD-equivalent conditions, CVD risk factors (Table 1) should be carefully assessed using the Framingham risk score to determine the patient’s 10-year risk of CV events (Table 2).7

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Goals of Therapy For patients with CHD or CHD-equivalent disease, the NCEP recommends the LDL-C goal of ≤100 mg/dL, with <70 mg/dL a therapeutic option for patients considered at very high risk for CV events.8 For patients with 2 or more CV risk factors but with a 10-year Framingham risk of less than 20%, the LDL-C goal is <130 mg/dL, with <100 mg/dL a therapeutic option. Finally, for patients with 0 to 1 risk factors, the LDL-C target is <160 mg/dL.8 Therapeutic Lifestyle Changes The NCEP Adult Treatment Panel III guidelines recommend that therapeutic lifestyle changes be implemented for all patients at risk for CVD.7 These changes include reducing intake of saturated fats and cholesterol while increasing soluble fiber intake and physical activity. Optimization of weight, moderation of alcohol consumption, and cessation of smoking are also encouraged. If drug therapy is needed, it should be used as an addition to, rather than a substitute for, therapeutic lifestyle changes.

Treatment Initiation Since the clinical evidence of benefit is greatest with the statin drug class, the American College of Cardiology (ACC) recommends drug therapy begin with a statin and that titration to goal or the maximally tolerated dose of a statin be achieved before consideration of adding other agents.11 Regardless of the initial treatment chosen, it is critical that the patient be reevaluated and therapy titrated or added until the goal LDL-C is attained.

For patients with 0 to 1 risk factors and no CHD, treatment is initiated with therapeutic lifestyle changes with reassessment after 6 weeks. If goal LDL of <160 mg/dL is not reached at 6 weeks, lifestyle changes should be intensified and reinforced and a visit with a dietitian considered. If after 12 weeks of therapeutic lifestyle changes the patient is not at the LDL-C goal of <160 mg/dL, drug therapy, usually a statin, should be added.

For patients at moderate risk, with 2 or more risk factors and a 10-year CV risk of less than 20%, treatment begins with therapeutic lifestyle changes. Drug therapy, usually a statin, can be initiated concurrently if the LDL is >100 mg/dL at baseline or if LDL-C remains >100 mg/dL after a 6-week trial of lifestyle changes.

For the highest risk patients with CHD or equivalent conditions, statin therapy and therapeutic lifestyle changes should be initiated simultaneously for all

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Cholesterol Management

Table 2 An Overview of Cholesterol Management

HDL indicates high-density lipoprotein; BP, blood pressure.

Reprinted with permission from Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.

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patients with LDL-C >100 mg/dL. Drug therapy may also be considered in very high-risk patients with LDLC <100 mg/dL targeted to achieve the optional goal of <70 mg/dL.8

Pharmacotherapy Options A variety of lipid-lowering agents are available, including 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, bile acid sequestrants, cholesterol absorption inhibitors, fibrates, nicotinic acid derivatives, and omega-3 fatty acids. Dosage ranges, US Food and Drug Administration (FDA) indications, evidence of clinical outcome benefit, and side effects are highlighted in Table 3.

These are the most prescribed drugs in the world and are considered the most effective lipid-lowering agents available.

HMG-CoA Reductase Inhibitors (Statins) HMG-CoA reductase inhibitors, or statins, are the recommended first-line therapy for most patients.

These are the most prescribed drugs in the world and are considered the most effective lipid-lowering agents available, both in lowering LDL-C levels and in the prevention of CV events. Statins are similar in structure to HMG-CoA, a precursor of cholesterol, and act as competitive inhibitors of HMG-CoA reductase, the last regulated enzymatic step in cholesterol synthesis.

Therefore, statins reduce the rate of synthesis of cholesterol. The liver responds by increasing the number of LDL receptors, which increases hepatic uptake and catabolism of circulating LDL-C. Statins reduce LDL-C by 24% to 60% and decrease triglycerides (TGs) by 5% to 50% (percentages are based on the various package inserts), depending on the agent selected and the baseline lipid profile. HDL-C levels are usually increased.

The effects on HDL are a class effect and are small relative to the effects on LDL-C and TGs. In addition, statins have a variety of anti-inflammatory effects that are independent of the LDL-C lowering, which may contribute to the clinical benefit in CVD, especially early in therapy.12 However, a recent meta-analysis of 23 lipid-lowering trials demonstrated that the majority (89%-98%) of the anti-inflammatory effects of lipidlowering therapy is related to the degree of LDL reduction,13 which suggests a limited influence of a non-LDL-

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Câ&#x20AC;&#x201C;related anti-inflammatory mechanism.

Adverse events, relatively uncommon with this class, include gastrointestinal (GI) disturbances, muscle aches, and asymptomatic transaminasemia. Rare serious adverse events may include myopathy and rhabdomyolysis. FDA-approved labeling recommends assessment of liver function at baseline, after 12 weeks of therapy, after dose escalation, and twice yearly thereafter. However, the National Lipid Association has suggested that this practice does not increase the safety of statin therapy, but merely increases cost.14

Bile Acid Sequestrants Bile acid sequestrants bind to bile acids in the intestine, reducing absorption of cholesterol and other lipids.

The resultant decrease in available cholesterol causes an increase in the number of LDL receptors on hepatocytes, further promoting clearance of LDL-C from the blood. Bile acid sequestrants are recommended as second-line therapy for patients with elevated cholesterol, but not elevated TGs, as both VLDL-C and TG concentrations may increase during therapy. Agents in this class lower LDL-C by 15% to 30% and increase HDL-C by 3% to 5% on average.9 Patient adherence with these agents is frequently poor due to the need for frequent dosing, poor palatability, and frequent GI side effects.

Since these drugs remain in the GI tract, systemic adverse effects are minimal; however, these agents can interfere with absorption of concomitantly administered drugs as well as fat-soluble vitamins.

Nicotinic Acid Derivatives Niacin reduces synthesis of VLDL-C in the liver and therefore reduces LDL-C production. Pharmacologic doses of niacin (1.5-2 g/day) lower LDL-C and TGs by 15% to 20% and 30% to 40%, respectively, and increase HDL-C by 15% to 25%. Niacin is used as second-line therapy in concert with other lipid-lowering agents. The most common adverse events include vasodilation with flushing and pruritis, which frequently is dose-limiting. Other adverse events include dyspepsia, gastric ulceration, hyperuricemia, palpitations, and, rarely, peripheral neuropathy.

Niacin-induced hyperglycemia may be problematic for patients with diabetes mellitus or with impaired glucose tolerance, particularly in the first 6 months of therapy, but long-term clinical benefits have been demonstrated in these patients.15 The most serious side effect is hepatotoxicity; cases of fatal fulminant hepatic failure have been associated with niacin administration, particularly with older formulations.16

November/December 2008

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VOL. 1

NO. 9 50-, 150-mg capsules 54-, 160-mg tablets 67-,134-, 200-mg capsules

43-130 mg/d

Lipofen* (fenofibrate) 50-150 mg/d 54-200 mg/d 48-145 mg/d 50-160 mg/d 600-1200 mg/d, 2 divided doses

Antara* (fenofibrate)

Lofibra* (fenofibrate)

TriCor* (fenofibrate)

Triglide (fenofibrate)

Lopid* (gemfibrozil)

10-, 20-, 40-, 80-mg tablets

600-mg tablets

50-, 160-mg tablets

48-, 145-mg tablets

•Primary prevention of MI, stroke in patients w/type 2 DM and other CHD risk factors •Primary prevention of MI, stroke, revascularization, hospitalization for heart failure and angina in patients w/clinically evident CAD •Primary hypercholesterolemia or mixed dyslipidemia •Hypertriglyceridemia •Primary dysbetalipoproteinemia •Homozygous FH in adolescents •Heterozygous FH in adolescents

•Reducing CHD risk in patients w/type 2b dyslipidemia and inadequate response to TLC, other drug therapy, who have high LDL, low HDL, high TG •Familial type IV or V hyperlipidemia

•Hypertriglyceridemia •Primary hyperglyceridemia •Mixed dyslipidemia

•Primary hyperlipidemia •Mixed dyslipidemia •Homozygous familial hypercholesterolemia •Homozygous sitosterolemia

Adjunct therapy for primary hypercholesterolemia

TG↓ 25%-45%

TG↓ 20%-50%

LDL-C↓ 10%-20%

LDL-C↓ 10%-20%

LDL-C↓ 10%-18%

LDL-C↓ 10%-30%

•Patients w/hypertension and LDL-C↓ ≥3 CHD risk factors (ASCOT4) 39%-60% •Patients w/type 2 DM and no history of CVD (CARDS5) •Patients w/stable CHD (TNT,6 IDEAL,7 ALLIANCE,8 and and AVERT 9) •Patients w/atherosclerotic stroke or TIA w/o documented CHD (SPARCL10) •Patients w/ACS (PROVE-IT,11 MIRACL12)

•Men w/primary dyslipidemia (Helsinki Heart Study2) •Men w/CHD and low HDL-C (VA Hit3)

Men with primary hypercholesterolemia (LRC-CTTP1)

Primary effect on lipids

$$$$

$$$$

Cost, 30-day supply

Abdominal pain, constipation, flatulence, indigestion, increased liver enzymes, headache, myalgia

Rash, abdominal pain, diarrhea, flatulence, indigestion, xerostomia, myalgia

Rash, diarrhea, flatulence, nausea and vomiting, myalgia, rhinitis

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$$$

$

$$

$$$

Continued

Headache, diarrhea, abdominal pain, arthralgia, backache, myalgia, sinusitis

Abdominal distension, ab$$$ dominal pain, constipation, musculoskeletal pain, headache

Asthenia, constipation, indigestion, pharyngitis, myalgia

Abdominal discomfort, constipation, flatulence, nausea and vomiting, vitamin A, D deficiency

Side effects (most often reported)

10:55 AM

10-80 mg/d

43-, 130-mg capsules

10 mg/d

Zetia (ezetimibe)

1-g tablets

•Adjuct therapy of hypercholesterolemia •Adjunct therapy to improve glycemic control in type 2 DM

•Adjuct therapy of hypercholesterolemia •Pruritis due to partial biliary obstruction

Indications

Populations w/ demonstrated event reduction†

11/25/08

Lipitor (atorvastatin)

10-mg tablets

2-16 g/d 2 divided doses

Colestid* (colestipol)

625-mg tablets

3.75 g/d

Welchol (colesevelam)

Questran Light: packets and powder (each 5 g contain 4 g anhydrous cholestyramine resin) Questran: powder and packets (each 9 g contain 4 g anhydrous cholestyramine resin)

Available doses

8-24 g/d, 2 divided doses

Dosage range

Questran* (cholestyramine)

Drug

Table 3 Pharmacotherapy for Lipid Disorders

ClinicalSchaiiff_NovDec .qxp:Cover Page 43

43

44 80-mg extendedrelease tablets 10-, 20-, 40-mg tablets

80-mg mg/d 10-80 mg/d

10-80 mg/d

Lescol XL (fluvastatin ER)

Mevacor* (lovastatin)

Pravachol* (pravastatin)

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0.5-2 g/d

Niaspan (niacin ER)

0.25-6 g/d, 3 divided doses

0.5-2 g/d

Slo-Niacin CR* (controlled-release niacin)

Immediate-release niacin*

5-, 10-, 20- 40-, 80-mg tablets

5-80 mg/d

Zocor* (simvastatin)

500-mg tablets

Niacin ER: 500-, 750-, 1000-mg tablets

Niacin CR: 250-, 500-, 750-mg tablets

5-, 10-, 20-, 40-mg tablets

5-40 mg/d

•Primary hypercholesterolemia or mixed dyslipidemia (alone or with lovastatin) •Severe hypertriglyceridemia •To reduce risk of recurrent MI in patients w/hypercholesterolemia and history of MI •W/bile acid–binding resin to slow progression or induce regression of coronary atherosclerosis in patients w/CAD and hypercholesterolemia •W/bile acid–binding resin: primary hypercholesterolemia

LDL-C↓ 45%-60%

Men w/history of MI (CDP21; LDL↓ immediate-release dosage form) 5%-15% TG↓ 15%-30% HDL↑ 15%-20%

•Existing CHD and elevated LDL-C↓ 35%-50% total cholesterol (4S19) •Patients at high risk of CV events from existing CHD, history of stroke, other cerebrovascular disease, peripheral artery disease, or hypertension in men ≥65 yr (HPS20)

•Primary hyperlipidemia Men ≥55 and women ≥65 and mixed dyslipidemia w/LDL ≤130 mg/dL and CRP •Primary hypertriglyceridemia ≥2 mg/L (JUPITER18) •Homozygous familial hypercholesterolemia •To slow the progression of atherosclerosis •Prevention of CHD mortality and CV events in patients w/existing CHD, history of stroke, diabetes, or peripheral artery disease •Hypercholesterolemia •Heterozygous FH in adolescents

LDL-C↓ 25%-45%

LDL-C↓ 20%-35%

•Men w/o history of MI LDL-C↓ w/elevated LDL (WOSCOPS15) 25%-40% •Patients w/MI in preceding 3-20 mo (CARE16) •Patients w/MI or unstable angina in previous 3-36 mo (LIPID17)

High risk (elevated LDL-C w/low HDL-C) patients w/o clinical CHD (AFCAPS-TexCaps14)

Patients with CHD who had coronary intervention (LIPS13)

Primary effect on lipids

$$$$

$$$

Cost, 30-day supply

$$

Constipation, flushing, pruritis, GI irritation, nausea, vomiting

Constipation, GI irritation, headache, upper respiratory infection, myalgia, increased hepatic transaminase levels

$

$$$$$

$$

$$

Abdominal pain, constipation, $$$$ nausea, arthralgia, asthenia, headache, myalgia, increased hepatic transaminase levels

Diarrhea, flatulence, heartburn, nausea, vomiting, asthenia, headache, myalgia

Abdominal pain, constipation, $$ diarrhea, nausea, headache, myalgia, increased hepatic transaminase levels

Abdominal pain, diarrhea, dyspepsia, nausea, headache, myalgia

Side effects (most often reported)

10:55 AM

Crestor (rosuvastatin)

•Primary prevention of MI, revascularization, and CV mortality •Reduction in total mortality by reducing coronary death, MI, revascularization, stroke, and to slow progression of coronary atherosclerosis in patients with CHD •Hypercholesterolemia •Heterozygous FH in adolescents

•Primary prevention of MI, unstable angina, coronary revascularization •To slow progression of coronary atherosclerosis in CHD •Hypercholesterolemia •Heterozygous FH in adolescents

•Reduce coronary revascularization in CHD •Reduce progression of coronary atherosclerosis in CHD •Hypercholesterolemia •Heterozygous FH in adolescents

Indications

Populations w/ demonstrated event reduction†

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10-, 20-, 40-, 80-mg tablets

20-, 40-mg capsules

20-80 mg/d

Lescol (fluvastatin)

Available doses

Dosage range

Drug

Table 3 Pharmacotherapy for Lipid Disorders Continued

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NO. 9 Niacin-ER 500 mg– simvastatin 20 mg/d to niacin-ER 2000 mg– simvastatin 40 mg/d Ezetimibe 10 mg– simvastatin 10 mg/d to ezetimibe 10 mg– simvastatin 80 mg/d

Simcor (niacin-ER/ simvastatin)

Vytorin (ezetemibe/ simvastatin)

Ezetimibe– simvastatin 10 mg-10 mg 10 mg-20 mg 10 mg-40 mg 10 mg-80 mg

Niacin-ER– simvastatin 500 mg-20 mg 750 mg-20 mg 1000 mg-20 mg

Niacin-ER– lovastatin 500 mg-20 mg 750 mg-20 mg 1000 mg-20 mg

•Primary hyperlipidemia or mixed hyperlipidemia •Homozygous FH

•Hypercholesterolemia •Mixed dyslipidemia •Hypertriglyceridemia (all when monotherapy inadequate)

•Hypercholesterolemia •Mixed dyslipidemia

Hypertriglyceridemia (TG ≥500 mg/dL)

Indications •Hypercholesterolemic Japanese patients (over statin background therapy) (JELIS22) •Patients w/recent MI (GISSI-Prevenzione23)

LDL↓ 45%-60%

LDL↓ 10%-15% HDL↑ 20%-30% TG↓ 15%-40% (from baseline treatment w/ simvastatin 0-20 mg/d)

LDL↓ 30%-45% HDL↑ 20%-30% TG↓ 30%-45%

TG↓ 25%-45%

Primary effect on lipids

See under components

Increased bleeding/bruising, burping, indigestion, altered taste sense

Side effects (most often reported)

$$$$

$$$

$$$$

$$

Cost, 30-day supply

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*Generic available. †Studies listed in this column may not be included in FDA-approved indications.

LDL-C indicates low-density lipoprotein cholesterol; DM, diabetes mellitus; TG, triglycerides; CHD, coronary heart disease; TLC, therapeutic lifestyle changes; HDL-C, high-density lipoprotein cholesterol; MI, myocardial infarction; CAD, coronary artery disease; FH, familial hypercholesterolemia; CVD, cardiovascular disease; TIA, transient ischemic attack; ACS, acute coronary syndrome; CV, cardiovascular; GI, gastrointestinal; CR, controlled release; ER, extended release.

1. Lipid Research Clinics Program: the lipid research clinics coronary primary prevention trial results. I. Reduction in incidence of coronary heart disease. JAMA. 1984;251:351-364.

2. Helsinki Heart Study. Primary prevention trial with gemfibrozil in middle-aged men with dyslipidemia. N Engl J Med. 1987;317:1237-1245.

3. Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med. 1999;341:410-418.

4. Sever PS, Dahlöf B, Poulter NR, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet. 2003;361:1149-1158.

5. Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebocontrolled trial. Lancet. 2004;364:685-696.

6. LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352:1425-1435.

7. Pedersen TR, Faergeman O, Kastelein JJ, et al. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA. 2005;294:2437-2445.

8. Koren MJ, Hunninghake DB; ALLIANCE Investigators. Clinical outcomes in managed-care patients with coronary heart disease treated aggressively in lipid-lowering disease management clinics: the ALLIANCE study. J Am Coll Cardiol. 2004;44:1772-1779.

9. Pitt B, Waters D, Brown WV, et al. Aggressive lipid-lowering therapy compared with angioplasty in stable coronary artery disease. N Engl J Med. 1999;341:70-76.

10. Schwartz GG, Olsson AG, Ezekowitz MD, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA. 2001;285:1711-1718.

11. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350:1495-1504.

12. Amarenco P, Bogousslavsky J, Callahan A 3rd, et al. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;355:549-559.

13. Serruys PW, De Feyter PJ, Benghozi R, et al. The Lescol(R) Intervention Prevention Study (LIPS): a double-blind, placebo-controlled, randomized trial of the long-term effects of fluvastatin after successful transcatheter therapy in patients with coronary heart disease. Int J Cardiovasc Intervent. 2001;4:165-172.

14. Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA. 1998;279:1615-1622.

15. Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med. 1995;333:1301-1307.

16. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med. 1996;335:1001-1009.

17. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998;339:1349-1357.

18. Ridker PM, Danielson MIA, Fonseca AH, et al, for the JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2195-2207.

19. The Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383-1389.

20. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:7-22.

21. Canner PL, Berge KG, Wenger NK, et al. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol. 1986;8:1245-1255.

22 Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomized, open-label, blinded endpoint analysis. Lancet. 2007;369:1090-1098.

23. Marchioli R, Schweiger C, Tavazzi L, Valagussa F. Efficacy of n-3 polyunsaturated fatty acids after myocardial infarction: results of GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico.

Lipids. 2001;36(suppl):S119-S126.

Cost: $ 0-25, $$ 26-50, $$$ 51-100, $$$$ 101-200, $$$$$ >200 Sources: Clinical data compiled from Micromedex website. http://www.thomsonhc.com. Accessed August 22, 2008. Cost information from www.drugstore.com. Accessed August 22, 2008.

Niacin-ER 500 mg–lovastatin 20 mg/d to niacin-ER 2000 mg–lovastatin 40 mg/d

Various

2-4 g/d

Omega-3 fatty acid* (Lovaza)

Advicor (niacin-ER/ lovastatin)

Available doses

Dosage range

Drug

Populations w/ demonstrated event reduction†

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Fibrates Fibric acid derivatives, or fibrates, such as gemfibrozil and fenofibrate, are agonists of the peroxisomeactivated receptor-α in muscle, liver, and other tissues.

Fibrates can lower TG levels by up to 50% and are therefore considered the first-line agents in patients with hypertriglyceridemia (TG >400 mg/dL).

However, LDL-C reduction is variable (10%-15%), with some patients exhibiting increased levels of LDLC. HDL-C levels may be increased up to 25% in patients with very high TG levels at baseline.17 The most common adverse events are rash and dyspepsia for fenofibrate and GI disturbances for gemfibrozil.

All fibrates may increase the risk of gallstones. In addition, gemfibrozil has been shown to increase plasma concentration of statins, thereby increasing the risk of muscle toxicity.18 Ezetimibe As with bile acid sequestrants, ezetimibe inhibits the absorption of cholesterol. However, since it does not interfere with the absorption of other dietary fats, it is better tolerated. Ezetimibe localizes at the brush border of the small intestine, where it binds to a critical mediator of cholesterol absorption, the Niemann-Pick C1like 1 protein on the GI tract epithelial cells19 and liver cells. Like the bile acid sequestrants, by reducing the availability of LDL-C, ezetimibe also induces LDL receptor upregulation leading to increased uptake of LDL-C into cells, further lowering circulating LDL-C levels. While ezetimibe effectively lowers LDL-C, studies assessing clinical event reduction are lacking. In a recent study, no additional decrease in the carotid intima-media thickness was demonstrated with ezetimibesimvastatin combination therapy compared with simvastatin alone, despite significantly greater reduction in LDL-C in the combination group.20 In addition, in another study, an increased risk of cancer death was observed in the simvastatin-ezetimibe group compared with the placebo group,21 but an analysis of more than 20,000 patients in ongoing randomized trials revealed no increase in cancer risk in patients receiving ezetimibe compared with placebo.22 However, given the lack of documented outcome benefit with this agent, the ACC recommends that it be reserved for patients who cannot reach LDL-C goal with maximal dose statins.11 Omega-3 Fatty Acids Epidemiologic studies have demonstrated that people who have diets rich in omega-3 fatty acids have a

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lower risk of CV events compared with those with a typical Western diet. Studies of omega-3 fatty acid administration have demonstrated reductions in TGs of up to 45% in patients with baseline TG levels >500 mg/dL.23 Smaller reductions are expected in patients with lower baseline levels. In addition to the reduction in TGs, HDL-C levels may be increased by as much as 9%. The addition of omega-3 fatty acids to statin therapy produces further reductions in VLDL-C and TGs and further elevations in HDL-C. The putative mechanisms for TG reduction with high-dose omega-3 fats include increased beta oxidation. ■

Conclusion Elevated cholesterol level is a major risk factor for CVD, the leading cause of death worldwide. Reduction of LDL-C has been shown to decrease the risk of CV events in a large number of clinical trials. Because they are the best studied, have a favorable risk/benefit profile, and have been demonstrated to produce clinical benefits in many large trials, statins are the first-line treatment for patients with hypercholesterolemia.

Disclosure Statement Dr Moe is on the Speakers’ Bureau for Pfizer, BMS, Novartis, Abbott, and GlaxoSmithKline. Drs Burns Schaiff and Krichbaum are employees of Pfizer, Inc. Limited editorial support was provided by Paul Lane, PhD, at Envision Pharma, Ltd, and was funded by Pfizer, Inc.

References 1. Mensah GA, Brown DW. An overview of cardiovascular disease burden in the United States. Health Aff (Millwood). 2007;26:38-48.

2. Rosamond W, Flegal K, Furie K, et al. Heart disease and stroke statistics—2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation.

2008;117:e25-146.

3. The Lipid Research Clinics Coronary Primary Prevention Trial Results. I. Reduction in incidence of coronary heart disease. JAMA. 1984;251:351-364.

4. Brown G, Albers JJ, Fisher LD, et al. Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. N Engl J Med. 1990;323:1289-1298.

5. Manson JE, Hsia J, Johnson KC, et al. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med. 2003;349:523-534.

6. Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med. 2007;357:2109-2122.

7. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285:2486-2497.

8. Grundy SM, Cleeman JI, Bailey Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110:227-239.

9. National Kidney Foundation. K/DOQI Clinical practice guidelines for managing dyslipidemias in chronic kidney disease. Part 3: treating dyslipidemias. Am J Kidney Dis. 2003;41(4 suppl 3):S39-S58.

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10. Adams RJ, Albers G, Alberts MJ, et al. Update to the AHA/ASA recommendations for the prevention of stroke in patients with stroke and transient ischemic attack. Stroke. 2008;39:1647-1652.

11. American College of Cardiology. ACC Statement on ENHANCE Trial. January 15, 2008. http://www.acc.org/enhance_statement.htm.

Accessed October 10, 2008.

12. Libby P. Current concepts of the pathogenesis of atherosclerosis.

Circulation. 2001;104:365-372.

13. Kinlay S. Low density lipoprotein-dependent and independent effects of cholesterol lowering therapies on C-reactive protein: a metaanalysis. J Am Coll Cardiol. 2007;49:2003-2009.

14. Cohen DE, Anania FA, Chalasani N; National Lipid Association Statin Safety Task Force Liver Expert Panel. An assessment of statin safety by hepatologists. Am J Cardiol. 2006;97(8A):77C-81C. 15. Canner PL, Furberg CD, Terrin ML, McGovern ME. Benefits of niacin by glycemic status in patients with healed myocardial infarction (from the Coronary Drug Project). Am J Cardiol. 2005;95:254-257.

16. Ferenchick G, Rovner D. Hepatitis and hematemesis complicating nicotinic acid use. Am J Med Sci. 1989;298:191-193.

17. Guay DR. Micronized fenofibrate: a new fibric acid hypolipidemic agent. Ann Pharmacother. 1999;33:1083-1103.

18. Noé J, Portmann R, Brun ME, Funk C. Substrate-dependent drugdrug interactions between gemfibrozil, fluvastatin and other organic anion-transporting peptide (OATP) substrates on OATP1B1, OATP2B1, and OATP1B3. Drug Metab Dispos. 2007;35:1308-1314.

19. Garcia-Calvo M, Lisnock J, Bull HG, et al. The target of ezetimibe is Niemann-Pick C1-Like 1 (NPC1L1). Proc Natl Acad Sci. 2005;102: 8132-8137.

20. Kastelein JP, Akdim F, Stroes ES, et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med. 2008;358: 1431-1443.

21. Rossebo AB, Pedersen TR, Boman K, et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med. 2008; 359:1343-1356.

22. Peto R, Emberson J, Landray M, et al. Analysis of cancer data from three ezetimibe trials. N Engl J Med. 2008;359:1357-1366.

23. Kris-Etherton PM, Harris WS, Appel LJ; American Heart Association. Nutrition Committee. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation. 2002;106:2747-2757.

Stakeholder Perspectives Experts Debate Meaning of JUPITER for Clinical Practice PHYSICIANS/PAYERS: Should the indications for statins be expanded? This was the question that had many cardiovascular (CV) experts talking, but with little consensus, in light of the findings from the JUPITER (Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin) study released in November 2008 at the American Heart Association annual meeting and then published in the New England Journal of Medicine.1 The results have also created a buzz among P & T Committee members: Should they change plan benefits for statins? Will physicians begin to prescribe the drugs to a new patient population even off-label?

JUPITER showed that apparently healthy individuals with unremarkable levels of low-density lipoprotein cholesterol (LDL-C) but with elevated levels of high-sensitivity C-reactive protein (hsCRP)—2.0 mg/L or more—had a dramatic reduction in the risk for CV events by taking rosuvastatin (Crestor) compared with placebo.

The large benefit of rosuvastatin—a 44% relative reduction in CV risk—surpassed the expectations of the lead investigator, Paul Ridker, MD, Director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital, who has championed the use of hs-CRP to estimate CV risk for quite some time. “Getting CRP down appears to have incremental benefit to lowering LDL cholesterol,” Dr Ridker said. “There was a large number in our

study who had an elevation of CRP without other risk factors, and this group had a benefit from rosuvastatin as well.” Of those who fit the profile of the study population, 25 patients would need to be treated to prevent 1 CV event, which is “smaller than we anticipated,” said Dr Ridker.

Steve Nissen, MD, Chairman of the Department of Cardiovascular Medicine at the Cleveland Clinic, is a believer in CRP testing and is already using it to guide treatment decisions. He noted that the reduction in death and major CV events with rosuvastatin was larger than in any other trial of a statin, and he was impressed that it occurred after only an average of 1.9 years of treatment (the study had been planned to last 5 years but was terminated early because of the large benefit found).

According to Dr Nissen, applying the findings from JUPITER to the US population could add 10 million persons who could benefit from statins.

Critics point out that although the magnitude of the 44% relative reduction in risk was large, the absolute risk reduction was rather small—only 0.9% (1.8% in the placebo group had an event compared with 0.9% in the rosuvastatin group). Of note, subjects enrolled in the trial were at low risk at baseline, and this low risk accounted for the small reduction in absolute risk. Only 157 of 8901 subjects taking placebo had an event compared with 83 of 8901 randomized to rosuvastatin.

Continued

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Continued Using Crestor to prevent 1 death in persons with elevated CRP levels has been estimated at $500,000, a cost that may be too high. Some suggest that prescribing Crestor to reduce CRP could add $8.9 billion to the cost of treatment in this country. But this cost would be reduced to about $25,000 to prevent 1 death, using a generic statin, if generic statins are as effective as the brand drug at reducing CRP levels.

Evidence indicates that all the statins reduce CRP, but to different degrees.

1. Ridker PM, Danielson E, Fonseca FAH, et al, for the JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2195-2207.

Wayne Kuznar Medical Writer

Cholesterol Management: The Complexity of Multiple Effectives Treatments PAYERS: High levels of serum cholesterol have long been recognized as a significant risk factor for the development and progression of atherosclerosis.

Lowering cholesterol has been shown to effectively reduce mortality and morbidity associated with acute coronary syndromes and stroke—2 of the top 3 causes of death in the United States. As our understanding of the role of cholesterol has evolved, we have come to realize the individual effects that low-density lipoprotein (LDL) and high-density lipoprotein can have in risk assessment and modification.

As the authors of this article highlight, a large number of effective treatments are available. The availability of multiple agents adds to the complexity of their use: Are all these agents equal in their ability to affect lipid levels? Are they equal in their ability to influence outcomes? For an individual patient with a specific set of risk factors and a specific lipid profile, which agents will best affect their lipid panel and their overall risk of cardiovascular or cerebrovascular complications?

The availability of several effective treatments also raises questions about thresholds for screening and treatment. A number of organizations have provided such guidance, including the American Heart Association, the National Cholesterol Education Program, the United States Preventive Services Task Force (USPSTF), and the American Academy of Pediatrics. As is often the case for the clinician attempting to determine the best recommendation for a given patient, or for the patient attempting to participate in decision-making—the rapid development of new science and research and the conflicting guidance of expert panel recommendations can compound the confusion. For example, the USPSTF currently recommends screening of patients older than 20 years, citing insufficient evidence for screening younger populations. Meanwhile, a recommen-

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dation issued in 2008 by the American Academy of Pediatrics is much more aggressive with regard to screening, and even treatment, of children with certain risk factors.1 This complexity is further increased with the publicity related to the early termination of the JUPITER trial (see previous page), which was published in November 2008.2 In JUPITER, patients without a history of cardiovascular disease, with LDL levels <130 mg/dL but with high-sensitivity C-reactive protein levels of 2.0 mg/L or more, were randomized to receive rosuvastatin or placebo. The trial was ended early because patients in the treatment group showed very significant reductions in myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes. This study will raise questions regarding the thresholds that must be met to initiate therapy. It will also raise issues concerning the relative effectiveness of various agents, depending on their ability to affect “inflammation” as a separate risk factor for atherosclerosis.

Until the evidence becomes clearer, we must empower clinicians facing these decisions with as many options as possible. They must be able to personalize therapy—the best agent for the individual patient—without undue restrictions.

1. Daniels SR, Greer FR; Committee on Nutrition. Lipid screening and cardiovascular health in childhood. Pediatrics. 2008;122:198208.

2. Ridker PM, Danielson E, Fonseca FAH, et al, for the JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008; 359:2195-2207.

Thomas McCarter, MD, FACP Chief Clinical Officer Executive Health Resources

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Promotion of Medical Tourism in the Media Creates a Trend J. Warren Salmon, PhD

W

hether Americans are flocking overseas for medical care remains a question. One estimate put the number at 150,000 in 2006,1 jumping to 750,000 in 2007.2 Nevertheless, the popular press continues to devote articles to this phenomenon that may very well be creating the market.

The Lure The lure of medical tourism for patients is the ability to obtain services for relatively cheap cost, which can help uninsured and underinsured Americans gain access to care; allow richer patients to get services quicker; or enable private health plans to arrange “bargain care” elsewhere for their insured patients. This has fostered a thriving industry in some countries, and the lay press has found such outsourcing a source for attractive stories—“recovering from a medical procedure while lying on a palm-swept beach, relaxing by the hotel pool, or shopping for terrific bargains sounds good.”3 Just a few years ago, medical tourism was depicted as care associated with an exotic vacation or with an attendant spa recovery postsurgery. Yet escalating medical costs began to make the travel portion seem reasonable for those who were denied access at home.

Travel sections of newspapers featured pleased uninsured working and poorer patients who received a much-needed operation at a mere fraction of the US cost. Major publications (eg, New York Times, Los Angeles Times), generally in states bordering the Pacific Rim and Latin America, published stories accompanied by advertisements for touring agencies, and thus began the fledgling middleman industry that generated attention to medicine overseas.

The Los Angeles Times ran articles first examining medical tourism, later denoting its growth, and then marking it as a trend. Articles appeared in Arkansas, Tennessee, Washington, and other states removed from the nonstop airplane routes, as the public gradually became acquainted with travel for healthcare. Fox, CNN, and CBS’s “60 Minutes” ran segments on people Dr Salmon is Professor of Health Policy and Administration, School of Public Health, University of Illinois at Chicago, IL.

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traveling for services. Forbes and the Wall Street Journal focused on the business aspects of the phenomenon, as middlemen aggressively marketed it to consumers, employers, and insurers.

“Hot destinations” came into the spotlight— Singapore, India, Thailand, Mexico, Costa Rica, China, and more. And the base broadened. Europeans opting out of their national health systems, along with wealthy clientele from the Middle East and other regions, were identified as medical tourists. The Internet further facilitated clever marketing campaigns by private providers seeking to service the burgeoning international market.

Cheaper care for dental services, cosmetic interventions, and specialty pharmacy began to be proffered in travel packages to lure patients to providers who arranged “customer care” in luxurious hotels, touting huge savings for “quality care.” Inroads into “bargain surgery” in modern facilities with advanced equipment were made. Lower-cost facelifts, hormone therapy, and the like now appeal to “aging cohorts” in the developed world.

Many of the private hospitals across Asia have English-speaking and American-trained staff, who now can deliver organ and bone marrow transplants, orthopedic, oncology, cardiovascular, and more hi-tech and complex care. In 2007, Forbes’s article “Open-Heart Surgery—90% off!” highlighted the differences in cost and quality of care between the United States and other countries.4 Thus, the media caught the fancy of comparative costs as a way to promote access to affordable healthcare for Americans, including small businesses. The Financial Times and San Francisco Chronicle covered the 2008 Deloitte study, which found that almost 40% of Americans would travel abroad for care, provided that quality appeared comparable with that in the United States.5 People with private insurance were more likely to consider traveling.

In the medical literature, a discussion amongst payers and providers has begun concerning medical tourism. A 2006 New England Journal of Medicine article warned that “American physicians who are concerned about the growth of this phenomenon have two

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choices: they can denounce and attempt to restrict it, or they can lead and more actively support efforts by others to speed the discovery and uptake of more efficient domestic healthcare delivery methods.”6

Policy Concerns Doubts about patient care quality abroad and potential safety issues emerged in the popular press before the professional literature. Can quality be assured? What about complications when returning home? Will follow-up care at home be available? What is the legal recourse in nations without malpractice laws or “a culture” of suing doctors? A series of cautions is clearly needed for an unregulated medical tourism industry.

As the hubs for foreign care are investigated, assurances on such concerns are hard to come by. The USbased Joint Commission International accredits more than 140 hospitals overseas, with a doubling of that number projected in 2 years. But this is by no means a complete safeguard to a botched surgery. Location analyses of provider destinations are necessary, along with specific reviews of providers, the host of entrepreneurial middlemen making travel arrangements, and even the motives and diligence of new US insurers and employers who are looking for potential savings from sending their insured members overseas.

AlterNet raises a concern that medical tourism may pose competition to the US healthcare system: “The problem with turning to medical tourism as an answer to healthcare problems goes beyond personal stories and into the realm of hard policy. There are lots of stakeholders that are eager to trump up medical tourism as a silver bullet for healthcare costs….[Some suggest that ] since insurers and employers can pay less to cover procedures, the US healthcare system will benefit greatly from medical tourism.”7 It will be interesting to see how US payers respond to all this. And how the US government and others

react to this emerging phenomenon will be critical.

Tourism is a trade that is under World Trade Organization consideration. Siphoning off the wealthy to posh concierge care in private health systems overseas and leaving a subpar public sector for the poorer masses pose ethical dilemmas. At a time of rising global epidemics, for developing nations to neglect regulatory directions to preserve and protect their public health is a concern.8 The lay press’ attention to medical tourism has helped to create a new market, spurring entrepreneurial enterprises stateside to facilitate it, as well as setting up a host of private providers overseas to capitalize on this nascent trend. This phenomenon has also provoked issues that force us to reflect on the impact of globalization at home and abroad. ■

References 1. AMA press release. AMA provides first ever guidance on medical tourism. June 16, 2008. http://www.ama-assn.org/ama/pub/category/ 18678.html. Accessed November 3, 2008.

2. Madden CL. Medical tourism causes complications. October 27, 2008. http://www.policyinnovations.org/ideas/briefings/data/000083.

Accessed November 3, 2008.

3. Kaderli B, Kaderli A. Medical vacations: the retiree health-care solution? MotleyFool.com. August 12, 2008. http://www.fool.com/ personal-finance/retirement/2008/08/12/medical-vacations-theretiree-health-care-solution. aspx. Accessed November 3, 2008.

4. Forbes S. Open-heart surgery—90% off! Forbes. August 13, 2007. http://www.forbes.com/columnists/forbes/2007/0813/021.html. Accessed November 3, 2008.

5. Deloitte. Medical tourism: consumers in search of value, 2008. http://www.deloitte.com/dtt/cda/doc/content/us_chs_MedicalTourism Study(1).pdf. Accessed November 3, 2008.

6. Milstein A, Smith M. America’s new refugees—seeking affordable surgery offshore. N Engl J Med. 2006;355:1637-1640.

7. Mahar M. Medical tourism is great—for those who can afford it.

AlterNet. August 21, 2008. http://www.alternet.org/healthwellness/ 95827/medical_tourism_is_great_—_for_those_who_can_afford_it/.

Accessed November 3, 2008.

8. Salmon JW, Aruru M. Health tourism to India: challenges against resource competition to sustaining a viable public health infrastructure for the local populace. Presented at the Annual Expo and Meeting of the American Public Health Association; San Diego, CA; October 27, 2008.

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NOT EVERYONE IS CUT OUT FOR THE SAME TREATMENT. 1 in 4 adults suffer from a diagnosable mental disorder in any given year.1

Open Access.

Because different people have different needs.

Open access is especially important in the treatment of mental disorders because the response to therapy can vary greatly from individual to individual and from one medication to the next. Restrictions in the form of prior authorizations and preferred lists may have the unintended consequences of jeopardizing patient health while failing to reduce costs.

Bristol-Myers Squibb supports open and unrestricted access to mental health medications. For people with mental illness, having access to newer and potentially more effective medications can be a crucial component of treatment.

SUPPORT OPEN ACCESS AND GIVE PROVIDERS THE FREEDOM TO FIND THE MOST APPROPRIATE MEDICATION FOR EACH INDIVIDUAL. 1. National Institute of Mental Health. Available at: http://www.nimh.nih.gov/healthinformation/statisticsmenu.cfm.

Accessed August 7, 2006.

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Erythropoiesis-Stimulating Agents in a Meta-Stable State Interview (Part 2) with Samuel M. Silver, MD, PhD

In this second interview, Dr Silver, director of the Cancer Center Network at the Division of Hematology/Oncology at the University of Michigan Health Systems, focuses on the impact of Medicare coverage decision for erythropoiesis-stimulating agents (ESAs), and why ESAs are so important for patients. He emphasizes the risk of transfusions to cancer patients and why policy decisions that restrict the use of ESAs can have profound implications for patients. Dr Silver, who is also Assistant Dean for Research at the University of Michigan, calls for new studies, to be funded by the manufacturers of the 2 major ESAs, to inves-

tigate the concerns for tumor progression and thromboembolic events that are potentially associated with these expensive medications. Such research could better guide policy decisions by Medicare and improve patient care. Despite the very high cost of the ESAs, the issue of transfusions in cancer patients is beyond economics, Dr Silver says, since they expose patients to unnecessary risks. And although Medicare is not supposed to consider costs in its decisions, cost is an underlying context for coverage decisions, especially for as expensive medications as ESAs, which nevertheless may reduce hospitalization for transfusions, he says.

Role for Automated Communication Strategies in Medication Adherence Management

By S. Michael Ross, MD, MHA

Medication nonadherence is a major cause of morbidity and mortality in the United States. Nonadherence to drug therapy is also a major contributor to escalating costs of healthcare. Lack of information and forgetfulness are 2 main reasons cited by patients for lack of adherence. These 2 causes can be positively influenced by improved patientâ&#x20AC;&#x201C;provider communication, Dr Ross explains. With chronic diseases estimated to involve hundreds of millions of patients, the scale of disease management enrollment is too great to be costeffective using traditional outreach methods. The challenge is to scale outreach programs efficiently, without

losing the personal touch necessary to help change behavior. Using communication automation to augment traditional call center outreach can help to mediate patient medication-taking behaviors. Dr Ross reports results of his new study that involved an automated telephony to 304 elderly patients with hypertension. Using this automated system helped reduce costs and improve the blood pressure monitoring of patients.

In addition to significant improvements in outcomes, 174 patients had their antihypertensive regimen altered based on their responses to the survey part of the automated system.

An Overview of Cholesterol Management

By Robyn A. Burns Schaiff, PharmD, BCPS; Richard M. Moe, MD, PhD; Daniel W. Krichbaum, PharmD

Cardiovascular disease (CVD) remains the leading cause of death worldwide. Hypercholesterolemia and dyslipidemia are significant risk factors for the development of CVD, which affects more than 80 million Americans. A team of 3 experts discusses the relationship between cholesterol levels and the risk of CVD, outlining the National Cholesterol Education Program guidelines for assessment and treatment of dyslipidemia, and summarizing current cholesterol targets. The first goal of therapy in hypercholesterolemia is reduction of low-density lipoprotein (LDL) cholesterol levels.

Evidence shows that statins are the most effective lipidlowering agents available. Drs Schaiff, Moe, and

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Krichbaum provide an extensive drug table that covers all lipid-lowering classes, their mechanisms of action, place in therapy, side effects, as well as costs. Finally, new evidence from the recently published JUPITER study has shown that in addition to lowering lipid levels, statins are important for preventing vascular events in patients with elevated C-reactive protein (CRP) levels, even in those with normal cholesterol levels. A debate is currently raging among experts and decision makers whether persons with normal lipid levels but with elevated CRP levels should be taking a statin on a regular basis. These results may have implications for all health benefit programs.

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Brief Summary of Prescribing Information USE IN PREGNANCY When used in pregnancy during the second and third trimesters, drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus. When pregnancy is detected, MICARDIS® tablets should be discontinued as soon as possible.

See WARNINGS: Fetal/Neonatal Morbidity and Mortality INDICATIONS MICARDIS is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents.

CONTRAINDICATIONS MICARDIS (telmisartan) is contraindicated in patients who are hypersensitive to any component of this product.

WARNINGS Fetal/Neonatal Morbidity and Mortality Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature in patients who were taking angiotensin converting enzyme inhibitors. When pregnancy is detected, MICARDIS (telmisartan) tablets should be discontinued as soon as possible. The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug. These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to an angiotensin II receptor antagonist only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should have the patient discontinue the use of MICARDIS tablets as soon as possible. Rarely (probably less often than once in every thousand pregnancies), no alternative to an angiotensin II receptor antagonist will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intra-amniotic environment. If oligohydramnios is observed, MICARDIS tablets should be discontinued unless they are considered life-saving for the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Infants with histories of in utero exposure to an angiotensin II receptor antagonist should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. There is no clinical experience with the use of MICARDIS tablets in pregnant women. No teratogenic effects were observed when telmisartan was administered to pregnant rats at oral doses of up to 50 mg/kg/day and to pregnant rabbits at oral doses up to 45 mg/kg/day. In rabbits, embryolethality associated with maternal toxicity (reduced body weight gain and food consumption) was observed at 45 mg/kg/day [about 12 times the maximum recommended human dose (MRHD) of 80 mg on a mg/m2 basis]. In rats, maternally toxic (reduction in body weight gain and food consumption) telmisartan doses of 15 mg/kg/day (about 1.9 times the MRHD on a mg/m2 basis), administered during late gestation and lactation, were observed to produce adverse effects in neonates, including reduced viability, low birth weight, delayed maturation, and decreased weight gain. Telmisartan has been shown to be present in rat fetuses during late gestation and in rat milk. The no observed effect doses for developmental toxicity in rats and rabbits, 5 and 15 mg/kg/day, respectively, are about 0.64 and 3.7 times, on a mg/m2 basis, the maximum recommended human dose of telmisartan (80 mg/day). Hypotension in Volume-Depleted Patients In patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients (e.g., those being treated with high doses of diuretics), symptomatic hypotension may occur after initiation of therapy with MICARDIS® tablets. This condition should be corrected prior to administration of MICARDIS tablets, or treatment should start under close medical supervision with a reduced dose. If hypotension does occur, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.

PRECAUTIONS General. Impaired Hepatic Function: As the majority of telmisartan is eliminated by biliary excretion, patients with biliary obstructive disorders or hepatic insufficiency can be expected to have reduced clearance. MICARDIS (telmisartan) tablets should be used with caution in these patients. Impaired Renal Function: As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensinaldosterone system (e.g., patients with severe congestive heart failure), treatment with angiotensinconverting enzyme inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. Similar results may be anticipated in patients treated with MICARDIS tablets. In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen were observed. There has been no long term use of MICARDIS tablets in patients with unilateral or bilateral renal artery stenosis but an effect similar to that seen with ACE inhibitors should be anticipated. Information for Patients. Pregnancy: Female patients of childbearing age should be told about the consequences of second- and third-trimester exposure to drugs that act on the renin-angiotensin system, and they should also be told that these consequences do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. These patients should be asked to report pregnancies to their physicians as soon as possible. Drug Interactions.

Digoxin: When telmisartan was coadministered with digoxin, median increases in digoxin peak plasma concentration (49%) and in trough concentration (20%) were observed. It is, therefore, recommended that digoxin levels be monitored when initiating, adjusting, and discontinuing telmisartan to avoid possible overor under-digitalization. Warfarin: Telmisartan administered for 10 days slightly decreased the mean warfarin trough plasma concentration; this decrease did not result in a change in International Normalized Ratio (INR).

Other Drugs: Coadministration of telmisartan did not result in a clinically significant interaction with acetaminophen, amlodipine, glibenclamide, simvastatin, hydrochlorothiazide or ibuprofen. Telmisartan is not metabolized by the cytochrome P450 system and had no effects in vitro on cytochrome P450 enzymes, except for some inhibition of CYP2C19. Telmisartan is not expected to interact with drugs that inhibit cytochrome P450 enzymes; it is also not expected to interact with drugs metabolized by cytochrome P450 enzymes, except for possible inhibition of the metabolism of drugs metabolized by CYP2C19.

Carcinogenesis, Mutagenesis, Impairment of Fertility There was no evidence of carcinogenicity when telmisartan was administered in the diet to mice and rats for up to 2 years. The highest doses administered to mice (1000 mg/kg/day) and rats (100 mg/kg/day) are, on a mg/m2 basis, about 59 and 13 times, respectively, the maximum recommended human dose (MRHD) of telmisartan. These same doses have been shown to provide average systemic exposures to telmisartan >100 times and >25 times, respectively, the systemic exposure in humans receiving the MRHD (80 mg/day). Genotoxicity assays did not reveal any telmisartanrelated effects at either the gene or chromosome level. These assays included bacterial mutagenicity tests with Salmonella and E. coli (Ames), a gene mutation test with Chinese hamster V79 cells, a cytogenetic test with human lymphocytes, and a mouse micronucleus test. No drug-related effects on the reproductive performance of male and female rats were noted at 100 mg/kg/day (the highest dose administered), about 13 times, on a mg/m2 basis, the MRHD of telmisartan. This dose in the rat resulted in an average systemic exposure (telmisartan AUC as determined on day 6 of pregnancy) at least 50 times the average systemic exposure in humans at the MRHD (80 mg/day). Pregnancy Pregnancy Categories C (first trimester) and D (second and third trimesters). See WARNINGS, Fetal/Neonatal Morbidity and Mortality. Nursing Mothers It is not known whether telmisartan is excreted in human milk, but telmisartan was shown to be present in the milk of lactating rats. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Of the total number of patients receiving MICARDIS in clinical studies, 551 (18.6%) were 65 to 74 years of age and 130 (4.4%) were 75 years or older. No overall differences in effectiveness and safety were observed in these patients compared to younger patients and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

ADVERSE REACTIONS MICARDIS (telmisartan) has been evaluated for safety in more than 3700 patients, including 1900 treated for

g

over six months and more than 1300 for over one year. Adverse experiences have generally been mild and transient in nature and have only infrequently required discontinuation of therapy. In placebo-controlled trials involving 1041 patients treated with various doses of telmisartan (20-160mg) monotherapy for up to 12 weeks, an overall incidence of adverse events similar to that of placebo was observed. Adverse events occurring at an incidence of 1% or more in patients treated with telmisartan and at a greater rate than in patients treated with placebo, irrespective of their causal association, are presented as follows: The most common adverse events occurring with MICARDIS Tablets monotherapy at a rate of ≥1% and greater than placebo, respectively, were: upper respiratory tract infection (URTI) (7%, 6%), back pain (3%, 1%), sinusitis (3%, 2%), diarrhea (3%, 2%), and pharyngitis (1%, 0%). In addition to the adverse events, the following events occurred at a rate of 1% but were at least as frequent in the placebo group: influenza-like symptoms, dyspepsia, myalgia, urinary tract infection, abdominal pain, headache, dizziness, pain, fatigue, coughing, hypertension, chest pain, nausea and peripheral edema. Discontinuation of therapy due to adverse events was required in 2.8% of 1455 patients treated with MICARDIS tablets and 6.1% of 380 placebo patients in placebo-controlled clinical trials. The incidence of adverse events was not dose-related and did not correlate with gender, age, or race of patients. The incidence of cough occurring with telmisartan in six placebo-controlled trials was identical to that noted for placebo-treated patients (1.6%). In addition to those listed above, adverse events that occurred in more than 0.3% of 3500 patients treated with MICARDIS monotherapy in controlled or open trials are listed below. It cannot be determined whether these events were causally related to MICARDIS tablets: Autonomic Nervous System: impotence, increased sweating, flushing; Body as a Whole: allergy, fever, leg pain, malaise; Cardiovascular: palpitation, dependent edema, angina pectoris, tachycardia, leg edema, abnormal ECG; CNS: insomnia, somnolence, migraine, vertigo, paresthesia, involuntary muscle contractions, hypoaesthesia; Gastrointestinal: flatulence, constipation, gastritis, vomiting, dry mouth, hemorrhoids, gastroenteritis, enteritis, gastroesophageal reflux, toothache, non-specific gastrointestinal disorders; Metabolic: gout, hypercholesterolemia, diabetes mellitus; Musculoskeletal: arthritis, arthralgia, leg cramps; Psychiatric: anxiety, depression, nervousness; Resistance Mechanism: infection, fungal infection, abscess, otitis media; Respiratory: asthma, bronchitis, rhinitis, dyspnea, epistaxis; Skin: dermatitis, rash, eczema, pruritus; Urinary: micturition frequency, cystitis; Vascular: cerebrovascular disorder; and Special Senses: abnormal vision, conjunctivitis, tinnitus, earache. During initial clinical studies, a single case of angioedema was reported (among a total of 3781 patients treated with telmisartan). Clinical Laboratory Findings In placebo-controlled clinical trials, clinically relevant changes in standard laboratory test parameters were rarely associated with administration of MICARDIS tablets.

Hemoglobin: A greater than 2 g/dL decrease in hemoglobin was observed in 0.8% telmisartan patients compared with 0.3% placebo patients. No patients discontinued therapy due to anemia. Creatinine: A 0.5 mg/dL rise or greater in creatinine was observed in 0.4% telmisartan patients compared with 0.3% placebo patients. One telmisartan-treated patient discontinued therapy due to increases in creatinine and blood urea nitrogen. Liver Enzymes: Occasional elevations of liver chemistries occurred in patients treated with telmisartan; all marked elevations occurred at a higher frequency with placebo. No telmisartan-treated patients discontinued therapy due to abnormal hepatic function. Post-Marketing Experience The following adverse reactions have been identified during post-approval use of MICARDIS tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to MICARDIS tablets. The most frequently spontaneously reported events include: headache, dizziness, asthenia, coughing, nausea, fatigue, weakness, edema, face edema, lower limb edema, angioneurotic edema, urticaria, hypersensitivity, sweating increased, erythema, chest pain, atrial fibrillation, congestive heart failure, myocardial infarction, blood pressure increased, hypertension aggravated, hypotension (including postural hypotension), hyperkalemia, syncope, dyspepsia, diarrhea, pain, urinary tract infection, erectile dysfunction, back pain, abdominal pain, muscle cramps (including leg cramps), myalgia, bradycardia, eosinophilia, thrombocytopenia, uric acid increased, abnormal hepatic function/liver disorder, renal impairment including acute renal failure, anemia, and increased CPK. Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers, including MICARDIS. OVERDOSAGE Limited data are available with regard to overdosage in humans. The most likely manifestation of overdosage with MICARDIS (telmisartan) tablets would be hypotension, dizziness and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, supportive treatment should be instituted. Telmisartan is not removed by hemodialysis.

DOSAGE AND ADMINISTRATION Dosage must be individualized.The usual starting dose of MICARDIS (telmisartan) tablets is 40 mg once a day. Blood pressure response is dose related over the range of 20-80 mg. Special Populations: Patients with depletion of intravascular volume should have the condition corrected or MICARDIS tablets should be initiated under close medical supervision (see WARNINGS, Hypotension in Volume-Depleted Patients). Patients with biliary obstructive disorders or hepatic insufficiency should have treatment started under close medical supervision (see PRECAUTIONS, General, Impaired Hepatic Function, and Impaired Renal Function). Most of the antihypertensive effect is apparent within two weeks and maximal reduction is generally attained after four weeks. When additional blood pressure reduction beyond that achieved with 80 mg MICARDIS is required, a diuretic may be added. No initial dosing adjustment is necessary for elderly patients or patients with mild-to-moderate renal impairment, including those on hemodialysis. Patients on dialysis may develop orthostatic hypotension; their blood pressure should be closely monitored. MICARDIS tablets may be administered with other antihypertensive agents. MICARDIS tablets may be administered with or without food.

Rx only MC-BS (03/07)

Copyright © 2007, Boehringer Ingelheim Pharmaceuticals, Inc. All rights reserved.

Printed in U.S.A.

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Get patients with difficult-to-control hypertension to goal1

MICARDIS. More than POWER…

BP PROTECTION in the early morning2

USE IN PREGNANCY When used in pregnancy during the second and third trimesters, drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus. When pregnancy is detected, MICARDIS Tablets should be discontinued as soon as possible (see WARNINGS, Fetal/Neonatal Morbidity and Mortality).

MICARDIS is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents.

MICARDIS is contraindicated in patients who are hypersensitive to any component of this product. The most common adverse events occurring with MICARDIS Tablets monotherapy at a rate of ≥1% and greater than placebo, respectively, were: upper respiratory tract infection (URTI) (7%, 6%), back pain (3%, 1%), sinusitis (3%, 2%), diarrhea (3%, 2%), and pharyngitis (1%, 0%).

Please see Brief Summary of Product Information on adjacent page.

References: 1. Weber MA,White WB,Giles TD,et al.An effectiveness study comparing algorithm-based antihypertensive therapy with previous treatments using conventional and ambulatory blood pressure measurements. J Clin Hypertens.

2006;8:241-250. 2. White WB,Giles T,Bakris GL,et al.Measuring the efficacy of antihypertensive therapy by ambulatory blood pressure monitoring in the primary care setting. Am Heart J. 2006;151:176-184.

Please visit www.micardis.com for more information, including Prescribing Information.

Copyright © 2007, Boehringer Ingelheim Pharmaceuticals, Inc. All rights reserved.

Printed in U.S.A.

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GENERIC DRUG TRENDS

Focus on Lowest Net Cost Drug Reduces Costs for Patients, Plan Sponsors Dana H. Felthouse, MBA

T

he use of generic drugs is one of the key drivers of value in the pharmacy benefit today. Both drug benefit plan sponsors and beneficiaries realize cost-savings by increasing the use of generic drugs when medically appropriate. On average, generic drugs cost 30% to 80% less than their brand-name counterparts.1 It is important for plan sponsors and plan beneficiaries to understand the safety and efficacy of generic drugs, as well as the potential cost-savings.

Therapeutic Scope of Generics The increasing availability of generic drug therapies is slowing the rate of growth in prescription drug expenditures. For the first time since the mid-1980s, the growth in per-capita spending on prescription drugs has dropped below the percentage of growth in the US healthcare expenditures.2 The average rate of increase for drug expenditures for US employers in 2008 was 4.86%,3 according to findings from the 2008 Pharmacy Benefit Management Institute (PBMI)’s annual drug benefit plan design survey of US employers.3 This growth rate represents the lowest cost increase since PBMI began conducting its annual survey in 1995. This new survey, conducted in May and June 2008, was completed by 223 employers, representing 15,137,168 members. The increasing use of generic drugs contributes to this single-digit growth in expenditures.

When purchasers and consultants discuss generic drugs, they refer to 2 different rates or metrics—genericdispensing rate and generic substitution rate (Table 1).

Generic-dispensing rate is a clear metric for tracking progress in the use of lower-cost prescription drugs. In most cases, the generic-dispensing rate is the most Ms Felthouse is President, Pharmacy Benefit Management Institute (PBMI), Scottsdale, AZ. She has been the lead author of PBMI’s annual Prescription Drug Benefit Cost and Plan Design Report and PBM Customer Satisfaction Report since 2001. She can be reached at dfelthouse@pbmi. com. The annual reports can be accessed at www.pbmi.com.

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AMERICAN HEALTH & DRUG BENEFITS

actionable metric to monitor improvement in generic use and the associated savings. PBMI’s 2008 study also documents continued increases in average generic-dispensing rates for US employers in retail and in mail dispensing since 2002 (Table 2).3 Generic-dispensing rates will continue to increase as more brand-name drugs used by ambulatory populations become available as generics.

The creation of incentives for plan members to use generic drugs is essential for a high-performing drug benefit program. Generic incentives are of increasing importance in 2008 as more branded drugs come off patent.

The result is a growing range of generic drug options to treat allergies, arthritis, asthma, depression, elevated cholesterol levels, hypertension, and chronic pain.

Education Tools for Plan Members Drug companies are spending billions of dollars to encourage consumers to request high-cost, brand-name drugs from their physicians. Consumers and drug benefit plan sponsors will realize reduced prescription drug costs if consumers make the choice to purchase the lowest-cost drug that is medically appropriate for their needs. Empowering consumers to make that choice is a challenge.

Complex benefit designs make it difficult for consumers to keep track of their plans’ preferred drugs and beneficiary cost-sharing, and discuss this information with their prescribing physicians. Consumers need access to up-to-the-minute information on their plans’ copayments and prescription costs to make educated, cost-effective decisions.

Repetition Research has shown that people often need to see or hear a message multiple times (as many as 7) before it makes an impression. Repetition is good, as is using a variety of ways to communicate because people have different learning styles. Organizations should leverage every available opportunity to deliver messages that increase confidence in and encourage the use of generics. Messaging opportunities include: • Direct mail targeted to high utilizers of prescription drugs

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Table 1 Must-Know Generic Terms

Tracking Availability and Price of Generic Drugs

• Generic-Dispensing Rate: Percentage of total prescriptions filled with a generic drug • Generic Substitution Rate: Percentage of total prescriptions that could be filled with a generic drug that actually are filled with a generic Source: Pharmacy Benefit Management Institute.

The ABCs of Generic Drugs. White Paper Series. 2008. http://www.pbmi.com/pbm101white paperseries.asp.

Table 2 Trends in Average Generic-Dispensing Rates Year

Average retail generic-dispensing rate, %

Average mail generic-dispensing rate, %

2002 2003 2004 2005-2006 2007 2008

42.0 44.0 47.0 51.0 54.5 60.4

32.0 34.0 38.0 39.0 41.7 49.3

Source: Pharmacy Benefit Management Institute. Prescription Drug Benefit Cost and Plan Design Report, 2008-2009 Edition. 2008. www. pbmi.com/2008_report/index.html.

• Employee meetings • Employee/retiree/member publications, both print and electronic • Employee/member intranet • Online tools for comparing brand and generic alternatives • Payroll envelopes and electronic funds transfer notifications • Podcasts • Posters in break rooms and high-traffic areas • Retiree association events.

Consumer Resources The following consumer-focused resources can supplement plan benefits communication efforts: • Consumer Reports Best Buy Drugs is an independent, online resource that helps beneficiaries learn about generic alternatives and empowers them to discuss cost-effective options with their physicians.

Beneficiaries can obtain free reports that compare the safety, efficacy, and cost of brand-name and generic drug options for 16 different medical conditions (www.crbestbuydrugs.org).

• The Generic Pharmaceutical Association offers consumer education on generics, including a frequently asked question-and-answer section and downloadable brochures (www.gphaonline.org/AM/ Template.cfm?Section=About_Generics).

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Using generic drugs to save money is a winning strategy for every drug benefit program. The savings begin when a brandname drug goes off patent. Here is a list of tools to help track the availability and price of generic drugs.

• Trends in Manufacturer Prices of Prescription Drugs Used by Medicare Beneficiaries: The AARP’s Public Policy Institute’s annual report on changes in manufacturer list prices for brand-name and generic drugs. Includes average annual percent change in manufacturer prices for the top 25 generic prescription drugs. Shows price changes by manufacturer and therapeutic category for the most widely used generic drugs. www.aarp.org/research/health/drugs/rx_ watchdog.html.

• Drug Patent Watch: Information on drugs and their patent expirations. Subscribe to free bulletins on imminent patent expirations. www.drugpatentwatch.com/.

• Drugs@FDA: Monthly drug approval reports. Searchable database of FDA-approved drugs. Search by brand name or active ingredient for availability of generic alternatives. www. accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm.

• FDA Electronic Orange Book: Searchable database of all FDAapproved prescription drugs—brand-name and generic drugs, with therapeutic equivalence evaluations. Daily updates for new generic approvals. www.fda.gov/cder/ob/.

• FDA Generic Drug Approvals: Monthly reports on first-time generic drug approvals. www.fda.gov/cder/ogd/approvals/ default.htm.

• Generic Pharmaceutical Association: Statistics and resources for consumers and researchers. Includes list of generic prescription medications recently approved by the FDA and guidelines for navigating the Drugs@FDA website. www.gphaonline.org/AM/Template.cfm?Section=Home.

• The US Food and Drug Administration (FDA) offers consumer education materials that can be downloaded, ordered in quantities, or used as resources for developing employer-specific materials.

Resources available in multiple languages include print brochures, posters, articles, PowerPoint presentations, audio presentations and handouts (www.fda. gov/cder/consumerinfo/generic_all_re sources.htm).

Aligning your drug benefit plan to encourage the utilization of the lowest net cost drug that is medically appropriate for a patient will enhance the clinical and economic returns of your investment in prescription drugs. ■

References 1. Generic Pharmaceutical Association. About generics: same medicine, same results, lower cost. http://www.gphaonline.org/AM/Template.cfm?

Section=About_Generics. Accessed November 10, 2008.

2. PricewaterhouseCoopers Health Research Institute. Behind the Numbers: Healthcare Cost Trends for 2008. 2008. www.pwc.com/extweb/ pwcpublications.nsf/docid/88FF5DC2E5E1143085257300006C68B1.

Accessed November 10, 2008.

3. Pharmacy Benefit Management Institute. Prescription Drug Benefit Cost and Plan Design Report, 2008-2009 Edition. 2008. www.pbmi. com/2008_report/index.html. Accessed November 10, 2008.

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“We either do it right or we don’t do it at all.” ©2008 Mylan Pharmaceuticals Inc.

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He’s kept his word for 47 Years.

In 1961, two U.S. Army buddies, Milan (Mike) Puskar and Don Panoz, founded a pharmaceutical company with a handful of employees in a small town in West Virginia. From the beginning, the founders were determined to build a company based on quality and integrity and to follow Mike’s philosophy—

“We either do it right or we don't do it at all.”

Over the past 47 years, that company, Mylan Pharmaceuticals, has grown to become the largest U.S.-based manufacturer of generic pharmaceuticals by total prescriptions*. . . and Mike Puskar is still Chairman of the Board. His no-compromise attitude continues to guide all aspects of company business, from research and development, to manufacturing and distribution.

Today, every employee in the Mylan family is always ready to take the extra step necessary to ensure that Mylan Products deliver the high quality that patients expect and deserve. This unwavering commitment assures that products from Mylan will always offer quality and affordability for the patients who need them and peace of mind for the pharmacists who dispense them.

*IMS National Prescription Audit. Total Prescriptions: June 2007 - June 2008.

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Erythropoiesis-Stimulating Agents in a Meta-Stable State: Guidelines, Economics, and Policy in Flux Interview (Part 2) with Samuel M. Silver, MD, PhD Medicare coverage of erythropoiesis-stimulating agents is a complex issue with implications for a variety of healthcare stakeholders. In the first part of the interview (see AHDB, May 2008), Samuel M. Silver, MD, PhD, examined the evolution and clinical implications of the Medicare coverage decisions and the eventual shift in clinical practice away from the approved indication to situations involving quality-of-life issues. In this second part, Dr Silver discusses with F. Randy Vogenberg, RPh, PhD, the clinical implications of the Medicare coverage decision regarding erythropoiesis-stimulating agents, pointing out the noneconomic reasons why transfusions can be risky to cancer patients, and how such policy decisions can have profound implications for patients. Dr Silver calls for new studies to be initiated, which would be funded by the 2 major manufacturers of these drugs, to investigate the concerns regarding tumor progression and thromboembolic events that are potentially associated with these expensive and potentially toxic medications. The discussion resumes where Dr Silver explains why it would be good to compare claims data of cancer patients who are receiving these medications and their transfusion requirements. [ADHB. 2008;1(9):14-18.]

F. Randy Vogenberg: There have been attempts to look at large claim databases (eg, WellPoint’s) of patients receiving erythropoiesis-stimulating agents (ESAs). News about the cutback on ESA use was accompanied by reports about the rise in the number of transfusions. At the same time, articles published in pharmacy and hospital journals were advocating the use of ESAs to avoid transfusions. So, the message is mixed. What people are doing in an inventory environment is not the same as what they are doing in an institutional inpatient environment. And hospitals may continue to use ESAs to avoid the more costly transfusion, a purely cost consideration. Is this how you see it?

Samuel Silver: I think this may be true. But the issue of transfusion is beyond cost, especially in the outpatient setting today, where 85% of cancer patient care occurs in the community and not in academic medical centers.

The first issue is that giving transfusions at centers such as the University of Michigan is relatively simple, and our facilities are well prepared to administer them.

Dr Silver is Professor of Internal Medicine, Director, Cancer Center Network, Division of Hematology/Oncology, and Assistant Dean for Research, University of Michigan Health Systems, Ann Arbor, MI.

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We have a good blood bank on site and plenty of chairs for transfusions, so we can get people set up, and we have blood irradiators (see below). But in the community, physicians by and large don’t give transfusions in their offices because of the administrative and procedural hassle. Rather, they send patients to their hospital outpatient infusion area, which is usually very small, where they can run out of transfusion chairs relatively rapidly, so that we now have a group of patients either requiring admission for transfusion or experiencing a significant delay waiting for an outpatient chair. And these are not patients with shortness of breath who require admission but rather it’s a quality-of-life (QOL) matter, because of the requirement of an inpatient stay.

The second issue is that the typical Medicare beneficiary has many comorbid conditions (eg, heart failure) in addition to cancer. Thus, we are no longer talking only about potential infectious complications of transfusion but also about issues of fluid overload that would not occur when using an ESA. The third concern is that many patients receiving chemotherapy, especially those with hematologic malignancies, are immunosuppressed. They require irradiated blood products to avoid transfusion-associated graft-versus-host disease. Irradiating blood is very easy; any university blood bank will have a blood irra-

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diator. It does not require much time, but it will add some expense. Nonetheless, it is well worth it.

However, if the patient is in a suburban or rural community, that patient may not have immediate access to irradiated blood and will have to wait a day or two to get it. So, all of a sudden something that would be simple for me at the University of Michigan becomes a process that takes several days for a patient that receives chemotherapy in a suburban or rural facility.

These are some of the noneconomic, procedural issues that are involved in giving transfusions.

Vogenberg: The other side of this issue concerns younger populations. The 50- to 60-year-old patient may still have a commercial insurance and not Medicare. Thus, there are also direct economic costs to consider, such as absence from work, particularly when the patient may be tied up for a day or two, as you said. There are many repercussions for Medicare, which is the focus for the Centers for Medicare & Medicaid Services (CMS), and for commercial insurers and employers, who are paying the bills. This is not well understood; the tendency is to just look at the drug cost and the drug companies, and this is more emotional than rational.

KEY POINTS ▲ Despite the high costs of the ESAs, the issue of transfusions

in cancer patients is beyond economics. ▲ The noneconomic issues surrounding transfusions that trans-

late to unnecessary risks for patients are: 1. Inadequate facilities that mean long waiting periods 2. Many patients are Medicare beneficiaries and thus often have multiple comorbidities 3. These patients are often immunosuppressed, requiring irradiated blood products, which could be a problem in nonacademic centers. ▲ Although Medicare is not supposed to consider costs in its

decisions, cost is an underlying context for Medicare coverage for these very expensive medications, which, nevertheless, may reduce hospitalization for transfusions.

Silver: In the meantime, Representatives Peter Stark and Henry Waxman are saying they are protecting the patients from this “miracle grow for tumors.”

And because we have no quality-of-life (QOL) data, there are no improvements in QOL issues. Now what do we do? We definitely require more data.

Silver: True. And the next thing we know, we are talking about Medicare Part B, and we begin to reach out to Medicare Part A, when we start admitting people to the hospital. Apparently those involved in Medicare Part B decisions don’t see this, but we certainly see this as citizens and on the private side. And the employers see this. So the US Food and Drug Administration (FDA) has issued new warnings, which essentially reflect the concerns about potential tumor progression, venous thromboembolism, and keeping the hemoglobin level at <12 g/dL (although this cut-off measure was dropped by the FDA from the most recent ESA labeling).

The FDA reiterated this in its most recent statement. That is where we are from the point of view of the FDA and CMS. And the Senate passed a nonbinding resolution about it, since the Senate has a sense that the National Coverage Decision (NCD) has no weight and should be changed.

Silver: CMS is not transparent at all. When you read the NCD, their background materials have been tightened up a bit. But the intellectual basis to bridge between the final coverage decision background material and the rules is missing.

Vogenberg: This NCD issue probably comes at a good time for CMS, because the current Congress is deadlocked on many issues. So nothing is going to happen. There are no repercussions against CMS’s decision about ESAs, and it can come back and say it has saved a lot of money, while preventing further harm to their beneficiaries. It is really almost a neutral situation from a public policy perspective.

Vogenberg: This is very typical of what you would see in almost any insurance company. You get caught up in this dynamic of economics and cost, and you are trying to provide just enough access so that people are happy, but at the same time less attention is paid to QOL than to the science, so it really is about economics. For CMS, it appears to be about money. They had to stay within a budget, and they

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The next thing we know, we are talking about Medicare Part B, and we begin to reach out to Medicare Part A, when we start admitting people to the hospital.

Vogenberg: How transparent is CMS regarding its data?

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knew the ESA coverage was a budget buster and a highexpenditure category, as it is for any employer. This is the perfect moment to come up with a Solomon-like decision.

CMS is not required to disclose as much as the FDA. This makes it easier for the commercial carriers to follow suit.

Medicare is not supposed to talk about costs or to consider it in its decisions, but of course it is the underlying context.

Silver: In addition, CMS will identify 10 more questions that should be answered, as they did 1 year ago, even though many of these questions are unanswerable, because the data don’t exist, and CMS knows it; a true Catch-22.

Vogenberg: This points to an interesting dichotomy between what the Agency for Healthcare Research and Quality is doing and Medicare Part D initiatives and the general Medicare initiatives about quality issues in hospitals, such as pay-for-performance. On one hand, CMS is saying it is going to pay for improved performance and outcomes in the hospitals, which, based on the current literature, suggests they would be using ESAs; these drugs lead to better results and reduce complications and readmissions, which are the criteria for quality. But on the other hand, Medicare coverage decision, which was based on an outpatient basis, prevents clinicians from using these drugs.

Silver: That brings up an interesting point. In CMS’s Physicians’ Quality Reporting Initiative, one of the early reporting initiatives dealt with the use of ESAs in myelodysplastic syndrome (MDS). It was necessary to make sure patients had sufficient iron stores, which was a quality point. Yet, the payment for MDS associated with ESAs was denied at that time, as we discussed in the first part of this interview (AHDB. May 2008;1[4]:46-50).

Vogenberg: And then it could be argued that the cost of these medications is too high?

Silver: Actually, Medicare is not supposed to talk about costs or to consider it in its decisions, but of course it is the underlying context.

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Vogenberg: And what is the Veterans Administration (VA) doing with the coverage?

Silver: I do not have the answer to that. The VA has an excellent electronic medical records system; however, in the past few months the VA was unable to use any of their data for Health Services Research purposes because of confidentiality and HIPAA (Health Insurance Portability and Accountability Act) issues.

Vogenberg: There must have been some kind of analyses done within the VA military review structure when all this was transpiring, because they are so cost and quality conscious. I wonder what the VA system is doing about TRICARE and the active military, which represents a large population?

Silver: This is a very important issue. The FDA has asked the American Society of Clinical Oncology (ASCO) and the American Society of Hematology (ASH) to determine what studies should be done in the future. ASH has asked the American Association of Cancer Research (AACR) to participate in this initiative. We are trying to convene a meeting with representatives from the FDA, CMS, ASH, ASCO, and AACR to determine what trials are needed and who should be running them.

Vogenberg: Would they be doing a corresponding health economics analysis with clinical studies parameters?

Silver: That would be an important thing to look at as well, but the executive committee of ASH believes that the National Institutes of Health (NIH) should not be paying for such studies to help determine the best hemoglobin range for ESA use. The Executive Committee is concerned that this type of study costs a lot of money. And diverting NIH money for this clinical question would leave less money for important basic science research.

Vogenberg: That is a good point.

Silver: It would be important to engage both Johnson & Johnson and Amgen to design an open study that would be funded by an unrestricted grant from both drug manufacturers to examine the pathophysiology of ESA-associated thromboembolism. And maybe we should involve the NIH and the National Cancer Institute or the National Institute of Diabetes and Kidney Disease to address issues surrounding end-

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stage renal disease (ESRD). So we need to focus on 3 aspects of the drugs—tumor promotion, the biology of venous thromboembolism, and the relationship to ESRD, which can teach us a lot. And these 3 things should happen in parallel, along with the economic issues that are related to these clinical considerations.

Vogenberg: Clinically speaking, where would you want the focus of these studies to remain?

Silver: Future studies should somehow focus on QOL in a meaningful way. Combining the efforts of Johnson & Johnson and Amgen may be effective. In that way, individual marketing agendas could be put aside. For at least the moment, private payers have been using the ASH/ASCO guidelines as opposed to Medicare guidelines. This, of course, could change tomorrow. When I spoke with Dr Lee Newcomer of UnitedHealthcare a while back, he made no promises. He seemed to think it was very reasonable to use the ASH/ASCO guidelines, using an initial hemoglobin level of <10 g/dL, and then maintaining patients at hemoglobin levels between 10 g/dL and 12 g/dL. As I mentioned in the previous article in this journal (May 2008), oncologists have come to view this issue with concern; we are generally maintaining patients at or below hemoglobin levels of 12 g/dL. Vogenberg: Are physicians still providing ESAs as freely as they had before the new Medicare coverage ruling was announced?

Silver: No. In fact, the number of those using ESAs has declined significantly. This may have been associated with the FDA issuing the black box warnings in March 2007. I think the bottom line is that most physicians want to use drugs in a reasonable way, and perhaps they overcompensate when they hear the cynical perspective about perverse physician incentives. So when the black box warning was issued, there was a great deal of self-correction.

Vogenberg: Carriers will be more willing to take the soft approach UnitedHealthcare has taken, unlike that taken by Medicare. They will seek the benefit of the reduced expenditures by informing their provider networks and offering them the opportunity to avoid potential complications and to be in compliance with the guidelines. This could be a winwin situation for everybody.

Silver: Possibly. But it is a complicated issue. Pa-

tients getting chemotherapy are receiving toxic agents with therapeutic ratios that are some of the most difficult in medicine. Many of the patients, especially those in the Medicare population, have incurable cancers; they are receiving chemotherapy mainly for palliation.

The goal is to give them as high a QOL as possible. If they are receiving chemotherapy and spend the last 2 months of their lives in the hospital, we are not doing the right thing.

Debilitating patients for the majority of their remaining time to shrink a tumor is not good care. A Pyrrhic victory in this scenario is no victory at all. And using a drug that potentially can cause thromboembolic events only complicates this picture.

I was called to an FDA meeting in which a patient representative was anxiously going on about tumor growth associated with ESAs that patient was receiving. This is a difficult thing to say, but having progression of an incurable cancer is not always the worst thing that can happen. Chemotherapy is rarely provided with curative intent in this population. Appropriate palliation may include chemotherapy along with adjunctive therapies, such as ESAs, that may cause a small risk of tumor growth.

We need to focus on 3 aspects of the drugs—tumor promotion, the biology of venous thromboembolism, and the relationship to ESRD, which can teach us a lot.

Vogenberg: This is a valid point that many people forget. Patients who are seriously ill often lose sight of reality or don’t want to face it.

Silver: Right. Sometimes we need to reach deeper into the bag for more information.

As I have said, finding this would be tantamount to finding the Holy Grail, and unfortunately, you cannot infallibly predict outcomes. ■ Disclosure Statement Dr Silver is a consultant to Bear Stearns, Lehman Brothers, and the Gerson Lehrman Group, and receives grant/research support from Blue Cross Blue Shield of MI.

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Stakeholder Perspective The Clinical and Economic Complexity of Biologics PAYERS/PATIENTS: The inability to predict outcomes with erythropoiesis-stimulating agents (ESAs) or with other biologic agents is emerging as a key concern. Whether in rheumatoid arthritis, multiple sclerosis, or erythropoiesis, unintended or unknown effects from these new biologic medication technologies are gradually better detected and better understood, helping to determine the most appropriate uses. From the perspective of economic decision makersâ&#x20AC;&#x201D;patients, health plans, or employersâ&#x20AC;&#x201D;the easy clinical decision to use biologic medications has become muddier, while these same (typically elderly) patients are rethinking their need for a wider variety of end-of-life therapies that have focused more on quality-of-life issues than on changing the lifespan.

ESAs provide an interesting insight into the complexity of clinical use of biologics and their economic impacts on all payers, as well as the types of clinical service providers. Given that many patients who are using biologics are covered under a Medicare drug plan but also have multiple comorbidities, this further illustrates the dilemma of finding a technological advancement end point where costs become more predictable. As Dr Silver points out in the interview, several concerns involving patients who receive ESA therapy go beyond a single decision point.

Because of the paucity of data to clearly guide the multipoint clinical and coverage decisions, the Centers for Medicare & Medicaid Services (CMS) and private insurers are erring on the side of limited coverage, following the evidence-based medicine (EBM) model. Although in itself not siding with any coverage position, EBM can conveniently be used for any stakeholderâ&#x20AC;&#x2122;s position, whether economic or clinical. In the case of ESAs, there seems to be a clinical and an economic dilemma forebod-

ing of the bigger and more expansive decisions our society faces through the lens of healthcare insurance coverage for the growing pipeline of biologicbased technologies.

The role of regulators (CMS, US Food and Drug Administration) and system researchers (Association for Healthcare Research and Quality, quality improvement organizations) should be determined by Congress to better align incentives, along with a clearer direction for the use of new technologies (diagnostic or therapeutic). Mixed messages and misalignment of incentives has long been an albatross around the US healthcare system that has fed many debates and articles arguing the myriad of issues relevant to each of the stakeholders.

This has been good for academics, consultants, and special interest lobbyists, but not for frontline patients and healthcare professionals, or those paying the bills for care.

Based on reports from the recent presidential campaign and from groups such as the Kaiser Foundation or the Wall Street Journal, neither party nor either of the candidates has had the single obvious solution to our looming healthcare crisis in the next decade. Perhaps our economic distress will aid patients, as reflective of our society, in establishing new parameters around life-and-death decisions that will help our healthcare system seek a new balance in harnessing technologies for the most appropriate use, which will then determine its hierarchical cost in our economy.

F. Randy Vogenberg, RPh, PhD Chief Strategy Officer Employer-based Pharmaceutical Strategies, LLC Senior Scholar, Department of Health Policy Thomas Jefferson University, Jefferson Medical School

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Early and intensive treatment can help patients reach their A1C goal Are your plan members not taking their type 2 diabetes medications? s Many patients are not reaching the ADA A1C target goal of <7%, and many are stopping their medications.1,2

Recent data show a drop in the use of oral antidiabetic medications3 2,500

TRx (000s)

2,400 2,300 2,200

OAD TRx 4 week moving avg

Trend (Pre-NEJM)

2,100 2,000 3/16/2007

Days

6/6/2008

The need for early treatment s Because many patients already have chronic complications at the time of diagnosis, treatment plans must be aggressive from the start to optimally manage type 2 diabetes.4 s Long-term benefits of diabetes medications can only be realized if patients adhere to their treatment regimen.2

“Early, intensive intervention has the potential to get patients to glycaemic goals more quickly and be more effective at keeping them at goal...” 5

References: 1. Hoerger TJ, Segel JE, Gregg EW, Saaddine JB. Is glycemic control improving in U.S. adults? Diabetes Care. 2008;31:81-86. 2. Rodgers K. Ensuring compliance in patients with diabetes. In: Diabetes: Disease Management Guide. 4th ed. Montvale, NJ: Thomson PDR; 2004:501-505.

3. Data on file, Takeda Pharmaceuticals North America, Inc. 4. Cornell SA. Clinical case study: achieving long-term control of insulin resistance. J Manag Care Pharm. 2007;13(suppl B):S11-S15. 5. Goldstein BJ, Gomis R, Lee H-K, Leiter LA, on behalf of the Global Partnership for Effective Diabetes Management. Type 2 diabetes—treat early, treat intensively. Int J Clin Pract. 2007;61(suppl 157):16-21. ©2008 Takeda Pharmaceuticals North America, Inc.

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Role for Automated Communication Strategies in Medication Adherence Management S. Michael Ross, MD, MHA Lack of medication adherence is a prevalent problem that causes a broad range of healthand health-economics–related issues. Adherence management is therefore an important strategy, but it also presents its own set of challenges. Interventional communication from care support teams at managed care organizations and disease management and wellness programs has proved effective at modifying patients’ medication adherence and reporting behaviors. However, these communications do not work well from an economic standpoint.

It is not economically feasible to scale call centers and the numbers of clinical and professional staff to communicate with the increasing number of patients with chronic diseases who require ongoing medication use. Using communication automation to augment traditional call center outreach can help to mediate patient medication-taking behaviors. Specific design criteria for the automation of this interaction are discussed in this article, offering supporting data from a recent trial of 304 elderly patients with hypertension, and showing the benefits of using such a system for effective blood pressure monitoring, at reduced costs. [AHDB. 2008;1(9):20-27.]

“Drugs don’t work in patients who don’t take them.” —C. Everett Koop, former US Surgeon General

A

dherence to medications is essential for patients with chronic disease for optimizing clinical outcomes. When used appropriately, medication is a very cost-effective method for treatment and prevention of disease. Patients who fail to take their medications as prescribed do not get the full benefit from the drugs, and they may also end up with unnecessary hospitalizations, emergency department visits, and nursing home admissions. Cost-effective, scalable interventions are essential to reduce nonadherence. In this article, we examine the use of automated phone-based patient communication to support outreach efforts, as well as the impact this type of intervention can have on clinical outcomes and costs.

In their 2005 study of medication-taking behaviors, Osterberg and Blaschke observed that, “Common barriers to adherence are under the patient’s control, so attention to them is a necessary and important step in improving adherence.”1 In that study, the following reasons were cited by patients for not adhering to their

Dr Ross is Vice President of Healthcare, Varolii Corporation, Seattle, WA.

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medication regimens1: • Forgetfulness—30% • No reason—27% • Other priorities—16% • Decision to omit doses—11% • Lack of information—9% • Emotional factors—7%.

Lack of information and forgetfulness combined comprise 39% of the reasons cited in this study for poor medication ahderence.1 These 2 areas can be positively affected by improved communications between the care provider and the patient that, in turn, can improve medication adherence.

One other common and well-documented reason for poor adherence is side effects.2,3 Patients who experience unpleasant or unexpected side effects may stop taking their medications, often without informing their physicians or other care providers.2,3 In their study, Osterberg and Blaschke further observe that there are 4 general methods to help improve patient adherence1: 1. Patient education 2. Revised dosing schedules

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3. Expanded hours when the clinic is open, including evening hours 4. Shorter wait times and improved communication between physicians and patients.

Although not all of these general methods are relevant to our topic, patient education and communication between physicians and patients are 2 areas that can be affected by effective communications.

Illustrative Case Tom’s blood pressure (BP) was elevated during his past 2 visits to his physician. At the most recent visit, his doctor suggests an antihypertensive regimen and prescribes lisinopril. Tom fills the prescription order for lisinopril at the local pharmacy and takes it home. As part of his routine care, Tom schedules a follow-up examination. After a period of time, we may expect a reduction in Tom’s BP level. But instead, at his follow-up visit, Tom’s BP is still elevated. Was lisinopril ineffective in Tom’s case? Not necessarily. In fact, the medication might well have proved effective if Tom had remembered to take it. But Tom took the first day’s dosage, put the bottle in his medicine chest, and then promptly forgot about it. He also was not reminded to take the medication.

The Challenge: Improving Care for 10 Million “Toms” Tom is not alone. Findings from Osterberg and Blaschke’s study show that, “Of all medication-related hospital admissions in the United States, 33% to 69% are due to poor medication adherence, with a resultant cost of approximately $100 billion a year.”1 In addition, according to well-documented surveys, failure to adhere to treatment, also known as noncompliance, is a large-scale problem.4,5 The 2006 Case Management Adherence Guidelines, issued by the Case Management Society of America, offer insight into the magnitude of the issue, noting that “the number one problem in treating illness today is patients’ failure to take prescription medications correctly, regardless of patient age.”4 In a 2003 study, the World Health Organization found that approximately 50% of the 1.8 billion prescription medications dispensed annually in the United States are not taken correctly by patients.5 It is reasonable to assume that at least some of these nonadherent patients are not receiving the full benefits of the prescribed medication. In 1998, nonadherence to heart disease medication regimens alone was reported to be the cause of 125,000 preventable deaths each year in the United States.6 This places medication nonadherence among the major causes of health-related deaths in the

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KEY POINTS ▲ Medication nonadherence is a major cause of morbidity and

mortality, and is a large contributor to escalating healthrelated economic costs. ▲ Lack of information and forgetfulness are 2 main reasons for

nonadherence that can be positively affected by improved patient–provider communication. ▲ With chronic diseases estimated to involve hundreds of

millions of patients, the scale of disease management enrollment is too great to be cost-effective using traditional outreach methods. ▲ The challenge is to scale outreach programs efficiently, with-

out losing the personal touch necessary to help change behavior. ▲ In a new study of automated telephony for blood pressure

monitoring, this technology reduced the cost of blood pressure reading by 95% compared with supportive care reading. ▲ The study results suggest that efficient, effective automated

communications with patients can produce positive clinical outcomes at reduced costs.

Table

Medication Nonadherence Major Cause of Death in the United States Condition Annual deaths, N 1. Heart disease 652,091 2. Cancer 559,312 3. Stroke 143,579 4. Chronic lower respiratory diseases 130,933 5. Medication nonadherence 125,000* 6. Diabetes 75,119 7. Alzheimer’s disease 71,599

* This number refers to medication nonadherence deaths from heart disease alone; the number for all deaths from medication nonadherence could therefore be higher. Source: McCarthy R. The price you pay for the drug not taken.

Bus Health. 1998;16:27-33.

Source: Kung HC, Hoyert DL, Xu JQ, Murphy SL. Deaths: final data for 2005.

Natl Vital Stat Rep. 2008;56:1-120.

United States, after heart disease, cancer, stroke, and chronic lower respiratory diseases, according to the 2005 National Vital Statistics Reports (Table).7 In reality, deaths from all medication nonadherence could be much larger than the 125,000 deaths for heart disease only.

Patients who stop taking medication as a result of forgetfulness, lack of information, or side effects can often be helped by effective outreach from their physician or clinical care professionals to remind patients to take their medications, elicit information about side effects and their impact on noncompliance, offer encouragement, and even connect them with their

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Figure 1 Average Annual Prescriptions Filled by Noninstitutionalized Medicare Enrollees, ≥65 y Prescriptions filled, % 60

57

50 42

40

32

30

30 23 20

23

24

18 10

10 0

1992 1996 2000 Year

0 1-2 3-4 5+ Chronic conditions (N), 2000

Yes No Rx coverage, 2000

Source: Cherry DK, Woodwell DA, Rechtsteiner EA. National Ambulatory Medical Care Survey: 2005 summary. Adv Data. 2007;(387):1-39.

clinical care team, if needed. This, in fact, is one of the key premises around which managed care organizations (MCOs) and wellness programs are organized: by offering regular, relevant “interventional” communications in a structured program, these organizations can positively affect medication-taking behaviors of their program members.

Health Economics: The Costs of Noncompliance Adherence is critical to everyone involved in healthcare: from patients and payers (insurance, government, employers) to retail pharmacies and pharmaceutical manufacturers. And it is the sheer number of these patients that forms the heart of the adherence challenge. For patients, adherence is an important factor in improving clinical outcomes; this issue has been well documented in the literature.1 Indeed, the Case Management Society of America observes, “Nonadherence to medications is a common factor that prevents patients from achieving the full therapeutic benefit of their therapies.”4 For organizations, improved patient adherence means the ability to deliver better care while reducing medical expense ratios driven by unnecessary hospitalizations, emergency department visits, nursing home admissions, and excess consumption of interventional treatments.5 For manufacturers and retail pharmacies, whose nonadherent patients do not fill prescriptions as indicated, or who have poor medication possession ratios, improving patient adherence is not only important to

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patient health but can also affect bottom-line revenues.

Let’s return briefly to our hypertensive patient, Tom. During the follow-up appointment, Tom’s doctor asks if he is taking his medication as prescribed. Tom sheepishly admits he has forgotten. Tom’s doctor reminds him of the importance of taking medications as prescribed, and provides information about hypertension, the associated health risks of stroke and heart attack, and strongly encourages him to “stick” with the medication regimen. Concerned about his health and encouraged by his healthcare provider, Tom signs up for a wellness program through his employer. A care representative from the wellness program contacts Tom, enrolls him in the program, and begins to provide him with information, tips, and additional encouragement.

The outcome? Tom’s BP is much better managed now, and he will likely have an improved clinical outcome as a result.

Of course, Tom is a hypothetical patient, but this is a common story for millions of real patients with hypertension. Illustrative of the scale of this particular condition, the 2005 National Ambulatory Medical Care Survey revealed that there were 44 million visits to office-based physicians with hypertension as a primary diagnosis.8 Further complicating the issue is the fact that many of these patients may be older and may take more than 1 medication regularly.4 We live in a society experiencing a “graying” of its population, as the baby boom generation begins to mature past the age of 65 years.

Many boomers, as well as millions of others, will be prescribed multiple medications (Figure 1) for chronic conditions, such as hypertension, high cholesterol, depression, and diabetes.8 The Centers for Disease Control and Prevention’s (CDC) Health, United States, 2007, survey shows that slightly more than 30% of all individuals between the ages of 45 and 64 had taken 3 or more prescription medications in the past month.9

Provider Communication It is well-documented that clear, consistent provider communication can have a positive impact on patient well-being. In an article on literature searches for physician–patient relations, Stewart notes that “Most of the studies reviewed demonstrated a correlation between effective physician–patient communication and improved patient health outcomes.”10 Thus, it is not surprising that regular, consistent communications from care support teams, such as those in wellness organizations, can have the same

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effect. If it were just 1 doctor effectively communicating to 1 patient the importance of consistently taking medication as prescribed, it might be easier to resolve the adherence problem. But, as we have noted, there are tens of millions of “Toms” with a variety of chronic conditions who require this type of outreach. The CDC notes in its Health, United States, 2007, that in 2005, the percentage of adults with 3 or more chronic conditions increased with age from 7% of adults aged 45 to 54 years to 37% of adults aged 75 years and older.9 Although managing chronic conditions is a problem of scale, the real challenge lies in scaling efficiently, without losing the personal touch necessary to help change behavior.

tive (and often is with small populations). For the organizations paying for these programs, cost benefits are largely dependent on the ability to reach large numbers of patients, enroll them, and provide ongoing health and wellness support. Considering that the number of individuals with chronic diseases is estimated to be in the hundreds of millions, the scale of enrollment is too great to manage cost-effectively with traditional outreach methods.

For organizations, improved patient adherence means the ability to deliver better care while reducing medical expense ratios driven by unnecessary hospitalizations and excess interventions.

The Economics of Outreach: Scaling Clinical Call Centers Is Expensive Clinical outreach centers typically employ a blend of trained care professionals and clinical care professionals, such as registered nurses and pharmacists. The fully loaded hourly wage of these individuals can exceed $50, which means the cost of even a relatively brief (15-20 minute) phone call can approach $20. This figure is conservative, given that the industry-standard cost for a call for technical support centers ranges between $20 and $40,11 using significantly less costly staff. This cost does not decrease with increased call center staff or with larger numbers of patients to call, so organizations’ abilities to scale outreach programs using care representatives are significantly limited.

Today, health plans and disease management programs are evolving new strategies and solutions to help their patient populations adhere to treatment plans.

We suggest that any strategy must meet 2 primary tests: 1. Is it efficient? Efficient solutions scale well and offer a low marginal cost of operation.

2. Is it effective? Effective solutions deliver similar response rates and engagement rates as the current gold standard—human outreach by care support representatives.

Communication Works, but Not Cost-Effective In the Medicare Health Support phase 1 study, the Centers for Medicare & Medicaid Services determined that the value delivered by these programs does not overcome program costs.12 It was simply not cost-efficient (nor economically feasible) for clinical staff or care support specialists to communicate with even moderately large at-risk populations. And yet, the same study found that this type of interventional communication had a clear beneficial impact on participants.

“Participating beneficiaries tend to be a healthier and less-costly subset of the intervention group. Thus, high participation rates will likely be a factor in the ability of the [Medicare Health Support organizations] to impact their assigned intervention populations.”12 And although human communication is certainly the benchmark for clinical results, automating communication shows some positive results. Properly implemented, this form of communication may deliver similar clinical results at a far lower marginal cost.

What Needs to Be Done Today and Tomorrow Traditionally, MCOs and disease management programs use a broad range of outreach methods, including nurses or other specialty practitioners to contact participants, review program benefits, respond to questions, and ultimately, enroll members. Once enrolled, these same specialists may contact members for surveys, health status updates, medication reminders, and other communications designed to foster compliance.

In principle, this form of operation should be effec-

Communications Automation: Scalable Interaction for Large Populations As noted earlier, any type of automated communication must be able to connect efficiently with large numbers of patients or members. Automated communication must also connect effectively, by delivering an experience that resembles an actual clinician–patient interaction. Modern communications systems can be modeled against good examples of productive clinical interactions (eg, a system could emulate the voice and

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persona of an experienced call center representative or an outreach nurse).

Effective interventional dialogue with patients involves understanding the patient’s specific concerns and health beliefs, embracing that information, and then using it to tailor interventions specific to their needs. When insights such as these are applied to the treatment regimen, adherence improves dramatically.13 And as discussed before, improved adherence can provide a positive boost to health outcomes, both proximal and for the long-term.

Automated patient communication offers additional potential benefits. With the majority of contacts managed through an automated system, organizations can optimize the use of live agent care support resources by triaging those patients most in need, thereby responding more efficiently to critical patient care questions (see below).

The ability to deliver automated patient communication programs efficiently and effectively may offer additional distinct advantages, including increased scope and improved health economics.

The ability to deliver automated patient communication programs efficiently (at a low unit cost) and effectively (with a positive result across the majority of respondents) may offer additional distinct advantages, including increased scope (the lowered unit cost improves the provider’s ability to reach out to more patients or members) and improved health economics (improved individual outcomes across a broad segment of the at-risk population that contributes to improvement in the aggregate outcome profile).

Key Criteria for Successful Automation of Patient Outreach Communications Varolii Corporation’s healthcare division has been communicating with tens of millions of patients on a monthly basis on a variety of healthcare-related areas.

Based on the experience of delivering these automated calls, and on Varolii’s general experience in delivering billions of automated notifications over the past several years in a variety of industries, we believe that 5 key criteria can determine whether automated communica-

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tions will serve as a useful adjunct to patient outreach.

These criteria revolve around the concepts of efficiency and effectiveness discussed earlier: 1. Scalability. If you cannot reach large populations cost-effectively, then any other enabling criteria will not matter.

2. Clarity. Most people, particularly older or at-risk individuals, find artificial voices, varying intonations, pace, and variable volume levels not only annoying, but difficult to understand.14 3. Personalization and Interactivity. “Personalization,” or tailoring the message to specifically address individual concerns, enables automated communications to more closely match the experience of conversing with a clinician or specialty representative.

Results of Datamonitor’s Patient Compliance Survey, 2004, authored by Adele Schulz, “support the idea that personalized communication with patients is an important tool in compliance initiatives.”15 “Interactivity” is the ability to accept patient responses either through keypad presses or voice response, and deliver the next question or information based on the previous response. Interactivity can help ensure regulatory compliance by enabling appropriate authentication. As an example, HIPAA (Health Insurance Portability and Accountability Act) compliance through authentication, sometimes known as right party contact, could be managed as follows: • Before giving any personalized information, an automated system could ask the individual to confirm that he/she is the correct party • If further authentication is required, the system could ask for appropriate credentials.

This type of interactivity can also be used to collect survey data and patient feedback through survey questions.

4. Reporting Visibility. Reporting is important both to understand aggregate behaviors and make useful program changes, as well as to provide substantiated, auditable performance data. Automation offers significant advantages in data collection and speed of analysis. Reporting can help organizations measure the results of their outreach efforts more effectively.

Demonstration of results against required objectives, such as the Health Effectiveness Data and Information Set and other programs from accrediting and regulatory bodies, may enable organizations to satisfy these requirements more efficiently with a better outcome.

5. Analytics. Analytics underlies useful personalization. Applying a detailed scoring model helps the

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evaluation of several key factors, Figure 2 Survey Call Flow such as which patients are most likely to take action, and whether Greeting call they are being contacted too litDynamic prompts Auth tle, too much, or the right amount using the best method. At a deep“Did you check your er level, analytics also provides Answering blood pressure?”

Yes No insight on the best approach for machine Message contacting patients, evaluating 3rd party retrieval with PIN “What such treatment strategies as the “What were prevented you from best calling windows, media the results?” checking it?”

Within (voice, e-mail, text message, or a Out of limits limits combination of these), persona, “Did you take your retry strategy, among near-infinite medication?” combinations of these.

The impact of automated comNo Yes Immediate “Thank you” “Why not?” munication is further enhanced transfer to care specialist by tailoring interventional strategies on a per-patient basis, combining analysis of historical patient clinical data along with My doctor I didn’t I didn’t think I forgot discontinued Rx feel well it was working actual patient response data. For example, an analytics-enabled solution may initially help deter“Thank you” mine which patients should be contacted first, based on drug and Source: Montijo M, Ross M. Use of automated telephony to optimize blood pressure and medication therapeutic categories, number of management of hypertensive frail elderly patients. Presented at the Disease Management Association maintenance medications, comof America 9th Annual Disease Management Leadership Forum and Integrated Case Summit; September 16, 2007; Las Vegas, NV. plexity of medication regimen, or patient demographics. lower is better. The TTT also bases optimal target By looking at the history of patient refill behaviors, ranges on specific patient diagnoses, such as BP the system can determine whether, when, and how fre<140/90 mm Hg for patients with heart failure (HF) quently to communicate with the individual patient. but BP <130/80 mm Hg for patients with diabetes.

Over time, the system can become increasingly “intelFor the present trial, a cohort of approximately 800 ligent” and better capable of determining the profile of patients was selected from the MHS pilot population, the most receptive patients. based on a primary diagnosis of HF or diabetes and Results from automated systems capable of decisionrecently reported BP readings above the established tarmaking can support effective personalized communicaget range.16 Of these, 318 agreed to participate in a trial tions with many patients on an individualized basis. This of an automated telephony system and home BP moniprocess is sometimes referred to as “mass personalization.” toring. A matched cohort of 304 hypertensive beneficiAutomated Communication Improves BP Monitoring aries continued to receive the usual nurse-based disease in Frail Elderly: New Study Results management services of the MHS program as a comparThe following study was developed to address ison group. The study examined whether frail, elderly uncontrolled hypertension and the use of automated (median age, 75 years) patients with hypertension were communication in a patient cohort from the Medicare willing and able to listen and respond to weekly autoHealth Support (MHS) pilot program in Maryland and mated phone calls that provided support for therapeutic the District of Columbia during a 2-month period and medication regimens, while offering care support (March 19, 2007-May 24, 2007).16 personnel with weekly reporting on the results. The The Treat to Target (TTT) initiative approaches study covered 2 areas—patient BP and patient adheruncontrolled hypertension by the simple principle that ence to specific antihypertensive regimens. The objec-

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tives were to improve quality of care and lower care support personnel utilization.

The study posed a series of questions using branching logic to generate targeted questioning of yes/no and multiple choice questions. Figure 2 depicts the format of the survey, showing the nature of the logic, the location of the transfers to human clinical support, and

Perhaps the most important outcome of this study was that 174 patients (54% of the study group) had their antihypertensive regimens altered. the types of questions asked. The main results of this survey were16: • 245 patients (87.5%) achieved systolic BP within target or had marked improvement from baseline >160 mm Hg • 302 patients (96.8%) achieved diastolic BP within target or significantly improved from baseline >100 mm Hg • 66% of the contacts validated as a “live answer” (ie, the patient answered the call, or someone else in the household handed the phone to the patient, after which the patient validated) • Of those responding, 581 (33%) completed the entire survey, and 33% were transferred to a care support specialist for additional assistance • No difference was seen between the automatedtelephony and nurse-contacted cohorts in percent achieving targeted systolic and diastolic BP or percent receiving antihypertensive medication adjustment • Cost of automated telephony for a BP reading was 95% lower than using a care support representative to retrieve the reading.

Perhaps the most important outcome of this study was that 174 patients (54% of the study group) had their antihypertensive regimens altered based on survey responses.16 The clear inference is that frequent reporting on patient BP and medication-taking behaviors, along with the ability to efficiently gather and analyze that information, offers clinicians significant insights on ongoing titration of medication or other elements of a therapeutic regimen.

Better Health and Health Economics Results of this study show how applying certain forms of automated communication to treatment adherence programs may potentially offer distinct

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advantages to patients and organizations.16 In addition to the improvements in clinical outcomes delivered by regular communications, automating outreach programs may enable MCOs and disease management/ wellness programs to: • Reach out to more patients cost-effectively • Target and reach substantially more patients, and enroll more patients overall into existing programs for improved return on investment • Consistently manage patient adherence across large populations • Gain potential insights into patient medication-taking and other relevant behaviors for further analysis • Empower existing care support staff by driving inbound, interested patients into the call center and by triaging the more acute or at-risk individuals.

Conclusions It is well understood that regular, consistent communications from care teams can mediate medication-taking behaviors in many patients with chronic diseases and, in many cases, the health outcomes are dependent on those behaviors. These communications comprise a focus area in healthcare that can be extended by using modern automated communications to augment other outreach strategies. Although all the data from the new study cited here are not in yet, automated communications satisfying the criteria outlined in this article are demonstrating some ability to connect with, and mediate behavior in, large populations of chronically ill patients. Our hope is that in the future, automated communications systems will enable organizations to provide communications at a scale that will improve health outcomes, both proximal and longer-term, for the millions of “Toms” with chronic conditions. ■ References 1. Osterberg L, Blaschke T. Adherence to medication. N Engl J Med. 2005;353:487-497.

2. Pharmaceutical Safety Institute. Pharmaceutical Safety Institute and Harris Interactive Consumer Drug Safety Perception Survey Results. http://www.psisafety.org/images/InstituteHarrisSurvey.pdf. Accessed September 12, 2008.

3. Sud A, Kline-Rogers E, Fang J, et al. Reasons for non-adherence to cardiac medications in patients discharged with acute coronary symptoms. Presented at the American College of Cardiology Annual Scientific Session; March 7-10, 2004; New Orleans, LA. 4. Case Management Society of America. Case Management Adherence Guidelines, Version 2.0. http://www.cmsa.org/portals/0/pdf/CMAG2.pdf.

Accessed June 7, 2008.

5. Sabaté E, ed. Adherence to long-term therapies: evidence for action [monograph online]. World Health Organization; 2003. http://whqlibdoc. who.int/publications/2003/9241545992.pdf. Accessed June 9, 2008.

6. McCarthy R. The price you pay for the drug not taken. Bus Health.

1998;16:27-33. http://findarticles.com/p/articles/mi_m0903/is_n10_v16/ ai_n27541886/pg_1?tag=artBody;col1. Accessed October 22, 2008.

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7. Kung HC, Hoyert DL, Xu JQ, Murphy SL. Deaths: final data for 2005.

Natl Vital Stat Rep. 2008;56:1-120.

8. Cherry DK, Woodwell DA, Rechtsteiner EA. National Ambulatory Medical Care Survey: 2005 summary. Adv Data. 2007;387:1-39.

9. Centers for Disease Control and Prevention. National Center for Health Statistics. Health, United States, 2007. Hyattsville, MD: US Department of Health and Human Services; 2007. http://www.cdc. gov/nchs/data/hus/hus07.pdf. Accessed June 8, 2008.

10. Stewart MA. Effective physician-patient communication and health outcomes: a review. Can Med Assoc J [serial online]. 1995;152:1423-1433. http://www.cmaj.ca/cgi/content/abstract/152/9/1423. Accessed June 7, 2008.

11. HDI Advisory Services. Advisory Services Q&A page. http:// www.thinkhdi.com/library/deliverfile.aspx?filecontentid=350. Accessed June 12, 2008.

12. McCall N, Cromwell J, Bernard S. Evaluation of Phase I of Medicare Health Support (Formerly Voluntary Chronic Care Improvement) Pilot Program Under Traditional Fee-for-Service Medicare. Baltimore, MD: RTI

International; June 2007. Project No: 0207960.002. Contract No: 50000-0022. Sponsored by Centers for Medicare & Medicaid Services.

13. Friedman RH, Kazis LE, Jette A, et al. A telecommunications system for monitoring and counseling patients with hypertension: impact on medication adherence and blood pressure control. Am J Hypertens.

1996;9:285-292.

14. Boehm E, for Forrester Research Inc. Designing interactions for an aging population. July 2007. http://www.forrester.com/Research/PDF/ 0,5110,42827,00.pdf. Accessed November 6, 2008.

15. Non-compliance costs drug industry dear. September 6, 2004. http://www.in-pharmatechnologist.com/layout/set/print/content/view/ print/183261. Accessed October 22, 2008.

16. Montijo M, Ross M. Use of automated telephony to optimize blood pressure and medication management of hypertensive frail elderly patients. Presented at the Disease Management Association of America 9th Annual Disease Management Leadership Forum and Integrated Case Summit; September 16, 2007; Las Vegas, NV.

Stakeholder Perspective Efficient Automated Call System Improves Adherence, but What about Net Costs?

PAYERS/FINANCIAL OFFICERS: Managed care organizations (MCOs) strive to deliver the highest level of value for each healthcare dollar that the organization must spend. An MCO incurs an expense to buy pharmaceuticals for its members and, in turn, those medications should improve the health of the member/patient. The MCO, in return, wants its members to improve their health, maintain their current health, or avoid catastrophic health problems because of their member’s adherence to a prescribed medication regimen. Dr Ross describes an outgoing automated phone calling system that he reports improves adherence for patients in following their prescribed antihypertensive medication regimen. He reports results of his recent study that follows 304 elderly patients with hypertension who are matched to another 304 control patients.

An automated phone system makes outbound calls to these patients. Dr Ross reports this automated calling system as having variable costs that are less expensive than those calls initiated from the clinical outreach call centers of disease management companies. It is appropriate to note that Dr Ross is Vice President of Healthcare for Varolii Corporation, which provides such automated calling systems.

At MCOs, the chief medical officers, medical directors, directors of pharmacy, directors of utiliza-

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tion management, and directors of quality management are all interested in methods that improve patient compliance, improve outcomes for patients, or improve the documentation of that compliance.

The chief financial officers of these organizations, however, want to know if these programs that improve medication adherence will also save the MCO money. The present article clearly addresses the first issue by proposing a method where an MCO can efficiently improve pharmacy compliance. In that, this article is useful for those involved in medication compliance.

The article, however, does not address the chief financial officer’s usual question, “How does efficiently increasing medication adherence save the MCO money in the long run?” That question is important and is worthy of further research, by Dr Ross or by others. It could be reframed as, “Will the cash outflows spent to operate an automated call center yield a positive net present value when measured against the future savings (ie, decreased cash outflows) in medical expenses on those same targeted patients?”

Geoffrey P. Cole, MD, MBA Chief Medical Officer Health Plan Select Athens, Georgia

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For Anemic Cancer Patients With Metastatic, Non-myeloid Malignancies Receiving Chemotherapy…

CONTROL THE RESPONSE MANAGE HEMOGLOBIN AND REDUCE TRANSFUSIONS When Treating Your Patients: • Evaluate for other treatable etiologies of anemia (iron, folate, or B12 deficiency, hemolysis, or bleeding) to treat appropriately • PROCRIT therapy should not be initiated at hemoglobin (Hb) levels 10 g/dL • The dose of PROCRIT should be titrated for each patient to achieve and maintain the lowest Hb level sufficient to avoid the need for red blood cell (RBC) transfusion • The rate of Hb increase should not exceed 1 g/dL in any 2-week period • Monitor Hb weekly until stable, and then regularly during therapy

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PROCRIT Indication

Additional Important Safety Information

PROCRIT is indicated for the treatment of anemia due to the effect of concomitantly administered chemotherapy based on studies that have shown a reduction in the need for RBC transfusions in patients with metastatic, non-myeloid malignancies receiving chemotherapy for a minimum of 2 months. Studies to determine whether PROCRIT increases mortality or decreases progression-free/recurrence-free survival are ongoing.

• PROCRIT is not indicated for use in patients receiving hormonal agents, therapeutic biologic products, or radiotherapy unless receiving concomitant myelosuppressive chemotherapy.

• PROCRIT is not indicated for patients receiving myelosuppressive therapy when the anticipated outcome is cure due to the absence of studies that adequately characterize the impact of PROCRIT on progression-free and overall survival (see WARNINGS: Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence).

• PROCRIT is not indicated for the treatment of anemia in cancer patients due to other factors such as iron or folate deficiencies, hemolysis, or gastrointestinal bleeding (see PRECAUTIONS: Lack or Loss of Response).

• PROCRIT use has not been demonstrated in controlled clinical trials to improve symptoms of anemia, quality of life, fatigue, or patient well-being.

• Patients with chronic renal failure experienced greater risks for death and serious cardiovascular events (including myocardial infarction, stroke, congestive heart failure, and hemodialysis vascular access thrombosis) when administered ESAs to target higher versus lower hemoglobin levels (13.5 vs.11.3 g/dL; 14 vs. 10 g/dL) in two clinical studies; these risks also increased in controlled clinical trials of patients with cancer. A rate of hemoglobin rise of >1 g/dL over 2 weeks may contribute to these risks.

• PROCRIT therapy should not be initiated at hemoglobin levels 10 g/dL. • The dose of PROCRIT should be titrated for each patient to achieve and maintain the lowest hemoglobin level sufficient to avoid the need for blood transfusion.

• When the hemoglobin reaches a level needed to avoid transfusion or, increases by more than 1 g/dL in a 2-week period, the PROCRIT dose should be reduced by 25%. Withhold the dose of PROCRIT if the hemoglobin exceeds a level needed to avoid transfusion. Restart dose at 25% below the previous dose when the hemoglobin approaches a level where transfusions may be required. Discontinue if after 8 weeks of therapy there is no response as measured by hemoglobin levels or if transfusions are still required.

• Monitor hemoglobin regularly during therapy, weekly until hemoglobin becomes stable.

• Cases of pure red cell aplasia (PRCA) and of severe anemia, with or without other cytopenias, associated with neutralizing antibodies to erythropoietin have been reported in patients treated with PROCRIT; predominantly in patients with chronic renal failure receiving PROCRIT by subcutaneous administration. If any patient develops a sudden loss of response to PROCRIT, accompanied by severe anemia and low reticulocyte count, and anti-erythropoietin antibody-associated anemia is suspected, withhold PROCRIT and other erythropoietic proteins.

Contact ORTHO BIOTECH (1-888-2ASKOBI or 1-888-227-5624) to perform assays for binding and neutralizing antibodies. If erythropoietin antibody-mediated anemia is confirmed, PROCRIT should be permanently discontinued and patients should not be switched to other erythropoietic proteins.

• The safety and efficacy of PROCRIT therapy have not been established in patients with a known history of a seizure disorder or underlying hematologic disease (e.g., sickle cell anemia, myelodysplastic syndromes, or hypercoagulable disorders).

• In some female patients, menses have resumed following PROCRIT therapy; the possibility of pregnancy should be discussed and the need for contraception evaluated.

• Prior to and regularly during PROCRIT therapy monitor iron status; transferrin saturation should be 20% and ferritin should be 100 ng/mL. During therapy absolute or functional iron deficiency may develop and all patients will eventually require supplemental iron to adequately support erythropoiesis stimulated by PROCRIT. • Treatment of patients with grossly elevated serum erythropoietin levels (e.g., >200 mUnits/mL) is not recommended.

• During PROCRIT therapy, blood pressure should be monitored carefully and aggressively managed, particularly in patients with an underlying history of hypertension or cardiovascular disease.

• Seizures in PROCRIT-treated patients have been reported in the context of a significant increase in hemoglobin from baseline; increases in blood pressure were not always observed; and patients may have had other underlying central nervous system pathology.

• The most commonly reported side effects (>10%) for PROCRIT in clinical trials were pyrexia, diarrhea, nausea, vomiting, edema, asthenia, fatigue, shortness of breath, paresthesia, and upper respiratory infection.

Important Safety Information WARNINGS: INCREASED MORTALITY, SERIOUS CARDIOVASCULAR and THROMBOEMBOLIC EVENTS, and INCREASED RISK OF TUMOR PROGRESSION OR RECURRENCE Renal failure: Patients experienced greater risks for death and serious cardiovascular events when administered erythropoiesis-stimulating agents (ESAs) to target higher versus lower hemoglobin levels (13.5 vs. 11.3 g/dL; 14 vs. 10 g/dL) in two clinical studies. Individualize dosing to achieve and maintain hemoglobin levels within the range of 10 to 12 g/dL. Cancer: • ESAs shortened overall survival and/or increased the risk of tumor progression or recurrence in some clinical studies in patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers (see WARNINGS: Table 1).

• To decrease these risks, as well as the risk of serious cardio- and thrombovascular events, use the lowest dose needed to avoid red blood cell transfusion.

• Use ESAs only for treatment of anemia due to concomitant myelosuppressive chemotherapy.

• ESAs are not indicated for patients receiving myelosuppressive therapy when the anticipated outcome is cure.

• Discontinue following the completion of a chemotherapy course.

Perisurgery: PROCRIT® (Epoetin alfa) increased the rate of deep venous thromboses in patients not receiving prophylactic anticoagulation. Consider deep venous thrombosis prophylaxis.

Contraindications • PROCRIT is contraindicated in patients with uncontrolled hypertension or with known hypersensitivity to albumin (human) or mammalian cell-derived products.

Please see Brief Summary of Prescribing Information, including Boxed WARNINGS, on adjacent page.

Manufactured by: Amgen Inc., Thousand Oaks, California 91320-1789 Distributed by: Ortho Biotech Products, L.P., Bridgewater, New Jersey 08807-0914 © Ortho Biotech Products, L.P. 2008 11/08 08PCTC2487 308470

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BRIEF SUMMARY OF PROCRIT® PRESCRIBING INFORMATION FOR THE TREATMENT OF ANEMIA IN CANCER PATIENTS ON CHEMOTHERAPY PROCRIT® (Epoetin alfa) FOR INJECTION FOR FULL PRESCRIBING INFORMATION FOR ALL INDICATIONS, REFER TO THE PHYSICIANS’ DESK REFERENCE® WARNINGS: INCREASED MORTALITY, SERIOUS CARDIOVASCULAR and THROMBOEMBOLIC EVENTS, and INCREASED RISK OF TUMOR PROGRESSION OR RECURRENCE Renal failure: Patients experienced greater risks for death and serious cardiovascular events when administered erythropoiesis-stimulating agents (ESAs) to target higher versus lower hemoglobin levels (13.5 vs. 11.3 g/dL; 14 vs. 10 g/dL) in two clinical studies. Individualize dosing to achieve and maintain hemoglobin levels within the range of 10 to 12 g/dL. Cancer: • ESAs shortened overall survival and/or increased the risk of tumor progression or recurrence in some clinical studies in patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers (see WARNINGS: Table 1).

• To decrease these risks, as well as the risk of serious cardio- and thrombovascular events, use the lowest dose needed to avoid red blood cell transfusion.

• Use ESAs only for treatment of anemia due to concomitant myelosuppressive chemotherapy.

• ESAs are not indicated for patients receiving myelosuppressive therapy when the anticipated outcome is cure.

• Discontinue following the completion of a chemotherapy course.

Perisurgery: PROCRIT® increased the rate of deep venous thromboses in patients not receiving prophylactic anticoagulation. Consider deep venous thrombosis prophylaxis.

(See WARNINGS: Increased Mortality, Serious Cardiovascular and Thromboembolic Events, WARNINGS: Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence, INDICATIONS AND USAGE, and DOSAGE AND ADMINISTRATION in full Prescribing Information.)

INDICATIONS AND USAGE PROCRIT® is indicated for the treatment of anemia due to the effect of concomitantly administered chemotherapy based on studies that have shown a reduction in the need for RBC transfusions in patients with metastatic, non-myeloid malignancies receiving chemotherapy for a minimum of 2 months. Studies to determine whether PROCRIT® increases mortality or decreases progression-free/recurrence-free survival are ongoing.

• PROCRIT® is not indicated for use in patients receiving hormonal agents, therapeutic biologic products, or radiotherapy unless receiving concomitant myelosuppressive chemotherapy.

• PROCRIT® is not indicated for patients receiving myelosuppressive therapy when the anticipated outcome is cure due to the absence of studies that adequately characterize the impact of PROCRIT® on progressionfree and overall survival (see WARNINGS: Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence).

• PROCRIT ® is not indicated for the treatment of anemia in cancer patients due to other factors such as iron or folate deficiencies, hemolysis, or gastrointestinal bleeding (see PRECAUTIONS: Lack or Loss of Response).

• PROCRIT ® use has not been demonstrated in controlled clinical trials to improve symptoms of anemia, quality of life, fatigue, or patient well-being.

CONTRAINDICATIONS PROCRIT® is contraindicated in patients with: 1. Uncontrolled hypertension. 2. Known hypersensitivity to mammalian cell-derived products. 3. Known hypersensitivity to Albumin (Human).

WARNINGS Pediatrics Risk in Premature Infants The multidose preserved formulation contains benzyl alcohol. Benzyl alcohol has been reported to be associated with an increased incidence of neurological and other complications in premature infants which are sometimes fatal.

Adults Increased Mortality, Serious Cardiovascular and Thromboembolic Events Patients with chronic renal failure experienced greater risks for death and serious cardiovascular events when administered erythropoiesis-stimulating agents (ESAs) to target higher versus lower hemoglobin levels (13.5 vs. 11.3 g/dL; 14 vs. 10 g/dL) in two clinical studies. Patients with chronic renal failure and an insufficient hemoglobin response to ESA therapy may be at even greater risk for cardiovascular events and mortality than other patients. PROCRIT® and other ESAs increased the risks for death and serious cardiovascular events in controlled clinical trials of patients with cancer. These events included myocardial infarction, stroke, congestive heart failure, and hemodialysis vascular access thrombosis. A rate of hemoglobin rise of > 1 g/dL over 2 weeks may contribute to these risks.

In a randomized prospective trial, 1432 anemic chronic renal failure patients who were not undergoing dialysis were assigned to Epoetin alfa (rHuEPO) treatment targeting a maintenance hemoglobin concentration of 13.5 g/dL or 11.3 g/dL. A major cardiovascular event (death, myocardial infarction, stroke, or hospitalization for congestive heart failure) occurred among 125 (18%) of the 715 patients in the higher hemoglobin group compared to 97 (14%) among the 717 patients in the lower hemoglobin group (HR 1.3, 95% CI: 1.0, 1.7, p = 0.03).

Increased risk for serious cardiovascular events was also reported from a randomized, prospective trial of 1265 hemodialysis patients with clinically evident cardiac disease (ischemic heart disease or congestive heart failure). In this trial, patients were assigned to PROCRIT® treatment targeted to a maintenance hematocrit of either 42 ± 3% or 30 ± 3%. Increased mortality was observed in 634 patients randomized to a target hematocrit of 42% [221 deaths (35% mortality)] compared to 631 patients targeted to remain at a hematocrit of 30% [185 deaths (29% mortality)]. The reason for the increased mortality observed in this study is unknown, however, the incidence of non-fatal myocardial infarctions (3.1% vs. 2.3%), vascular access thromboses (39% vs. 29%), and all other thrombotic events (22% vs. 18%) were also higher in the group randomized to achieve a hematocrit of 42%. An increased incidence of thrombotic events has also been observed in patients with cancer treated with erythropoietic agents.

In a randomized controlled study (referred to as Cancer Study 1 - the ‘BEST’ study) with another ESA in 939 women with metastatic breast cancer receiving chemotherapy, patients received either weekly Epoetin alfa or placebo for up to a year. This study was designed to show that survival was superior when an ESA was administered to prevent anemia (maintain hemoglobin levels between 12 and 14 g/dL or hematocrit between 36% and 42%). The study was terminated prematurely when interim results demonstrated that a higher mortality at 4 months (8.7% vs. 3.4%) and a higher rate of fatal thrombotic events (1.1% vs. 0.2%) in the first 4 months of the study were observed among patients treated with Epoetin alfa. Based on Kaplan-Meier estimates, at the time of study termination, the 12-month survival was lower in the Epoetin alfa group than in the placebo group (70% vs. 76%; HR 1.37, 95% CI: 1.07, 1.75; p = 0.012).

A systematic review of 57 randomized controlled trials (including Cancer Studies 1 and 5 - the ‘BEST’ and ‘ENHANCE’ studies) evaluating 9353 patients with cancer compared ESAs plus red blood cell transfusion with red blood cell transfusion alone for prophylaxis or treatment of anemia in cancer patients with or without concurrent antineoplastic therapy. An increased relative risk of thromboembolic events (RR 1.67, 95% CI: 1.35, 2.06; 35 trials and 6769 patients) was observed in ESA-treated patients. An overall survival hazard ratio of 1.08 (95% CI: 0.99, 1.18; 42 trials and 8167 patients) was observed in ESA-treated patients.

An increased incidence of deep vein thrombosis (DVT) in patients receiving Epoetin alfa undergoing surgical orthopedic procedures has been observed (see ADVERSE REACTIONS, Surgery Patients: Thrombotic/Vascular Events in full Prescribing Information). In a randomized controlled study (referred to as the ‘SPINE’ study), 681 adult patients, not receiving prophylactic anticoagulation and undergoing spinal surgery, received either 4 doses of 600 U/kg Epoetin alfa (7, 14, and 21 days before surgery, and the day of surgery) and standard of care (SOC) treatment, or SOC treatment alone. Preliminary analysis showed a higher incidence of DVT,

determined by either Color Flow Duplex Imaging or by clinical symptoms, in the Epoetin alfa group [16 patients (4.7%)] compared to the SOC group [7 patients (2.1%)]. In addition, 12 patients in the Epoetin alfa group and 7 patients in the SOC group had other thrombotic vascular events. Deep venous thrombosis prophylaxis should be strongly considered when ESAs are used for the reduction of allogeneic RBC transfusions in surgical patients (see BOXED WARNINGS and DOSAGE AND ADMINISTRATION in full Prescribing Information).

Increased mortality was also observed in a randomized placebo-controlled study of PROCRIT® in adult patients who were undergoing coronary artery bypass surgery (7 deaths in 126 patients randomized to PROCRIT® versus no deaths among 56 patients receiving placebo). Four of these deaths occurred during the period of study drug administration and all four deaths were associated with thrombotic events. ESAs are not approved for reduction of allogeneic red blood cell transfusions in patients scheduled for cardiac surgery.

Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence Erythropoiesis-stimulating agents resulted in decreased locoregional control/progression-free survival and/or overall survival (see Table 1). These findings were observed in studies of patients with advanced head and neck cancer receiving radiation therapy (Cancer Studies 5 and 6), in patients receiving chemotherapy for metastatic breast cancer (Cancer Study 1) or lymphoid malignancy (Cancer Study 2), and in patients with non-small cell lung cancer or various malignancies who were not receiving chemotherapy or radiotherapy (Cancer Studies 7 and 8).

Table 1: Randomized, Controlled Trials with Decreased Survival and/or Decreased Locoregional Control Adverse Achieved Outcome for Hemoglobin Hemoglobin Primary ESA-containing Study / Tumor / (n) Target (Median Q1,Q3) Endpoint Arm Chemotherapy Cancer Study 1 Metastatic breast 12-14 g/dL 12.9 g/dL 12-month overall Decreased 12-month cancer (n=939) 12.2, 13.3 g/dL survival survival Cancer Study 2 Lymphoid 13-15 g/dL (M) 11.0 g/dL Proportion of Decreased overall malignancy (n=344) 13-14 g/dL (F) 9.8, 12.1 g/dL patients achieving survival a hemoglobin response Cancer Study 3 Early breast 12.5-13 g/dL 13.1 g/dL Relapse-free and Decreased 3 yr. cancer (n=733) 12.5, 13.7 g/dL overall survival relapse-free and overall survival Cancer Study 4 Cervical Cancer 12-14 g/dL 12.7 g/dL Progression-free Decreased 3 yr. (n=114) 12.1, 13.3 g/dL and overall survival progression-free and locoregional and overall survival control and locoregional control Radiotherapy Alone Cancer Study 5 Head and neck ≥15 g/dL (M) Not available Locoregional Decreased 5-year cancer (n=351) ≥14 g/dL (F) progression-free locoregional survival progression-free survival Decreased overall survival Cancer Study 6 Head and neck 14-15.5 g/dL Not available Locoregional Decreased cancer (n=522) disease control locoregional disease control No Chemotherapy or Radiotherapy Cancer Study 7 Non-small cell 12-14 g/dL Not available Quality of life Decreased overall lung cancer (n=70) survival Cancer Study 8 Non-myeloid 12-13 g/dL 10.6 g/dL RBC transfusions Decreased overall malignancy (n=989) 9.4, 11.8 g/dL survival

Decreased overall survival: Cancer Study 1 (the ‘BEST’ study) was previously described (see WARNINGS: Increased Mortality, Serious Cardiovascular and Thromboembolic Events). Mortality at 4 months (8.7% vs. 3.4%) was significantly higher in the Epoetin alfa arm. The most common investigator-attributed cause of death within the first 4 months was disease progression; 28 of 41 deaths in the Epoetin alfa arm and 13 of 16 deaths in the placebo arm were attributed to disease progression. Investigator assessed time to tumor progression was not different between the two groups. Survival at 12 months was significantly lower in the Epoetin alfa arm (70% vs. 76%, HR 1.37, 95% CI: 1.07, 1.75; p = 0.012).

Cancer Study 2 was a Phase 3, double-blind, randomized (darbepoetin alfa vs. placebo) study conducted in 344 anemic patients with lymphoid malignancy receiving chemotherapy. With a median follow-up of 29 months, overall mortality rates were significantly higher among patients randomized to darbepoetin alfa as compared to placebo (HR 1.36, 95% CI: 1.02, 1.82).

Cancer Study 7 was a Phase 3, multicenter, randomized (Epoetin alfa vs. placebo), double-blind study, in which patients with advanced non-small cell lung cancer receiving only palliative radiotherapy or no active therapy were treated with Epoetin alfa to achieve and maintain hemoglobin levels between 12 and 14 g/dL. Following an interim analysis of 70 of 300 patients planned, a significant difference in survival in favor of the patients on the placebo arm of the trial was observed (median survival 63 vs. 129 days; HR 1.84; p = 0.04).

Cancer Study 8 was a Phase 3, double-blind, randomized (darbepoetin alfa vs. placebo), 16-week study in 989 anemic patients with active malignant disease, neither receiving nor planning to receive chemotherapy or radiation therapy. There was no evidence of a statistically significant reduction in proportion of patients receiving RBC transfusions. The median survival was shorter in the darbepoetin alfa treatment group (8 months) compared with the placebo group (10.8 months); HR 1.30, 95% CI: 1.07, 1.57.

Decreased progression-free survival and overall survival: Cancer Study 3 (the ‘PREPARE’ study) was a randomized controlled study in which darbepoetin alfa was administered to prevent anemia conducted in 733 women receiving neo-adjuvant breast cancer treatment.

After a median follow-up of approximately 3 years, the survival rate (86% vs. 90%, HR 1.42, 95% CI: 0.93, 2.18) and relapse-free survival rate (72% vs. 78%, HR 1.33, 95% CI: 0.99, 1.79) were lower in the darbepoetin alfatreated arm compared to the control arm.

Cancer Study 4 (protocol GOG 191) was a randomized controlled study that enrolled 114 of a planned 460 cervical cancer patients receiving chemotherapy and radiotherapy. Patients were randomized to receive Epoetin alfa to maintain hemoglobin between 12 and 14 g/dL or to transfusion support as needed. The study was terminated prematurely due to an increase in thromboembolic events in Epoetin alfa-treated patients compared to control (19% vs. 9%). Both local recurrence (21% vs. 20%) and distant recurrence (12% vs. 7%) were more frequent in Epoetin alfa-treated patients compared to control. Progression-free survival at 3 years was lower in the Epoetin alfa-treated group compared to control (59% vs. 62%, HR 1.06, 95% CI: 0.58, 1.91).

Overall survival at 3 years was lower in the Epoetin alfa-treated group compared to control (61% vs. 71%, HR 1.28, 95% CI: 0.68, 2.42).

Cancer Study 5 (the ‘ENHANCE’ study) was a randomized controlled study in 351 head and neck cancer patients where Epoetin beta or placebo was administered to achieve target hemoglobin of 14 and 15 g/dL for women and men, respectively. Locoregional progression-free survival was significantly shorter in patients receiving Epoetin beta (HR 1.62, 95% CI: 1.22, 2.14; p = 0.0008) with a median of 406 days Epoetin beta vs. 745 days placebo. Overall survival was significantly shorter in patients receiving Epoetin beta (HR 1.39, 95% CI: 1.05, 1.84; p = 0.02).

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Decreased locoregional control: Cancer Study 6 (DAHANCA 10) was conducted in 522 patients with primary squamous cell carcinoma of the head and neck receiving radiation therapy randomized to darbepoetin alfa with radiotherapy or radiotherapy alone. An interim analysis on 484 patients demonstrated that locoregional control at 5 years was significantly shorter in patients receiving darbepoetin alfa (RR 1.44, 95% CI: 1.06, 1.96; p = 0.02). Overall survival was shorter in patients receiving darbepoetin alfa (RR 1.28, 95% CI: 0.98, 1.68; p = 0.08).

Pure Red Cell Aplasia Cases of pure red cell aplasia (PRCA) and of severe anemia, with or without other cytopenias, associated with neutralizing antibodies to erythropoietin have been reported in patients treated with PROCRIT®. This has been reported predominantly in patients with chronic renal failure (CRF) receiving PROCRIT® by subcutaneous administration. Any patient who develops a sudden loss of response to PROCRIT®, accompanied by severe anemia and low reticulocyte count, should be evaluated for the etiology of loss of effect, including the presence of neutralizing antibodies to erythropoietin (see PRECAUTIONS: Lack or Loss of Response). If anti-erythropoietin antibody-associated anemia is suspected, withhold PROCRIT® and other erythropoietic proteins. Contact ORTHO BIOTECH at 1 888 2ASK OBI (1-888-227-5624) to perform assays for binding and neutralizing antibodies.

PROCRIT® should be permanently discontinued in patients with antibody-mediated anemia. Patients should not be switched to other erythropoietic proteins as antibodies may cross-react (see ADVERSE REACTIONS: Immunogenicity).

Albumin (Human) PROCRIT® contains albumin, a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin.

PRECAUTIONS The parenteral administration of any biologic product should be attended by appropriate precautions in case allergic or other untoward reactions occur (see CONTRAINDICATIONS). In clinical trials, while transient rashes were occasionally observed concurrently with PROCRIT® therapy, no serious allergic or anaphylactic reactions were reported (see ADVERSE REACTIONS in full Prescribing Information for more information regarding allergic reactions).

The safety and efficacy of PROCRIT® therapy have not been established in patients with a known history of a seizure disorder or underlying hematologic disease (eg, sickle cell anemia, myelodysplastic syndromes, or hypercoagulable disorders).

In some female patients, menses have resumed following PROCRIT® therapy; the possibility of pregnancy should be discussed and the need for contraception evaluated.

Hematology: Exacerbation of porphyria has been observed rarely in patients with CRF treated with PROCRIT®.

However, PROCRIT® has not caused increased urinary excretion of porphyrin metabolites in normal volunteers, even in the presence of a rapid erythropoietic response. Nevertheless, PROCRIT® should be used with caution in patients with known porphyria.

In preclinical studies in dogs and rats, but not in monkeys, PROCRIT® therapy was associated with subclinical bone marrow fibrosis. Bone marrow fibrosis is a known complication of CRF in humans and may be related to secondary hyperparathyroidism or unknown factors. The incidence of bone marrow fibrosis was not increased in a study of adult patients on dialysis who were treated with PROCRIT® for 12 to 19 months, compared to the incidence of bone marrow fibrosis in a matched group of patients who had not been treated with PROCRIT®.

Cancer patients should have hemoglobin measured once a week until hemoglobin has been stabilized, and measured periodically thereafter.

Lack or Loss of Response: If the patient fails to respond or to maintain a response to doses within the recommended dosing range, the following etiologies should be considered and evaluated: 1. Iron deficiency: Virtually all patients will eventually require supplemental iron therapy (see IRON EVALUATION); 2. Underlying infectious, inflammatory, or malignant processes; 3. Occult blood loss; 4. Underlying hematologic diseases (ie, thalassemia, refractory anemia, or other myelodysplastic disorders); 5. Vitamin deficiencies: Folic acid or vitamin B12; 6. Hemolysis; 7. Aluminum intoxication; 8. Osteitis fibrosa cystica; 9. Pure Red Cell Aplasia (PRCA) or anti-erythropoietin antibody-associated anemia: In the absence of another etiology, the patient should be evaluated for evidence of PRCA and sera should be tested for the presence of antibodies to erythropoietin (see WARNINGS: Pure Red Cell Aplasia).

Iron Evaluation: During PROCRIT® therapy, absolute or functional iron deficiency may develop. Functional iron deficiency, with normal ferritin levels but low transferrin saturation, is presumably due to the inability to mobilize iron stores rapidly enough to support increased erythropoiesis. Transferrin saturation should be at least 20% and ferritin should be at least 100 ng/mL. Prior to and during PROCRIT® therapy, the patient’s iron status, including transferrin saturation (serum iron divided by iron binding capacity) and serum ferritin, should be evaluated. Virtually all patients will eventually require supplemental iron to increase or maintain transferrin saturation to levels which will adequately support erythropoiesis stimulated by PROCRIT®.

Drug Interaction: No evidence of interaction of PROCRIT® with other drugs was observed in the course of clinical trials.

Carcinogenesis, Mutagenesis, and Impairment of Fertility: Carcinogenic potential of PROCRIT® has not been evaluated. PROCRIT® does not induce bacterial gene mutation (Ames Test), chromosomal aberrations in mammalian cells, micronuclei in mice, or gene mutation at the HGPRT locus. In female rats treated IV with PROCRIT®, there was a trend for slightly increased fetal wastage at doses of 100 and 500 Units/kg.

Pregnancy Category C: PROCRIT® has been shown to have adverse effects in rats when given in doses 5 times the human dose. There are no adequate and well-controlled studies in pregnant women. PROCRIT® should be used during pregnancy only if potential benefit justifies the potential risk to the fetus.

In studies in female rats, there were decreases in body weight gain, delays in appearance of abdominal hair, delayed eyelid opening, delayed ossification, and decreases in the number of caudal vertebrae in the F1 fetuses of the 500 Units/kg group. In female rats treated IV, there was a trend for slightly increased fetal wastage at doses of 100 and 500 Units/kg. PROCRIT® has not shown any adverse effect at doses as high as 500 Units/kg in pregnant rabbits (from day 6 to 18 of gestation).

Nursing Mothers: Postnatal observations of the live offspring (F1 generation) of female rats treated with PROCRIT® during gestation and lactation revealed no effect of PROCRIT® at doses of up to 500 Units/kg. There were, however, decreases in body weight gain, delays in appearance of abdominal hair, eyelid opening, and decreases in the number of caudal vertebrae in the F1 fetuses of the 500 Units/kg group. There were no PROCRIT®-related effects on the F2 generation fetuses.

It is not known whether PROCRIT® is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PROCRIT® is administered to a nursing woman.

Pediatric Use: See WARNINGS: Pediatrics Pediatric Cancer Patients on Chemotherapy: The safety and effectiveness of PROCRIT® were evaluated in a randomized, double-blind, placebo-controlled, multicenter study (see CLINICAL EXPERIENCE, Weekly (QW) Dosing, Pediatric Patients in full Prescribing Information).

Geriatric Use: Insufficient numbers of patients age 65 or older were enrolled in clinical studies of PROCRIT® for the treatment of anemia associated with pre-dialysis chronic renal failure, cancer chemotherapy, and Zidovudine-treatment of HIV infection to determine whether they respond differently from younger subjects.

Information for Patients Patients should be informed of the increased risks of mortality, serious cardiovascular events, thromboembolic events, and increased risk of tumor progression or recurrence (see WARNINGS). In those situations in which the physician determines that a patient or their caregiver can safely and effectively administer PROCRIT® at home,

instruction as to the proper dosage and administration should be provided. Patients should be instructed to read the PROCRIT® Medication Guide and Patient Instructions for Use and should be informed that the Medication Guide is not a disclosure of all possible side effects. Patients should be informed of the possible side effects of PROCRIT® and of the signs and symptoms of allergic drug reaction and advised of appropriate actions. If home use is prescribed for a patient, the patient should be thoroughly instructed in the importance of proper disposal and cautioned against the reuse of needles, syringes, or drug product. A puncture-resistant container should be available for the disposal of used syringes and needles, and guidance provided on disposal of the full container.

Hypertension: Hypertension, associated with a significant increase in hemoglobin, has been noted rarely in patients treated with PROCRIT®. Nevertheless, blood pressure in patients treated with PROCRIT® should be monitored carefully, particularly in patients with an underlying history of hypertension or cardiovascular disease.

Seizures: In double-blind, placebo-controlled trials, 3.2% (n = 2/63) of patients treated with PROCRIT® TIW and 2.9% (n = 2/68) of placebo-treated patients had seizures. Seizures in 1.6% (n = 1/63) of patients treated with PROCRIT® TIW occurred in the context of a significant increase in blood pressure and hematocrit from baseline values. However, both patients treated with PROCRIT® also had underlying CNS pathology which may have been related to seizure activity.

In a placebo-controlled, double-blind trial utilizing weekly dosing with PROCRIT®, 1.2% (n = 2/168) of safetyevaluable patients treated with PROCRIT® and 1% (n = 1/165) of placebo-treated patients had seizures.

Seizures in the patients treated with weekly PROCRIT® occurred in the context of a significant increase in hemoglobin from baseline values however significant increases in blood pressure were not seen. These patients may have had other CNS pathology.

Thrombotic Events: In double-blind, placebo-controlled trials, 3.2% (n = 2/63) of patients treated with PROCRIT® TIW and 11.8% (n = 8/68) of placebo-treated patients had thrombotic events (eg, pulmonary embolism, cerebrovascular accident), (see WARNINGS: Increased Mortality, Serious Cardiovascular and Thromboembolic Events).

In a placebo-controlled, double-blind trial utilizing weekly dosing with PROCRIT®, 6.0% (n = 10/168) of safetyevaluable patients treated with PROCRIT® and 3.6% (n = 6/165) (p = 0.444) of placebo-treated patients had clinically significant thrombotic events (deep vein thrombosis requiring anticoagulant therapy, embolic event including pulmonary embolism, myocardial infarction, cerebral ischemia, left ventricular failure and thrombotic microangiopathy). A definitive relationship between the rate of hemoglobin increase and the occurrence of clinically significant thrombotic events could not be evaluated due to the limited schedule of hemoglobin measurements in this study.

The safety and efficacy of PROCRIT® were evaluated in a randomized, double-blind, placebo-controlled, multicenter study that enrolled 222 anemic patients ages 5 to 18 receiving treatment for a variety of childhood malignancies. Due to the study design (small sample size and the heterogeneity of the underlying malignancies and of anti-neoplastic treatments employed), a determination of the effect of PROCRIT® on the incidence of thrombotic events could not be performed. In the PROCRIT® arm, the overall incidence of thrombotic events was 10.8% and the incidence of serious or life-threatening events was 7.2%.

ADVERSE REACTIONS Immunogenicity As with all therapeutic proteins, there is the potential for immunogenicity. Neutralizing antibodies to erythropoietin, in association with PRCA or severe anemia (with or without other cytopenias), have been reported in patients receiving PROCRIT® (see WARNINGS: Pure Red Cell Aplasia) during post-marketing experience.

There has been no systematic assessment of immune responses, i.e., the incidence of either binding or neutralizing antibodies to PROCRIT®, in controlled clinical trials.

Where reported, the incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies across products within this class (erythropoietic proteins) may be misleading.

Adverse Experiences Reported in Clinical Trials In double-blind, placebo-controlled studies of up to 3 months duration involving 131 cancer patients, adverse events with an incidence > 10% in either patients treated with PROCRIT® or placebo-treated patients were as indicated below: Percent of Patients Reporting Event

Event Pyrexia Diarrhea Nausea Vomiting Edema Asthenia Fatigue Shortness of Breath Parasthesia Upper Respiratory Infection Dizziness Trunk Pain * Statistically significant

Patients Treated With PROCRIT® (n = 63) 29% 21%* 17%* 17% 17%* 13% 13% 13% 11% 11% 5% 3%*

Placebo-treated Patients (n = 68) 19% 7% 32% 15% 1% 16% 15% 9% 6% 4% 12% 16%

Although some statistically significant differences between patients being treated with PROCRIT® and placebotreated patients were noted, the overall safety profile of PROCRIT® appeared to be consistent with the disease process of advanced cancer. During double-blind and subsequent open-label therapy in which patients (n = 72 for total exposure to PROCRIT®) were treated for up to 32 weeks with doses as high as 927 Units/kg, the adverse experience profile of PROCRIT® was consistent with the progression of advanced cancer.

Three hundred thirty-three (333) cancer patients enrolled in a placebo-controlled double-blind trial utilizing Weekly dosing with PROCRIT® for up to 4 months were evaluable for adverse events. The incidence of adverse events was similar in both the treatment and placebo arms.

OVERDOSAGE The expected manifestations of PROCRIT® overdosage include signs and symptoms associated with an excessive and/or rapid increase in hemoglobin concentration, including any of the cardiovascular events described in WARNINGS and listed in ADVERSE REACTIONS in full Prescribing Information. Patients receiving an overdosage of PROCRIT® should be monitored closely for cardiovascular events and hematologic abnormalities. Polycythemia should be managed acutely with phlebotomy, as clinically indicated. Following resolution of the effects due to PROCRIT® overdosage, reintroduction of PROCRIT® therapy should be accompanied by close monitoring for evidence of rapid increases in hemoglobin concentration (>1 gm/dL per 14 days). In patients with an excessive hematopoietic response, reduce the PROCRIT® dose in accordance with the recommendations described in DOSAGE AND ADMINISTRATION in full Prescribing Information.

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PROCRIT ® (Epoetin alfa) FOR INJECTION DOSAGE AND ADMINISTRATION IMPORTANT: See BOXED WARNINGS and WARNINGS: Increased Mortality, Serious Cardiovascular and Thromboembolic Events.

Prior to initiating treatment with PROCRIT® a hemoglobin should be obtained to establish that it is >10 to ≤ 13 g/dL. The recommended dose of PROCRIT® is 300 Units/kg/day subcutaneously for 10 days before surgery, on the day of surgery, and for 4 days after surgery.

An alternate dose schedule is 600 Units/kg PROCRIT® subcutaneously in once weekly doses (21, 14, and 7 days before surgery) plus a fourth dose on the day of surgery.

All patients should receive adequate iron supplementation. Iron supplementation should be initiated no later than the beginning of treatment with PROCRIT® and should continue throughout the course of therapy. Deep venous thrombosis prophylaxis should be strongly considered (see BOXED WARNINGS).

PREPARATION AND ADMINISTRATION OF PROCRIT® 1. Do not shake. It is not necessary to shake PROCRIT®. Prolonged vigorous shaking may denature any glycoprotein, rendering it biologically inactive.

2. Protect the solution from light. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use any vials exhibiting particulate matter or discoloration.

3. Using aseptic techniques, attach a sterile needle to a sterile syringe. Remove the flip top from the vial containing PROCRIT®, and wipe the septum with a disinfectant. Insert the needle into the vial, and withdraw into the syringe an appropriate volume of solution.

4. Single-dose: 1 mL vial contains no preservative. Use one dose per vial; do not re-enter the vial. Discard unused portions.

Multidose: 1 mL and 2 mL vials contain preservative. Store at 2° to 8°C after initial entry and between doses. Discard 21 days after initial entry.

5. Do not dilute or administer in conjunction with other drug solutions. However, at the time of SC administration, preservative-free PROCRIT® from single-use vials may be admixed in a syringe with bacteriostatic 0.9% sodium chloride injection, USP, with benzyl alcohol 0.9% (bacteriostatic saline) at a 1:1 ratio using aseptic technique. The benzyl alcohol in the bacteriostatic saline acts as a local anesthetic which may ameliorate SC injection site discomfort. Admixing is not necessary when using the multidose vials of PROCRIT® containing benzyl alcohol.

Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, CA 91320-1799 Distributed by: Ortho Biotech Products, L.P. Raritan, New Jersey 08869-0670 Revised 08/2008 © OBPLP 2000 10112802BC

The Obama Administration and the FDA Mark Senak, JD

T

alk is swirling around Washington as to who may replace Dr Andrew C. von Eschenbach at the helm of the US Food and Drug Administration (FDA). One well-known blogger has even begun a voting contest where readers can choose from several candidates for FDA Commissioner and cast a vote. There is little question that the policy environment is pregnant with change, but in most cases, it is quite possibly less important who is appointed rather than what the changes may entail.

This was obviously true with the presidential election. Given that both the McCain and Obama positions favored the import of prescription drugs, the ability of the government to negotiate prices under Medicare Part D, and the increasing uptake of generic drugs before the campaign, it is virtually certain that the outcome of the presidential contest mattered less to the pharmaceutical and biotechnology industries than the contests in Congress. Not only did the November 4 election decide that Democrats were to achieve solid majorities in both chambers, it has also paved the way for new congressional committee assignments and chairs.

This is the one area where “who” may matter, although only in a matter of degree. Consider the case of the chairmanship for the Committee on Energy and Commerce.

A clash of the titans emerged between 2 powerful and prominent members of Congress—Congressman John D. Dingell, the current chair, and Congressman Henry Waxman, who emerged the winner. This committee is key to the oversight of various aspects of the FDA and the regulation of pharmaceutical industry. The activity of this committee for October 2008 includes the following investigations, announcements, statements, and reports: • Dingell, Stupak to Investigate Melamine Contamination in Chinese Milk Products (10/2) • Dingell, Stupak Question FDA’s No-Bid Contract with a PR Firm (10/2) • Dingell, Stupak Question Whether FDA Knowingly Allowed Dangerous Drugs to be Sold to U.S. Consumers (10/8) • Dingell, Stupak Continue DTC Ad Investigation (10/14)

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• Dingell, Stupak Continue Investigation into FDA’s Questionable Handling of Bisphenol A (10/14) • Dingell, Stupak Request Interview with von Eschenbach on Bisphenol A (10/15) • GAO Report Finds FDA’s Foreign Drug Inspection Program Needs Significant Improvement (10/22).

Ironically, Congressman Dingell made the case that he is the preferable chair, because he is friendlier to industry with this 1-month track record. Now that Congressman Waxman has prevailed over Congressman Dingell for the chairmanship, one can expect a great deal more intensity in terms of the breadth and depth regarding scrutiny of the FDA and the pharmaceutical industry than was shown in October 2008.

However, for the balance of the change, “who” is not as important as “what” in terms of what must be accomplished.

There is also a great deal of unfinished business with respect to the FDA itself. Once a gold standard agency, the FDA has suffered tremendously during the past 8 years and will have a great deal to do to reclaim its position as a flagship agency overseeing one fourth of the nation’s economy.

The following qualities are the ones that PresidentElect Obama may seek for the individual who will take over the FDA. That person must: • Have a solid grasp of the pharmaceutical industry, without being directly associated with it. There are members in the Senate, particularly Senator Kennedy, who may insist that the individual have no ties to the pharmaceutical industry itself. Still, the designee must have a good understanding of clinical research and public health.

• Be able to balance the policymakers hunger for safety, while assuring that the pipeline produces to provide access. Although the public appetite is extremely risk averse, our slant to caution may bring a slowdown in new drug approvals. Longer approval time in the end means potentially higher drug prices, as patented drugs will have less time on the market to recoup research and development costs.

• Have the credibility and gravitas to tell policymakers on the Hill to stop using the agency as a political means, to gently remind members of Congress that it is a new administration, that there is a 1-party rule, and that most of them are in that very same party.

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• Possess solid visionary and have noteworthy communication skills. The agency is in trouble not only from a functional point of view, but it has also done very little to proactively address the descent of its image and to communicate and assure the public and policymakers that it has a vision. In fact, the agency does not seem to acknowledge much of a problem, much less to have a plan for solving it. The new commissioner will need to understand this, act on it, and seize leadership.

In addition to these qualities, the first order of priority should be to completely implement the Food and Drug Administration Amendment Act (FDAAA).

Right now the pipeline is getting clogged with Complete Response Letters and shifting the Prescription Drug User Fee Act dates, as the FDA tries to understand and implement the FDAAA. The FDA has been charged with implementing a fairly broad scope of reforms, but the longer it takes to identify and follow a roadmap for doing so, the more in the dark drug sponsors are going to be, which again contributes to a sluggish pipeline.

And as the policy and the communications environments undergo breathtaking changes, it is important that the agency enunciate some points of view about the uses of digital and social media by pharmaceutical companies in marketing. The potential uses for social and digital media are extraordinary, from public service announcements to patient education videos, to risk management tools; however, because regulatory cultures of most pharmaceuticals are generally conservative, most are waiting for the FDA to say something with regard to the use of such media.

The FDA appears nowhere near doing this, even though other industries have begun to embrace and strategically anticipate and respond to the migration into digital media. It is time for the FDA to be a leader, not continue to be a follower, and give companies some guidance. And that guidance should be the medium, not the message.

All this and more needs to be accomplished by an Obama-appointed FDA Commissioner, and in no short order, for the sake of the agency, public health, and the economy. ■ Mr Senak is Senior Vice President at Fleishman-Hillard in Washington, DC, and writes the Eye on FDA blog, www.eyeonfda.com.

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AHA MEETING HIGHLIGHTS

The Antiplatelet Drug Pipeline: Some Promising Candidates

By Wayne Kuznar

S

everal antithrombotic drugs in late-stage development were featured at the 2008 Scientific Sessions of the American Heart Association (AHA).

Prasugrel. A new analysis of the antiplatelet drug prasugrel, a direct-acting P2Y12 antagonist currently under US Food and Drug Administration review, questions this agent’s supposed superiority over the current standard in this class, clopidogrel (Plavix). Results of the pivotal phase 3 Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel (TRITON), which compared prasugrel and clopidogrel, were released in late 2007.

Among patients being considered for coronary stents, prasugrel prevented more future cardiac events than clopidogrel, but with excess bleeding. Despite this excess risk, the net benefit still favored prasugrel—23 fewer myocardial infarctions (MIs) per 1000 patients treated, at a cost of 6 extra bleeding events.

More recent analyses of TRITON have shown that much of the benefit of prasugrel in preventing ischemic events occurs early on, but the excess bleeding occurs after 30 days of use. New analyses have shown that prasugrel is better than clopidogrel at preventing stent thrombosis (blood clots forming in stents).

At the AHA, a team of investigators at CedarsSinai Medical Center in Los Angeles discussed its independent statistical analysis (using a Bayesian method), showing that the true superiority of prasugrel in TRITON was not as large. In their analysis, the probability of a 10% or more benefit with prasugrel over clopidogrel is less than 80%, and the chance that prasugrel is 20% better than clopidogrel in preventing cardiac events is less than 5%. If bleeding events are considered, the probability of a net benefit with prasugrel is even smaller, they argued.

Because of the risk-benefit ratio, Sanjay Kaul, MD, MPH, Director of the Vascular Physiology and Thrombosis Research Laboratory at the Burns and Allen Research Institute at Cedars-Sinai, and lead investigator of the reanalysis, proposed a strategy for using prasugrel. “One potential approach to optimizing

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the benefit-risk profile of prasugrel could involve giving it during the first 30 days as acute ‘induction’ therapy, followed by maintenance ‘consolidation’ therapy with a less potent antiplatelet agent, such as clopidogrel, in patients who receive stents,” he said.

Rivaroxaban. This oral drug factor Xa inhibitor—a new class of anticlotting agents—is entering a phase 3 trial (and will enroll 16,000 patients) after the release of phase 2 data at the AHA. The data showed that rivaroxaban could reduce MI and stroke risk, with an acceptable bleeding risk at its 2 lowest doses.

That study enrolled 3491 stable patients with a recent MI who were taking aspirin and clopidogrel (if necessary). Patients were randomized to placebo or 1 of 4 doses of rivaroxaban (2.5-10 mg twice daily) for 6 months, and were followed for 1 month after stopping therapy. As expected, higher doses of rivaroxaban increased the rate of clinically significant bleeding.

Rivaroxaban reduced the risk of ischemic events by 21% relative to placebo, but this difference was not definitive, given the small number of patients enrolled, reported C. Michael Gibson, MD, Chief of Clinical Research, Beth Israel Deaconess Medical Center, Boston. “We have decided to go forward to phase 3 with the 2 lower doses—2.5 mg and 5 mg twice daily,” he said. These doses reduced the risk of death, MI, and stroke by 46% compared with placebo (P = .08) and were associated with a major bleeding rate of 1.2%.

There was no drug-induced liver injury with rivaroxaban. The development of an oral direct thrombin inhibitor—ximelagatran—was derailed as a result of liver toxicity.

Other late-phase antithrombotic/antiplatelet drugs investigated for various thrombotic indications were discussed at the meeting, including: • Apixaban, another oral factor Xa inhibitor • Cangrelor, another direct-acting P2Y12 antagonist • Dabigatran, an oral direct thrombin inhibitor, which was recently approved in Europe (brand name, Pradaxa) • Idraparinux, a long-acting factor Xa inhibitor. ■

November/December 2008

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AMCP MEETING HIGHLIGHTS

Specialty Pipeline Dominated by Biologics

By Alice Goodman

A

number of new specialty products are in late stages of development, said Deborah B. Cooper, PharmD, Clinical Advisor, Pipeline Series, CVS/Caremark, at the 2008 educational conference of the Academy of Managed Care Pharmacy. Specialty products comprise 49% of new chemical compounds currently in phase 3 and 55% of the phase 3 ambulatory care agents. The 53 new specialty drugs slated for launch in 2008-2009 are for these categories (several products are included in more than 1 category): • Oncology—17 • Rare or orphan diseases—11 • Metabolic diseases—8 • Immunology—6 • Infectious diseases—5 • Neurologic disorders—5 • Cardiovascular disorders—3 • Respiratory disorders—3 • Dermatology—2 • Gastrointestinal disorders—2.

Key trends for the specialty pipeline include (1) increased numbers of drugs for rare/orphan diseases, (2) emergence of more drugs with Risk Evaluation and Mitigation Strategy (REMS) programs, (3) expansion of adjunctive/additive agents for multiple disease states, and (4) a shift from injectable to oral therapies.

Rheumatoid Arthritis Toxilizumab (Actemra), an anti-interleukin-6 receptor monoclonal antibody, is pending approval for rheumatoid arthritis (RA) and is expected to be launched with a REMS program. It is administered intravenously every 4 weeks. Adverse events reported include infections, hypersensitivity reactions, headache, nasopharyngitis, and pleurisy.

Golimumab is a humanized anti-tumor necrosis factor drug pending approval for RA, psoriatic arthritis, and ankylosing spondylitis. It is administered as a subcutaneous injection every 4 weeks. An intravenous (IV) formulation is in phase 2, to be administered every 12 weeks. Adverse events included headache and injection-site and allergic reactions.

Multiple Sclerosis Fampridine SR is a twice-daily oral agent in phase 3, for the symptomatic treatment of multiple sclerosis (MS), to be used in conjunction with other MS drugs.

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It blocks potassium channels on axons of nerves and increases walking speed and/or muscle strength. Adverse events reported include falls, insomnia, paresthesias, dizziness, urinary tract infections, and nausea. Seizures have been reported with high doses of the drug.

Fingolimod is a once-daily oral immunosuppressant in phase 3, which, if approved, will be the first oral disease-modifying agent for MS. It causes a dose-related reduction in the number of circulating lymphocytes, leading to a decrease in the number of activated T-cells in the blood and central nervous system. Adverse events include headache and dose-dependent upper respiratory tract infection.

Psoriasis Ustekinumab (Stelara) is a fully humanized monoclonal antibody that targets interleukin-12 and -23, which are thought to be proinflammatory cytokines.

Approval is pending for chronic moderate-to-severe psoriasis. The drug is administered subcutaneously every 12 weeks. Adverse reactions include headache, infections, injection-site reactions, and respiratory tract infections.

SLE Epratuzumab, a monoclonal antibody that targets the CD22 antigen on the surface of B cells, is in phase 3 for the treatment of moderate-to-severe systemic lupus erythematosus (SLE). The CD22 receptor is implicated in inflammation. Epratuzumab is administered as an IV infusion every other week. Adverse reactions in clinical trials include arthralgia, hypotension, nausea, and palpitations.

Belimumab (LymphoStat-B), also in phase 3 for SLE, is a fully human monoclonal antibody that inhibits the biologic activity of B-lymphocyte stimulator, which at high levels may contribute to the pathogenesis of autoimmune diseases (eg, SLE, RA). It is administered intravenously every 28 days. It has shown a significant reduction in SLE flares and disease activity.

Hepatitis C Two drugs in phase 3 trials for hepatitis C virus (HCV) show very promising results for those who failed therapy with pegylated interferon alfa and ribavirin: Zadaxin (thymalfasin), an immunomodulator that stimulates T-cells and decreases viral replication; telaprevir, the first protease inhibitor for HCV, to be used with current therapies.

Approval and launch are expected in 2009 or 2010. ■

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AMCP MEETING HIGHLIGHTS

Real-World Data Better than RCTs for Formulary Decisions

By Alice Goodman

R

eal-world data on a new therapy and a userfriendly assessment tool to evaluate real-world studies facilitate formulary and reimbursement decisions, said Diana Brixner, PhD, RPh, Professor and Chair, Department of Pharmacotherapy, and Executive Director, Pharmacy Outcomes Research Center, University of Utah, at the 2008 educational conference of the Academy of Managed Care Pharmacy.

Payers need information beyond randomized controlled trials (RCTs) to make the best decisions about how to deploy limited budgets for large patient populations. RCTs are conducted in a select patient population, according to strict protocols, and the results are not generalizable to large patient populations.

Supplemental observational open-label trials and postmarketing surveillance provide data on the effect of new treatments that are more relevant for managed care organizations (MCOs), such as quality-adjusted life-years, productivity, and absenteeism.

Dr Brixner summarized the proceedings of 2 roundtables that addressed issues surrounding use of real-world data in managed care. A roundtable in July 2007 included 4 MCO directors and 4 economists. The panel tackled the quality of real-world evidence, the complexity of real-world research, the lack of consistency in quality assurance and assessment in decision-making, and the time delay between accrual of real-world data and product launch. Recommendations for further study include: • Analysis of tools for quality assessment of observational studies • Development of a consolidated instrument to measures the quality assurance of these data • Establishment of a process to support application of a comprehensive quality assessment tool • Development of training for producers and users of observational studies on the consolidated tool.

“Our healthcare system is fragmented. A consolidated tool would reduce the impact of fragmentation,” said Dr Brixner.

Developing a new tool for quality assurance to evaluate real-world studies is a daunting task, and is still ongoing, Dr Brixner explained. In analyzing existing checklists, participants found that none of them fulfilled the criteria for a simple-to-use, comprehensive

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checklist to evaluate published real-world studies.

Existing checklists were either too long or too academic to support decision-making.

A second roundtable, held in March 2008, discussed how to act on the recommendations of the first roundtable. Participants agreed on the need: • For quality and convenience in assessment of realworld data • To recognize that the process of implementation of a new tool is as important as the new tool itself • For peer validation of a new tool • To educate all constituents about the tool and its implementation.

A small survey of 4 MCOs found that although none of them currently uses a checklist to evaluate realworld studies, they would use a tool if it was short and concise, validated, and recommended by a national organization, Dr Brixner said. ■

Unmanaged Moment

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CLINICAL

An Overview of Cholesterol Management Robyn A. Burns Schaiff, PharmD, BCPS; Richard M. Moe, MD, PhD; Daniel W. Krichbaum, PharmD Cardiovascular disease is the leading cause of death worldwide. Elevated cholesterol (hypercholesterolemia) and abnormal lipid profiles (dyslipidemia) are important risk factors for the development of cardiovascular disease. This article discusses the role of cholesterol in the body and the relationship between different cholesterol fractions and the risk of cardiovascular disease. The guidelines for assessment and treatment of dyslipidemia from the National Cholesterol Education Program are outlined, and cholesterol targets and goals of therapy are discussed. The mechanism of action, place in therapy (eg, first-line, second-line, or add-on), and common side effects are also discussed for each of the available classes of drugs used in the treatment of dyslipidemia. [ADHB. 2008;1(9):39-48.]

C

ardiovascular (CV) disease (CVD) is the leading cause of mortality and one of the leading causes of disability worldwide.1 In the United States alone, more than 80 million adults have at least one type of CVD, with hypertension, coronary heart disease (CHD), stroke, and heart failure among the most common forms of the disease. Elevated levels of cholesterol (hypercholesterolemia) and abnormal lipid profiles (dyslipidemia) are important risk factors for CVD. The American Heart Association (AHA) estimates that more than 100 million Americans have elevated cholesterol levels (>200 mg/dL) and 34 million have cholesterol levels that necessitate treatment.2 Cholesterol is an essential component of cell membranes and steroid hormones. The body synthesizes most of its required cholesterol with the remainder coming from the diet. Since cholesterol is mostly insoluble in blood, it is packaged with proteins and phospholipids to form lipoprotein complexes that circulate in the bloodstream. The types of cholesterolcontaining lipoproteins are high-density lipoproteins (HDL-C), low-density lipoproteins (LDL-C), very lowdensity lipoproteins (VLDL-C), and chylomicrons.

High levels of LDL-C are associated with increased CV risk in epidemiologic studies. In addition, numerous clinical studies using a variety of therapies have demonstrated decreased CV events and mortality with LDL reduction. Therefore, the first goal of therapy is

Dr Burns Schaiff is Senior Director, Regional Medical & Research Specialist, Pfizer, Inc, New York, NY; Dr Moe is Clinical Associate Professor, University of Missouri-Kansas City, Kansas City, MO; Dr Krichbaum is Senior Director Team Leader, Regional Medical & Research Specialist, Pfizer, Inc, New York, NY.

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reduction of LDL-C levels for the most common forms of dyslipidemia. Conversely, high levels of HDL-C are associated with decreased risk of CV events. However, clinical trials assessing the morbidity and mortality benefits of drug therapies that raise HDL-C levels have had varied results. HDL-C–modifying trials with niacin have demonstrated CV event reduction.3,4 Conversely, other treatments that raise HDL-C, including hormone replacement therapy5 and torcetrapib,6 have not decreased CV events. Because of this, in the absence of large clinical outcome trials, therapies that elevate HDL cannot be assumed to produce clinical event reduction.

Approach to Patient Assessment, Treatment The National Cholesterol Education Program (NCEP) evaluates evidence and develops guidelines for lipid management. The approach to patient management provided here comes primarily from the guidelines published in 2001 and updated in 2004.7,8 Since the primary goal of lipid management is to decrease the risk of CV events and death, the first step in management is to assess the patient’s overall CV risk. To make this assessment, a fasting lipoprotein analysis should be obtained to determine the patient’s LDL-C. Optimal levels for LDL-C and total cholesterol are <100 mg/dL and <200 mg/dL, respectively. The NCEP guidelines recommend that a fasting lipid panel be drawn at least every 5 years in all adults older than 20 years.7 In addition to LDL-C levels, the presence or absence of CHD or CHD-equivalent conditions must be assessed. CHD-equivalent conditions listed by the NCEP include diabetes mellitus, peripheral vascular disease, abdominal aortic aneurysm, symptomatic carotid disease, and a 10-year CV risk of less than 20%

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KEY POINTS ▲ Cholesterol is an essential component of cell membranes

and steroid hormones. ▲ Hypercholesterolemia and dyslipidemia are important risk

factors for cardiovascular disease, which affects more than 80 million Americans. ▲ Evidence shows that high levels of LDL-C are associated

with increased cardiovascular risk; reducing LDL levels has been associated with significant reduction in mortality. ▲ The first goal of therapy in hypercholesterolemia is reduc-

tion of LDL-C levels. ▲ Statins are considered the most effective lipid-lowering

agents available, both in lowering LDL levels and in the prevention of cardiovascular events.

Table 1 Major Risk Factors (Exclusive of LDL-C) that Modify LDL Goals* Cigarette smoking Hypertension (blood pressure ≥140/90 mm Hg or on antihypertensive medication) Low HDL-C (<40 mg/dL)† Family history of premature CHD (CHD in male first-degree relative <55 y, CHD in female first-degree relative <55 y) Age (men ≥45 y; women ≥55 y) *

Diabetes is regarded a CHD risk equivalent.

HDL cholesterol ≥60 mg/dL counts as a negative risk factor; its presence removes 1 risk factor from the total count.

LDL-C indicates low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; CHD, coronary heart disease.

Reprinted with permission from Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497. †

calculated with the Framingham risk calculator.7 Although not addressed by the NCEP, the National Kidney Foundation also considers chronic kidney disease (glomerular filtration rate <60 mL/min) to be a high-risk state and recommends that this patient group be treated as having a CHD-equivalent disease.9 Likewise, the AHA and the American Stroke Association recommend the use of a statin with intensive lipid-lowering effects in patients with atherosclerotic stroke or transient ischemic attack, even in the absence of known CHD.10 In the absence of CHD or CHD-equivalent conditions, CVD risk factors (Table 1) should be carefully assessed using the Framingham risk score to determine the patient’s 10-year risk of CV events (Table 2).7

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Goals of Therapy For patients with CHD or CHD-equivalent disease, the NCEP recommends the LDL-C goal of ≤100 mg/dL, with <70 mg/dL a therapeutic option for patients considered at very high risk for CV events.8 For patients with 2 or more CV risk factors but with a 10-year Framingham risk of less than 20%, the LDL-C goal is <130 mg/dL, with <100 mg/dL a therapeutic option. Finally, for patients with 0 to 1 risk factors, the LDL-C target is <160 mg/dL.8 Therapeutic Lifestyle Changes The NCEP Adult Treatment Panel III guidelines recommend that therapeutic lifestyle changes be implemented for all patients at risk for CVD.7 These changes include reducing intake of saturated fats and cholesterol while increasing soluble fiber intake and physical activity. Optimization of weight, moderation of alcohol consumption, and cessation of smoking are also encouraged. If drug therapy is needed, it should be used as an addition to, rather than a substitute for, therapeutic lifestyle changes.

Treatment Initiation Since the clinical evidence of benefit is greatest with the statin drug class, the American College of Cardiology (ACC) recommends drug therapy begin with a statin and that titration to goal or the maximally tolerated dose of a statin be achieved before consideration of adding other agents.11 Regardless of the initial treatment chosen, it is critical that the patient be reevaluated and therapy titrated or added until the goal LDL-C is attained.

For patients with 0 to 1 risk factors and no CHD, treatment is initiated with therapeutic lifestyle changes with reassessment after 6 weeks. If goal LDL of <160 mg/dL is not reached at 6 weeks, lifestyle changes should be intensified and reinforced and a visit with a dietitian considered. If after 12 weeks of therapeutic lifestyle changes the patient is not at the LDL-C goal of <160 mg/dL, drug therapy, usually a statin, should be added.

For patients at moderate risk, with 2 or more risk factors and a 10-year CV risk of less than 20%, treatment begins with therapeutic lifestyle changes. Drug therapy, usually a statin, can be initiated concurrently if the LDL is >100 mg/dL at baseline or if LDL-C remains >100 mg/dL after a 6-week trial of lifestyle changes.

For the highest risk patients with CHD or equivalent conditions, statin therapy and therapeutic lifestyle changes should be initiated simultaneously for all

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Cholesterol Management

Table 2 An Overview of Cholesterol Management

HDL indicates high-density lipoprotein; BP, blood pressure.

Reprinted with permission from Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.

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patients with LDL-C >100 mg/dL. Drug therapy may also be considered in very high-risk patients with LDLC <100 mg/dL targeted to achieve the optional goal of <70 mg/dL.8

Pharmacotherapy Options A variety of lipid-lowering agents are available, including 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, bile acid sequestrants, cholesterol absorption inhibitors, fibrates, nicotinic acid derivatives, and omega-3 fatty acids. Dosage ranges, US Food and Drug Administration (FDA) indications, evidence of clinical outcome benefit, and side effects are highlighted in Table 3.

These are the most prescribed drugs in the world and are considered the most effective lipid-lowering agents available.

HMG-CoA Reductase Inhibitors (Statins) HMG-CoA reductase inhibitors, or statins, are the recommended first-line therapy for most patients.

These are the most prescribed drugs in the world and are considered the most effective lipid-lowering agents available, both in lowering LDL-C levels and in the prevention of CV events. Statins are similar in structure to HMG-CoA, a precursor of cholesterol, and act as competitive inhibitors of HMG-CoA reductase, the last regulated enzymatic step in cholesterol synthesis.

Therefore, statins reduce the rate of synthesis of cholesterol. The liver responds by increasing the number of LDL receptors, which increases hepatic uptake and catabolism of circulating LDL-C. Statins reduce LDL-C by 24% to 60% and decrease triglycerides (TGs) by 5% to 50% (percentages are based on the various package inserts), depending on the agent selected and the baseline lipid profile. HDL-C levels are usually increased.

The effects on HDL are a class effect and are small relative to the effects on LDL-C and TGs. In addition, statins have a variety of anti-inflammatory effects that are independent of the LDL-C lowering, which may contribute to the clinical benefit in CVD, especially early in therapy.12 However, a recent meta-analysis of 23 lipid-lowering trials demonstrated that the majority (89%-98%) of the anti-inflammatory effects of lipidlowering therapy is related to the degree of LDL reduction,13 which suggests a limited influence of a non-LDL-

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Câ&#x20AC;&#x201C;related anti-inflammatory mechanism.

Adverse events, relatively uncommon with this class, include gastrointestinal (GI) disturbances, muscle aches, and asymptomatic transaminasemia. Rare serious adverse events may include myopathy and rhabdomyolysis. FDA-approved labeling recommends assessment of liver function at baseline, after 12 weeks of therapy, after dose escalation, and twice yearly thereafter. However, the National Lipid Association has suggested that this practice does not increase the safety of statin therapy, but merely increases cost.14

Bile Acid Sequestrants Bile acid sequestrants bind to bile acids in the intestine, reducing absorption of cholesterol and other lipids.

The resultant decrease in available cholesterol causes an increase in the number of LDL receptors on hepatocytes, further promoting clearance of LDL-C from the blood. Bile acid sequestrants are recommended as second-line therapy for patients with elevated cholesterol, but not elevated TGs, as both VLDL-C and TG concentrations may increase during therapy. Agents in this class lower LDL-C by 15% to 30% and increase HDL-C by 3% to 5% on average.9 Patient adherence with these agents is frequently poor due to the need for frequent dosing, poor palatability, and frequent GI side effects.

Since these drugs remain in the GI tract, systemic adverse effects are minimal; however, these agents can interfere with absorption of concomitantly administered drugs as well as fat-soluble vitamins.

Nicotinic Acid Derivatives Niacin reduces synthesis of VLDL-C in the liver and therefore reduces LDL-C production. Pharmacologic doses of niacin (1.5-2 g/day) lower LDL-C and TGs by 15% to 20% and 30% to 40%, respectively, and increase HDL-C by 15% to 25%. Niacin is used as second-line therapy in concert with other lipid-lowering agents. The most common adverse events include vasodilation with flushing and pruritis, which frequently is dose-limiting. Other adverse events include dyspepsia, gastric ulceration, hyperuricemia, palpitations, and, rarely, peripheral neuropathy.

Niacin-induced hyperglycemia may be problematic for patients with diabetes mellitus or with impaired glucose tolerance, particularly in the first 6 months of therapy, but long-term clinical benefits have been demonstrated in these patients.15 The most serious side effect is hepatotoxicity; cases of fatal fulminant hepatic failure have been associated with niacin administration, particularly with older formulations.16

November/December 2008

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VOL. 1

NO. 9 50-, 150-mg capsules 54-, 160-mg tablets 67-,134-, 200-mg capsules

43-130 mg/d

Lipofen* (fenofibrate) 50-150 mg/d 54-200 mg/d 48-145 mg/d 50-160 mg/d 600-1200 mg/d, 2 divided doses

Antara* (fenofibrate)

Lofibra* (fenofibrate)

TriCor* (fenofibrate)

Triglide (fenofibrate)

Lopid* (gemfibrozil)

10-, 20-, 40-, 80-mg tablets

600-mg tablets

50-, 160-mg tablets

48-, 145-mg tablets

•Primary prevention of MI, stroke in patients w/type 2 DM and other CHD risk factors •Primary prevention of MI, stroke, revascularization, hospitalization for heart failure and angina in patients w/clinically evident CAD •Primary hypercholesterolemia or mixed dyslipidemia •Hypertriglyceridemia •Primary dysbetalipoproteinemia •Homozygous FH in adolescents •Heterozygous FH in adolescents

•Reducing CHD risk in patients w/type 2b dyslipidemia and inadequate response to TLC, other drug therapy, who have high LDL, low HDL, high TG •Familial type IV or V hyperlipidemia

•Hypertriglyceridemia •Primary hyperglyceridemia •Mixed dyslipidemia

•Primary hyperlipidemia •Mixed dyslipidemia •Homozygous familial hypercholesterolemia •Homozygous sitosterolemia

Adjunct therapy for primary hypercholesterolemia

TG↓ 25%-45%

TG↓ 20%-50%

LDL-C↓ 10%-20%

LDL-C↓ 10%-20%

LDL-C↓ 10%-18%

LDL-C↓ 10%-30%

•Patients w/hypertension and LDL-C↓ ≥3 CHD risk factors (ASCOT4) 39%-60% •Patients w/type 2 DM and no history of CVD (CARDS5) •Patients w/stable CHD (TNT,6 IDEAL,7 ALLIANCE,8 and and AVERT 9) •Patients w/atherosclerotic stroke or TIA w/o documented CHD (SPARCL10) •Patients w/ACS (PROVE-IT,11 MIRACL12)

•Men w/primary dyslipidemia (Helsinki Heart Study2) •Men w/CHD and low HDL-C (VA Hit3)

Men with primary hypercholesterolemia (LRC-CTTP1)

Primary effect on lipids

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Abdominal pain, constipation, flatulence, indigestion, increased liver enzymes, headache, myalgia

Rash, abdominal pain, diarrhea, flatulence, indigestion, xerostomia, myalgia

Rash, diarrhea, flatulence, nausea and vomiting, myalgia, rhinitis

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Headache, diarrhea, abdominal pain, arthralgia, backache, myalgia, sinusitis

Abdominal distension, ab$$$ dominal pain, constipation, musculoskeletal pain, headache

Asthenia, constipation, indigestion, pharyngitis, myalgia

Abdominal discomfort, constipation, flatulence, nausea and vomiting, vitamin A, D deficiency

Side effects (most often reported)

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10 mg/d

Zetia (ezetimibe)

1-g tablets

•Adjuct therapy of hypercholesterolemia •Adjunct therapy to improve glycemic control in type 2 DM

•Adjuct therapy of hypercholesterolemia •Pruritis due to partial biliary obstruction

Indications

Populations w/ demonstrated event reduction†

11/25/08

Lipitor (atorvastatin)

10-mg tablets

2-16 g/d 2 divided doses

Colestid* (colestipol)

625-mg tablets

3.75 g/d

Welchol (colesevelam)

Questran Light: packets and powder (each 5 g contain 4 g anhydrous cholestyramine resin) Questran: powder and packets (each 9 g contain 4 g anhydrous cholestyramine resin)

Available doses

8-24 g/d, 2 divided doses

Dosage range

Questran* (cholestyramine)

Drug

Table 3 Pharmacotherapy for Lipid Disorders

ClinicalSchaiiff_NovDec .qxp:Cover Page 43

43

44 80-mg extendedrelease tablets 10-, 20-, 40-mg tablets

80-mg mg/d 10-80 mg/d

10-80 mg/d

Lescol XL (fluvastatin ER)

Mevacor* (lovastatin)

Pravachol* (pravastatin)

AMERICAN HEALTH & DRUG BENEFITS

November/December 2008

VOL. 1

0.5-2 g/d

Niaspan (niacin ER)

0.25-6 g/d, 3 divided doses

0.5-2 g/d

Slo-Niacin CR* (controlled-release niacin)

Immediate-release niacin*

5-, 10-, 20- 40-, 80-mg tablets

5-80 mg/d

Zocor* (simvastatin)

500-mg tablets

Niacin ER: 500-, 750-, 1000-mg tablets

Niacin CR: 250-, 500-, 750-mg tablets

5-, 10-, 20-, 40-mg tablets

5-40 mg/d

•Primary hypercholesterolemia or mixed dyslipidemia (alone or with lovastatin) •Severe hypertriglyceridemia •To reduce risk of recurrent MI in patients w/hypercholesterolemia and history of MI •W/bile acid–binding resin to slow progression or induce regression of coronary atherosclerosis in patients w/CAD and hypercholesterolemia •W/bile acid–binding resin: primary hypercholesterolemia

LDL-C↓ 45%-60%

Men w/history of MI (CDP21; LDL↓ immediate-release dosage form) 5%-15% TG↓ 15%-30% HDL↑ 15%-20%

•Existing CHD and elevated LDL-C↓ 35%-50% total cholesterol (4S19) •Patients at high risk of CV events from existing CHD, history of stroke, other cerebrovascular disease, peripheral artery disease, or hypertension in men ≥65 yr (HPS20)

•Primary hyperlipidemia Men ≥55 and women ≥65 and mixed dyslipidemia w/LDL ≤130 mg/dL and CRP •Primary hypertriglyceridemia ≥2 mg/L (JUPITER18) •Homozygous familial hypercholesterolemia •To slow the progression of atherosclerosis •Prevention of CHD mortality and CV events in patients w/existing CHD, history of stroke, diabetes, or peripheral artery disease •Hypercholesterolemia •Heterozygous FH in adolescents

LDL-C↓ 25%-45%

LDL-C↓ 20%-35%

•Men w/o history of MI LDL-C↓ w/elevated LDL (WOSCOPS15) 25%-40% •Patients w/MI in preceding 3-20 mo (CARE16) •Patients w/MI or unstable angina in previous 3-36 mo (LIPID17)

High risk (elevated LDL-C w/low HDL-C) patients w/o clinical CHD (AFCAPS-TexCaps14)

Patients with CHD who had coronary intervention (LIPS13)

Primary effect on lipids

$$$$

$$$

Cost, 30-day supply

$$

Constipation, flushing, pruritis, GI irritation, nausea, vomiting

Constipation, GI irritation, headache, upper respiratory infection, myalgia, increased hepatic transaminase levels

$

$$$$$

$$

$$

Abdominal pain, constipation, $$$$ nausea, arthralgia, asthenia, headache, myalgia, increased hepatic transaminase levels

Diarrhea, flatulence, heartburn, nausea, vomiting, asthenia, headache, myalgia

Abdominal pain, constipation, $$ diarrhea, nausea, headache, myalgia, increased hepatic transaminase levels

Abdominal pain, diarrhea, dyspepsia, nausea, headache, myalgia

Side effects (most often reported)

10:55 AM

Crestor (rosuvastatin)

•Primary prevention of MI, revascularization, and CV mortality •Reduction in total mortality by reducing coronary death, MI, revascularization, stroke, and to slow progression of coronary atherosclerosis in patients with CHD •Hypercholesterolemia •Heterozygous FH in adolescents

•Primary prevention of MI, unstable angina, coronary revascularization •To slow progression of coronary atherosclerosis in CHD •Hypercholesterolemia •Heterozygous FH in adolescents

•Reduce coronary revascularization in CHD •Reduce progression of coronary atherosclerosis in CHD •Hypercholesterolemia •Heterozygous FH in adolescents

Indications

Populations w/ demonstrated event reduction†

11/25/08

10-, 20-, 40-, 80-mg tablets

20-, 40-mg capsules

20-80 mg/d

Lescol (fluvastatin)

Available doses

Dosage range

Drug

Table 3 Pharmacotherapy for Lipid Disorders Continued

ClinicalSchaiiff_NovDec .qxp:Cover Page 44

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NO. 9 Niacin-ER 500 mg– simvastatin 20 mg/d to niacin-ER 2000 mg– simvastatin 40 mg/d Ezetimibe 10 mg– simvastatin 10 mg/d to ezetimibe 10 mg– simvastatin 80 mg/d

Simcor (niacin-ER/ simvastatin)

Vytorin (ezetemibe/ simvastatin)

Ezetimibe– simvastatin 10 mg-10 mg 10 mg-20 mg 10 mg-40 mg 10 mg-80 mg

Niacin-ER– simvastatin 500 mg-20 mg 750 mg-20 mg 1000 mg-20 mg

Niacin-ER– lovastatin 500 mg-20 mg 750 mg-20 mg 1000 mg-20 mg

•Primary hyperlipidemia or mixed hyperlipidemia •Homozygous FH

•Hypercholesterolemia •Mixed dyslipidemia •Hypertriglyceridemia (all when monotherapy inadequate)

•Hypercholesterolemia •Mixed dyslipidemia

Hypertriglyceridemia (TG ≥500 mg/dL)

Indications •Hypercholesterolemic Japanese patients (over statin background therapy) (JELIS22) •Patients w/recent MI (GISSI-Prevenzione23)

LDL↓ 45%-60%

LDL↓ 10%-15% HDL↑ 20%-30% TG↓ 15%-40% (from baseline treatment w/ simvastatin 0-20 mg/d)

LDL↓ 30%-45% HDL↑ 20%-30% TG↓ 30%-45%

TG↓ 25%-45%

Primary effect on lipids

See under components

Increased bleeding/bruising, burping, indigestion, altered taste sense

Side effects (most often reported)

$$$$

$$$

$$$$

$$

Cost, 30-day supply

11/25/08 10:55 AM

*Generic available. †Studies listed in this column may not be included in FDA-approved indications.

LDL-C indicates low-density lipoprotein cholesterol; DM, diabetes mellitus; TG, triglycerides; CHD, coronary heart disease; TLC, therapeutic lifestyle changes; HDL-C, high-density lipoprotein cholesterol; MI, myocardial infarction; CAD, coronary artery disease; FH, familial hypercholesterolemia; CVD, cardiovascular disease; TIA, transient ischemic attack; ACS, acute coronary syndrome; CV, cardiovascular; GI, gastrointestinal; CR, controlled release; ER, extended release.

1. Lipid Research Clinics Program: the lipid research clinics coronary primary prevention trial results. I. Reduction in incidence of coronary heart disease. JAMA. 1984;251:351-364.

2. Helsinki Heart Study. Primary prevention trial with gemfibrozil in middle-aged men with dyslipidemia. N Engl J Med. 1987;317:1237-1245.

3. Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med. 1999;341:410-418.

4. Sever PS, Dahlöf B, Poulter NR, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet. 2003;361:1149-1158.

5. Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebocontrolled trial. Lancet. 2004;364:685-696.

6. LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352:1425-1435.

7. Pedersen TR, Faergeman O, Kastelein JJ, et al. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA. 2005;294:2437-2445.

8. Koren MJ, Hunninghake DB; ALLIANCE Investigators. Clinical outcomes in managed-care patients with coronary heart disease treated aggressively in lipid-lowering disease management clinics: the ALLIANCE study. J Am Coll Cardiol. 2004;44:1772-1779.

9. Pitt B, Waters D, Brown WV, et al. Aggressive lipid-lowering therapy compared with angioplasty in stable coronary artery disease. N Engl J Med. 1999;341:70-76.

10. Schwartz GG, Olsson AG, Ezekowitz MD, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA. 2001;285:1711-1718.

11. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350:1495-1504.

12. Amarenco P, Bogousslavsky J, Callahan A 3rd, et al. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;355:549-559.

13. Serruys PW, De Feyter PJ, Benghozi R, et al. The Lescol(R) Intervention Prevention Study (LIPS): a double-blind, placebo-controlled, randomized trial of the long-term effects of fluvastatin after successful transcatheter therapy in patients with coronary heart disease. Int J Cardiovasc Intervent. 2001;4:165-172.

14. Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA. 1998;279:1615-1622.

15. Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med. 1995;333:1301-1307.

16. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med. 1996;335:1001-1009.

17. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998;339:1349-1357.

18. Ridker PM, Danielson MIA, Fonseca AH, et al, for the JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2195-2207.

19. The Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383-1389.

20. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:7-22.

21. Canner PL, Berge KG, Wenger NK, et al. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol. 1986;8:1245-1255.

22 Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomized, open-label, blinded endpoint analysis. Lancet. 2007;369:1090-1098.

23. Marchioli R, Schweiger C, Tavazzi L, Valagussa F. Efficacy of n-3 polyunsaturated fatty acids after myocardial infarction: results of GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico.

Lipids. 2001;36(suppl):S119-S126.

Cost: $ 0-25, $$ 26-50, $$$ 51-100, $$$$ 101-200, $$$$$ >200 Sources: Clinical data compiled from Micromedex website. http://www.thomsonhc.com. Accessed August 22, 2008. Cost information from www.drugstore.com. Accessed August 22, 2008.

Niacin-ER 500 mg–lovastatin 20 mg/d to niacin-ER 2000 mg–lovastatin 40 mg/d

Various

2-4 g/d

Omega-3 fatty acid* (Lovaza)

Advicor (niacin-ER/ lovastatin)

Available doses

Dosage range

Drug

Populations w/ demonstrated event reduction†

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Fibrates Fibric acid derivatives, or fibrates, such as gemfibrozil and fenofibrate, are agonists of the peroxisomeactivated receptor-α in muscle, liver, and other tissues.

Fibrates can lower TG levels by up to 50% and are therefore considered the first-line agents in patients with hypertriglyceridemia (TG >400 mg/dL).

However, LDL-C reduction is variable (10%-15%), with some patients exhibiting increased levels of LDLC. HDL-C levels may be increased up to 25% in patients with very high TG levels at baseline.17 The most common adverse events are rash and dyspepsia for fenofibrate and GI disturbances for gemfibrozil.

All fibrates may increase the risk of gallstones. In addition, gemfibrozil has been shown to increase plasma concentration of statins, thereby increasing the risk of muscle toxicity.18 Ezetimibe As with bile acid sequestrants, ezetimibe inhibits the absorption of cholesterol. However, since it does not interfere with the absorption of other dietary fats, it is better tolerated. Ezetimibe localizes at the brush border of the small intestine, where it binds to a critical mediator of cholesterol absorption, the Niemann-Pick C1like 1 protein on the GI tract epithelial cells19 and liver cells. Like the bile acid sequestrants, by reducing the availability of LDL-C, ezetimibe also induces LDL receptor upregulation leading to increased uptake of LDL-C into cells, further lowering circulating LDL-C levels. While ezetimibe effectively lowers LDL-C, studies assessing clinical event reduction are lacking. In a recent study, no additional decrease in the carotid intima-media thickness was demonstrated with ezetimibesimvastatin combination therapy compared with simvastatin alone, despite significantly greater reduction in LDL-C in the combination group.20 In addition, in another study, an increased risk of cancer death was observed in the simvastatin-ezetimibe group compared with the placebo group,21 but an analysis of more than 20,000 patients in ongoing randomized trials revealed no increase in cancer risk in patients receiving ezetimibe compared with placebo.22 However, given the lack of documented outcome benefit with this agent, the ACC recommends that it be reserved for patients who cannot reach LDL-C goal with maximal dose statins.11 Omega-3 Fatty Acids Epidemiologic studies have demonstrated that people who have diets rich in omega-3 fatty acids have a

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lower risk of CV events compared with those with a typical Western diet. Studies of omega-3 fatty acid administration have demonstrated reductions in TGs of up to 45% in patients with baseline TG levels >500 mg/dL.23 Smaller reductions are expected in patients with lower baseline levels. In addition to the reduction in TGs, HDL-C levels may be increased by as much as 9%. The addition of omega-3 fatty acids to statin therapy produces further reductions in VLDL-C and TGs and further elevations in HDL-C. The putative mechanisms for TG reduction with high-dose omega-3 fats include increased beta oxidation. ■

Conclusion Elevated cholesterol level is a major risk factor for CVD, the leading cause of death worldwide. Reduction of LDL-C has been shown to decrease the risk of CV events in a large number of clinical trials. Because they are the best studied, have a favorable risk/benefit profile, and have been demonstrated to produce clinical benefits in many large trials, statins are the first-line treatment for patients with hypercholesterolemia.

Disclosure Statement Dr Moe is on the Speakers’ Bureau for Pfizer, BMS, Novartis, Abbott, and GlaxoSmithKline. Drs Burns Schaiff and Krichbaum are employees of Pfizer, Inc. Limited editorial support was provided by Paul Lane, PhD, at Envision Pharma, Ltd, and was funded by Pfizer, Inc.

References 1. Mensah GA, Brown DW. An overview of cardiovascular disease burden in the United States. Health Aff (Millwood). 2007;26:38-48.

2. Rosamond W, Flegal K, Furie K, et al. Heart disease and stroke statistics—2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation.

2008;117:e25-146.

3. The Lipid Research Clinics Coronary Primary Prevention Trial Results. I. Reduction in incidence of coronary heart disease. JAMA. 1984;251:351-364.

4. Brown G, Albers JJ, Fisher LD, et al. Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. N Engl J Med. 1990;323:1289-1298.

5. Manson JE, Hsia J, Johnson KC, et al. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med. 2003;349:523-534.

6. Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med. 2007;357:2109-2122.

7. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285:2486-2497.

8. Grundy SM, Cleeman JI, Bailey Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110:227-239.

9. National Kidney Foundation. K/DOQI Clinical practice guidelines for managing dyslipidemias in chronic kidney disease. Part 3: treating dyslipidemias. Am J Kidney Dis. 2003;41(4 suppl 3):S39-S58.

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10. Adams RJ, Albers G, Alberts MJ, et al. Update to the AHA/ASA recommendations for the prevention of stroke in patients with stroke and transient ischemic attack. Stroke. 2008;39:1647-1652.

11. American College of Cardiology. ACC Statement on ENHANCE Trial. January 15, 2008. http://www.acc.org/enhance_statement.htm.

Accessed October 10, 2008.

12. Libby P. Current concepts of the pathogenesis of atherosclerosis.

Circulation. 2001;104:365-372.

13. Kinlay S. Low density lipoprotein-dependent and independent effects of cholesterol lowering therapies on C-reactive protein: a metaanalysis. J Am Coll Cardiol. 2007;49:2003-2009.

14. Cohen DE, Anania FA, Chalasani N; National Lipid Association Statin Safety Task Force Liver Expert Panel. An assessment of statin safety by hepatologists. Am J Cardiol. 2006;97(8A):77C-81C. 15. Canner PL, Furberg CD, Terrin ML, McGovern ME. Benefits of niacin by glycemic status in patients with healed myocardial infarction (from the Coronary Drug Project). Am J Cardiol. 2005;95:254-257.

16. Ferenchick G, Rovner D. Hepatitis and hematemesis complicating nicotinic acid use. Am J Med Sci. 1989;298:191-193.

17. Guay DR. Micronized fenofibrate: a new fibric acid hypolipidemic agent. Ann Pharmacother. 1999;33:1083-1103.

18. Noé J, Portmann R, Brun ME, Funk C. Substrate-dependent drugdrug interactions between gemfibrozil, fluvastatin and other organic anion-transporting peptide (OATP) substrates on OATP1B1, OATP2B1, and OATP1B3. Drug Metab Dispos. 2007;35:1308-1314.

19. Garcia-Calvo M, Lisnock J, Bull HG, et al. The target of ezetimibe is Niemann-Pick C1-Like 1 (NPC1L1). Proc Natl Acad Sci. 2005;102: 8132-8137.

20. Kastelein JP, Akdim F, Stroes ES, et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med. 2008;358: 1431-1443.

21. Rossebo AB, Pedersen TR, Boman K, et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med. 2008; 359:1343-1356.

22. Peto R, Emberson J, Landray M, et al. Analysis of cancer data from three ezetimibe trials. N Engl J Med. 2008;359:1357-1366.

23. Kris-Etherton PM, Harris WS, Appel LJ; American Heart Association. Nutrition Committee. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation. 2002;106:2747-2757.

Stakeholder Perspectives Experts Debate Meaning of JUPITER for Clinical Practice PHYSICIANS/PAYERS: Should the indications for statins be expanded? This was the question that had many cardiovascular (CV) experts talking, but with little consensus, in light of the findings from the JUPITER (Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin) study released in November 2008 at the American Heart Association annual meeting and then published in the New England Journal of Medicine.1 The results have also created a buzz among P & T Committee members: Should they change plan benefits for statins? Will physicians begin to prescribe the drugs to a new patient population even off-label?

JUPITER showed that apparently healthy individuals with unremarkable levels of low-density lipoprotein cholesterol (LDL-C) but with elevated levels of high-sensitivity C-reactive protein (hsCRP)—2.0 mg/L or more—had a dramatic reduction in the risk for CV events by taking rosuvastatin (Crestor) compared with placebo.

The large benefit of rosuvastatin—a 44% relative reduction in CV risk—surpassed the expectations of the lead investigator, Paul Ridker, MD, Director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital, who has championed the use of hs-CRP to estimate CV risk for quite some time. “Getting CRP down appears to have incremental benefit to lowering LDL cholesterol,” Dr Ridker said. “There was a large number in our

study who had an elevation of CRP without other risk factors, and this group had a benefit from rosuvastatin as well.” Of those who fit the profile of the study population, 25 patients would need to be treated to prevent 1 CV event, which is “smaller than we anticipated,” said Dr Ridker.

Steve Nissen, MD, Chairman of the Department of Cardiovascular Medicine at the Cleveland Clinic, is a believer in CRP testing and is already using it to guide treatment decisions. He noted that the reduction in death and major CV events with rosuvastatin was larger than in any other trial of a statin, and he was impressed that it occurred after only an average of 1.9 years of treatment (the study had been planned to last 5 years but was terminated early because of the large benefit found).

According to Dr Nissen, applying the findings from JUPITER to the US population could add 10 million persons who could benefit from statins.

Critics point out that although the magnitude of the 44% relative reduction in risk was large, the absolute risk reduction was rather small—only 0.9% (1.8% in the placebo group had an event compared with 0.9% in the rosuvastatin group). Of note, subjects enrolled in the trial were at low risk at baseline, and this low risk accounted for the small reduction in absolute risk. Only 157 of 8901 subjects taking placebo had an event compared with 83 of 8901 randomized to rosuvastatin.

Continued

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Continued Using Crestor to prevent 1 death in persons with elevated CRP levels has been estimated at $500,000, a cost that may be too high. Some suggest that prescribing Crestor to reduce CRP could add $8.9 billion to the cost of treatment in this country. But this cost would be reduced to about $25,000 to prevent 1 death, using a generic statin, if generic statins are as effective as the brand drug at reducing CRP levels.

Evidence indicates that all the statins reduce CRP, but to different degrees.

1. Ridker PM, Danielson E, Fonseca FAH, et al, for the JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2195-2207.

Wayne Kuznar Medical Writer

Cholesterol Management: The Complexity of Multiple Effectives Treatments PAYERS: High levels of serum cholesterol have long been recognized as a significant risk factor for the development and progression of atherosclerosis.

Lowering cholesterol has been shown to effectively reduce mortality and morbidity associated with acute coronary syndromes and stroke—2 of the top 3 causes of death in the United States. As our understanding of the role of cholesterol has evolved, we have come to realize the individual effects that low-density lipoprotein (LDL) and high-density lipoprotein can have in risk assessment and modification.

As the authors of this article highlight, a large number of effective treatments are available. The availability of multiple agents adds to the complexity of their use: Are all these agents equal in their ability to affect lipid levels? Are they equal in their ability to influence outcomes? For an individual patient with a specific set of risk factors and a specific lipid profile, which agents will best affect their lipid panel and their overall risk of cardiovascular or cerebrovascular complications?

The availability of several effective treatments also raises questions about thresholds for screening and treatment. A number of organizations have provided such guidance, including the American Heart Association, the National Cholesterol Education Program, the United States Preventive Services Task Force (USPSTF), and the American Academy of Pediatrics. As is often the case for the clinician attempting to determine the best recommendation for a given patient, or for the patient attempting to participate in decision-making—the rapid development of new science and research and the conflicting guidance of expert panel recommendations can compound the confusion. For example, the USPSTF currently recommends screening of patients older than 20 years, citing insufficient evidence for screening younger populations. Meanwhile, a recommen-

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AMERICAN HEALTH & DRUG BENEFITS

dation issued in 2008 by the American Academy of Pediatrics is much more aggressive with regard to screening, and even treatment, of children with certain risk factors.1 This complexity is further increased with the publicity related to the early termination of the JUPITER trial (see previous page), which was published in November 2008.2 In JUPITER, patients without a history of cardiovascular disease, with LDL levels <130 mg/dL but with high-sensitivity C-reactive protein levels of 2.0 mg/L or more, were randomized to receive rosuvastatin or placebo. The trial was ended early because patients in the treatment group showed very significant reductions in myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes. This study will raise questions regarding the thresholds that must be met to initiate therapy. It will also raise issues concerning the relative effectiveness of various agents, depending on their ability to affect “inflammation” as a separate risk factor for atherosclerosis.

Until the evidence becomes clearer, we must empower clinicians facing these decisions with as many options as possible. They must be able to personalize therapy—the best agent for the individual patient—without undue restrictions.

1. Daniels SR, Greer FR; Committee on Nutrition. Lipid screening and cardiovascular health in childhood. Pediatrics. 2008;122:198208.

2. Ridker PM, Danielson E, Fonseca FAH, et al, for the JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008; 359:2195-2207.

Thomas McCarter, MD, FACP Chief Clinical Officer Executive Health Resources

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Promotion of Medical Tourism in the Media Creates a Trend J. Warren Salmon, PhD

W

hether Americans are flocking overseas for medical care remains a question. One estimate put the number at 150,000 in 2006,1 jumping to 750,000 in 2007.2 Nevertheless, the popular press continues to devote articles to this phenomenon that may very well be creating the market.

The Lure The lure of medical tourism for patients is the ability to obtain services for relatively cheap cost, which can help uninsured and underinsured Americans gain access to care; allow richer patients to get services quicker; or enable private health plans to arrange “bargain care” elsewhere for their insured patients. This has fostered a thriving industry in some countries, and the lay press has found such outsourcing a source for attractive stories—“recovering from a medical procedure while lying on a palm-swept beach, relaxing by the hotel pool, or shopping for terrific bargains sounds good.”3 Just a few years ago, medical tourism was depicted as care associated with an exotic vacation or with an attendant spa recovery postsurgery. Yet escalating medical costs began to make the travel portion seem reasonable for those who were denied access at home.

Travel sections of newspapers featured pleased uninsured working and poorer patients who received a much-needed operation at a mere fraction of the US cost. Major publications (eg, New York Times, Los Angeles Times), generally in states bordering the Pacific Rim and Latin America, published stories accompanied by advertisements for touring agencies, and thus began the fledgling middleman industry that generated attention to medicine overseas.

The Los Angeles Times ran articles first examining medical tourism, later denoting its growth, and then marking it as a trend. Articles appeared in Arkansas, Tennessee, Washington, and other states removed from the nonstop airplane routes, as the public gradually became acquainted with travel for healthcare. Fox, CNN, and CBS’s “60 Minutes” ran segments on people Dr Salmon is Professor of Health Policy and Administration, School of Public Health, University of Illinois at Chicago, IL.

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traveling for services. Forbes and the Wall Street Journal focused on the business aspects of the phenomenon, as middlemen aggressively marketed it to consumers, employers, and insurers.

“Hot destinations” came into the spotlight— Singapore, India, Thailand, Mexico, Costa Rica, China, and more. And the base broadened. Europeans opting out of their national health systems, along with wealthy clientele from the Middle East and other regions, were identified as medical tourists. The Internet further facilitated clever marketing campaigns by private providers seeking to service the burgeoning international market.

Cheaper care for dental services, cosmetic interventions, and specialty pharmacy began to be proffered in travel packages to lure patients to providers who arranged “customer care” in luxurious hotels, touting huge savings for “quality care.” Inroads into “bargain surgery” in modern facilities with advanced equipment were made. Lower-cost facelifts, hormone therapy, and the like now appeal to “aging cohorts” in the developed world.

Many of the private hospitals across Asia have English-speaking and American-trained staff, who now can deliver organ and bone marrow transplants, orthopedic, oncology, cardiovascular, and more hi-tech and complex care. In 2007, Forbes’s article “Open-Heart Surgery—90% off!” highlighted the differences in cost and quality of care between the United States and other countries.4 Thus, the media caught the fancy of comparative costs as a way to promote access to affordable healthcare for Americans, including small businesses. The Financial Times and San Francisco Chronicle covered the 2008 Deloitte study, which found that almost 40% of Americans would travel abroad for care, provided that quality appeared comparable with that in the United States.5 People with private insurance were more likely to consider traveling.

In the medical literature, a discussion amongst payers and providers has begun concerning medical tourism. A 2006 New England Journal of Medicine article warned that “American physicians who are concerned about the growth of this phenomenon have two

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choices: they can denounce and attempt to restrict it, or they can lead and more actively support efforts by others to speed the discovery and uptake of more efficient domestic healthcare delivery methods.”6

Policy Concerns Doubts about patient care quality abroad and potential safety issues emerged in the popular press before the professional literature. Can quality be assured? What about complications when returning home? Will follow-up care at home be available? What is the legal recourse in nations without malpractice laws or “a culture” of suing doctors? A series of cautions is clearly needed for an unregulated medical tourism industry.

As the hubs for foreign care are investigated, assurances on such concerns are hard to come by. The USbased Joint Commission International accredits more than 140 hospitals overseas, with a doubling of that number projected in 2 years. But this is by no means a complete safeguard to a botched surgery. Location analyses of provider destinations are necessary, along with specific reviews of providers, the host of entrepreneurial middlemen making travel arrangements, and even the motives and diligence of new US insurers and employers who are looking for potential savings from sending their insured members overseas.

AlterNet raises a concern that medical tourism may pose competition to the US healthcare system: “The problem with turning to medical tourism as an answer to healthcare problems goes beyond personal stories and into the realm of hard policy. There are lots of stakeholders that are eager to trump up medical tourism as a silver bullet for healthcare costs….[Some suggest that ] since insurers and employers can pay less to cover procedures, the US healthcare system will benefit greatly from medical tourism.”7 It will be interesting to see how US payers respond to all this. And how the US government and others

react to this emerging phenomenon will be critical.

Tourism is a trade that is under World Trade Organization consideration. Siphoning off the wealthy to posh concierge care in private health systems overseas and leaving a subpar public sector for the poorer masses pose ethical dilemmas. At a time of rising global epidemics, for developing nations to neglect regulatory directions to preserve and protect their public health is a concern.8 The lay press’ attention to medical tourism has helped to create a new market, spurring entrepreneurial enterprises stateside to facilitate it, as well as setting up a host of private providers overseas to capitalize on this nascent trend. This phenomenon has also provoked issues that force us to reflect on the impact of globalization at home and abroad. ■

References 1. AMA press release. AMA provides first ever guidance on medical tourism. June 16, 2008. http://www.ama-assn.org/ama/pub/category/ 18678.html. Accessed November 3, 2008.

2. Madden CL. Medical tourism causes complications. October 27, 2008. http://www.policyinnovations.org/ideas/briefings/data/000083.

Accessed November 3, 2008.

3. Kaderli B, Kaderli A. Medical vacations: the retiree health-care solution? MotleyFool.com. August 12, 2008. http://www.fool.com/ personal-finance/retirement/2008/08/12/medical-vacations-theretiree-health-care-solution. aspx. Accessed November 3, 2008.

4. Forbes S. Open-heart surgery—90% off! Forbes. August 13, 2007. http://www.forbes.com/columnists/forbes/2007/0813/021.html. Accessed November 3, 2008.

5. Deloitte. Medical tourism: consumers in search of value, 2008. http://www.deloitte.com/dtt/cda/doc/content/us_chs_MedicalTourism Study(1).pdf. Accessed November 3, 2008.

6. Milstein A, Smith M. America’s new refugees—seeking affordable surgery offshore. N Engl J Med. 2006;355:1637-1640.

7. Mahar M. Medical tourism is great—for those who can afford it.

AlterNet. August 21, 2008. http://www.alternet.org/healthwellness/ 95827/medical_tourism_is_great_—_for_those_who_can_afford_it/.

Accessed November 3, 2008.

8. Salmon JW, Aruru M. Health tourism to India: challenges against resource competition to sustaining a viable public health infrastructure for the local populace. Presented at the Annual Expo and Meeting of the American Public Health Association; San Diego, CA; October 27, 2008.

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AMERICAN HEALTH & DRUG BENEFITS

November/December 2008

VOL. 1

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NOT EVERYONE IS CUT OUT FOR THE SAME TREATMENT. 1 in 4 adults suffer from a diagnosable mental disorder in any given year.1

Open Access.

Because different people have different needs.

Open access is especially important in the treatment of mental disorders because the response to therapy can vary greatly from individual to individual and from one medication to the next. Restrictions in the form of prior authorizations and preferred lists may have the unintended consequences of jeopardizing patient health while failing to reduce costs.

Bristol-Myers Squibb supports open and unrestricted access to mental health medications. For people with mental illness, having access to newer and potentially more effective medications can be a crucial component of treatment.

SUPPORT OPEN ACCESS AND GIVE PROVIDERS THE FREEDOM TO FIND THE MOST APPROPRIATE MEDICATION FOR EACH INDIVIDUAL. 1. National Institute of Mental Health. Available at: http://www.nimh.nih.gov/healthinformation/statisticsmenu.cfm.

Accessed August 7, 2006.

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EXECUTIVE SUMMARIES

Erythropoiesis-Stimulating Agents in a Meta-Stable State Interview (Part 2) with Samuel M. Silver, MD, PhD

In this second interview, Dr Silver, director of the Cancer Center Network at the Division of Hematology/Oncology at the University of Michigan Health Systems, focuses on the impact of Medicare coverage decision for erythropoiesis-stimulating agents (ESAs), and why ESAs are so important for patients. He emphasizes the risk of transfusions to cancer patients and why policy decisions that restrict the use of ESAs can have profound implications for patients. Dr Silver, who is also Assistant Dean for Research at the University of Michigan, calls for new studies, to be funded by the manufacturers of the 2 major ESAs, to inves-

tigate the concerns for tumor progression and thromboembolic events that are potentially associated with these expensive medications. Such research could better guide policy decisions by Medicare and improve patient care. Despite the very high cost of the ESAs, the issue of transfusions in cancer patients is beyond economics, Dr Silver says, since they expose patients to unnecessary risks. And although Medicare is not supposed to consider costs in its decisions, cost is an underlying context for coverage decisions, especially for as expensive medications as ESAs, which nevertheless may reduce hospitalization for transfusions, he says.

Role for Automated Communication Strategies in Medication Adherence Management

By S. Michael Ross, MD, MHA

Medication nonadherence is a major cause of morbidity and mortality in the United States. Nonadherence to drug therapy is also a major contributor to escalating costs of healthcare. Lack of information and forgetfulness are 2 main reasons cited by patients for lack of adherence. These 2 causes can be positively influenced by improved patientâ&#x20AC;&#x201C;provider communication, Dr Ross explains. With chronic diseases estimated to involve hundreds of millions of patients, the scale of disease management enrollment is too great to be costeffective using traditional outreach methods. The challenge is to scale outreach programs efficiently, without

losing the personal touch necessary to help change behavior. Using communication automation to augment traditional call center outreach can help to mediate patient medication-taking behaviors. Dr Ross reports results of his new study that involved an automated telephony to 304 elderly patients with hypertension. Using this automated system helped reduce costs and improve the blood pressure monitoring of patients.

In addition to significant improvements in outcomes, 174 patients had their antihypertensive regimen altered based on their responses to the survey part of the automated system.

An Overview of Cholesterol Management

By Robyn A. Burns Schaiff, PharmD, BCPS; Richard M. Moe, MD, PhD; Daniel W. Krichbaum, PharmD

Cardiovascular disease (CVD) remains the leading cause of death worldwide. Hypercholesterolemia and dyslipidemia are significant risk factors for the development of CVD, which affects more than 80 million Americans. A team of 3 experts discusses the relationship between cholesterol levels and the risk of CVD, outlining the National Cholesterol Education Program guidelines for assessment and treatment of dyslipidemia, and summarizing current cholesterol targets. The first goal of therapy in hypercholesterolemia is reduction of low-density lipoprotein (LDL) cholesterol levels.

Evidence shows that statins are the most effective lipidlowering agents available. Drs Schaiff, Moe, and

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Krichbaum provide an extensive drug table that covers all lipid-lowering classes, their mechanisms of action, place in therapy, side effects, as well as costs. Finally, new evidence from the recently published JUPITER study has shown that in addition to lowering lipid levels, statins are important for preventing vascular events in patients with elevated C-reactive protein (CRP) levels, even in those with normal cholesterol levels. A debate is currently raging among experts and decision makers whether persons with normal lipid levels but with elevated CRP levels should be taking a statin on a regular basis. These results may have implications for all health benefit programs.

November/December 2008

VOL. 1

NO. 9