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Come see What Is Possible here. Froedtert Health’s strong partnership with the Medical College of Wisconsin has benefited patients, health care professionals and the region since 1980. With three hospitals and more than 30 primary and specialty care health centers and clinics, the Froedtert & the Medical College of Wisconsin health network provides a work environment where medical and non-clinical professionals can feel encouraged, respected, valued and highly regarded. We are currently seeking Pharmacists for our Froedtert Hospital campus who are committed to helping us maintain our strong reputation for outstanding patient care and innovative medicine.
Froedtert Hospital • Hem/Onc Staff Pharmacist • Staff Pharmacist We are proud to be an Equal Opportunity Employer. As a federal contractor/subcontractor, we take affirmative action in employment based on race, sex, disability and status as a protected veteran. We welcome protected veterans to share their priority consideration status with us at 414-777-1680. We maintain a drug-free workplace and perform pre-employment substance abuse testing.
To learn more about the Froedtert & the Medical College health network and to apply for our Pharmacist positions, please visit froedtert.com/careers.
froedtert.com/careers
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2014
contents
September/October
thecover
6 2014 Immunization Update
pharmacypractice FEATURES
10 WPQC Update: Transitions of Care
13 WPQC Operations: How to Improve CMR/A Acceptance Rates: Tips From the Field and From Patient Mini-Focus Groups
18 Journal Series: Statistics Review Part 7: Case-Control and Cohort Studies
21 Pharmacotherapy Perspectives: Considerations for Selecting Anticoagulation Therapy for Patients with NonValvular Atrial Fibrillation
67 S pecialty Pharmaceuticals: Oral Disease Modifying Agents for Multiple Sclerosis
correspondence
3 Up Front:
4 M ember Viewpoints: “How are pharmacy technicians at your site taking on new roles?”
72 C ommentary: The Price to Save a Life: Pharmacists’ Role in the Growing Area of Specialty Drugs
PSWnews
20 Announcements: New Members
25 Drug Updates: Oral Anticancer Agents
30 C E for Pharmacists: Statins, Statins, and More Statins and JNCF Better Late Than Never?
70 Open Letter to the WI Pharmacy Community: Comments From Jeanette Roberts
71 Meet the Deans
42 C E for Technicians: Specialty Pharmacy and the Role of the Pharmacy Technician
Advertisers, PSW Calendar
originalcontributions
47 An Integrated Care Approach to Specialty Pharmacy
50 University of Wisconsin School of Pharmacy Student Writing Club: Immunizing the Immunosuppressed: Recommendations for Vaccinating Patients on High-Level Immunosuppressive Therapy
52 PSW Pharma-Athletes Part II
54 What's New in Pulmonary Hypertension in 2014?
60 H uman Papillomavirus: A Brief Overview and Recommendations for Pharmacists
64 P harmacist Involvement in Cardiac Rehabilitation Programs in Wisconsin
Pictured: 2014 Immunization Update PAGE 6 On the Cover: Specialty Pharmacy Specialty Pharmacy and the Role of the Pharmacy Technician PAGE 42 An Integrated Care Approach to Specialty Pharmacy PAGE 47 Specialty Pharmaceuticals: Oral Disease Modifying Agents for Multiple Sclerosis PAGE 71
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The Journal of the Pharmacy Society of Wisconsin is a professional publication for original research, review, experience, and opinion articles that link science with contemporary pharmacy practice to improve patient care. Together we can inspire each other to advance our profession with the single purpose of enhancing the lives of our patients. Editor ANNA LEGREID DOPP, PharmD, annad@pswi.org Managing Editor MEGAN GRANT, mgrant@pswi.org Peer Review Coordinator AMANDA MARGOLIS, PharmD, MS
PSW Executive Board MIKE BETTIGA, RPh Chairman of the Board
DEAN GRUBER, RPh Treasurer
PATRICK CORY, PharmD President
CHRISTOPHER DECKER, RPh Executive Vice President & CEO
MIKE GRUNSKE, PharmD, BCPS President-Elect
PSW Board
Editorial Advisory Board LEENA AMINE, PharmD Clinical Pharmacist, University of Wisconsin Hospital and Clinics, Madison
SUSIE MORONEY, PharmD, MS Regional Scientific Director in Immunology, Novartis, Fitchburg
JOANNE ANTONOPOULOS, PharmD, BCPS Pharmacist, Froedtert Hospital, Milwaukee
GRETA NEMERGUT, PharmD Clinical Pharmacist, University of Wisconsin Hospital and Clinics, Madison
KASSANDRA BARTELME, PharmD, BCACP Assistant Professor of Pharmacy Practice, Concordia University Wisconsin School of Pharmacy, Mequon
MIKE OCHOWSKI, RPh, BBA Formulary Pharmacist, Group Health Cooperative of South Central Wisconsin, Madison
CARRIE BOECKELMAN, RPh Manager, Ambulatory Pharmacy Services, University of Wisconsin Hospital and Clinics, Madison
ROHAN PRADHAN, PharmD Clinical Pharmacist, University of Wisconsin Hospital and Clinics, Madison KATHERINE ROTZENBERG, PharmD Drug Information Pharmacist, St. Mary’s Hospital, Madison
JANE S. BUBIK, PharmD Drug Information/Investigational Drugs Coordinator, Aurora St. Luke’s Medical Center, Milwaukee
RYAN SERVAIS, PharmD, BCPS Clinical Pharmacist, Aurora St. Luke’s Medical Center, Milwaukee
LOREN CARRELL, PharmD Clinical Pharmacist/Pharmacist in Charge, Gundersen Health System, La Crosse
TRISHA SEYS RANOLA, PharmD, CDE Home Based Primary Care Clinical Pharmacist, William S. Middleton Memorial Veterans Hospital, Madison
ANN EBERT, PharmD Perinatal Clinical Specialist, Meriter Hospital, Madison
ANTHONY G. STARESINIC, PharmD Clinical Pharmacy Consultant, Physicians Plus Insurance, Madison
ASHLEY FELDT, PharmD, MBA Manager, Inpatient Pharmacy, Aurora St. Luke’s Medical Center, Milwaukee
AARON L. STEFFENHAGEN, PharmD, BCPS Pharmacy Manager, Patient Care Services and JEFFREY FISH, PharmD, BCPS Emergency Preparedness, University of Wisconsin Senior Clinical Pharmacist, University of Wisconsin Hospital and Clinics, Madison Hospital and Clinics, Madison KATIE VALDOVINOS, PharmD, BCPS DAVE GRINDER, RPh, MS Assistant Professor of Pharmaceutical Sciences, Director of Pharmacy, Monroe Clinic, Monroe Concordia University Wisconsin School of Pharmacy, Mequon JULIE KARPINSKI, PharmD, BCPS Drug Information Pharmacist, Pharmacy/ PAUL WINDISCH, PharmD Drug Policy, Froedtert & The Medical College System Coordinator - Drug Use Policy, Aurora of Wisconsin, Milwaukee Health Care, Milwaukee JUSTIN PAUL KONKOL, PharmD, BCPS Clinical Pharmacy Manager, Froedtert & The Medical College of Wisconsin, Milwaukee
AARON STEFFENHAGEN, PharmD, BCPS Region A Director 2013-15
JAKE OLSON, PharmD Director-at-Large 2014-16
RANDOLPH MILLER, RPh Region B Director 2014-16
TAMARA RAVN, PharmD Director-at-Large 2013-15
JILL MICHAUD, PharmD, BCPS Region C Director 2013-15
MELISSA THEESFELD, PharmD Director-at-Large 2014-16
GEORGE GOSZ, RPh Region D Director 2014-16
DEAN ARNESON, PharmD, PhD Dean Concordia University Wisconsin
NICHOLAS OLSON, PharmD, BCACP, AAHIVP Region E Director 2013-15
STEVE SWANSON, PhD Dean UW School of Pharmacy
MICHAEL GILLARD, PharmD, BCPS Region F Director 2014-16
MARIA WOPAT, PharmD, BCACP, TTS Senior & LTC Section Chair 2014-2015
JORDAN DOW, MS, PharmD Director-at-Large 2013-15
BONNIE CHAON, CPhT Technician Section President 2014-2015
VANESSA FREITAG, PharmD Director-at-Large 2014-16
BRIDGET ELLERMAN CSPA Liaison
JANET FRITSCH, RPh Director-at-Large 2013-15
KRISTIN WIDMER President WSPS
PSW Staff JESSICA BENJAMIN, PharmD ELLEN BRUMMEL ANNE CORY, MBA CHRISTOPHER DECKER, RPh ANNA LEGREID DOPP, PharmD ERIKA HORSTMANN, PharmD MEGAN GRANT EJA LARICO JOYLYN MOORE, PharmD
CHAD NECHVATAL, CPA ANH NGUYEN, PharmD, BCACP SARA LYNN PETERSON, PharmD LAURA RICHARDS KAY SCHELL KATHLEEN SKIBINSKI, MS, RPh SARAH SORUM, PharmD KARI TRAPSKIN, PharmD
Send correspondence to: Anna Legreid Dopp, PharmD, Pharmacy Society of Wisconsin, 701 Heartland Trail, Madison, WI 53717, phone: 608-827-9200, fax: 608-827-9292, thejournal@pswi.org Authors are encouraged to submit manuscripts to be considered for publication in The Journal. For Author Guidelines, see http://www.pswi.org/Get-Involved/Publish-articles-in-The-Journal Advertising inquiries: Megan Grant, Pharmacy Society of Wisconsin, 701 Heartland Trail, Madison, WI 53717, phone: 608-827-9200, fax: 608-827-9292, mgrant@pswi.org
JENNIFER ZIMMER-YOUNG, PharmD, CCRP Educator, Clinical Pharmacist, ThedaCare, Appleton
AMANDA MARGOLIS, PharmD, MS Clinical Pharmacist, William S. Middleton Memorial VA, Madison & Assistant Researcher, UW-Madison School of Pharmacy, Madison
The Journal of the Pharmacy Society of Wisconsin (ISSN 1098-1853) is the official publication of the Pharmacy Society of Wisconsin. Subscription included in membership dues. Non-member subscription $90 per year. Outside North America, add $60. Single copies $25 ($50 if outside North America). Periodical postage paid at Madison, WI and additional offices. Published bimonthly by the Pharmacy Society of Wisconsin, 701 Heartland Trail, Madison, WI 53717. Postmaster: Send address changes to PSW, 701 Heartland Trail, Madison, WI 53717. Opinions expressed by contributors do not necessarily reflect those of PSW.
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Up Front:
Grassroots Advocacy: Next Steps
B
y the time you receive this issue of The Journal, elections will be less than 65 days away. In anticipation of the 2015-2017 budget and legislative session, PSW is working hard on your behalf to communicate budget needs, craft policy agendas, and identify grassroots advocacy strategies. The purpose of this UpFront column is to share some exciting news on efforts to more efficiently and effectively engage and grassroots advocates. PSW has launched our first ever grassroots advocacy system. This will allow us to build advocacy campaigns for state and federal legislative and regulatory issues and mobilize our members to communicate with targeted government officials. Once you register with your home address, the system will connect you with your state and federal elected officials. We will provide a briefing on the issue and a sample message that can be edited prior to sending. To find it on our website, go to the Advocacy Tab and select “PLAN Grassroots Advocacy.” On this page, you can find links to PSW's advocacy campaigns and look up your officials based on your home zip code and street address. Once you walk through the steps and register with the system, it will remember you the next time you act on an advocacy campaign.
I urge you to access and register for the system today. There is one advocacy campaign loaded for you to act on which aims to garner support for cosponsorship of the Federal Provider Status Legislation, H.R. 4190. By clicking "Take Action," you will find a page that provides some guidelines for formatting your message and talking points for H.R.4190. Further below on the page is a sample message for you to edit and send to your U.S. Representatives. Please note that this message will NOT be sent to Representatives Pocan and Moore as they have already cosponsored H.R.4190; upon clicking submit, you will receive an alert indicating that your message was not sent. However, there is merit in you walking through the steps so that your information is saved in the system, despite a message not being sent to them. After editing your message and providing an optional customized signature, enter in your email and zip code and click continue to enter the necessary information to link you with your elected official(s). By selecting the boxes to receive future alerts and remember you, you will only need to complete this step one time. This is an exciting opportunity to leverage our advocacy efforts and make your voice heard. More advocacy alerts will be added in early 2015 as the Federal and State legislative activity increases!
—Anna Legreid Dopp Vice President of Public Affairs and Editor of The Journal
M
y name is Megan Grant and I am the new Manager of Marketing, Communication and Design at the Pharmacy Society of Wisconsin. I recently graduated from the University of Wisconsin-Platteville where I earned my Bachelor’s degree in media studies with an emphasis in imaging media and a minor in public relations. I also have an Associate of Art degree from Highland Community College in Freeport, Ill. Originally from a small town in Illinois, the move to Madison was a big change for me but I have grown to really love Madison and the many differnt activities and places to visit. Besides grauating, relocating to Madison, and starting my new job, I also got married to my best friend, Ethan Grant on August 9, 2014 at the Mississippi River Museum in Dubuque, Iowa. My first few months at PSW have been busy ones, but I could not have asked for a better job, with better people to work with. The PSW staff and members have made me feel welcome and I am so grateful for all of their suppport. I look forward to many years working with PSW and its wonderful members. —Megan Grant Manager of Marketing, Communication & Design
Erratum: There were two errors in the printed July/August issue that we would like to bring to your attention. Both errors were in the “Managing Pain, One Pearl at a Time” article found on page 34. The first was an omission of an author from the pearl, “Does perioperative intravenous acetaminophen reduce opioid and antiemetic utilization 24-hours post-operatively?” In addition to Jennifer Tempelis, Justin Martin, PharmD also contributed to this article. Second, a table was erroneously deleted from the pearl, “Implementing The Joint Commission Sentinel Event Alert: Safe use of opioids in hospitals.” Both errors have been corrected on the electronic version of the issue and can be found on the PSW website at http://pswi.org/thejournal. www.pswi.org
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correspondence “How are pharmacy technicians at your site taking on new roles?” Editor’s note: In each issue of The Journal, PSW features Member Viewpoints – PSW member responses to key questions. Stay tuned to Fast Facts and the PSW Facebook page to weigh in on future questions.
Berook Addisu, PharmD, BCPS Associate Chief, Pharmacy Service William S. Middleton Memorial Veterans Hospital, Madison
This year we have created two new pharmacy technician roles: Medication History Technician and Clinical Pharmacy Technician. The Medication History Technician compiles an accurate outpatient medication list via interview, EMR review, and contacting outside organizations (e.g. pharmacies). The technician is responsible for identifying and documenting discrepancies between the prescribed outpatient regimen and how the patient was taking their medications pre-admission. The Clinical Pharmacy Technician just started this month and will provide clinical and clerical support to our outpatient anticoagulation service. This will include managing therapeutic INR patient encounters, providing telephone triage support, and assisting with various administrative duties. Rebecca Bryan, RHIT, CPhT Project Manager – Pharmacy Gundersen Health System, La Crosse
Pharmacy technicians hold an important role in our organization, as Clinical Informaticists. This group of pharmacy technicians, many who are CPhT, work closely with the Information Systems Pharmacy team and hospital and clinic pharmacies. The Clinical Informaticists possess solid pharmacy knowledge,
understanding of pharmacy operations, pharmacy state and federal laws, and have a solid understanding on workflows. This aligns the pharmacy technician to move into the pharmacy information systems role and places them in a position to succeed, create efficiencies, manage pharmacy applications, and tie the information systems world into pharmacy. This advanced role allows them to remain close to the pharmacy world while advancing their careers. Michelle Farrell, PharmD Pharmacist/Owner Boscobel Pharmacy, Inc., Boscobel
My entire staff has flexed with role changes as technology and pharmacy needs have evolved. My pharmacy assistants have become versed at verifying multiple identifiers in triaging customers and prepping pharmacists for consultation. My pharmacy technicians demand multiple identifiers to avoid safety concerns while learning to flag intervention opportunities for WPQC. Additionally, my technicians and pharmacy assistants have learned to properly read blood pressures, check blood glucose, and check weights. Finally, my pharmacy technicians are reviewing medication profiles and documenting medication changes and lab data in software platforms. All of this has been incredibly helpful in our successful implementation of WPQC.
Staci Schnaderbeck, RPh Clinical Pharmacist Aurora Pharmacy, Oshkosh
My clinic pharmacy collaborated with the inpatient pharmacy and the hospital to start a discharge program. At time of discharge, the nurse sends prescriptions through the hospital tube system to our clinic pharmacy. Our technicians prepare the orders as if the patient was here waiting. Once checked by the pharmacist, the tech calls the patient for payment information and hands the phone to a pharmacist for counseling. The tech processes the order through the register and hand delivers the meds to the patient’s room. The tech gets a patient signature and makes sure they have no questions before leaving. Bonnie Niemuth, CPhT Pharmacy Application Support Tech Aurora Health Care, Milwaukee
I am a pharmacy automation implementation and management technician. Some of my tasks include maintaining matching formularies between our HIS, Carousels, and ADS systems, setting up and installing new equipment or software, staff training for pharmacy and caregivers on new equipment or changes in software. I work closely with inpatient pharmacy managers to find ways to improve efficiencies in work flow thru use of automation. I also gather and review data to help identify areas where inventory adjustments can be made to reduce redundant refills, as well as reduce excessive cost due to overstock.
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Jill Senkerik, RPh Pharmacy Manager Pulaski Health Mart Pharmacy, Pulaski
Our techs are starting the paperwork whenever we need to contact physicians for 90 day supplies. They also will put the pediatric dosing slip with the pediatric medication prescriptions and fill out whatever they can from the prescription. If the pharmacist has to do a formulary change due to allergy, interaction, etc. they will also fill out what they are able to on our paperwork. One tech weekly does the billing for everything we documented. They also will put the paperwork in with the prescription if they notice a very late or early refill on a maintenance medication or if a patient is getting a first time device like an inhaler is prescribed. They also will try to get a brief patient history at the drop off window for new patients. Jamie Statz-Paynter, RPh Pharmacy Administrative Manager Dean Clinic, Madison
Dean has five different areas where pharmacy technicians work. Dean Clinic Corporate Office (DCCO) has seven technicians. One technician oversees the scheduling and training of 66 pharmacists/technicians across eight locations. One technician oversees reconciliation of all insurance claims and audits. One technician oversees adherence to contract terms and looks for MTM opportunities. One technician facilitates resolution of problems relating to computer hardware/software, IVR, printers, scanners, robotics, counting technology and POS system. Three pharmacy technicians remotely process multiple pharmacy site prescriptions using CIM to ensure the correct NDC is chosen. In addition they pend refill requests within Epic EMR to decrease calls or faxes to Dean Providers. www.pswi.org
All technicians at DCCO oversee their dayto-day activities with minimal pharmacist direction. Dean Clinic Medication Warehouse has three technicians who are responsible for obtaining all medications used within 60 Clinics. They work closely with departments for critical medications to maximize inventory turns while ensuring contract rates for volume based purchasing. They maximize value for our drug spend and with clinical committees for medication use, storage, and record keeping. Dean Clinic Pharmacy technicians are liaisons for insurance, coordination of benefits, prior authorizations, formulary, and vaccine billing. They utilize Epic for patient’s weight, labs, diagnosis, renal function and WIR for vaccine history. They contact alternate vendors if drug shortages exist. They compound prescriptions under pharmacist oversight. They help identify MTM opportunities which allow pharmacists more time to perform MTM services. They are the face of the pharmacy to patients and clinic staff. Dean Clinic Sterile Product technicians prepare sterile products for patient infusions and support nursing and provider staff with pharmaceutical inventory management. When they work in the regional clinics, Dean Pharmacists check their work via telepharmacy with a live camera and audio connection to our centralized oncology and infusion pharmacies in Madison. They work within Epic to complete patient charging and drug waste billing. They are involved with patients and insurers for our oral chemotherapy monitoring program in conjunction with the oncology pharmacists. Dean Specialty Pharmacy has two technicians who ensure all patients receive high level of standardized care from initial pharmacist training to the last refill. They manage patient refill scheduling to ensure patients receiving their medications before starting their next course of medication. They provide new patients with information regarding manufacturer programs, injection assistance, starter kits, on-call nursing programs, and adherence tools. Dean pharmacy technicians are a valued member of the Dean team and our pharmacists would not be able to have moved into new roles without them.
Mark Jacobs, RPh Vice President of Operations PAAS National, Stoughton
At PAAS National, pharmacy technicians are really using their skills to their fullest by consulting and teaching member pharmacies on correct filling and billing procedures, plan compliance issues, insurance audit preparation, and strategies for appeal. Pharmacy technicians are some of the most knowledgeable professionals when it comes to insurance and other provider requirements. Many insurance auditors will also place an emphasis on compliance with state and federal law. Some of the information our pharmacy technicians provide was traditionally reserved for pharmacists. Now, in their new role, technicians are expected to be knowledgeable on pharmacy regulations and must be familiar with both state and federal law in order to guide pharmacists who are concerned with audit compliance.
November/December 2014 Member Viewpoints Question:
How have you implemented a culture of medication safety in your pharmacy/ institution? To submit a response, please email Sarah Sorum at sarahs@pswi.org. Accompanying your response should be a high resolution headshot (preferably a minimum of a wallet size at 300 dpi or greater). Deadline to submit a response is September 21st.
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2014 Immunization Update by Mary S. Hayney, PharmD, MPH, FCCP, BCPS
T
he 2013 Adult Immunization Survey conducted by the American Pharmacists Association showed that almost 90% of immunizing pharmacies administered influenza vaccine.1 Almost as many also administered pneumococcal and zoster vaccines. Pharmacists, and all adult immunization providers, give many doses of influenza vaccine but should take advantage of the opportunity to increase adult immunization rates by offering other vaccines at all times of the year. The National Vaccine Advisory Committee published updated standards of practice for adult immunization in early 2014.2 Although administering the vaccine is the event that improves adult immunization rates, the updated standards challenge all health care providers to assess
The Affordable Care Act and Immunization
The Affordable Care Act (ACA) requires that insurers provide certain preventative services without any patient and recommend immunization during cost sharing (co-payments, deductibles, or every patient contact. An emphasis is also co-insurance), also known as “first dollar placed on use of immunization information coverage”.3 Routine adult immunizations systems, also called immunization registries. for which coverage is specifically required Health care professionals should know how includes influenza, meningococcal, tetanusto access the Wisconsin Immunization diphtheria or tetanus-diphtheria-acellular Registry (WIR, pronounced “were”) for pertussis, human papillomavirus (HPV), client records, and immunizers should pneumococcal, hepatitis A, hepatitis B, and enter immunization records in the WIR so zoster vaccines. 4 that they are available to other health care Interestingly, these requirements do not providers and others with look-up privileges. replace Medicare Parts B or D coverage for For information on using the WIR at your vaccines for individuals over 65 years of pharmacy, visit http://www.dhs.wisconsin. age. Note that an economic advantage is gov/immunization/wir.htm. Pharmacyavailable to the individual who seeks zoster based immunization services likely fully vaccine between the ages of 60 and 64 years. practice within the standards. However, all After the individual is eligible for Medicare immunizers should examine their practices Part D, he will likely be required to make a by reading the document. copayment for zoster vaccine. This annual immunization update is Another peculiar feature of the program a compilation of recent changes in the is that no coverage for HPV vaccines immunization field. for males is required. The Advisory
FIGURE 1. VACCINE COVERAGE RATES AMONG PRESCHOOL-AGED CHILDREN – UNITED STATES, 1967-20125
Abbreviations: DTP/DTaP = diphtheria, tetanus, pertussis or diphtheria, tetanus, acellular pertussis; MMR = measles, mumps, and rubella; Hib = Haemophilus influenzae type b; Hep B = hepatitis B; PCV = pneumococcal conjugate vaccine; RV = rotavirus vaccine; Hep A = hepatitis A. Sources: United States Immunization Survey (1967–1985), National Health Interview Survey (1991–1993), and National Immunization Survey (1994–2012). No data are available for 1986–1990. * Children in the United States Immunization Survey and National Health Interview Survey were aged 24–35 months. Children in the National Immunization Survey were aged 19–35 months. † Numbers in parentheses refer to the number of doses of that vaccine being tracked in this figure. § For rotavirus vaccine, 2 or 3 doses are tracked, depending on the type of rotavirus vaccine received.
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FIGURE 2. Mumps
Population of 1000 Two doses of mumps vaccine 70% One dose of mumps vaccine 25%
Mumps outbreak
Unimmunized 5%
70% of unimmunized get mumps
35 cases
36% of those with single dose get mumps
90 cases
10% of those with 2 doses get mumps
70 cases
Mumps immunization paradox. More cases of mumps occurred among the immunized children. However, the infection rate is dramatically higher among the unimmunized individuals and the individuals who received only one dose of mumps-containing vaccine.
Committee on Immunization Practices (ACIP) recommendation for routine HPV immunization of males for HPV was made after the ACA was passed. As of yet, no provision for updating the coverage has been determined. Coverage of these services is required of private insurers including self-insurers with few exceptions. These private insurers can choose to cover immunization services in pharmacies. The extent to which insurers offer this coverage to their clients is variable. Patients or pharmacy staff may have to contact the plans to determine the process. Patient cost is often cited as a barrier to appropriate use of preventative services.3 Although this first dollar coverage does not replicate the Vaccines for Children Program exactly, it is a good start toward such. Historically, the Vaccines for Children Program is temporally associated with a move toward very high childhood immunization rates (Figure 1.).5 Pharmacy-based immunization services are poised to help deliver this important preventative service. However, at least two issues need resolution: 1) the variability in the willingness of private insurers to pay for immunization services in pharmacies, and 2) a plan to update the vaccines for which coverage is required.
Mumps Outbreak
A mumps outbreak is percolating in Wisconsin. Almost 60% of the 55 cases so far have occurred in college students. Clinical cases of mumps are defined by www.pswi.org
parotitis or other involvement of the salivary gland or a complication of mumps infection. With increasing improvement in diagnostic technology, polymerase chain reaction (PCR) confirmation is required for mumps cases in the current outbreak. Although a much larger outbreak occurred in 2006 (842 cases), many clinicians may not be familiar with its clinical presentation. In the prevaccine era, an estimated 20% of cases were asymptomatic. In the postvaccine era, experts assume that the incidence of asymptomatic infections is higher in immunized individuals.6 Most of the cases reported thus far have been in individuals who were immunized. Although waning immunity following mumps immunization is a hypothesis that is being investigated, the effectiveness of a single dose of mumps vaccine is less than 80% with improvement up to about 90% with a second dose.6,7 Because immunization rates are high in this population, the case count shows most people who have mumps were immunized. Counting cases without considering the denominator is misleading (Figure 2.). The ACIP compiled and published an updated recommendation for control of mumps last year.6 Universal mumps immunization has been recommended since 1977 for all individuals born on or after January 1, 1957. During the large multistate outbreak in 2006, the ACIP redefined evidence of mumps immunity to include two doses of a mumps-containing vaccine for school-aged children and adults at high
risk. Adults at high risk are those who work in health care, international travelers, and students at post-high school educational institutions.6 The ACIP also recommends immunization of health care workers born prior to 1957 without other evidence of immunity during outbreaks. Many individuals received two doses of a mumpscontaining vaccine as part of complying with the recommendation for two doses of a measles-containing vaccine.6 The Wisconsin Immunization Program compiles periodic reports on the mumps outbreak to keep clinicians informed. This information about the evolving mumps outbreak is sent to the PSW immunizing pharmacist listserv. TABLE 1. Abbreviations ACA
Affordable Care Act
ACIP
Advisory Committee on Immunization Practices
HPV
Human papillomavirus vaccine
LAIV
Live attenuated influenza vaccine
MMR
Measles-mumps-rubella vaccine
Increased Number of Measles Cases in United States Endemic measles was eliminated from the United States in 2000. This means that sustained measles transmission was interrupted, and recent cases of measles have been imported by international
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travelers. However, as of June 1, 2014, almost 300 cases of measles have been reported to public health authorities.8 This is the most cases that have been reported since the elimination of measles; almost all of these cases are linked to an international importation. Eighteen states, including Wisconsin, have reported cases. Although some of the individuals who have contracted measles are too young for immunization, about 85% of those with measles infection refused immunization on religious, philosophical, or personal beliefs. Immunization rates are sufficiently high to ward off widespread measles. However, geographic variation in immunization coverage permits local outbreaks to occur.8 Because of the highly contagious nature of measles, diligent attention to maintaining high immunization rates is necessary. Assurance of immunity to measles prior to any international travel is a high priority (Table 1.). In addition, infants aged 6-11 months should receive a dose of measlesmumps-rubella vaccine (MMR) prior to international travel. This dose should not be counted as their first dose. Rather, they should receive MMR vaccine according to TABLE 2. Presumptive evidence of immunity to measles Two doses of measles-containing vaccine administered after age 12 months and at least 4 weeks apart (One dose for preschool children or adults not at high risk) Laboratory-evidence of immunity Laboratory confirmation of disease Birth before 1957 Reference 6
the usual childhood immunization schedule with a dose at age 12 months and a second dose at age 4-6 years.6
Which Influenza Vaccine to Choose
Recent vaccine developments have brought clinicians several options for influenza immunization. Although a few clients will ask for a specific preparation, the choice of product is left to the clinician most of the time. The ACIP has given little guidance regarding which preparation should be used for specific patient populations until now. At their June 2014 meeting, the ACIP recommended that live attenuated influenza vaccine (LAIV) preferentially be administered to healthy children aged 2-8 years when it is available.9 Use of LAIV provides several advantages over inactivated influenza vaccine, as shown in head-to-head comparative studies.10 Indeed, LAIV resulted in fewer influenza cases in vaccine-naive children receiving either two doses or one of the two intended doses compared with trivalent inactivated influenza vaccine. Vaccination with LAIV also had higher rates of efficacy compared with trivalent inactivated influenza vaccine in children who were immunized in previous seasons. It demonstrated higher efficacy when circulating H3N2 strains were mismatched with the vaccine. Finally, the duration of protection with LAIV was greater than trivalent inactivated influenza vaccine.11 The results should not be extrapolated to adults. In fact, LAIV may provide equal or poorer protection compared with trivalent inactivated influenza vaccine in adults.12 Although these studies have shown the superiority of LAIV
over inactivated influenza vaccines in young children, the behavior of future influenza viruses is impossible to predict. Recognize that these studies were done when both vaccines were trivalent preparations. However, the potential advantages of LAIV, including that all doses are quadrivalent, over trivalent inactivated influenza vaccine should be considered when vaccinating healthy children, as LAIV may provide better protection in this vulnerable population. Again this season, LAIV is available only as quadrivalent vaccine. Although many preparations of inactivated influenza vaccine are quadrivalent, some trivalent vaccine is still available. Influenza B is a particular threat to infants, children, and young adults. Infection with influenza B is a significant cause of clinic visits, hospitalizations and death within all age groups.13 Hospitalization may be more common in pediatric patients infected with type B influenza than type A.14 The B viruses cause approximately 20-25% of infections and lead to influenza epidemics every 2 to 4 years, making adequate protection from both strains vital in prevention of seasonal influenza. The use of LAIV for healthy children aged 2-8 years makes the quadrivalent choice automatic. When a child with asthma or another chronic condition presents for immunization, choose quadrivalent inactivated influenza vaccine for him. This recommendation goes beyond the current recommendations of the ACIP which is to choose LAIV for healthy children aged 2-8 years when it is available.
Commit to Change
A well-known, but poorly implemented practice to increase adult immunization includes a strong recommendation from a health care provider. Patients value your recommendation; they will follow your advice. Additionally, access to immunization is associated with increases in immunization rates. Pharmacy-based immunization services increase access, but certainly not without the strong recommendation for immunization just mentioned. Finally, decreasing the cost of adult immunization can increase uptake. The Affordable Care Act with its coverage of preventative services, including immunization, makes significant strides.15 With these three important interventions, the first—a strong
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recommendation for a vaccine today—is the one that pharmacists can adopt and incorporate into their practices today. Commit to recommending vaccines at every patient contact. ● Mary S. Hayney is a Professor of Pharmacy (CHS) at the University of Wisconsin School of Pharmacy, Madison, WI.
References
1. American Pharmacists Association. Annual pharmacy-based influenza and adult immunization survey 2013. Final Report—December 15, 2013 http://www.pharmacist.com/sites/default/files/ files/Annual%20Immunization%20Survey%20 Report.pdf Accessed July 10, 2014. 2. National Vaccine Advisory Committee. Recommendations from the National Vaccine Advisory Committee: Standards for adult immunization practice. Public Health Reports 2014;129:115-23. 3. The Henry J. Kaiser Family Foundation. Preventive services covered by private health plans under the Affordable Care Act. Focus on Health Reform. Menlo Park, CA: The
Kaiser Family Foundation; 2011. 4. U.S. Department of Health & Human Services. The Affordable Care Act and immunization. http://www.hhs.gov/healthcare/ facts/factsheets/2010/09/The-Affordable-Care-Actand-Immunization.html Access July 11, 2014 5. Centers for Disease Control and Prevention. Benefits from immunization during the Vaccines for Children Program era--United States, 1994-2013. MMWR Morb Mortal Wkly Rep 2014;63:352-5. 6. Centers for Disease Control and Prevention. Prevention of measles, rubella, congenital rubella syndrome, and mumps, 2013. Summary recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2013;62:1-33. 7. Harling R, White JM, Ramsay ME, et al. The effectiveness of the mumps component of the MMR vaccine: a case control study. Vaccine 2005;23:4070-4. 8. Gastanaduy PA, Redd SB, Fiebelkorn AP, et al. Measles--United States, January 1-May 23, 2014. MMWR Morb Mortal Wkly Rep 2014;63:1-4. 9. Centers for Disease Control and Prevention. Advisory Committee on Immunization Practices (ACIP) recommends a preference for using the nasal spray flu vaccine. Press release. June 25, 2014. http:// www.cdc.gov/media/releases/2014/s0625-acip.html 10. Ambrose CS, Wu X, Knuf M, Wutzler
P. The efficacy of intranasal live attenuated influenza vaccine in children 2 through 17 years of age: A meta-analysis of 8 randomized controlled studies. Vaccine 2012;30:886-92. 11. Ambrose CS, Wu X, Belshe RB. The efficacy of live attenuated and inactivated influenza vaccine in children as a function of time postvaccination. Pediatr Infect Dis J 2010;29:806-11. 12. Ambrose CS, Levin MJ, Belshe RB. The relative efficacy of trivalent live attenuated and inactivated influenza vaccines in children and adults. Influenza and Other Respiratory Viruses 2011;5:67-75. 13. Hite LK, Glezen WP, Demmler GJ, Munoz FM. Medically attended pediatric influenza during the resurgence of the Victoria lineage of influenza B virus. Int J Infect Dis 2007;11:40-7. 14. Simonsen L, Fukuda K, Schonberger LB, Cox NJ. The impact of influenza epidemics on hospitalizations. J Infect Dis 2000;181:831-7. 15. Centers for Disease Control and Prevention. Improving influenza and pneumococcal polysaccharide, and hepatitis B vaccination coverage among adults aged <65 years at high risk. A report on recommendations of the Task Force on Community Preventative Services. MMWR Morb Mortal Wkly Rep 2005;54:1-11.
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pharmacypractice feature
WPQC UPDATE:
Transitions of Care By: Beth Gribble, 2015 PharmD Candidate, and Kari Trapskin, PharmD
S
everal gaps have been identified in transitions of care from the inpatient or long term care settings to the outpatient setting, which can often result in poor patient outcomes and decreased quality of care.1,2 Many moving parts play imperative roles in maintaining a certain standard of care while discharging a patient from the hospital or long term care facility, which is why Transitions of Care (TOC) continues to be an important topic for the WPQC program to focus on.3 This article highlights efforts that WPQC and PSW are making to increase awareness and quality of care in this area.
Role of WPQC Level II Services in Transitions of Care Community pharmacists are often seen well before patients follow up with their primary care providers after hospital or nursing home discharge.4 WPQC-certified pharmacists have the ability to serve recently-discharged patients in a unique way by providing WPQC Transition of Care (TOC) services. By having the opportunity to sit down with these patients to discuss changes that took place during and after the hospitalization or time in the nursing home, WPQC pharmacists can perform medication reconciliation, assess how well the patient understands medication changes to be implemented at home, provide tools for the patient to aid adherence and provide vital communication with other care providers to ensure continuity of care for the patient. Though the TOC service is a Level II service, there are some important differences between the standard Level II Comprehensive Medication Review and Assessment (CMR/A) service and the TOC service. Recent clarification of the service by the WPQC Steering Committee provides exciting opportunities for WPQC pharmacists and Wisconsin patients.
of Care service within 14 days of discharge from the hospital or long term care facility. The TOC service is considered a Level II service, but no follow-up visits are granted for this service. Therefore, the TOC services do not count against the other CMR/As the patient may have received. Specific payer limitations may apply to the number of UA's available to the patient throughout the year. Please use the recently updated/clarified policy summary of the TOC service found below to help identify patients that could benefit from this service. Who can receive the Transition of Care Service? • Any patient (or patient’s caregiver) discharged from the hospital or long term care facility (LTCF) covered by a participating payer can receive this service, as long as it is provided within 14 days of the date of discharge. • Service can be performed each time the patient experiences a discharge from a hospital or LTCF; it is a stand-alone service (no follow-up visits attached). Specific payer intervention limits may apply. • Transition of Care Services may only be performed by a WPQC-certified
pharmacist affiliated (directly or indirectly) (please refer to the WPQC Policy on Non-traditional Pharmacy Sites) with a WPQC-accredited pharmacy where the patient’s medications are filled on a routine basis. The exceptions are: ˏˏ Patients who do not fill their medications routinely at a WPQC-accredited pharmacy (i.e. mail order, no prescriptions filled previously) may receive the service from a WPQC-accredited pharmacy. ˏˏ If the patient plans to fill their medications in the future at the WPQC-accredited pharmacy offering this service, they may receive the service from the WPQC-certified pharmacist affiliated (directly or indirectly) (please refer to the WPQC Policy on Non-traditional Pharmacy Sites) with that WPQC-accredited pharmacy. ˏˏ Patients who do not meet any of the above criteria may pay for the Transition of Care Service based on the pharmacy’s Usual & Customary fee.
WPQC Transition of Care Service
Patients can receive a WPQC Transition
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Role for Inpatient Pharmacists
WPQC Policy on Non-traditional Pharmacy Sites Payer
General Overview
Commercial Payers
WPQC-certified pharmacist directly affiliated with a WPQCaccredited dispensing pharmacy; contract pharmacists permitted
Wisconsin Medicaid
WPQC-certified pharmacist directly or indirectly affiliated with a WPQC-accredited Medicaid provider pharmacy; location determined by place of service codes in Forward Health policy; payment provided to dispensing pharmacy; contract pharmacists permitted
Directly affiliated: pharmacist whose salary is funded directly by the WPQC-accredited dispensing pharmacy for either dispensing-related activities or service-based activities Indirectly affiliated: pharmacist who does not receive payment directly from the WPQC-accredited dispensing pharmacy for service-based activities.
What are the Transition of Care Service expectations? • WPQC Pharmacist performing the Transition of Care Service will: ˏˏ Obtain a complete medication list of the prescription and over-thecounter medications the patient was taking prior to admission. If the pharmacist performing the service does not have a complete pre-admission medication list, it is expected that he/she contact the patient’s pharmacy/pharmacies to obtain this information. Note: an admission history obtained solely from an Electronic Medical Record (EMR) does not fulfill this requirement. ˏˏ Obtain the discharge medication orders and compare to the preadmission medication list. ˏˏ Upon conclusion of the service, provide the updated Personal Medication List (PML) to the patient which highlights changes made to the patient’s preadmission medication regimen. Provide Medication Action Plan (MAP) to the patient which reminds the patient of action items he/she should take until follow up with his/her primary care provider. Note: If the final MAP is not able to www.pswi.org
be provided at the end of the service, the preliminary MAP should be provided. The final MAP must then be provided to the patient within 14 days of service provision. ˏˏ If applicable, contact the patient’s other pharmacies and inform them that a transition of care service was performed. Provide applicable information to the pharmacy staff. ˏˏ Follow up: Attempt to contact the patient after the visit to ensure and reinforce understanding of the post-discharge medication regimen. (Best practice: meet with the patient in person or attempt to contact the patient a minimum of 3 times via phone.)
WPQC’s main barrier relating to Level II CMR/A services is patient recruitment. By using the information above, inpatient pharmacists can aid in promoting the Level II TOC service to appropriate patients upon discharge. Research demonstrates that medication reconciliation after discharge can help decrease hospital readmissions, which benefits both the patient and the institution. Creating awareness of the availability of these services to qualifying patients at the time of discharge can help to alleviate fears of leaving the institution by providing security that another provider of pharmacy care can pick up where the inpatient pharmacy staff left off. These patients may be more inclined to meet with their community pharmacist if the service has already been coordinated or suggested rather than hearing about it for the first time at the community pharmacy.
Transitions of Care in Practice
The PSW Pharmacy Practice Model Initiative (PPMI) Leadership Team, a group of Wisconsin inpatient post graduate practice management pharmacy residents and administrators, is at the halfway point of a two-year initiative focused on Transitions of Care. As a component of this initiative, the PPMI Leadership Team has created an extensive toolkit specifically designed to facilitate and improve the transition between the hospital and anywhere care is to be continued. This toolkit was developed to provide resources to enable institutions to improve transitions of care in the following five domains: medication reconciliation, discharge medication management, discharge patient education, hand off, and follow-up. There are five Wisconsin institutions throughout
WPQC Callout A WPQC article focused on team-based care was recently published in WMJ, the Journal of the Wisconsin Medical Society. “The Wisconsin Pharmacy Quality Collaborative – A Team-Based Approach to Optimizing Medication Therapy Outcomes” called attention to the success of the WPQC program and how it can continue to expand with coordinated outreach to and collaboration with other health care providers.
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WPQC Registration Update (
as of July
8, 2014)
• 337 pharmacies registered/317 are WPQC-accredited • 1374 pharmacists registered/1193 are WPQC-certified • 642 technicians registered/509 are WPQC-certified • 252 students registered/196 are WPQC-certified the state currently serving as pilot sites utilizing the toolkit content to implement various pharmacy-driven transition of care services. The second year will build upon year one’s accomplishments as well as involve community pharmacy residents from across the state with increased focus on hand-off communication to the community setting. Last month at the PSW Annual Meeting, the topic of transitions of care was front and center, both covered during the Hospital Pharmacy Leadership Forum on Friday and a concurrent session on Saturday entitled “Cannonball! Jumping in and Tackling Medication Reconciliation at Care Transitions”. The Forum provided a keynote presentation by Maureen Layden (head of the central VA's medication
reconciliation initiative), covered the launch of the new PSW Transitions of Care Toolkit (available at http://www.pswi. org/Resources/PSW-Transitions-of-CareToolkit) and provided discussion about opportunities for engagement with external partners. The second portion of the Forum provided a chance for case-based dialogue relating to transitions of care between pharmacists working in different settings. Saturday’s concurrent session was presented by Kate Hartkopf, PharmD, BCACP, UW Health, and Jonathan Koehler, PharmD, Wheaton Franciscan Healthcare. They both provided examples of what their institutions struggle with and some of the strategies they have put into place to address medication reconciliation at the time of discharge and beyond.
The WPQC Transition of Care policy is available within the WPQC web portal and will be covered in more detail throughout the coming year through webinars and newsletter content. The WPQC team looks forward to working with pharmacies to implement the TOC service as another opportunity to improve care for patients in Wisconsin. ● Beth Gribble, 2015 PharmD Candidate and Kari Trapskin is the Vice President of Health Care Quality Initiatives at PSW.
References
1. National Transitions of Care Coalition. Improving transitions of care: The vision of the National Transitions of Care Coalition. http://www. ntocc.org/Portals/0/PDF/Resources/PolicyPaper. pdf. Created 2008. Accessed August 4, 2014. 2. Wong JD, Bajcar JM, Wong GG, et al. Medication reconciliation at hospital discharge: Evaluating discrepancies. Ann Pharmacother. 2008;42(10):1373-1379. 3. Hume AL, Kirwin J, et al. Improving care transitions: Current practice and future opportunities for pharmacists. Pharmacotherapy. 2012;32(11):e326-337. 4. Roughead EE, Kalisch LM, Ramsay EN, et al. Continuity of care: When do patients visit community healthcare providers after leaving hospital? Intern Med J. 2011;41(9):662-667.
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pharmacypractice feature
WPQC OPERATIONS:
How to Improve CMR/A Acceptance Rates: Tips from the Field and from Patient Mini-Focus Groups
by Lynda Latinen and Anh Nguyen, PharmD, BCACP.
W
hen visiting or speaking to pharmacists about the challenges of providing Medication Therapy Management (MTM) services, one of the biggest challenges that many pharmacists cite is how to get patients to agree to come in for a Comprehensive Medication Review and Assessment (CMR/A). The culture of MTM is changing and patients and providers are slowly becoming familiar with the term MTM, what pharmacists can do during a private sit-down visit with a patient, and how it differs from routine pharmacy services. Scheduling a Comprehensive Medication Review is an art form and it can be difficult and intimidating at first, but there are ways to make it easier and increase your success rate. This article will be divided in two parts; in the first section Lynda Latinen, a pharmacy technician at Lakeview Pharmacy, will be sharing her tips for scheduling success. She has an approximate 60% success rate for scheduling patients and has averaged approximately eight patients scheduled for CMR/As every month, or 24 patients per quarter, since they started providing CMR/As. To put it into perspective, the WPQC-accredited pharmacies are expected to provide LII services (initial and follow-up CMR/As) to a minimum of 30 patients (with a focus on asthma, diabetes, heart failure and geriatrics syndromes) annually and at present the average WPQC-accredited pharmacy performs two to seven Level II interventions per quarter. In the second section, we will highlight the key findings from three mini-focus groups where patients shared their rationale for agreeing to a CMR/A with the pharmacist. By sharing these tips and findings, we hope to improve the ability of WPQC-certified pharmacists and technicians to successfully invite patients to receive initial and follow-up CMR/A services.
Little Details Make a Big Difference
Prior to calling a patient to schedule a CMR/A appointment, first familiarize yourself with the patient’s profile. Take note what conditions are being treated and incorporate that into your introduction. Also familiarize yourself with their dispensing profile and assess their medication taking behavior. If they notice that you’ve done your research about them, they tend to respond more positively because it shows you are genuinely concerned about their health. When calling the patient, use the WPQC sample script to guide your invitation. Mention you are calling on behalf of the pharmacist and identify yourself to the patient. Also, make sure you are smiling because even as cliché as “Smile When You Dial” sounds, the tonal quality of your voice changes when smiling and patients will be able www.pswi.org
to hear the smile through the phone. Smiling also makes your voice sound less alarming to the patient when you are calling to discuss something they may consider to be concerning or confusing. This is really important to set the tone of the conversation. Lakeview Pharmacy is an independent pharmacy and many of the patients have been “regulars” for years. The staff is often familiar with the patient, his or her disease state(s) and how compliant or non-compliant the patient may be with their medications. Having a long-standing relationship with patients means that we have established trust with them. When I tell a patient “we now offer an exciting program that may help you understand your medications better or even save you money,” they are usually receptive. In addition, some patients may not understand what a CMR/A is, and they find the term "Medication Check-Up" to be more understandable. This is why we do not call it a CMR/A; we refer to it as a Medication-Check-Up service. Verbal cues are incredibly important. You can learn a lot about what matters to patients by their reaction or lack of reaction in response to certain key words or phrases. I have noticed more “hmm” reactions or “really?” statements when discussing that there is no charge to the patient for this service. I receive a similar reaction when I mention that the pharmacist takes into consideration all medications, including herbals and OTC’s, and double checks that nothing interacts with each other. It also helps to truly believe in the good that this service can do for a patient. I have witnessed tears and hugs when we implement the medication synchronization program to assist patients with their compliance. This display of satisfaction with the service we offer makes me feel confident in the value we provide to our patients, and it helps me “sell” this service to a prospective patient who knows nothing about it. Because CMR/As are a relatively new service, patients may not immediately understand what it entails and how they might benefit. Therefore, when a prospective patient has an objection
WPQC callout It also helps to truly believe in the good that this service can do for a patient. I have witnessed tears and hugs when we implemented the medication synchronization program to assist patients with their compliance. This display of satisfaction with the pharmacy's services helps me “sell” this program to a prospective patient who knows nothing about it.
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such as “I’m too busy” or “my doctor already does that for me”, when he or she pauses, or asks a question, it is usually a request for more information. Once you’ve provided the information they need to make an informed decision, it is important to bring the conversation back to the task at hand, which is to book the patient for an appointment. Thus, after each of your comments, it is important to always end with the following Closing Question: “So when would you like to come in? I have next Monday at ___ or ___ available.” Giving the patient a choice between two options makes it easier to pick one, rather than having them refer to their schedule. It is important to note that approximately 80% of prospects will decline four times before they say “yes.”1 This means you can expect to answer several questions, handle a few objections, and ask the Closing Question five times before the patient agrees to an appointment, so be persistent! Often, I run into problems with not being able to reach a patient via telephone. In those cases, I prepare a short letter to the patient and offer written information regarding CMR/A services and how it may be beneficial to them. In the envelope, I also send a WPQC MTM pamphlet and request a phone call or drop-in to
the pharmacy. This has proven to be quite effective at the very least in getting a call back. Then, I do my best to explain the service, why he or she was identified as a good candidate for a CMR/A, and then answer any questions he or she may have. In short, work with your individual patient. Take notes even as you speak to him or her and mark down the topics that seem to be of most interest or concern. You can use those topics to your benefit in selling this service. It also helps to figure out responses to questions or concerns before making your call. If you have answers ready you sound assured and confident in the services you offer. If a patient sounds interested in MTM but is worried about the allocated 30-45 minute window of time with the pharmacist, assure the patient that you can work around his or her schedule to ensure the meeting occurs at a convenient time. If a patient has concerns regarding coverage for this service the pharmacist should determine if services are covered and assure the patient. Again, preparation is important. If you familiarize yourself with your patient and prepare responses to common concerns, your scheduling success rate will be fantastic. And smile, don’t forget to smile! Table 1 lists the activities to accomplish before and during a CMR/A patient recruiting and scheduling call as well as how to
TABLE 1. How to Successfully Recruit and Schedule Patients for CMR/As Before the Call 1.
Familiarize yourself with the patient’s profile. Note why s/he is a good CMR/A candidate.
2.
Review and be comfortable with using the sample WPQC Level II CMR/A phone script.
3.
Be prepared with responses to common objections such as “I’m too busy”, “My doctor already does this”, etc..
4.
Truly believe in the good this service can do for your patient.
5.
“Smile When You Dial!”
During the Call “Hi this is (name) and I am a (title) at (name of pharmacy). May I speak to (patient name)?
Introduce Yourself
Hi (patient name), how are you?”
Describe the Service
“I am calling because we now offer an exciting program that may help you understand your medications better or even save you money.”
Personalize the Interaction
“I (or the pharmacist) was looking over your medication profile and noticed that (reason they are a good CMR/A candidate, e.g. you’re a diabetic/dealing with multiple medications/have more than one doctor, etc.). S/he asked me to call you because we think you would benefit from this Medication Check-Up service that we are offering. When would you prefer to come to the pharmacy for a private sit-down visit with the pharmacist?”
Describe the Features and Benefits of a CMR/A
CMR/A Features (numbered) and Benefits (bulleted): 1. Financial benefits • Service is covered by your insurance • Sometimes we can find ways to save you money on your medications 2. Private sit-down visit • Undivided attention of the pharmacist to discuss your questions and concerns • The pharmacist is very kind, knowledgeable, and understanding and can help you with any medication-related concerns you have about your health 3. Personalized review of all medications including herbals and OTC’s • Identify unnecessary medications if appropriate • Make sure you are getting the most from your medications • Reduce or avoid side effects • Double check that your medications do not interact with each other • Help you remember to take your medicines 4. Receive a Medication Action Plan and updated Medication List after the visit • Summary of the visit findings and your next steps • Updated and complete list of your medications to share with all your providers 5. Communicate with your doctors • Ensure you are receiving the best care possible. • Get their approval before making any medication changes
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Describe the Features of a CMR/A:
Assess and Adjust Based on Patient Response
“A Medication Check-Up is a service that is covered by your insurance and is no charge to you. It allows you to meet privately with your pharmacist to review all of your medicines. This involves a personalized review of all your medications including any herbals and OTCs you may be taking to make sure they work well for you. At the end the visit you will receive a Medication Action Plan summarizing the visit as well as an updated medication list. We will also communicate with your doctors regarding any suggestions the pharmacist has for medication changes.” Take notes during the call of verbal cues from the patient indicating points of interest or concern. Use these verbal clues as selling points for the CMR/A service, expanding on the specific benefits of the program when you hear them responding to a specific feature of the program. E.g. if they seemed interested when you mentioned the pharmacist would review all their medications in detail, expand on the Benefits listed in #3 in the row above.
(If Needed): Address Questions or Concerns
"I can’t afford it." • "There is no out of pocket cost to you. This program is covered by your insurance because they recognize how important face-to-face visits with your pharmacist are." "I’m too busy, I don’t have time." • "We completely understand the stresses of having a busy schedule, so we are flexible and can make sure the meeting occurs at a convenient time for you. The length of the visit will depend on what questions you have and what you and the pharmacist decide to focus on. Most visits take between 30 and 45 minutes, and to keep it short, we can review your top concerns and meet for a follow-up, if necessary." "My doctor/nurse already does this for me." • "We understand the importance of your relationship with your doctor and that’s why we work with all of your providers to make sure we are on the same page. Your doctor is your medical and health specialist, and your pharmacist is your medication expert who can help resolve your medication-related concerns. Together, we can make sure you are receiving the best care possible." "I want to make sure my doctor knows that this is happening." • "After the appointment, we will send a summary of the visit to your doctor and get their approval before making any changes." Each time you answer a question, review the CMR/A benefits specific to the patient, or handle an objection, always remember to end with the Closing Question:
Always End with the Closing Question
“So when would you like to come in? I have next Monday at ___ or ___ available.” (or whichever day/time slots you have) “Please be aware that we are making special staffing accommodations for this appointment with you. Should anything come up or your schedule changes, please notify us right away to reschedule. We are looking forward to meeting with you on (date) at (time)”
Firm Up the Appointment to Avoid No Shows
Other Reminders: • Bring all medications, devices, lab results, etc. (Use the WPQC “What to Bring” document to remind patient what s/he should bring along to the appointment.) • Arrive 10-15 minutes early so you can complete paperwork (or give/mail them the WPQC History & Physical paperwork to fill out beforehand) • Appointment Reminder card • Appointment Reminder call the day before the appointment
Troubleshooting Patients without a telephone: send a WPQC MTM brochure via mail with a request for the patient to call or come in to the pharmacy Practice makes perfect! Role play the script and conversation flow until you are comfortable and it comes easily.
troubleshoot to ensure a successful call.
Why I Met with My Pharmacist: Feedback from Patients Recently the WPQC team conducted mini-patient focus groups with the help of a trained facilitator to learn from patients what motivated them to meet with their pharmacist for a CMR/A. The majority of patients who participated in the mini-focus groups visited the same pharmacy routinely, had several disease states and were prescribed multiple drug therapies from different prescribers. The ages of the patients ranged from mid-thirties to eighties, with www.pswi.org
the average age in the mid- to late-fifties. Ninety percent of the participants in the mini-focus groups were female. According to a recent literature review, most patients have never heard of MTM services nor received these services.2,3 Patients in the WPQC mini-focus groups also had difficulty distinguishing how CMR/A services were different from the regular interactions with their pharmacist in part because they felt that these services are comprehensive and should be provided to all patients as standard practice. It was noticed that using terms like “Medication CheckUp” or “one-on-one sit-down visits” helped patients understand MTM services rather than using jargon such as “MTM” or “CMR/A”. The visit can be likened to a visit with their physician,
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but with a focus on resolving medication-related concerns. Two main factors were cited in the mini-focus groups for influencing a patient’s decision to receive MTM services: their relationship with their pharmacist, and the impact on the patient’s health following the visit (Table 2). First, an important factor in patient acceptance of a CMR/A is a positive one-on-one relationship between the pharmacist and the patient. Patients who accepted and completed CMR/As attributed it to the personal conversations with their pharmacist as well as the attitude of the pharmacist. Second, the pharmacist identified the patient as high-risk and was able to convince the patient how she or he could help address a clinical and/or financial issue that she or he noticed about the patient. TABLE 2. Primary Factors Influencing a Patient to Receive a CMR/A Reason Patients’ relationship with their pharmacist Potential for health improvement
Participants also noted the pharmacist was persistent in convincing the patient to receive the service. This highlights the positive impact that pharmacist-patient relationship may have on decision making. Participants recognized the need to improve their health and thus decided to meet with their pharmacist. One participant did not initially accept invitations to meet, but his health changed over time and he realized then he could benefit from the service. Thus it is important to recognize that although a patient may decline initially, they could accept the CMR/A invitation later. Remember to mark your calendar to invite the patient again for a CMR/A service. During their discussions with the pharmacist, the participants noted they were overwhelmed by the number of medications prescribed and were concerned by potential medication interactions and the safety of taking medications together, including OTC’s. They also voiced confusion regarding how to take medications throughout the day and how best to schedule medications as directed by the label on the prescription bottles. One patient specifically expressed a feeling of “being mixed up, confused, picking and choosing medications because I didn’t know what the medications were for.” Participants who accepted a CMR/A invitation and received this service came to value the ability of the pharmacist to simplify their medication regimen. For patients who are on multiple medications, emphasize that the pharmacist will discuss all the medications the patient is taking, including OTC’s and supplements, to make sure they are on the best medications for their conditions, the medications work well together, and how to best schedule the medications throughout the day . Participants also expressed not having enough time to spend with their prescribers during their regular clinic visits and appreciated the time the pharmacist spent with them. They appreciated that the pharmacist would coordinate their care when they were seeing more than one prescriber for the treatment of their health conditions. These are additional points that can be used as selling points when telling patients about MTM services and recruiting them for CMR/As.
WPQC callout Thus it is important to recognize that although a patient may decline initially, they could accept the CMR/A invitation later and to remember to mark the calendar to ask the patient again.
In the literature, there are common themes reported describing the patient-perceived value of MTM services (Table 3).3 A direct comparison of what is found in the literature versus what was cited in the patient mini-focus groups can be found in Table 3. In the mini-focus groups, participants repeatedly expressed appreciation for how accessible the pharmacist is and that they cared enough to take the time to meet with the patients. Some of these comments included: “The pharmacist was able to take the time to answer my questions and reviewed all of my medications and problems” and “That’s a pharmacist doing her job…caring for the patient.” The participants valued their relationship with the pharmacist and perceived that their health outcomes began to improve immediately following the Medication Check-Up visit. The participants also shared that they appreciated their pharmacist being someone they could confide in without feeling judged as well as their personal cheerleader for their health care. They enjoyed knowing that the pharmacist worked collaboratively with their other health care providers to coordinate their care. Participants expected and valued that the MTM visit was covered by their insurance, and that the pharmacist considered the patient’s cost of care when making recommendations to their providers. Finally, one patient noted that as consumers they can choose to go to any pharmacy, but they chose their current pharmacy because they valued the services offered by the pharmacist who works there. Knowing what patients find valuable during a CMR/A, pharmacy staff can use this information when recruiting prospective patients. Participants in the mini-focus groups were invited to the CMR/A either in person or via phone, and both methods work well. Reminder calls were provided by the majority of the pharmacists
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and were both helpful and effective. Older patients may benefit from an appointment reminder card, whereas younger patients could record their appointments via their phone or internet-based calendar. Participants also noted that they valued the scheduling of follow-up visits to ensure everything is progressing as expected. In summary, these recruiting and scheduling tips and the findings from the patient mini-focus groups may seem very simple, but they are very valuable pearls. Simple does not always mean easy, but if these tips are systematically implemented, reviewed, and adjusted to fit the specific needs of your pharmacy and your patient population, you will find they will lead to success. Instead of re-inventing the wheel we can learn from the successes of others and model it within our own practices. It is our hope that this article will help to improve the ability of WPQC-certified pharmacists and technicians to successfully invite patients to receive initial and follow-up CMR/A services. Should you need additional clarification or assistance, please feel free to reach out to your WPQC Regional Implementation Specialist.● Lynda Latinen, Customer Relations Specialist and WPQC Certified Technician and Anh Nguyen, PharmD, BCACP, WPQC Regional Implementation Specialist.
References
1. Clay, Robert. "Why 8% of Sales People Get 80% of the Sales." Web log post. Marketing Donut. N.p., n.d. Web. 28 July 2014. http:// www.marketingdonut.co.uk/marketing/sales/sales-techniques-andnegotiations/why-8-of-sales-people-get-80-of-the-sales. 2. Truong, H.A., Layson-Wolf C., de Bittner, M.R., Owen, J.A., Haupt, S. (2009). Perceptions of patients on Medicare Part D medication therapy management services. JAPhA, 49(3), 392-398. 3. Schultz, H., Westberg, S.M., de Oliveira, D.R., Brummel, A. (2012). Patient-perceived value of Medication Therapy Management (MTM) services: a series of focus groups. Innovations in Pharmacy, 3(4), 1-8.
TABLE 3. Patient-Perceived Value of MTM Services
Literature3
WPQC Patient Mini-Focus Groups
Pharmacist as an accessible resource for the patient’s medication-related The patients expressed their appreciation of the pharmacist taking the questions and concerns time to sit down with them in a private area to discuss the details of their medications, allowing them to ask questions and feel engaged in their plan. Pharmacist is the patient’s advocate and confidante
“The pharmacist was not judgmental of me or my medications.”
Collaboration with health care team on behalf of the patient
One patient valued the pharmacist as the mediator between them and their prescribers, resulting in using the correct medication for the correct condition.
Pharmacist is a coordinator for the patient’s health care
The pharmacist was the person identifying medication-related issues and then coordinating the solutions with the patients’ multiple physicians. Sometimes the pharmacist offered services complementary to the physician visits (i.e. foot exams for diabetic patients)
Financial Benefits from Participation in MTM Services
Patients also noted having to choose which medications to purchase based on their finances was stressful and appreciated that the pharmacist considered the patient’s cost of care when making suggestions (i.e. adding OTC’s to save money, and finding less costly medication alternatives).
MTM pharmacist as a specialist/competitive differentiator
“It’s not about the pharmacy, but the pharmacist; we can shop around because we are consumers, but we chose to get our services at that pharmacy”.
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pharmacypractice feature
JOURNAL SERIES:
Statistics Review Part 7: Case-Control and Cohort Studies by Claire Seidler, PharmD Candidate 2015, Amanda Margolis, PharmD, MS, BCACP, and Kevin Look, PharmD, PhD This article describes cohort and case-control studies, differences between the two study types and biases that observational research may be susceptible to.
Objectives:
1. Define cohort and case-control studies 2. Describe the differences between cohort and case-control studies 3. Describe different types of bias that observational research is susceptible to
O
bservational studies are often warranted and necessary when a randomized control trial is unethical to perform, when the outcome or condition of interest is rare, or as a hypothesis generating study to determine if future randomized control trials are warranted.1 Cohort and casecontrol studies are two commonly used observational study designs. In cohort studies, participants with an exposure of interest (e.g., a medication or lifestyle modification) are monitored over time for development of a particular outcome (the dependent variable such as heart attack, stroke, development of disease, side effect, etc.). In contrast, case control studies identify individuals with a particular outcome of interest and researchers retrospectively compare exposures between the two groups. However, the results of these studies should be interpreted with caution as these studies are subject to several biases.
Cohort Studies
Cohort studies divide participants into groups based on whether they have experienced an exposure of interest.1 Participants are followed over time to determine whether they develop the disease or outcome of interest. An example of an ongoing cohort study is the Millennium Family Cohort.2 The study is evaluating the impact of military service on family
members with a 21 year follow up period. Families are grouped based on the deployment status of service members and outcomes of interest include the mental health, coping skills and well-being of military personnel and their family members. Cohort studies are the best design for exploring potential relationships between rare exposures and development of an outcome (or disease), but are also widely used for common exposures as well. Cohort studies can be prospective or retrospective. Prospective studies follow participants from exposure until the outcome of interest occurs or the end of the observation period, while retrospective studies often utilize chart review from past patient records. Prospective studies are subject to less bias, but require
more time and resources than retrospective evaluations. The relationships between exposure and outcomes are often reported as a relative risk for experiencing the outcome between exposure groups (see part 2 of this series for a review of relative risk).1 Temporal effects (effects which may develop over time) can be evaluated in cohort studies as the exposures precede the outcome, which is one important aspect of determining causality. However, given the risk of confounding variables in cohort studies, results should be interpreted cautiously as there are many other aspects of causality which need to be considered.3 Given that this temporal relationship exists and that research on risk factors through randomized control trials are often considered unethical (e.g., smoking),
TABLE 2. Comparison of Observational Study Designs Study Type
Participant Groups (independent variable)
Study Outcome (dependent variable)
Scenario: A researcher is investigating the association between smoking and cancer
Cohort Study
Participant groups based on whether patient has encountered exposure of interest (e.g., grouped as smokers and nonsmokers)
Compares the rates of development of cancer between the two groups (e.g., would determine the relative risk of developing cancer between the smoking and nonsmoking groups.
Prospective or retrospective
Case-Control Study
Participant groups based on whether or not patient has the outcome of interest (e.g., grouped based on having cancer or not having cancer)
Compares the risk of exposure in the outcome group compared to the control group (e.g., would determine the odds of having been exposed to smoking)
Retrospective
Nested CaseControl Study
Participant groups based on whether or not patient has the outcome of interest within a cohort study (e.g., grouped based on having cancer or not having cancer but all participants are taken from the same cohort)
Same as case-control study
Can be prospective within a cohort study
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Prospective vs Retrospective
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cohort studies are often utilized in this area.1 An example of a large, cohort study now in its third generation of participants is the Framingham Heart Study in which researchers are looking to establish the effects of diet, exercise and medications on heart disease.4
TABLE 1. Bias in Observational Research Type of Bias
Selection Bias
The manner in which groups are determined results in study groups differing at baseline
A prospective cohort study is conducted investigating the relationship between ipratropium use and arrhythmias; however, patients who utilized ipratropium had more severe COPD.
Information Bias
Unequal collection of exposure data prompts a researcher to more preferentially search for a cause of the disease
A case-control study is investigating potential risk factors for a resistant infection. However, researchers collect exposure data face to face in a hospital for the infection group and over the phone for the control group.
Recall Bias
Patients with a disease have more “may be better able to remember past exposures a possible cause of the disease versus patients without the disease
A case-control study is investigating potential relationships between OTC medications and birth defects. Women who have children with birth defects may be more likely to remember medications that took than those with healthy children
Case-Control Studies
In case-control studies, participants with an outcome of interest are retrospectively matched with control group participants who have not experienced the outcome.1 Researchers retrospectively determine the risk of exposure for the participants in each group through the collection of past exposure data, and then evaluate how frequently they occur in each group. Choice of the control group is extremely important in case-control studies and can introduce bias if not chosen correctly. Everyone in the control group should have the opportunity to develop the outcome of interest; for example, men should not be included in a study of risk factors leading to ovarian cancer. Case-control studies can be used to help decide whether a specific exposure may have a relationship to the development of the outcome of interest .interest, or even to a rare side effect.1 However, given their weaker study design they are often primarily considered to be hypothesis-generating studies. hypothesis-generating studies. In some instances, case-control studies may be the only option for ethical reasons when studying rare outcomes or if there is a large time period between the exposures and the outcomes of interest. One example of such an occurrence involves the casecontrol study of the relationship between Creutzfeldt-Jakob disease and dietary risk factors.5 This four year study separated participants based on whether or not Creutzfeldt-Jakob disease was diagnosed and utilized a participant survey to examine the consumption of various types of meats. This survey was used to verify the increased risk of Creutzfeldt-Jakob disease associated with the meat consumption. Given that case-control studies are retrospective, these studies cannot be used to calculate relative risk directly; instead odd ratios are used to demonstrate relationships between the outcome and the exposure.6 Relative risk cannot be directly calculated because these studies do not determine the risk of an outcome; rather the likelihood of www.pswi.org
Example situation when the bias could be present
Brief Description of Bias
being exposed is calculated.1 An odds ratio in a case-control study is interpreted differently from the traditional definition. An odds ratio from a randomized control trial determines the odds of developing an outcome amongst those in an exposure group compared to the odds in a control. In a case-control study, the odds ratio determines the odds of exposure amongst a group of participants with an outcome compared to the odds in a control without the outcome of interest. For example, an odds ratio from a hypothetical case-control study about deep vein thrombosis may find that a sedentary lifestyle is four times as frequent in participants who developed a thrombus compared to participants with an active lifestyle. Although case-control studies are typically retrospective, an exception is the nested case-control design. A nested case-control is usually a sub-study “nested” within a cohort study.7 Both outcome and control group participants are drawn from the original cohort study, and participants are prospectively followed from exposure to outcome. The benefit of conducting a nested case-control study is the minimization of recall bias (described in the following section) or errors in medical records data extraction.
Biases
Selection bias occurs in an observational study when the two study groups differ
in some measured or unmeasured characteristics at baseline, or in the opportunity to develop the outcome being studied. Selection bias undermines the internal validity of an observational study, as it creates the question of whether the association found was truly due to what is being studied or due to a confounding variable such as differences between groups at baseline. Information bias stems from inconsistent data collection between study groups.8 For example in a casecontrol study, exposure information from those with the disease may be gathered bedside while a participant is hospitalized, whereas control group information may be gathered via telephone conversations. This difference in information gathering may trigger an observer to more thoroughly and preferentially research diseased participants for a cause. To prevent information bias, data collection in both cohort and casecontrol studies should be performed by a blinded observer who is unaware of the group allocations for each participant. Another potential data collection bias is recall bias. Since retrospective studies utilizing interviews often rely on the memory of participants or family members to recall an exposure, those participants who have the outcome often have more incentive to try to recall more possibilities” to “tend to be more likely to recall potential exposures.8 For example, a researcher might interview two groups of patients: those with
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New Members
Welcome to the newest members of PSW Kristen Aschbrenner, Wausau Kenneth Baker, PBA Health, Kansas City, MO Timothy Battisti, Genoa City Heidi Nicole Belekevich, De Pere Victoria Brouner, Concordia University Wisconsin, Mequon William A Brown, Traverse City Rachel A Buchanan, Madison Evelyn J Buss, RPh, Poynette Hometown Pharmacy, Poynette Uvi Castillo, Concordia University Wisconsin, Mequon Amanda Coffey, Walgreens #11858, Madison Daniel M. Cunningham, RPh, ThedaCare Pharmacy, Appleton Mike Faber, Fond Du Lac Tammy Ferry, Concordia University Wisconsin, Mequon Kate Gainer, Iowa Pharmacy Association, Des Moines, IA Steven Galley, Walgreens Pharmacy, Ashland Cynthia Habeck, Tomah Holly Heckert, Milwaukee Julie Ann Hodgeman, Randolph Harry Horn, Middleton Susan Jaeck, Milwaukee Jennifer M Jones, CPhT, Appleton James Karnau, Ministry Saint Joseph's Hospital, Marshfield Mary D. Kraus, RPh, Waukesha Rebecca Lackey, Milwaukee Emily T Lin, Milwaukee Nicole Lubcke, Verona Amanda Ludwig, Madison Cassandra J Lytle, Merrimac Jennifer Marie Soto Meyer, Madison Nicole A Meyer, CPhT, Marshfield Jamie Moline, Greenleaf Paula Napier, PRh, Madison Emily Catherine Neumann, Somerset Roger E Overton, RPh, Onalaska Joe Revak, PharmD, Crystal Lake, IL Jeffrey T. Robertson, PharmD, Verona Ann E Schenkel, Palatine, IL Joyce Schubring, Aurora Pharmacy #1242, Marinette David Scofield, RPh, Hartig Drug Stores Corp, Dubuque, IA Kimberly Smithers Kathryn R Taylor, PharmD, Chippewa Falls Janelle Vittetoe, Madison Scott M Weber, RPh, Burlington Frances Wenzel, Kohler Kimberly White-Faull, Mineral Point Erin Wilkes, Milwaukee George Wilkinson, Concordia University Wisconsin, Mequon Matthew L Wolf, Pewaukee Michelle Yu, New Berlin
and without active ulcers. Patients with ulcers may be more likely to propose several contributing factors for their ulcer such as stress, NSAID use, or alcohol consumption. In contrast, patients without ulcers may not note these exposures as they did not experience the ulcers themselves. Both information and recall bias reduce internal validity as they call into question whether the observed differences between the two groups were due to differences in how the data were gathered. Threats to external validity, can also be present in observational research and involve selection of the participant sample.8 If inclusion criteria are too restrictive, the ability to generalize of the results to a larger population decreases. Other common biases that can occur in observational studies are attrition bias and potential confounding factors, which were defined in part 6 of this series.
Conclusion
This article reviewed definitions and examples of case-control and cohort studies, and the different biases that can affect the internal and external validity of these observational studies.
Practice Question 1. Observational studies are useful in which types of situations? a. Unethical exposure risks b. Rare disease states c. Lengthy study time requirements d. All of the above 2. Participants grouped by an outcome of interest and then have exposure risks retrospectively determined is an example of which type of study? a. Cross-over Study b. Cohort Study c. Case-Control Study d. Randomized Control Trial 3. A researcher who collects exposure data inconsistently between patient groups in a case-control study places the study at risk for which bias? a. Information bias b. Selection bias c. Recall bias d. A decrease in external validity
Answers: 1. d. All of the reasons given are situations in which observational studies are useful and other study designs may not be appropriate. 2. c. Case-control studies group each patient set together based on the absence or presence of the outcome of interest. Exposure risks for each group are then retrospectively determined to produce an odds ratio. 3. a. Information bias becomes a risk when a data collector in an observational study is prompted or gives preference to more thoroughly searching for exposure data based on inconsistent data collection settings.
Claire Seidler, PharmD Candidate 2015, University of Wisconsin School of Pharmacy, Amanda Margolis, PharmD, MS, BCACP, University of Wisconsin School of Pharmacy, Kevin Look, PharmD, PhD, University of Wisconsin School of Pharmacy The authors of this article declare no real or potential conflicts or financial interest in any product or service mentioned in the manuscript, including grants, equipment, medications, employment, gifts and honoraria.
References
1. Mann CJ. Observational research methods. Research design II: cohort, cross sectional, and casecontrol studies. Emerg Med J. 2003;20(1):54-60. 2. Crum-Cianflone NF, Fairbank JA, Marmar CR, Schlenger W. The Millennium Cohort Family Study: a prospective evaluation of the health and well-being of military service members and their families. Int J Methods Psychiatr Res. 2014. [Epub ahead of print] 3. Steiner PM, Cook TD, Shadish WR, Clark MH. The importance of covariate selection in controlling for selection bias in observational studies. Psychol Methods. 2010;15(3):250-267. 4. Mahmood SS, Levy D, Vasan RS, Wang TJ. The Framingham Heart Study and the epidemiology of cardiovascular disease: a historical perspective. Lancet. 2014;383(9921):999-1008. 5. Davanipour Z, Sobel E, Ziogas A, et al. Dietary Risk Factors for Sporadic Creutzfeldt-Jakob Disease: A Confirmatory Case-Control Study. Br J Med Med Res. 2014;4(12):2388-2417. 6. Sedgwick P. Case-control studies: measures of risk. BMJ. 2013;346:f1185. 7. Ernster VL. Nested case-control studies. Prev Med. 1994;23(5):587-590. 8. Grimes DA, Schulz KF. Bias and causal associations in observational research. Lancet. 2002;359(9302):248-252.
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pharmacypractice
feature
Pharmacotherapy Perspectives:
Considerations For Selecting Anticoagulation Therapy for Patients with Non-Valvular Atrial Fibrillation by Jennifer Garber, PharmD, Katie Willenborg, PharmD, BCPS, Erin Robinson, PharmD, CACP, and Anne Rose, PharmD
A
trial fibrillation (AF) is the most common cardiac arrhythmia, is responsible for one-third of hospitalizations due to arrhythmia. Currently, AF affects 2.5 million people in the United States; however, this percentage is expected to increase to an estimated 16 million people by the year 2050, due to the aging “babyboomer” population.1 One of the most concerning sequelae associated with AF is ischemic stroke, with an incidence of about 5% per year in the absence of appropriate prophylaxis.2 Traditionally, dose-adjusted vitamin K antagonists, such as warfarin, have been used to prevent the occurrence of stroke in intermediate-to-high risk AF patients. However, the development of novel, target specific oral anticoagulants (TSOACs) have been shown to produce more predictable anticoagulation, do not require monitoring anticoagulation status, and have demonstrated improvement in patient outcomes. In 2012, The American College of Chest Physicians published an update to the Antithrombotic Therapy for Atrial Fibrillation Clinical Practice Guideline (CHEST). The CHEST guidelines recommend using dabigatran as first line therapy over warfarin for patients with non-valvular AF without mitral stenosis at an intermediate to high risk of stroke. This recommendation was based on the results of the RE-LY trial, which was the only trial comparing the use of a TSOAC to warfarin that was published at the time of the update. Although only dabigatran is mentioned in the CHEST guidelines, it is accepted that any of the TSOACs (dabigatran, rivaroxaban, or apixaban) could be considered as first line therapy.2 www.pswi.org
Abstract Atrial fibrillation (AF) is a growing health concern, affecting 2.5 million patients in the United States. One of the most concerning sequelae associated with AF is ischemic stroke, with an incidence of about 5% per year in the absence of appropriate prophylaxis. Traditionally, dose-adjusted vitamin K antagonist therapy with warfarin has been used to prevent the occurrence of stroke in patients with AF. Recently, newly developed target specific oral anticoagulants (TSOACs) have been shown to produce more predictable anticoagulant effects, require no monitoring, and have demonstrated improvement in patient outcomes compared to warfarin. The available TSOAC agents (dabigatran, rivaroxaban, and apixaban) have been studied compared to warfarin, but there are not yet any head-to-head trials comparing TSOACs directly, making it difficult to select the most appropriate anticoagulant therapy. The goal of this article is to help facilitate the appropriate selection of anticoagulants in patients with non-valvular atrial fibrillation who are at an intermediate- to high-risk of stroke. The individual patient’s stroke and bleeding risks should be carefully considered when making the decision to initiate anticoagulation. If anticoagulation is chosen, appropriate therapeutic options should be stratified based on patient-specific safety criteria. These criteria, along with an algorithm for quickly identifying therapeutic options, are included in this article. Once appropriate anticoagulant options have been identified, further considerations are provided to help narrow in on the most appropriate option for the individual patient.
Other guidelines that provide recommendations for the management of AF have also included TSOACs as considerations when oral anticoagulant therapy is indicated, but have not listed them as preferred agents at this time. This is likely due to TSOACs not being FDAapproved at the time of the guideline updates.3,4 The goal of this article is to help facilitate the appropriate selection of anticoagulants in patients with nonvalvular atrial fibrillation who are at an intermediate to high-risk of stroke. The recommendations provided are graded using the American Heart Association GRADE Criteria and are represented by a “Class” of risk versus benefit, as well as an associated “Level” of evidence. Class I recommendations should be performed or administered, Class IIa recommendations are reasonable to pursue, Class IIb recommendations may be considered, and Class III recommendations are not recommended. Level A derived data is from multiple randomized clinical trials or meta-
analyses; Level B derived data is from a single randomized trial or non-randomized studies; Level C derived data is based on consensus opinion of experts, case studies, or standard of care.5
Calculating Stroke Risk
The first step to choosing the most appropriate antithrombotic therapy for stroke prevention in AF is the evaluation of the individual patient’s stroke risk. (Class IIa, Level A)2,6 Risk assessment scores have been developed to help calculate individual annual stroke risk. The CHADS2 score was developed from two separate classification schemes – the AFI and SPAF schemes. This score includes risk factors that have been shown to independently increase the risk of stroke in patients with atrial fibrillation. These factors include heart failure, hypertension, age > 75, diabetes mellitus, and previous stroke. (Table 1.) This amalgam score provided greater predictive accuracy than did either AFI or SPAF schemes alone. Patients with a CHADS2 score of 0 are considered low risk and have
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TABLE 1. CHADS2 Stroke Risk Assessment Factors
Points
Congestive Heart Failure
1 pt
Hypertension
1 pt
Age ≥75
1 pt
Diabetes Mellitus
1 pt
Stroke history
2 pts
a predicted stroke rate of 1.9% per year, which is roughly equal to an event rate of 20% over a 10-year time span. The CHA2DS2VASc score is a newer stroke risk score that incorporates additional risk factors for stroke that were not included in the original CHADS2, including a younger age stratification, female gender, and vascular disease (Table 2). While CHA2DS2VASc is not as well validated as the CHADS2 score, it has been shown to more accurately identify low risk patients who may not benefit from anticoagulation. For example, a patient with a CHA2DS2VASc score of 0 has a predicted stroke rate of 0% per year.7 In the 2012 CHEST guidelines recommendations for considering initiation of antithrombotic agents in non-valvular AF are based on the CHADS2 risk score. The authors decided to use CHADS2 for the basis of their recommendations based on the validity of the risk scheme and ease of use since there are less risk factors for providers to remember. In 2012 the focused update of the European Society of Cardiology (ESC) Guidelines for the management of AF stressed the importance of identifying truly low stroke risk patients and therefore promotes the use of the CHA2DS2VASc score. TABLE 2. CHA2DS2VASc Stroke Risk Assessment Factors
Points
Congestive Heart Failure
1 pt
Hypertension
1 pt
Age ≥75
2 pts
Age 65-74
1 pt
Diabetes Mellitus
1 pt
Sex – Female
1 pt
Stroke/TIA/ Thromboembolism
2 pts
Vascular Disease (MI, PAD, aortic plaque)
1 pt
Despite the differences in annual stroke rates for patients with a CHADS2 or CHA2DS2VASc score of 0, the recommendations for when to initiate antithrombotic therapy is the same and outlined in Table 3. TABLE 3. Treatment Recommendations Based on Risk Score Score
Treatment Recommendations
0
• No antithrombotic therapy preferred • May consider aspirin therapy
1
• Oral anticoagulation preferred • Aspirin if unsuitable for anticoagulation
>2
• Oral anticoagulation preferred
Calculating Bleeding Risk
The ultimate goal of bleed risk stratification should not be to exclude patients from receiving anticoagulation if it is clinically indicated, particularly since many of the risk factors that may predispose patients to a bleeding event are also risk factors that increase their risk for stroke. To evaluate a particular patient’s risk for bleeding, the HAS-BLED score stratifies patients as low, moderate or high bleeding risk based on individual risk factors (Class IIb, Level A).8 It has been shown to more accurately predict the risk of major bleeding in patients receiving no antithrombotic or antiplatelet therapy than a more complex bleeding risk score, HEMORR2HAGES. The HAS-BLED score includes: hypertension, abnormal lab values (serum creatinine, bilirubin, AST/ALT/Alk Phos), history of stroke, history of bleeding, labile INRs, age, and the use of alcohol or NSAIDs. (Table 4) Before excluding a patient from receiving antithrombotic therapy, attempts should be made to correct modifiable risks, such as uncontrolled hypertension.7
Selecting Anticoagulation Therapy
Prior to initiating anticoagulation therapy the benefits and risks of anticoagulation should be discussed with the patient, being sure to incorporate their priorities in the decision making process. When anticoagulation has been identified as the therapy of choice to prevent ischemic stroke in AF, selection of the most appropriate agent should be individualized
based on both clinical evidence and patient specific risk factors. (Grade IIb, Level C) Based on the 2012 CHEST guidelines, the use of TSOACs may be preferred over warfarin for patients who qualify for their use (Grade IIb, Level C). Prior to selecting an oral anticoagulant, an individualized patient therapy plan should be developed. This plan should begin with stratifying patients based on 4 important safety points, and once safe agents have been identified, additional considerations should also be weighed. 1. Prosthetic Heart Valves The safety and efficacy of dabigatran in patients with mechanical prosthetic heart valves was evaluated in the REALIGN trial, which was terminated early due to the occurrence of significantly more thromboembolic events, and an excess of major bleeding as compared to warfarin.9 For this reason, dabigatran is contraindicated in this patient population, and should not be used in patients with AF and mechanical heart valves.2,3 (Grade IIb, Level B) Trials for rivaroxaban and apixaban excluded patients with mechanical or bioprosthetic heart valves. Due to the lack of data, factor Xa inhibitors (rivaroxaban, apixaban) should also not be used in patients with AF and a history of heart valve replacement.11,12 (Grade IIb, Level C) 2. Renal Function (Grade IIb, Level C) Recommendations for dose reductions for each agent in renal insufficiency should be followed to provide appropriate dosing for patients. In patients who have a CrCl < 15 mL/min, warfarin is the preferred agent due to the renal dosing parameters of each agent. However, prescribing recommendations now state that patients with end stage kidney disease who are on dialysis may receive apixaban. This recommendation is based on pharmacokinetic and pharmacodynamic data from a small patient data set.12 3. Age (Grade IIb, Level C) In patients who were over 75 years of age, there was a trend towards increased risk of bleeding with dabigatran when compared to warfarin in the RE-LY trial.13 This was further evaluated in a study by Eikelboom et al, that demonstrated higher bleed rates
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TABLE 4. HAS-BLED Risk Assessment Score Factors
Scoring
Hypertension (SBP >160 mmHg)
Score = 0-1: Low risk
Abnormal lab values • Creatinine > 2.26 mg/dL • Bilirubin > 2x the upper limit of normal (ULN) • and AST/ALT/AP > 3x ULN
Score = 2: Moderate risk Score ≥3: High risk
Stroke history Bleeding history or predisposition Labile INRs: Time in Therapeutic Range < 60% Elderly: > 65 years Drugs • EtOH abuse • ASA or NSAID use
in patients 75 years or older independent of their renal function.14 This trend between age and bleeding rates were not observed with other TSOACs.15,16 Due to this data, dabigatran should be avoided in patients who are greater than 75 years old, whereas the other agents may be used if renal function allows. 4. History of GI disease and/or GI bleeding in the past year (Grade IIb, Level C) In the RE-LY trial, the use of dabigatran 150 mg was associated with an increased risk of GI bleeding events compared to warfarin (RR 1.49 vs 1.09, P<0.001). This association was also seen with rivaroxaban versus warfarin in the ROCKET-AF trial (P<0.001).14,15 However, apixaban was shown to have a similar risk of GI bleeding compared to warfarin in the ARISTOTLE trial (P=0.37).16 In patients with a history of GI bleeding, dabigatran and rivaroxaban should be avoided. The algorithm depicted in figure 1. may be used to help facilitate patient stratification based on the above safety considerations, and provides the safest anticoagulant options. Once appropriate anticoagulant options have been identified using the algorithim, further considerations are provided to help narrow in on the most appropriate option for the individual patient. Medication Compliance and Dosing Strategies (Grade IIb, Level C) The TSOACs may be less preferable in patients who occasionally miss doses, as the duration of action is shorter than warfarin. One missed dose of these agents may place www.pswi.org
High bleed risk considerations: • Optimize blood pressure control • Check INRs frequently • Utilize anticoagulation clinic • Focus on fall prevention • Utilize TSOACs
anticoagulant therapy can significantly increase bleeding risk. Bleeding risk compared to stroke risk must be weighed when using concomitant therapy. Additionally, there is very little data on the use of the TSOACs in “triple therapy” regimens. It is recommended that “triple therapy” (aspirin, P2Y12 agents, plus an anticoagulant) or higher dose aspirin (> 100 mg) and anticoagulant should be avoided if possible. If triple therapy is required, warfarin may be preferred over the TSOACs. Intracranial Hemorrhage (Grade IIb, Level C) The TSOACs have been associated with a lower risk of intracranial hemorrhage (ICH) as compared to warfarin, which can make them favorable options when ICH is a concern. In the RE-LY trial, patients randomized to dabigatran had a 0.30% risk of ICH per year, compared to 0.74% risk per year (P<0.001).14 In the ROCKET AF trial, patients randomized to receive rivaroxaban had a 0.5% risk per year of having an ICH, compared to 0.7% risk
a patient at risk for stroke. Due to this risk, the FDA has added a Black Box Warning to all of the TSOACs warning of an increased risk of stroke if the agent is discontinued without adequate anticoagulation with an alternative agent. In patients who rarely achieve target INR range, warfarin may be less preferable, since the patient is not able to consistently maintain a therapeutic level of anticoagulation. Additionally, if it is challenging for patients to FIGURE 1. Algorithm to Facilitate Patient Stratificaion remember warfarin dose adjustments or who require Start multiple tablet strengths to make a daily dose, they may benefit from fixed dosing of Any TSOACs. prosthetic If a patient prefers heart valve? to take a once daily anticoagulant, rivaroxaban YES NO or warfarin would be the preferred agent. Dabigatran CrCl Use Warfarin (mL/min) and apixaban must be dosed twice daily in AF. <15 >15 Patients who utilize pill boxes or medication Age Use Warfarin (years) organizers to improve compliance may prefer using apixaban, rivaroxaban or >75 <75 warfarin. Dabigatran may be used, but it must be History of History of GI bleed? dispensed in blister packs GI bleed? as exposure to open air can compromise its effectiveness. NO YES YES
Combination Antiplatelet Therapy (Grade IIb, Level C) The addition of an antiplatelet medication to
Use Warfarin or apixaban
Use Warfarin, dabigatran, rivaroxaban, or apixaban
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NO
Use Warfarin, rivaroxaban, or apixaban
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per year in patients randomized to receive warfarin (P=0.02).15 Additionally, in the ARISTOTLE trial, those randomized to receive apixaban had a 0.33% risk of ICH per year, as compared to a 0.80% risk per year in those receiving warfarin (P<0.001).16
Phenobarbital, phenytoin, and rifampin) may decrease serum concentrations of these medications. Currently, practitioners are unable to monitor for an increase or decrease in effectiveness when the TSOACs are used with an interacting agent.10,111,12
Administration (Grade IIb, Level C) Dabigatran capsules must be swallowed whole, and cannot be crushed.10 Rivaroxaban, apixaban and warfarin may be crushed and placed down a feeding tube.11,12 However, rivaroxaban cannot be administered via a feeding tube placed distal to the stomach.11
History of dyspepsia (Grade IIb, Level C) In patients who have a history of dyspepsia, dabigatran may not be preferred. Dyspepsia is associated with dabigatran use in up to 11% of patients taking this medication. This agent may be trialed in this patient population, but if worsening dyspepsia occurs, it may be warranted to change to a different agent.10
Monitoring (Grade IIb, Level C) The TSOACs do not require laboratory monitoring of anticoagulation status and may be preferred in patients who dislike frequent lab draws. However, laboratory monitoring of complete blood count, serum creatinine, and liver function tests at baseline, after 3-6 months of therapy and then at least once a year may be considered. Warfarin requires laboratory monitoring of the INR to maintain therapeutic levels. The INR may be checked as frequently as every few days, and once a stable dose is achieved, at least every 4-8 weeks. Warfarin may be less preferable in patients who do not have the means or desire to commit to intensive laboratory monitoring. Drug Interactions (Grade IIb, Level C) Warfarin has many documented drug interactions to consider. Closely following the INR can help to monitor the effects of the drug interactions. However, there are fewer documented drug interactions with TSOACs. All three of the newer agents are substrates of P-glycoprotein (P-gp). The use of P-gp inhibitors (e.g. amiodarone, cyclosporine, ketoconazole, quinidine, verapamil) may increase serum concentrations of the medication, and/or its active metabolites. P-gp inducers (e.g. carbamazepine, dexamethasone, phenytoin, prazosin, rifampin) may decrease the serum concentration of the TSOACs, leading to decreased stroke protection. Additionally, rivaroxaban and apixaban are substrates of CYP3A4. Strong CYP3A4 inhibitors (e.g. azole antifungals, nicardipine, ritonavir) may increase serum concentrations of rivaroxaban and apixaban. Strong CYP3A4 inducers (e.g. carbamazepine, nafcillin,
Financial Considerations (Grade IIb, Level C) While warfarin is the least expensive medication, the cost of INR monitoring should also be considered when weighing the complete cost of therapy. Additionally, all TSOACs have medication assistance programs for patients who qualify, which may make these agents preferred from a cost standpoint.
Conclusion
Atrial fibrillation is an important and growing healthcare issue, and may lead to serious sequelae including stroke. With the advent of the TSOACs, patients who were originally not suitable for warfarin therapy may now be candidates for anticoagulation. Each individual patient should have their stroke and bleeding risks evaluated, with the goal of trying to reduce modifiable risk factors for bleeding. The patient should also be involved in the decision to pursue anticoagulation. If anticoagulation is chosen, these patients should be stratified based on their safety considerations. After safe options have been identified, additional considerations should be evaluated in order to choose the ideal agent. ● Jennifer Garber, PharmD; Pharmacy Practice Resident at the University of Wisconsin Hospital and Clinics, Katie Willenborg, PharmD, BCPS; Clinical Pharmacist at the University of Wisconsin Hospital and Clinics, Erin Robinson, PharmD, CACP; Clinical Pharmacist at the University of Wisconsin Hospital and Clinics, and Anne Rose, PharmD; Clinical Pharmacist and Coordinator of the UW Health Anticoagulation Management Stewardship
Program
References
1. Sellers MB, Newby LK. Atrial fibrillation, anticoagulation, fall risk, and outcomes in elderly patients. Am Heart J. 2011;161(2):241-6. 2. You JJ, Singer DE, Howard PA, Lane DA, Eckman MH, et al. Antithrombotic therapy for atrial fibrillation – antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. CHEST. 2012;141(2)(suppl)e531S-e575S. 3. Camm AJ, Kirchhof P, Lip G, Schotten U, Savelicva I, et al. Guideline for the management of atrial fibrillation. The Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology. Eur Heart J. 2010;31:2369-2429. 4. Wann LS, Curtis AB, January CT, Ellenbogen KA, Lowe JE, et al. 2011 ACCF/ AHA/HRS focused update on the management of patients with atrial fibrillation (updating the 2006 guideline). Heart Rhythm. 2011;8:157-176. 5. Tricoci P, Allen J, Kramer J, Califf R, Smith S. Scientific evidence underlying the ACC/AHA Clinical Practice Guidelines. JAMA. 2009;301(8):831-841. 6. Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, et al. Validation of clinical classification schemes for predicting stroke – results from the national registry of atrial fibrillation. JAMA. 2011;285(22):2864-2870. 7. Lane DA, Lip GY. Use of the CHA2DS2VASc and HAS-BLED scores to aid in decision making for thromboprophylaxis in nonvalvular atrial fibrillation. Circulation. 2012;126(7):860-865. 8. Pisters R, Lane DA, Nueuwlaat R, de Vos CB, Crijns HJ. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in atrial fibrillation: the euro heart survey. CHEST. 2010;138(5):1093-1100. 9. Eikelboom JW, Connolly SJ, Brueckmann M, Granger CB, Kappetein AP, et al. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med. 2013;369(13):1206-1214. 10. Pradaxa® [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; 2013. 11. Xarelto® [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc; 2013. 12. Eliquis® [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2013. 13. Connolly SJ, Ezekowitz MD, Yusuf S, et al; RELY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009 Sep 17;361(12):1139-51. 14. Eikelboom JW, Wallentin L, Connolly SJ, Ezekowitz M, Healey JS, et al. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation – an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial. Circulation. 2011;123:2363-2372. 15. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883-891. 16. Granger CB, Alexander JH, McMurray JJ, et al; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981-992.
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Drug Updates: Oral Anticancer Agents by Jason J. Bergsbaken, PharmD and Mary S. Mably, RPh, BCOP
his review provides a brief overview of some of the most recently approved oral anticancer agents, including clinical trial experience, counseling pearls and summary of place in therapy.
T
60 days of completion of the last therapy (see Table 1).2 Pomalidomide works via a combination of immunomodulatory and cytotoxic effects, as well as cyclooxygenase-2 inhibition. It also inhibits production of osteoclasts, which may benefit patients with myeloma disease in the bones.3
Pomalidomide (PomalystÂŽ)
Clinical Trial Experience
Multiple myeloma remains an incurable disease secondary to eventual resistance to available chemotherapy agents.1 Although the introduction of immunomodulatory drugs (thalidomide and lenalidomide) and proteasome inhibitors (bortezomib) has positively affected survival, new agents are being investigated to overcome resistance and improve outcomes. Pomalidomide, an immunomodulatory drug, was approved by the Food and Drug Administration (FDA) in February 2013 for patients with multiple myeloma who have received at least 2 prior therapies, including lenalidomide and bortezomib and have demonstrated progression on or within www.pswi.org
Pomalidomide was approved based on the efficacy and safety results of CC4047-MM-002, a Phase II, multicenter, randomized, open label trial.2 Patients were randomized to receive either pomalidomide 4 mg orally days 1 through 21 of a 28 day cycle or pomalidomide in the same dose and schedule with dexamethasone 40 mg orally once weekly. Zero patients (0%) achieved complete response (CR) and 8 patients (7.4%) achieved partial response (PR) in the pomalidomide arm. One patient (0.9%) achieved CR and 32 patients (28.3%) achieved PR in the pomalidomide plus dexamethasone arm. Every patient included in this study reported adverse
effects, however many may be attributed to underlying myeloma.4 The dose-limiting toxicity of pomalidomide is primarily myelosuppression.5 Grade 3 or 4 neutropenia has been observed in 26-66% of patients in studies, while anemia and thrombocytopenia are seen less frequently. Other common adverse effects (seen in >10% of patients) are fatigue, constipation, diarrhea, asthenia, nausea, back pain and dyspnea. Thromboembolic events are seen infrequently (<5%) when appropriate prophylaxis or treatment is provided (aspirin, warfarin, heparin, low-molecular weight heparin or clopidogrel).
Counseling Pearls
Pomalidomide should be taken on an empty stomach.5 It may cause fetal harm and is contraindicated in pregnant women; two negative pregnancy tests must be obtained prior to starting therapy. Women must either abstain from sexual intercourse or use two methods of birth control
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Clinical Trial Experience
TABLE 1. Pomalidomide (Pomalyst®)5 Indications
Multiple myeloma, in patients who have received at least 2 prior therapies (including lenalidomide and bortezomib) and have progressed on or within 60 days of completion of the last therapy
Dose
4mg orally on empty stomach once daily on days 1 thru 21 of 28 day cycle
Dose Adjustments
Renal: Avoid if serum creatinine >3.0 mg/dL Hepatic: Avoid if total bilirubin >2.0mg/dL and/or AST/ALT > 3.0 x upper limit of normal
Adverse Drug Effects
Common: Fatigue, asthenia, neutropenia, anemia, dizziness, confusion, constipation, diarrhea, nausea, upper respiratory tract infection, back pain, dyspnea Serious: Pneumonia, sepsis, neutropenic fever
Drug Interactions
Avoid strong inhibitors/inhibitors of CYP1A2, CYP3A4 or P-glycoprotein
How Supplied
4mg capsule, 3mg capsule, 2mg capsule, 1mg capsule
beginning 4 weeks prior to and continuing for at least 4 weeks after therapy. Pregnancy testing must continue weekly for the first month of therapy, and then monthly thereafter with regular menstrual cycles or every 2 weeks if irregular. While taking pomalidomide, men should use a condom during sexual contact with women of childbearing potential; this should continue for 4 weeks after stopping therapy due to the high concentration of this drug seen in semen. Due to the high embryo-fetal risk, pomalidomide is only available through a Risk Evaluation and Mitigation Strategies (REMS) program. The REMS program should include certification of physicians and pharmacists and a signed patientprescriber agreement regarding compliance to program requirements.
BRAF gene, causing downstream activation and proliferation of malignant pathways.7 Dabrafenib is a selective BRAF inhibitor approved for the treatment of unresectable or metastatic melanoma (with BRAF V600E mutation) in May 2013 (see Table 2).8 Dabrafenib is only indicated in patients with BRAF V600E mutation which may be detected via an FDA-approved test. It is the second selective BRAF inhibitor approved with the approval of vemurafenib in 2011; both of which offer improved response rates from previously utilized cytotoxic medications (interferon, dacarbazine, carboplatin, paclitaxel, etc.) in this malignancy. Currently no head-to-head trials between vemurafenib and dabrafenib have been performed.
The safety and efficacy of dabrafenib was evaluated in the BREAK-2 trial among 92 patients with metastatic melanoma.9 Among the 76 patients in this trial positive for BRAF V600E mutation, 45 patients (59%) had a confirmed response to therapy (95%CI 48.2-70.2), including 5 (7%) patients with a CR. Dabrafenib was evaluated against dacarbazine in a randomized, open-label phase III trial conducted in 250 patients with previously untreated BRAF V600E unresectable or metastatic melanoma; median patient age was 52 years.10 Dabrafenib demonstrated a significant increase in progression free survival (PFS) (5.1 versus 2.7 months, p<0.01) and objective response rate versus dacarbazine. The most common adverse events (≥10% incidence) during the trials were hyperkeratosis, alopecia, palmar-plantar erythrodysesthesia (PPES), rash, headache, pyrexia, arthralgia and papilloma.8 Rare, but serious adverse events, included new primary cutaneous or non-cutaneous malignancies, febrile drug reaction, hyperglycemia and hemolytic anemia in patients with G6PD deficiency. Trametinib, an oral MEK inhibitor, is another targeted kinase inhibitor which works within a similar pathway to dabrafenib; it has been recently FDA-approved as a single agent and in combination with dabrafenib for treatment of BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma.8 Information on this medication along with combination therapy is outside the scope of this review however
TABLE 2. Dabrafenib (Tafinlar®)8
Summary
Pomalidomide is a new agent used in the treatment of multiple myeloma after the progression on at least 2 prior therapies, including bortezomib and lenalidomide. Pomalidomide approval is based on response rate and an improvement in survival or symptoms has not yet been demonstrated.
Dabrafenib (Tafinlar®)
In 2013, approximately 77,000 individuals will be diagnosed with melanoma with 9,480 deaths.6 Approximately 50% of melanomas are caused by an oncogenic mutation of the
Indication
Unresectable or metastatic melanoma (BRAF V600E mutation)
Dosing
150 mg orally twice daily; 1 hour before or 2 hours after meals
Dose Adjustments
Renal: No recommendations Hepatic: No recommendations
Adverse Drug Effects
Common: Hyperkeratosis, alopecia, palmarplantar erythrodysesthia (PPES), rash, headache, pyrexia, arthralgia, papilloma Serious: New primary cutaneous malignancies, febrile drug reaction, hemolytic anemia in G6PD deficiency, hyperglycemia, uveitis, iritis
Drug Interactions
Avoid strong inhibitors/inhibitors of CYP3A4, CYP2C8 and P-glycoprotein
How Supplied
75 mg capsule, 50 mg capsule
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TABLE 3. Afatinib (Gilotrif®)15 Indication
First-line treatment of metastatic non-small cell lung cancer (NSCLC) with exon 19 deletions or exon 21 substitution epidermal growth factor receptor (EGFR) mutations
Dosing
40mg orally once daily on an empty stomach
Dose Adjustments
Renal: Monitor with moderate to severe renal failure (creatinine clearance < 60mL/min); adjust if not tolerated Hepatic: Monitor with severe hepatic impairment; adjust if not tolerated
Adverse Drug Effects
Common: Diarrhea, stomatitis, rash/dermatitis, dry skin, paronychia, pruritis, decreased appetite Serious: Pulmonary toxicity/interstitial lung disease-like reactions, sepsis, pneumonia, fatal hepatic impairment, left ventricular dysfunction
Drug Interactions
P-glycoprotein inhibitors (dose of afatinib should be reduced) and inducers (dose of afatinib should be increased by 10mg as tolerated)
How Supplied
40mg tablet, 30mg tablet, 20 mg tablet
this therapy is another potential option in this patient population.
Counseling Pearls
Dabrafenib is initially dosed at 150 mg orally twice daily; dose should be taken 1 hour before or 2 hours after meals.8 Dabrafenib may cause fetal harm and be excreted in breast milk thus risks should be communicated. Women must either abstain from sexual intercourse or use highly effective contraception during treatment and continuing for at least 2 weeks after therapy. Patients should be advised of risk of new primary malignancies and to report any new skin lesions, unusual bleeding, difficulty breathing, swelling, visual disturbances or fever.
Summary
Dabrafenib is a selective BRAF inhibitor approved for the treatment of unresectable or metastatic melanoma (with BRAF V600E mutation) based off of PFS and overall response benefit.8 Additional treatment options, including combination therapy with trametinib, an oral MEK inhibitor, are under investigation in this patient population.
Afatinib (Gilotrif®)
Lung cancer accounts for 14% of all cancer diagnoses and more deaths than any other cancer.11 It is divided into 2 main types, small- cell lung cancer and non-small cell lung cancer (NSCLC) which comprises about 85% of cases.12 The prognosis is poor for metastatic disease, with the 5 year survival rate only about 4%.11 Due to www.pswi.org
dismal survival rates, new treatments are being pursued, such as targeted therapies to known mutations occurring in NSCLC tumor cells. Afatinib, an oral tyrosine kinase inhibitor (TKI), was approved by the FDA in July 2013 for the first-line treatment of patients with metastatic NSCLC whose tumors express epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 substitution mutations as detected by an FDA-approved test (see Table 3).13
Clinical Trial Experience
The approval of afatinib was based on the phase III LUX-Lung 3 study comparing first line afatinib against cisplatin plus pemetrexed; the first study to compare firstline targeted therapy against pemetrexedcontaining chemotherapy in this patient population.13 This study demonstrated increased PFS in in the afatinib group
(11.1 versus 6.9 months, p<0.01).14 Additionally, patients treated with afatinib had statistically significant and clinically meaningful improvements in response rate and lung cancer symptoms; however, no difference in overall survival was seen. Toxicities most commonly seen with afatinib in trials include diarrhea, seen in approximately 96% of patients, including severe diarrhea (Grade 3 or greater) in 15%.15 Other commonly observed adverse effects include stomatitis, rash, paronychia, dry skin, decreased appetite and pruritus. Less common but serious side effects included hepatic toxicity, keratitis, left ventricular dysfunction, and interstitial lung disease.
Counseling Pearls
Afatinib should be taken on an empty stomach, 1 hour before or 2 hours after eating.15 Patients should be provided with an anti-diarrheal agent, such as loperamide, for self-administration beginning at the first sign of diarrhea and continuing until loose bowel movements do not occur for at least 12 hours. Afatinib should be avoided in pregnant or nursing women and highly effective contraception should be used during therapy and for at least 2 weeks after stopping treatment.
Summary
Afatinib is a recently approved oral TKI indicated for the treatment of patients with metastatic LSCLC whose tumors express EGFR exon 19 deletions or exon 21 substitution mutations.13 Afatinib improved PFS in patients with identified mutations and is generally well-tolerated
TABLE 4. Ibrutinib (Imbruvica®)20 Indication
Mantle cell lymphoma (MCL) chronic lymphocytic leukemia (CLL) in patients who have received at least one prior therapy
Dosing
MCL: 560 mg (four 140 mg capsules) by mouth once daily CLL: 420 mg (three 140 mg capsules) by mouth once daily
Dose Adjustments
Renal: No recommendations Hepatic: Caution in patients with AST or ALT ≥ 3.0 x upper limit of normal
Adverse Drug Effects
Common: diarrhea, fatigue, peripheral edema, nausea, constipation, rash, abdominal pain, thrombocytopenia, neutropenia, anemia
Drug Interactions
Substrate of CYP3A4; avoid strong CYP3A4 inhibitors/inducers; modify dose with moderate CYP3A4 inhibitors
How Supplied
140 mg capsule
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with the most common adverse events being gastrointestinal or dermatologic in nature.
Ibrutinib (Imbruvica®)
Mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) are distinctive malignancies both characterized by unregulated cell division and defective B-cell receptor signaling.16 Each of these diseases may be indolent, however patients presenting with stage III/IV disease requiring aggressive treatment, typically with cytotoxic chemotherapy.17 Novel targeted therapies directed against B-cell receptor signaling are under investigation. Ibrutinib is a Bruton’s TKI approved in November 2013 for the treatment of patients with relapsed or refractory MCL; it received additional approval in February 2014 for relapsed or refractory CLL (see Table 4).18 Ibrutinib works by impairing B-cell antigen receptor signaling and disrupting the proliferation and survival of malignant B-cells.19 It is dosed orally once daily; starting dose for MCL is 560 mg daily and CLL is 420 mg daily.20
Clinical Trial Experience
The safety and efficacy of ibrutinib in previously treated MCL was evaluated in a phase 2 open-label study of 111 patients.21 Patients received ibrutinib 560mg orally daily until disease progression or unacceptable toxicity (medium treatment duration 8.3 months); median age was 68 years. The primary endpoint, overall response rate (ORR), was 65.8% (95%CI 56.2-74.5). Secondary endpoints included PFS, which was estimated at 13.9 months. Ibrutinib efficacy and safety in previously treated CLL was evaluated in an open-label phase I/II study of 48 patients.20 Patients received ibrutinib 420mg orally daily until disease progression or unacceptable toxicity (median treatment duration 15.6 months). The primary endpoint, ORR, was 58.3% (95%CI 43.272.4). All responses were partial; no patient achieved a CR. Ibrutinib was well tolerated during these studies; most common adverse effects (≥20% of patients, all grades) were diarrhea, fatigue, nausea, peripheral edema, constipation, upper respiratory tract infection and vomiting.20 Grade 3 or 4 adverse events included pneumonia,
hypertension, atrial fibrillation and skin infection; hematologic grade 3 or 4 toxicities included neutropenia, thrombocytopenia and anemia. Adverse reactions led to medication discontinuation in 9% and 10% of MCL and CLL patients respectively.
Counseling Pearls
Iburtinib should be taken orally once daily with or without food at approximately the same time each day.20 Dosing is interrupted for grade 3 non-hematologic or grade 4 hematologic toxicities; the medication may be restarted at a reduced dose or ultimately discontinued if toxicities persist. Ibrutinib should be avoided with strong CYP3A4 inhibitors/inducers; dose may be modified with moderate CYP3A4 inhibitors. Ibrutinib may cause fetal harm and be excreted in breast milk thus risks should be communicated. Patients should report any signs/symptoms of unusual bleeding or infections.
Summary
Ibrutinib is a newly FDA-approved oral TKI indicated for patients with refractory or relapsed MCL or CLL.20 It has demonstrated rates of overall response and relatively low rates of discontinuation, however has yet to demonstrate a significant improvement in overall survival. ● Jason J. Bergsbaken, PharmD, Pharmacy Coordinator, Regional Oncology Services; University of Wisconsin Hospital and Clinics; Madison, WI 53792. Mary S. Mably, RPh, BCOP, Pharmacy Oncology Coordinator, PGY2 Oncology Pharmacy Residency Program Director; University of Wisconsin Hospital and Clinics; Madison, WI 53792 Disclosure: The author(s) declare no real or potential conflicts or financial interest in any product or service entioned in the manuscript, including grants, equipment, medications, employment, gifts, and honoraria.
References
1. National Comprehensive Cancer Network. NCCN clinical practice guidelines: multiple myeloma v2.2014. 2. Pomalidomide. Food and Drug Administration website. Available at: http://www. fda.gov/drugs/informationondrugs/approveddrugs/ ucm339286.htm. Accessed June 30, 2014. 3. Lacy MQ, Tefferi A. Pomalidomide therapy
for multiple myeloma and myelofibrosis: an update. Leuk Lymphoma. 2011;52(4):560-566. 4. Richardson PG, Siegel DS, Vij R, Hofmeister CC, et al. Pomalidomide alone or in combination with low-dose dexamethasone in relapsed and refractory multiple myeloma: a randomized phase 2 study. Blood. 2014;123(12):1826-1832. 5. Pomalidomide [Pomalyst®](package insert). Summit NCC, 2014. 6. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63(1):11-30. 7. Millington GW. Mutations of the BRAF gene in human cancer, by Davies et al. (Nature 2002; 417: 949-54). Clin Exp Dermatol. 2013;38(2):222-223. 8. Dabrafenib (Tafinlar®) [package insert]. Research Triangle Park NG, Inc., 2013. 9. Ascierto PA, Minor D, Ribas A, Lebbe C, et al. Phase II trial (BREAK-2) of the BRAF inhibitor dabrafenib (GSK2118436) in patients with metastatic melanoma. J Clin Oncol. 2013;31(26):3205-3211. 10. Hauschild A, Grob JJ, Demidov LV, Jouary T, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380(9839):358-365. 11. American Cancer Society. Cancer facts and figures 2013. Atlanta: American Cancer Society; 2013. 12. National Comprehensive Cancer Network. NCCN clinical practice guidelines: non-small cell lung cancer v.4.2014. 13. Afatinib. Food and Drug Administration website. Available at: www.fda.gov/Drugs/ InformationOnDrugs/ApprovedDrugs/ ucm360574.htm. Accessed June 27, 2014. 14. Sequist LV, Yang JC, Yamamoto N, O'Byrne K, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31(27):3327-3334. 15. Dabrafenib [Gilotrif®] (package insert). Ridgefield CBIPI, 2013. 16. Harris NL, Jaffe ES, Stein H, Banks PM, et al. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood. 1994;84(5):1361-1392. 17. McDermott J, Jimeno A. Ibrutinib for the treatment of chronic lymphocytic leukemia and mantle cell lymphoma. Drugs Today (Barc). 2014;50(4):291-300. 18. Ibrutinib. U.S. Food and Drug Administration Website. www.fda.gov/Drugs/ InformationOnDrugs/ApprovedDrugs/ ucm374857. htm. Accessed June 27, 2014. 19. Wiestner A. Targeting B-Cell receptor signaling for anticancer therapy: the Bruton's tyrosine kinase inhibitor ibrutinib induces impressive responses in B-cell malignancies. J Clin Oncol. 2013;31(1):128-130. 20. Ibrutinib [Imbruvica®] (package insert). Sunnyvale CP, Inc., 2013. 21. Wang ML, Rule S, Martin P, Goy A, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2013;369(6):507-516.
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pharmacypractice feature
Statins, Statins, and more Statins! Goodbye treating to a specific number, hello treating our individual patients! Goodbye Framingham calculations, hello... mobile app?! by Meghann R. Luc, PharmD, Michelle K. Bury, PharmD, John M. Dopp, PharmD CE FOR PHARMACISTS
Objectives
COMPLETE ARTICLE AND CE EXAM AVAILABLE ONLINE: WWW.PSWI.ORG
• List new blood pressure treatment goals from the JNC8 and American Society of Hypertension (ASH) guidelines • Identify appropriate first-line drug therapies for different patient populations as recommended by the JNC8 and ASH guidelines • Describe the key target populations that will benefit from LDL-C lowering as recommended by the new lipid guidelines • Identify patients who are candidates for high-intensity and moderate-intensity statin treatment • Describe the new recommendations for use of non-statins in management of lipids
Editor's Note:
The highly anticipated American College of Cardiology Foundation/American Heart Association Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults and the Evidence-Based Guideline for the Management of High Blood Pressure in Adults ( JNC8…better known as JNC-Late) were released in late 2013 and early 2014, respectively. The following two articles provide an overview of the recommendations that impact pharmacists and patients. Combined, the content will form this issue’s pharmacist continuing education activity. Assessment questions can be found on page 38.
I
n alignment with their goals, the American College of Cardiology (ACC) and the American Heart Association (AHA) collaborated with the National Heart, Lung, and Blood Institute (NHLBI) and other organizations to develop clinical practice guidelines to reduce cardiovascular risk. These guidelines focus on the assessment of cardiovascular disease risk, lifestyle modifications to reduce cardiovascular disease risk, and management of blood cholesterol, overweight and obesity in adults. The Blood Cholesterol Expert Panel appointed by ACC/AHA was charged to use data from randomized controlled trials (RCTs), systematic reviews, and meta-
analyses (with atherosclerotic cardiovascular disease (ASCVD) outcomes) to update the clinical practice recommendations for the treatment of blood cholesterol levels to reduce ASCVD risk. Like the new hypertension guidelines, these lipid guidelines addressed three critical questions. The three questions were:1 1. What is the evidence for LDL-C and Non-HDL-C goals for the secondary prevention of ASCVD? 2. What is the evidence for LDL-C and non-HDL-C goals for the primary prevention of ASCVD? 3. For primary and secondary prevention, what is the impact on lipid levels, effectiveness, and safety
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of specific cholesterol-modifying drugs used for lipid management in general and in selected subgroups?
New Aspects of the Guidelines
Previously, the third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) (ATP III) recommended titrating cholesterollowering drug therapy to achieve target LDL-C or non-HDL-C levels.2,3 In contrast, during their extensive systematic evidence review for new guidelines, the Expert Panel was unable to find evidence showing that titrating drug therapy to a specific target was associated with a reduction in ASCVD outcomes.1 In addition, they found that the benefits of nonstatin therapies do not provide acceptable ASCVD risk reduction compared to their potential for adverse effects. However, they did find evidence that supports the use of the appropriate intensity of HMG-CoA reductase inhibitor (statin) therapy to reduce both primary and secondary ASCVD risk in those most likely to benefit. Statins provided a consistent reduction in ASCVD events across the spectrum of baseline LDL-C levels ≥ 70 mg/ dL, with the exception of individuals with New York Heart Association (NYHA) class II-IV heart failure or receiving maintenance hemodialysis. The guidelines identified four groups of patients from RCTs who will derive benefits from statins. The three levels of intensity identified for statins includes high-intensity statin therapy (lowering LDL-C by approximately ≥ 50%), moderate-intensity statin (lowering LDL-C by approximately 30 to <50%), or low-intensity statin (lowering LDL-C by approximately <30%) (Table 1). The guidelines also provide recommendations based on RCTs to monitor for safety and efficacy of statin therapy, and provide expert guidance on management of statin-related adverse effects.1
TABLE 1. High, Moderate, and Low-Intensity Statin Therapy High-Intensity Statin Daily dose lowers LDL-C by approximately ≥50%) Atorvastatin 40-80 mg Rosuvastatin 20-40 mg
Moderate-Intensity Statin
Low-Intensity Statin
Daily dose lowers LDL-C by approximately 30 to <50%
Daily dose lowers LDL-C by approximately <30%
Atorvastatin 10-20 mg Rosuvastatin 5-10 mg Simvastatin 20-40 mg Pravastatin 40-80 mg Lovastatin 40 mg
Simvastatin 10 mg Pravastatin 10-20 mg Lovastatin 20 mg Fluvastatin 20-40 mg Pitavastatin 1 mg
Fluvastatin XL 80 mg Fluvastatin 40 mg BID Pitavastatin 2-4 mg * Statins and doses listed in italics are approved by the US Food and Drug Administration but were not tested in the Randomized Controlled Trials reviewed Adapted from reference 1
FIGURE 1. Major recommendations for statin therapy for ASCVD prevention * May not be a candidate for high-intensity statin therapy if there are contraindications to therapy, conditions or drug-drug interactions influencing statin safety, or a history of statin intolerance Figure used with permission from reference 1.
Statin Benefit Groups
Four patient groups were identified that would most likely benefit from statin therapy and the level of statin intensity initiated should be based on patient-specific considerations (Figure 1). These four groups include:1 1. Individuals with clinical ASVCD: www.pswi.org
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TABLE 2. Lifestyle Recommendations Topic General Diet
Strength of Recommendation
Recommendation 1. Emphasize intake of vegetables, fruits, and whole grains 2. Include low-fat dairy products, poultry, fish, legumes, nontropical vegetable oils, and nuts 3. Limit intake of sweets, sugar-sweetened beverages, and red meats 4. Adapt to appropriate calorie requirements, personal and cultural food preferences, and
Grade A - Strong
nutrition therapy for other medical conditions 5. May be achieved by following the DASH dietary pattern, USDA food pattern, or AHA diet Saturated Fat Intake
1. Reduce percent of calories from saturated fat 2. Attempt to limit saturated fat intake to 5-6% of total caloric intake
Grade A - Strong
Trans fat Intake
Reduce percent of calories from trans fat
Grade A - Strong
Physical Activity
Advise adults to engage in aerobic physical activity 3-4 times per week for an average of 40 minutes and involve a moderate-to-vigorous intensity of physical activity
Grade A - Strong
Adapted from reference 4
Clinical ASCVD is defined as a history of acute coronary syndrome, myocardial infarction, stable or unstable angina, coronary or other arterial revascularization, stroke, transient ischemic stroke, or peripheral arterial disease presumed to be of atherosclerotic origin. 2. Individuals with primary elevations of LDL-C ≥ 190 mg/dL 3. Individuals with diabetes aged 40-75 years with LDL-C 70 to 189 mg/dL and without clinical ASCVD 4. Individuals without clinical ASCVD or diabetes with LDL-C 70 to 189 mg/dL and estimated 10-year ASCVD risk ≥ 7.5%
Calculating Risk
ATP III recommended the use of the Framingham risk assessment to determine the estimated 10-year ASCVD risk. The new guidelines now recommend the use of the web-based ASCVD Risk Estimator, which is also available via mobile phone application for increased accessibility. The components needed to compute risk include:1 • Gender
• • • • • • • •
Age Race* Total cholesterol HDL-cholesterol Systolic blood pressure Diabetes* Treatment of hypertension Smoker
(*New considerations for the 10-year ASCVD Risk Estimator)
Calculation of cardiovascular risk allows recommendation of statin therapy to patients most likely to derive cardiovascular benefit.
Monitoring
For patients with clinical ASCVD, evaluation prior to statin therapy initiation includes obtaining a fasting lipid panel, alanine transaminase (ALT), and consideration of other secondary causes of dyslipidemia or conditions that may influence statin safety.1 Secondary causes may include diet, drugs, diseases, or disorders and altered states of metabolism. A baseline creatine kinase level may be useful in those with increased risk for adverse muscle events. For patients without clinical ASCVD, the same parameters must
be evaluated prior to statin initiation with the addition of hemoglobin A1c, if diabetes status is unknown.1 After initiation of statin therapy, a second fasting lipid panel should be obtained in 4-12 weeks to determine the patient’s adherence. Assessments should be performed every 3-12 months as clinically indicated thereafter. If patients experience intolerable adverse effects from the recommended intensity of statin therapy and other potential contributors have been resolved, the dose of the statin should be lowered or switched to an alternative appropriate statin. Routine measurement of creatine kinase is not recommended for individuals receiving statin therapy, and is only recommended for patients with muscle symptoms. Patients taking statins should be asked about muscle symptoms, such as muscle weakness or fatigue, aching, pain, tenderness, cramps, or stiffness.1
Use of Nonstatins
As mentioned above, the Expert Panel was unable to find data supporting the use of nonstatin medications as monotherapy or in addition to statin therapy to further reduce ASCVD events. The new guidelines recommend the addition of nonstatins in a select group of high risk individuals (those with clinical ASCVD, a baseline LDL-C ≥ 190 mg/dL, and diabetes) who either:1 • Have a less-than-anticipated response to statins • Are unable to tolerate a less-thanrecommended intensity of a statin • Who are completely statin intolerant
Lifestyle Management
One area consistent with the previous ATP III guidelines is the emphasis that lifestyle modifications remain a critical component of ASCVD risk reduction both before and during the use of cholesterollowering medication therapies. These guidelines reference the 2013 Lifestyle Management Work Group Guideline developed by ACC and AHA for appropriate recommendations for diet, weight management, physical activity, and tobacco cessation.4 Specific lifestyle recommendations are made for individuals who would benefit from LDL-C lowering in the new Lifestyle Mangement Group Guidelines (Table 2.).
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Controversy
The significant changes in these new guidelines have understandably generated much discussion and controversy. The shift away from the Framingham to a new risk assessment tool has been the most contentious issue. The biggest concern is the recommendation to use an assessment tool whose accuracy in predicting risk has not been prospectively evaluated. Given this concern, the ACC/AHA risk assessment tool was used to calculate 10-year risks of ASCVD events and was compared to actual event rates in the Women’s Health Study, the Physician’s Health Study, and the Women’s Health Initiative Observational Study by Harvard researchers.5 In all three cohorts, the new ACC/AHA risk prediction algorithm (endorsed by these guidelines) significantly overestimated (by 75-150%) observed risks of cardiovascular events.5 Similar findings are reported by the guideline developers themselves, in analysis of the risk assessment in subject cohorts from the Multi-Ethnic Study of Atherosclerosis.1,5 The Harvard researchers state that it is possible that up to 40-50% of patients who qualify for statins based on the new guidelines, do not actually have risk thresholds that exceed 7.5%.5 www.pswi.org
Overestimation of risk may lead to certain patients being falsely labeled as candidates for statin therapy.
Summary and Recommendations for Practitioners To navigate the new lipid guidelines and apply them to patients, clinicians will have to adjust their past perceptions and strategies. First, determine if a patient meets criteria for one of the four groups likely to benefit from statin therapy. Second, determine if the patient is a candidate for high-intensity or moderateintensity statin. To calculate the 10-year cardiovascular risk, the formula can be used online or in an app that can be downloaded onto a smartphone or tablet device. Finally, recommend appropriate monitoring for efficacy and toxicity and instruct patients about lifestyle recommendations as appropriate. With these new guideline recommendations, practitioners will need to shift focus away from LDL targets and increasingly focus on reducing overall cardiovascular risk. ● Meghann Luc, Pharm.D. is a PGY-2 Critical Care Pharmacy Resident at Froedtert Hospital,
Milwaukee, WI. Michelle Bury, Pharm.D. is a PGY2 Psychiatric Pharmacy Resident at the Clement J. Zablocki VA Medical Center, Milwaukee, WI. John M. Dopp, Pharm.D. is an Associate Professor (CHS) at the University of Wisconsin School of Pharmacy.
References
1. Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;00:000-000. 2. National Cholesterol Education Panel. 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) final report. Circulation. 2002;106(25):3143–421. 3. Grundy SM, Cleeman JI, Merz CN et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110(2):227–39. 4. Eckel RH, Jakicic JM, Ard JD, et al. 2013 AHA/ ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association task force on practice guidelines. Circulation. 2013;00:000–000. 5. Ridker PM, Cook NR. Statins: new American guidelines for prevention of cardiovascular disease. Lancet. 2013;382(9907):1762-65.
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Better Late than Never? 2014 Evidence-Based Guidelines for the Management of High Blood Pressure in Adults by the Eighth Joint National Committee (JNC8) by Michelle K. Bury, PharmD, Meghann R. Luc, PharmD, John M. Dopp, PharmD
T
en years after the publication of the previous hypertension guidelines, JNC8 was finally published in December, 2013. The new JNC8 guidelines faced the challenge of incorporating a large number of recent studies into guidelines that are comprehensive, yet relatively easy for clinicians to understand, interpret, and implement in their practices. Following the new standards for the development of “rigorous and trustworthy clinical practice guidelines” outlined by the Institute of Medicine,1 the JNC8 Committee evaluated thousands of studies for possible inclusion and integration into the guidelines. The Committee applied a high standard for the type of studies that meet criteria to be used as evidence in the guidelines, and only used evidence from randomized, controlled trials (RCT).2 In contrast to the more comprehensive approach taken by the JNC7 guidelines, the JNC8 panel focused on three high-priority questions related to hypertension management. The three critical questions were:2 1. In adults with hypertension (HTN), does initiating antihypertensive pharmacologic therapy at specific blood pressure (BP) thresholds improve health outcomes? 2. In adults with HTN, does treatment with antihypertensive pharmacologic therapy to a specified BP goal lead to improvements in health outcomes? 3. In adults with HTN, do various antihypertensive drugs or drug classes differ in comparative benefits and harms on specific health outcomes?
Studies whose results were incorporated into the JNC8 guidelines were subject to strict criteria.2 Studies were only included if they had more than 100 subjects, had more than one year follow-up period, and if they included the following health outcomes:2 • Overall mortality, mortality from cardiovascular disease, mortality from chronic kidney disease • Myocardial infarction, heart failure, hospitalization from heart failure, stroke • Coronary or other (carotid, renal, and lower extremity) revascularization • End-stage renal disease, doubling of serum creatinine level, halving of glomerular filtration rate Compared to JNC7, the new guidelines are decidedly less prescriptive, which could be somewhat unsettling for practitioners looking for specific clinical guidance. For example, whereas the JNC7 guidelines defined hypertension and pre-hypertension, JNC8 only defines thresholds for pharmacologic treatment. Furthermore, the JNC8 guidelines specify antihypertensive medication classes based on race or chronic kidney disease, but not other compelling indications as JNC7 did. Lastly, JNC8 focused on the three high-priority questions and did not address blood pressure measurement methods, patient evaluation, secondary hypertension, and hypertension in special populations as were addressed in JNC7.3 As a result, topics previously addressed were not covered in JNC8, leaving practitioners wondering if or how they should change aspects of hypertension management.
JNC8 Recommendations
The JNC8 guidelines consist of nine recommendations derived from the analysis of randomized controlled trials.3 The nine recommendations are summarized in Table 1. The previous hypertension goal of <140/90 mmHg for most adults (≥ 18 years old) remains the recommended
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goal for patients less than 60 years old. However, JNC8 now has relaxed the blood pressure goal for individuals age 60 and older to <150/90 mmHg. Previously recommended blood pressure goals for patients with diabetes and chronic kidney disease have changed from <130/80 mmHg to <140/90 mmHg. For the first time, the guidelines recommend specific drug classes for black and nonblack patients. The recommended initial drug treatment options for black patients are thiazide-type diuretics or calcium channel blockers. For nonblack patients, preferred initial drug treatment options include thiazide-type diuretics, angiotensin converting enzyme (ACE)-Inhibitors, angiotensin receptor blockers (ARBs), or calcium channel blockers (CCB). Of note, beta-blockers are not recommended as first line agents unless a compelling indication is present. Compelling indication recommendations from JNC7 were not included in the JNC8 guidelines, with the exception of ACEInhibitors or ARBs for chronic kidney disease.
TABLE 1. 2014 Recommendations for Management of Hypertension
Population
Global BP (mmHg)*
Strength of Recommendation
General > 60yo
<150/90 (Grade A)
Grade A
Initial Drug Treatment Options
For > 60yo, if antihypertensive medication therapy results in lower SBP, <140 mmHg, adjustment is not needed if treatment is well tolerated without adverse effects (Grade E)
Grade A for 3059yo for DBP goal & treatment General < 60yo
<140/90
Grade E for 1829yo for DBP goal & treatment Grade E for <60yo for SBP goal & treatment
Diabetes
<140/90
Nonblack: thiazide-type diuretic, ACEI, ARB, or CCB (Grade B) ** Black: thiazide-type diuretic or CCB (Grade B for nondiabetics & Grade C for diabetics)
1. Increasing the blood pressure goal will most likely reduce intensity of blood pressure management efforts in a large number of patients at high risk for cardiovascular events. www.pswi.org
If BP goal is not reached within one month of treatment, increase the dose of the initial medication or add a second medication (thiazide, CCB, or ACEI/ ARB) (Grade E) Medications from other antihypertensive classes can be used if the recommended classes are contraindicated or more than 3 drugs are needed to reach BP goal (Grade E)
Grade E for > 18yo
Controversy
The JNC8 guidelines left many practitioners puzzled by several recommendations that relax blood pressure goals and are far less comprehensive than previous guidelines. The guidelines are admittedly less comprehensive because of the focus on the three clinical questions. However, JNC7 was more detailed, leaving practitioners asking if JNC7 recommendations are still appropriate for topics not addressed by JNC8. For topics not addressed by JNC8, clinicians can find guidance in the guidelines published by the American Society of Hypertension in January 2014.4 Relaxing the blood pressure goals for adults aged 60 and above was controversial even amongst members of the JNC8 Committee. Shortly after the JNC8 guidelines were released, a paper from the dissenting authors was published outlining their concerns.5 The authors did not agree with the change in blood pressure goals and cite the following justifications:
Notes
Do not use an ACEI & an ARB together in the same patient (Grade E) General: ACEI or ARB (Grade B) Black (with proteinuria): ACEI or ARB
CKD
<140/90
Grade E for > 18yo
Black (without proteinuria): thiazide-type diuretic, CCB, ACEI, or ARB. If an ACEI or ARB is not used as the initial drug, then an ACEI or ARB can be added as a second-line drug if necessary to achieve goal BP >75yo: thiazide-type diuretic, CCB, ACEI, or ARB
Applies for <70yo with an eGFR/mGFR <60 mL/ min/1.73 m2 & to all ages with albuminuria defined as >30 mg of albumin/g of creatinine at any level of GFR (Grade E) For >70yo with eGFR <60 mL/min/1.73 m2, therapy should be individualized, taking into consideration factors such as frailty, comorbidities, and albuminuria (Grade E) Specified (No recommendation made)
Abbreviations: BP, blood pressure; SBP, systolic blood pressure; DBP, diastolic blood pressure; ACEI, angiotensinconverting enzyme inhibitor; ARB, angiotensin receptor blocker; CCB, calcium channel blocker; CKD, Chronic Kidney Disease; yo, year old; yrs, years; GFR, Strength of Recommendations: Grade A, Strong; Grade B, Moderate; Grade C, Weak; Grade D, Recommendation Against; Grade E, Expert Opinion; Grade N, No Recommendation for or against. * Initiate pharmacologic treatment to lower BP below stated goal. ** Not reviewed for recommendation: RCTs that were limited to specific non-hypertensive populations, such as those with coronary artery disease or heart failure.
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TABLE 3. Lifestyle Recommendations
Topic Diet
Recommendation Emphasize intake of vegetables, fruits, & whole grains
NHLBI Strength of Recommendation Grade A – Strong
Include low-fat dairy products, poultry, fish, legumes, nontropical vegetable oils, & nuts Limit intake of sweets, sugar-sweetened beverages, & red meats Adapt to appropriate calorie requirements, personal and cultural food preferences, and nutrition therapy for other medical conditions Recommended plans: DASH dietary pattern, USDA Food Pattern, or the AHA Diet Combine the DASH dietary pattern with lower sodium intake Sodium Intake
Low sodium intake
Grade A – Strong
Consume <2400 mg of sodium/day
Grade B – Moderate
Further reduction of sodium intake <1500 mg/day is desirable since it is associated with even greater reduction in BP Reduce intake by at least 1000 mg/day since that will lower BP, even if the desired daily sodium intake is not yet achieved Physical Activity
Advise adults to engage in aerobic physical activity 3-4 times per week for an average 40 minutes & involve a moderate-to-vigorous intensity of physical activity
Grade B – Moderate
Abbreviations: NHLBI, National Heart, Lung, and Blood Institute; DASH, Dietary Approaches to Stop Hypertension; USDA, U.S. Department of Agriculture; AHA, American Heart Association; BP, blood pressure Adapted from reference 11
2. The evidence supporting an increase in the blood pressure goal is not robust and is not consistent with evidence that was used for recommending a blood pressure goal <140 mmHg in patients < age 60. 3. Relaxing the blood pressure goal in patients ≥ age 60 may reverse the decline in cardiovascular disease that has occurred over the last few decades. 4. Observational studies and randomized controlled studies that were not included for consideration in JNC8 support a goal of <140
mmHg. Additionally, National Health and Nutrition Examination Survey (NHANES) data indicates that only 50% of hypertensive patients are at their blood pressure goal.6,7 NHANES showed that median SBPs in hypertensive adults > age 60 were 152 and 136 mmHg in untreated and treated hypertensive patients, respectively.8 As a result, increasing the systolic blood pressure goal to <150 mmHg would mean increased blood pressures in treated patients and almost half of the untreated patients would remain untreated.5 Lastly, a SBP goal <140 mmHg for adults > age 60 years has been recommended by a number of other recent
blood pressure guidelines, including the American Society of Hypertension,4 and blood pressure guidelines in the United Kingdom,9 and Europe.10
Lifestyle Modifications
The JNC8 panel did not conduct an evidence review of lifestyle recommendations. Instead, JNC8 advocates lifestyle recommendations based on the 2013 Lifestyle Work Group,11 authors of the 2013 AHA/ ACC Guideline on Lifestyle Management to Reduce Cardiovascular Risk (Table 3). Recommendations in Table 3. were specifically designed for adults (< age 80) who would benefit from blood pressure lowering.
Comparison to the American Society of Hypertension 20132014 Statement Shortly after JNC8 was published the American Society of Hypertension (ASH) and International Society of Hypertension released clinical practice guidelines to provide a straightforward approach to manage hypertension.4 Unlike JNC8, the ASH guidelines clearly define hypertension and classify prehypertension (120-139 mm Hg systolic blood pressure (SBP) or 80-89 mmgHg diastolic blood pressure (DBP)), stage 1 (140-149 mm Hg SBP or 90-99 mmHg DBP) and stage 2 (≥160 mmHg SBP or ≥100 mmHg DBP) hypertension.4 They discuss the epidemiology of HTN, review the causes and diagnostic methods, and elaborate on special issues with hypertension in black patients. Blood pressure goals recommended in the ASH guidelines are the same as the JNC8 recommendations with one exception (Table 4). While JNC8 recommends a blood pressure goal <150/90 mmHg for adults aged 60 or greater, ASH guidelines recommend <150/90 mmHg for adults age 80 or greater. The ASH guidelines recommend this goal based upon results of the HYVET study where blood pressure lowered below 150/90 mmHg reduced mortality and cardiovascular events in patients age 80 and above.12 Like JNC8, ASH guidelines recommend thiazide-type diuretics or calcium channel blockers for black patients
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treatment guidelines, guide practitioners, and help improve patient outcomes.
TABLE 4. ASH Treatment Goals Population
BP goal (mmHg)
Summary and Recommendations for Practitioners
General population, including patients with diabetes, CKD, and CAD
<140/90 (Some experts still recommend <130/80 for patients if albuminuria is present in patients with CKD)
> 80yo (without CKD or diabetes)
<150/90
< 50yo
DBP <90 (<140/90 or <130/80 can be considered in young adults)
Abbreviations: CKD, chronic kidney disease; CAD, coronary artery disease; BP, blood pressure; DBP, diastolic blood pressure.
as initial therapy for Stage 1 hypertension. The ASH guidelines recommend ACEInhibitors or ARBs as initial therapy of Stage 1 hypertension in nonblack patients < age 60 years, and CCB or thiazides in nonblack patients > age 60 years. For Stage 2 hypertension, ASH guidelines recommend starting with two drugs; CCB or thiazide AND ACE-Inhibitor or ARB. The ASH guidelines included drug recommendations for treating hypertension associated with other conditions (Table 5). These recommendations are similar to the “compelling indications” in JNC7 and may serve as guidance for practitioners when treating other conditions with hypertension. The ASH guidelines make specific lifestyle recommendations that advocate many of the same principles as JNC8. General recommendations include: weight loss, salt reduction, regular aerobic exercise, and smoking cessation. Interestingly, ASH guidelines recommend up to two alcoholic beverages per day to help protect against cardiovascular events; however, greater amounts of alcohol can increase BP. Alcohol should be limited to one drink per day for women.
JNC8 only considered randomized, controlled trials in crafting the guidelines. Observational studies, systematic reviews, and meta-analyses were not reviewed and included for consideration (as they were in JNC7). Lastly, there were a lack of high quality randomized controlled trials to guide recommendations. As a result, numerous recommendations (six) are based on expert opinion only and lack high quality evidence.5 There is one take-away from the JNC8 guidelines that should be universally acknowledged; more high-quality studies are needed to strengthen hypertension
TABLE 5. ASH Drug Therapy Recommendations for Hypertension Associated with Other Conditions
Associated Condition
First Recommendation
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Second Recommendation (if needed to reduce BP <140/90 mmHg)
Third Recommendation (if needed to reduce BP <140/90 mmHg)
Diabetes
ACE-inhibitor or ARB In black patients CCB or thiazides may be used first
CCB or thiazide diuretic* In black patients, if start with a CCB or thiazide, ACE-I or ARB should be second
Alternative 2nd drug (CCB or thiazide)
Stroke History
ACE-inhibitor or ARB
Thiazide diuretic or CCB For diuretics, indapamide has good evidence to support its use
Alternative 2nd drug (CCB or thiazide)
Clinical Coronary Artery Disease
Beta-blocker + ARB or ACE-inhibitor
CCB or thiazide diuretic
Alternative 2nd drug (CCB or thiazide)
Chronic Kidney Disease
ACE-inhibitor or ARB
CCB or thiazide diuretic If eGFR < 40mL/min, may need loop diuretic
Alternative 2nd drug (CCB or thiazide)
Heart Failure
Independent of blood pressure, heart failure patients typically should receive and ARB or ACE-inhibitor + Beta-blocker + diuretic + spironolactone
Limitations
It is important to remember that guidelines remain recommendations and not practice mandates. Clinical judgment should supersede individual guideline recommendations based on individual patient circumstances and clinician expert opinion. The JNC8 Guidelines explicitly state that they are not comprehensive, as they only focused on three questions. The scope of topics is small and JNC8 did not focus on many specific comorbidities.
Practitioners expecting JNC8 guidelines to resemble previous guidelines were undoubtedly surprised at both the limited scope and overhauled structure of JNC8. The focus on three strategic, clinical questions limited the focus of the guidelines, and consideration of only RCTs limited evidence used for recommendations. JNC8 is simpler than previous guidelines with one blood pressure goal for all patients (<140/90 mmHg) except patients ≥ age 60 without diabetes or chronic kidney disease (<150/90 mmHg). Thus, only age is used to determine blood pressure goals when following JNC8 recommendations. Specific drug classes are not explicitly recommended as initial therapy for most patients. The exceptions are black patients (thiazides or CCB) and individuals with chronic kidney disease (ACE-Inhibitor or ARB). For topics not addressed by JNC8, practitioners may find more comprehensive recommendations in the 2013-2014 American Society of Hypertension guidelines.4 ●
BP, blood pressure; ACE, angiotensin converting enzyme; ARB, angiotensin receptor blocker; CCB, calcium channel blocker Adapted from reference 4
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Meghann Luc, Pharm.D. is a PGY-2 Critical Care Pharmacy Resident at Froedtert Hospital, Milwaukee, WI. Michelle Bury, Pharm.D. is a PGY2 Psychiatric Pharmacy Resident at the Clement J. Zablocki VA Medical Center, Milwaukee, WI. John M. Dopp, Pharm.D. is an Associate Professor (CHS) at the University of Wisconsin School of Pharmacy.
References
1. Institute of Medicine. Standards for Developing Trustworthy Clinical Practice Guidelines. Institute of Medicine of the National Academies website. http://www.iom.edu/Reports/2011/ Clinical-Practice-Guidelines-We-Can-Trust/ Standards.aspx. Accessed May 12, 2014. 2. James PA, Oparil S, Carter BL, et al. 2014 Evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311(5):507-20. 3. Chobanian AV, Bakris GL, Black HR, et al. National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289(19):2560-72. 4. Weber MA, Schiffrin EL, White WB, et al. Clinical practice guidelines for the management of hypertension in the community: a statement by the American Society of Hypertension and the International Society of Hypertension. J Clin Hypertens. 2014;16(1):14-26. 5. Wright JT Jr, Fine LJ, Lackland DT, et al. Evidence supporting a systolic blood pressure goal of less than 150 mm Hg in patients aged 60 years or older: the minority view. Ann Intern Med. 2014;160(7):499-503. 6. Nwanko T, Yoon SS, Burt V, Gu Q. Hypertension among adults in the United States: National Health and Nutrition Examination Survey, 2011-2012. NCHS data brief no. 133. Hyattsville, MD: National Center for Health Statistics; 2013. 7. Guo F, He D, Zhang W, Walton RG. Trends in prevalence, awareness, management, and control of hypertension among United States adults, 1999 to 2010. J Am Coll Cardiol. 2012;60(7):599-606. 8. Wright JD, Hughes JP, Ostchega Y, et al. Mean systolic and diastolic blood pressure in adults aged 18 and over in the United States, 20012008. Natl Health Stat Report. 2011:1-22, 24. 9. National Institute for Health and Clinical Excellence. Hypertension: clinical management of primary hypertension in adults. Clinical guidelines: methods, evidence and
recommendations. London: National Institute for Health and Clinical Excellence; 2011. 10. Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2013;31(7):1281-1357. 11. Eckel RH, Jakicic JM, Ard JD, et al. 2013 AHA/ ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association task force on practice guidelines. Circulation. 2013;00:000–000. 12. Beckett NS, Peters R, Fletcher AE, et al. Treatment of hypertension in patients 80 years of age or older. N Engl J Med. 2008;358(18):1887-98.
4.
5.
Assessment Questions 1.
2.
3.
According to the JNC8 recommendation, the blood pressure goal for a 58 year-old male patient with diabetes is: a. <150/90 mmHg b. <130/80 mmHg c. <140/90 mmHg d. <140/80 mmHg e. <130/90 mmHg According to the JNC8 recommendation, what would be the best antihypertensive medication for a 47 year-old black patient who is newly diagnosed with hypertension? a. Lisinopril b. Metoprolol c. Furosemide d. Candesartan e. Amlodipine Relaxing the blood pressure goal to <150/90 mmHg in patients > age 60 years was controversial because some of the guideline authors felt that the evidence supporting an increase in the blood pressure goal was not consistent with evidence used for recommending a blood pressure goal <140/90 mmHg in patients <age 60 years. a. True b. False
6.
In contrast to the JNC8 guidelines, the American Society of Hypertension guidelines recommend specific medications for first line treatment of hypertension associated with other medical conditions. Which of the following is a correct recommended medication matched with a medical condition? a. Stroke history – ACE-inhibitor b. Chronic Kidney Disease – thiazide diuretic c. Diabetes – beta blocker d. Clinical Coronary Artery Disease – Loop diuretic e. All of the above are correct The updated AHA/ACC/NHLBI lipid guidelines identify four groups of patients who will derive benefits from statin therapy. Which of the following is a group of patients that will derive this benefit? a. Patients with clinical atherosclerotic cardiovascular disease b. Patients with LDL-C concentrations ≥190 mg/dL c. Patients 45-70 years old with LDL-C concentrations 70-189 mg/dL without atherosclerotic cardiovascular disease d. Patients without atherosclerotic cardiovascular disease or diabetes with LDL-C 70-189 mg/dL and 10- year cardiovascular risk ≥ 7.5% e. All of the above are correct Which of the following recommendations in the new lipid guidelines represents a significant change from the previous (ATP III) lipid guidelines? a. New guidelines recommend use of the Braunwald risk assessment to determine 20-year cardiovascular risk b. New guidelines do not recommend a specific LDL-C target concentration to guide statin therapy c. The new guidelines recommend routine measurement of creatinine kinase concentrations in patients receiving statins d. New guidelines make specific recommendations to use niacin in monotherapy
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7.
8.
e. None of the above Which of the following patients do the new lipid guidelines recommend high-intensity statins for? a. A 78 year-old patient with ASCVD b. A 54 year-old patient with diabetes and a 10-year ASCVD risk of 5% c. A 50 year-old patient without ASCVD with an LDL-C of 212 mg/dL d. A 63 year-old patient with diabetes and a 10-year ASCVD risk of 7% e. None of the above This activity met my educational needs. a. Met all educational needs related to the topic b. Met some educational needs related to the topic c. Did not meet my educational needs
Did the activity meet the stated learning objectives? 9.
Identify appropriate first-line drug therapies for different patient populations as reccommended by the JNC8 and ASH guidelines a. Yes b. No
10. Describe the key target populations that will benefit from LDL-C lowering as
recommended by the new lipid guidelines a. Yes b. No
15.
11. Identify patients who are candidates for high-intensity and moderate-intensity statin treatment a. Yes b. No 12. Describe the new recommendations for use of non-statins in management of lipids
How useful was the educational material? a. Very useful b. Somewhat useful c. Not useful
16. How effective were the learning methods used for this activity? a. Very effective b. Somewhat effective c. Not effective 17. Learning assessment questions were appropriate a. Yes b. No
13. How would you rate the ability of the author(s) to provide a high-quality educational activity? a. Very capable, article was well-written and provided good information b. Somewhat capable, most information was presented well c. Needs improvement
18. Was/were the author(s) free of bias? a. Yes b. No 19. If you answered “no” to question 10, please comment. 20. Please indicate the amount of time it took you to complete the educational activity (including the assessment questions).
14. How would you rate the ability of the author(s) to provide a high-quality educational activity? a. Very capable, article was well-written and provided good information b. Somewhat capable, most information was presented well c. Needs improvement
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The Journal 39
In moderate to severe Alzheimer’s disease
Once-daily 28 mg+AChEI* demonstrated improvements in cognition and global function1
■ In a 24-week study of 677 outpatients with moderate to severe Alzheimer’s disease on stable AChEI therapy, adding NAMENDA XR 28 mg was statistically significantly superior to placebo+AChEI (using an LOCF† analysis) in the co-primary endpoints of1: — Cognition as measured by the Severe Impairment Battery (2.6 unit mean difference)1 — Global function as measured by the Clinician’s Interview-Based Impression of Change (0.3 unit mean difference)1 ■ Studied in combination with leading AChEIs (donepezil, galantamine, or rivastigmine)1 ■ No titration required when switching from NAMENDA® (memantine HCI) to NAMENDA XR1 ■ The most commonly observed adverse reactions occurring at a frequency of at least 5% in NAMENDA XR-treated patients and at a higher frequency than placebo, respectively, were headache (6% vs 5%), diarrhea (5% vs 4%), and dizziness (5% vs 1%)1
Help slow symptom progression. Because there’s so much to lose. There is no evidence that NAMENDA XR or an AChEI prevents or slows the underlying disease process in patients with Alzheimer’s disease.
*AChEI=acetylcholinesterase inhibitor. † LOCF=last observation carried forward.
NAMENDA XR® (memantine hydrochloride) extendedrelease capsules are indicated for the treatment of moderate to severe dementia of the Alzheimer’s type.
Important Safety Information Contraindications ■ NAMENDA XR is contraindicated in patients with known hypersensitivity to memantine hydrochloride or to any excipients used in the formulation. Warnings and Precautions ■ NAMENDA XR should be used with caution under conditions that raise urine pH (including alterations by diet, drugs and the clinical state of the patient). Alkaline urine conditions may decrease the urinary elimination of memantine, resulting in increased plasma levels and a possible increase in adverse effects. ■ NAMENDA XR has not been systematically evaluated in patients with a seizure disorder. Adverse Reactions ■ The most commonly observed adverse reactions seen in patients administered NAMENDA XR (28 mg/day) in a controlled clinical trial, defined as those occurring at a frequency of at least 5% in the NAMENDA XR group and at a higher frequency than placebo were headache (6% vs 5%), diarrhea (5% vs 4%), and dizziness (5% vs 1%). Drug Interactions ■ No drug-drug interaction studies have been conducted with NAMENDA XR, specifically. The combined use of NAMENDA XR with other NMDA antagonists (amantadine, ketamine, or dextromethorphan) has not been systematically evaluated and such use should be approached with caution.
Dosage and Administration ■ The recommended starting dose of NAMENDA XR is 7 mg once daily. The recommended target dose is 28 mg once daily. The dose should be increased in 7 mg increments to 28 mg once daily. The minimum recommended interval between dose increases is one week, and only if the previous dose has been well tolerated. The maximum recommended dose is 28 mg once daily. ■ It is recommended that a patient who is on a regimen of 10 mg twice daily of NAMENDA tablets be switched to NAMENDA XR 28 mg once-daily capsules the day following the last dose of a 10 mg NAMENDA tablet. There is no study addressing the comparative efficacy of these 2 regimens. ■ It is recommended that a patient with severe renal impairment who is on a regimen of 5 mg twice daily of NAMENDA tablets be switched to NAMENDA XR 14 mg once-daily capsules the day following the last dose of a 5 mg NAMENDA tablet. Special Populations ■ NAMENDA XR should be administered with caution to patients with severe hepatic impairment. ■ A target dose of 14 mg/day is recommended in patients with severe renal impairment (creatinine clearance of 5-29 mL/min, based on the CockcroftGault equation). For more details, please visit www.NamendaXRHCP.com. Please see brief summary of Prescribing Information on adjacent page. Reference: 1. NAMENDA XR™ (memantine HCl) Prescribing Information. Forest Pharmaceuticals, Inc., St Louis, MO.
NAMENDA XR® is a registered trademark of Merz Pharma GmbH & Co. KGaA. ©2014 Forest Laboratories, LLC
NXR19469
08/14
NOT FOR REPRODUCTION
B:11.25”
T:11”
S:9.75”
NAMENDA XR (memantine hydrochloride) extended release capsules Brief Summary of full Prescribing Information Initial U.S. Approval: 2003 INDICATIONS AND USAGE: NAMENDA XR (memantine hydrochloride) extended-release capsules are indicated for the treatment of moderate to severe dementia of the Alzheimer’s type. CONTRAINDICATIONS: Hypersensitivity - NAMENDA XR is contraindicated in patients with known hypersensitivity to memantine hydrochloride or to any excipients used in the formulation [See Description in the full Prescribing Information]. WARNINGS AND PRECAUTIONS: Genitourinary Conditions - Conditions that raise urine pH may decrease the urinary elimination of memantine resulting in increased plasma levels of memantine. Seizures - NAMENDA XR has not been systematically evaluated in patients with a seizure disorder. In clinical trials of memantine, seizures occurred in 0.3% of patients treated with memantine and 0.6% of patients treated with placebo. ADVERSE REACTIONS: Clinical Trial Data Sources - NAMENDA XR was evaluated in a doubleblind placebo-controlled trial treating a total of 676 patients with moderate to severe dementia of the Alzheimer’s type (341 patients treated with NAMENDA XR 28 mg/day dose and 335 patients treated with placebo) for a treatment period up to 24 weeks. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions Leading to Discontinuation - In the placebo-controlled clinical trial of NAMENDA XR [See Clinical Studies in the full Prescribing Information], which treated a total of 676 patients, the proportion of patients in the NAMENDA XR 28 mg/day dose and placebo groups who discontinued treatment due to adverse events were 10.0% and 6.3%, respectively. The most common adverse reaction in the NAMENDA XR treated group that led to treatment discontinuation in this study was dizziness at a rate of 1.5%. Most Common Adverse Reactions The most commonly observed adverse reactions seen in patients administered NAMENDA XR in the controlled clinical trial, defined as those occurring at a frequency of at least 5% in the NAMENDA XR group and at a higher frequency than placebo were headache, diarrhea and dizziness. Table 1 in the full Prescribing Information lists treatment-emergent adverse reactions that were observed at an incidence of ≥ 2% in the NAMENDA XR treated group and occurred at a rate greater than placebo. The first value displays the percentage of patients in the placebo group (N=335) and the second shows the percentage in the group receiving 28 mg of NAMENDA XR (N=341). Gastrointestinal Disorders: Diarrhea (4%, 5%), Constipation (1%, 3%), Abdominal pain (1%, 2%), Vomiting (1%, 2%); Infections and infestations: Influenza (3%, 4%); Investigations: Weight, increased (1%, 3%); Musculoskeletal and connective tissue disorders: Back pain (1%, 3%); Nervous system disorders: Headache (5%, 6%), Dizziness (1%, 5%), Somnolence (1%, 3%); Psychiatric disorders: Anxiety (3%, 4%), Depression (1%, 3%), Aggression (1%, 2%); Renal and urinary disorders: Urinary incontinence (1%, 2%); Vascular disorders: Hypertension (2%, 4%), Hypotension (1%, 2%). Vital Sign Changes - NAMENDA XR and placebo groups were compared with respect to (1) mean change from baseline in vital signs (pulse, systolic blood pressure, diastolic blood pressure, and weight) and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. There were no clinically important changes in vital signs in patients treated with NAMENDA XR. A comparison of supine and standing vital sign measures for NAMENDA XR and placebo in Alzheimer’s patients indicated that NAMENDA XR treatment is not associated with orthostatic changes. Laboratory Changes - NAMENDA XR and placebo groups were compared with respect to (1) mean change from baseline in various serum chemistry, hematology, and urinalysis variables and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. These analyses revealed no clinically important changes in laboratory test parameters associated with NAMENDA XR treatment. ECG Changes - NAMENDA XR and placebo groups were compared with respect to (1) mean change from baseline in various ECG parameters and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. These analyses revealed no clinically important changes in ECG parameters associated with NAMENDA XR treatment. Other Adverse Reactions Observed During Clinical Trials of NAMENDA XR - Following is a list of treatment-emergent adverse reactions reported from 750 patients treated with NAMENDA XR for periods up to 52 weeks in double-blind or open-label clinical trials. The listing does not include those events already listed in Table 1, those events for which a drug cause was remote, those events for which descriptive terms were so lacking in specificity as to be uninformative, and those events reported only once which did not have a substantial probability of being immediately life threatening. Events are categorized by body system. Blood and Lymphatic System Disorders: anemia. Cardiac Disorders: bradycardia, myocardial infarction. Gastrointestinal Disorders: fecal incontinence, nausea. General Disorders: asthenia, fatigue, gait disturbance, irritability, peripheral edema, pyrexia. Infections and Infestations: bronchitis, nasopharyngitis, pneumonia, upper respiratory tract infection, urinary tract infection. Injury, Poisoning and Procedural Complications: fall. Investigations: weight decreased. Metabolism and Nutrition Disorders: anorexia, dehydration, decreased appetite, hyperglycemia. Musculoskeletal and Connective Tissue Disorders: arthralgia, pain in extremity. Nervous System Disorders: convulsion, dementia Alzheimer’s type, syncope, tremor. Psychiatric Disorders: agitation, confusional state, delirium, delusion, disorientation, hallucination, insomnia, restlessness. Respiratory, Thoracic and Mediastinal Disorders: cough, dyspnea. Memantine Immediate Release Clinical Trial and Post Marketing Spontaneous Reports - The following additional adverse reactions have been identified from previous worldwide experience with memantine (immediate release) use. These adverse reactions have been chosen for inclusion because of a combination of seriousness, frequency of reporting, or potential causal connection to memantine and have not been listed elsewhere in labeling. However, because some of these adverse reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship between their occurrence and the administration of memantine. These events include: Blood and Lymphatic System Disorders: agranulocytosis, leukopenia (including neutropenia), pancytopenia, thrombocytopenia, thrombotic thrombocytopenic purpura. Cardiac Disorders: atrial fibrillation, atrioventricular block (including 2nd and 3rd degree block), cardiac failure, orthostatic hypotension, and torsades de pointes. Endocrine Disorders: inappropriate antidiuretic hormone secretion. Gastrointestinal disorders: colitis, pancreatitis. General disorders and administration site conditions: malaise, sudden death. Hepatobiliary Disorders: hepatitis (including abnormal hepatic function test, cytolytic and cholestatic hepatitis), hepatic failure. Infections and infestations: sepsis. Investigations: electrocardiogram QT prolonged, international normalized ratio increased. Metabolism and Nutrition Disorders: hypoglycaemia, hyponatraemia. Nervous System Disorders: convulsions (including grand mal), cerebrovascular accident, dyskinesia, extrapyramidal disorder, hypertonia, loss of consciousness, neuroleptic malignant syndrome, Parkinsonism, tardive dyskinesia, transient ischemic attack. Psychiatric Disorders: hallucinations (both visual and auditory), restlessness, suicidal ideation. Renal and Urinary Disorders: acute renal failure (including abnormal renal function test), urinary retention. Skin Disorders: rash, Stevens Johnson syndrome. Vascular Disorders: pulmonary embolism, thrombophlebitis, deep venous thrombosis.
The following adverse events have been reported to be temporally associated with memantine treatment and are not described elsewhere in the product labeling: aspiration pneumonia, bone fracture, carpal tunnel syndrome, cerebral infarction, chest pain, cholelithiasis, claudication, depressed level of consciousness (including rare reports of coma), dysphagia, encephalopathy, gastritis, gastroesophageal reflux, intracranial hemorrhage, hyperglycemia, hyperlipidemia, ileus, impotence, lethargy, myoclonus, supraventricular tachycardia, and tachycardia. However, there is again no evidence that any of these additional adverse events are caused by memantine. DRUG INTERACTIONS: No drug-drug interaction studies have been conducted with NAMENDA XR, specifically. Use with other N-methyl-D-aspartate (NMDA) Antagonists - The combined use of NAMENDA XR with other NMDA antagonists (amantadine, ketamine, and dextromethorphan) has not been systematically evaluated and such use should be approached with caution. Effect of Memantine on the Metabolism of Other Drugs - In vitro studies conducted with marker substrates of CYP450 enzymes (CYP1A2, -2A6, -2C9, -2D6, -2E1, -3A4) showed minimal inhibition of these enzymes by memantine. In addition, in vitro studies indicate that at concentrations exceeding those associated with efficacy, memantine does not induce the cytochrome P450 isozymes CYP1A2, -2C9, -2E1 and -3A4/5. No pharmacokinetic interactions with drugs metabolized by these enzymes are expected. Pharmacokinetic studies evaluated the potential of memantine for interaction with donepezil (See Use with Cholinesterase Inhibitors) and bupropion. Coadministration of memantine with the AChE inhibitor donepezil HCl does not affect the pharmacokinetics of either compound. Memantine did not affect the pharmacokinetics of the CYP2B6 substrate bupropion or its metabolite hydroxybupropion. Effect of Other Drugs on Memantine - Memantine is predominantly renally eliminated, and drugs that are substrates and/or inhibitors of the CYP450 system are not expected to alter the pharmacokinetics of memantine. A clinical drug-drug interaction study indicated that bupropion did not affect the pharmacokinetics of memantine. Drugs Eliminated via Renal Mechanisms - Because memantine is eliminated in part by tubular secretion, coadministration of drugs that use the same renal cationic system, including hydrochlorothiazide (HCTZ), triamterene (TA), metformin, cimetidine, ranitidine, quinidine, and nicotine, could potentially result in altered plasma levels of both agents. However, coadministration of memantine and HCTZ/TA did not affect the bioavailability of either memantine or TA, and the bioavailability of HCTZ decreased by 20%. In addition, coadministration of memantine with the antihyperglycemic drug Glucovance® (glyburide and metformin HCl) did not affect the pharmacokinetics of memantine, metformin and glyburide. Furthermore, memantine did not modify the serum glucose lowering effect of Glucovance®, indicating the absence of a pharmacodynamic interaction. Drugs That Make the Urine Alkaline - The clearance of memantine was reduced by about 80% under alkaline urine conditions at pH 8. Therefore, alterations of urine pH towards the alkaline condition may lead to an accumulation of the drug with a possible increase in adverse effects. Urine pH is altered by diet, drugs (e.g. carbonic anhydrase inhibitors, sodium bicarbonate) and clinical state of the patient (e.g. renal tubular acidosis or severe infections of the urinary tract). Hence, memantine should be used with caution under these conditions. Drugs Highly Bound to Plasma Proteins - Because the plasma protein binding of memantine is low (45%), an interaction with drugs that are highly bound to plasma proteins, such as warfarin and digoxin, is unlikely [See Drug Interactions]. Use with Cholinesterase Inhibitors - Coadministration of memantine with the AChE inhibitor donepezil HCl did not affect the pharmacokinetics of either compound. In a 24-week controlled clinical study in patients with moderate to severe Alzheimer’s disease, the adverse event profile observed with a combination of memantine immediate-release and donepezil was similar to that of donepezil alone. USE IN SPECIFIC POPULATIONS: Pregnancy - Pregnancy Category B: There are no adequate and well-controlled studies of NAMENDA XR in pregnant women. NAMENDA XR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Memantine given orally to pregnant rats and pregnant rabbits during the period of organogenesis was not teratogenic up to the highest doses tested (18 mg/kg/day in rats and 30 mg/kg/day in rabbits, which are 6 and 21 times, respectively, the maximum recommended human dose [MRHD] on a mg/m2 basis). Slight maternal toxicity, decreased pup weights and an increased incidence of non-ossified cervical vertebrae were seen at an oral dose of 18 mg/kg/day in a study in which rats were given oral memantine beginning pre-mating and continuing through the postpartum period. Slight maternal toxicity and decreased pup weights were also seen at this dose in a study in which rats were treated from day 15 of gestation through the post-partum period. The no-effect dose for these effects was 6 mg/kg, which is 2 times the MRHD on a mg/m2 basis. Nursing Mothers - It is not known whether memantine is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when memantine is administered to a nursing mother. Pediatric Use - The safety and effectiveness of memantine in pediatric patients have not been established. DRUG ABUSE AND DEPENDENCE: Memantine is not a controlled substance. Memantine is a low to moderate affinity uncompetitive NMDA antagonist that did not produce any evidence of drug-seeking behavior or withdrawal symptoms upon discontinuation in 3,254 patients who participated in clinical trials at therapeutic doses. Post marketing data, outside the U.S., retrospectively collected, has provided no evidence of drug abuse or dependence. OVERDOSAGE: Signs and symptoms most often accompanying overdosage with other formulations of memantine in clinical trials and from worldwide marketing experience, alone or in combination with other drugs and/or alcohol, include agitation, asthenia, bradycardia, confusion, coma, dizziness, ECG changes, increased blood pressure, lethargy, loss of consciousness, psychosis, restlessness, slowed movement, somnolence, stupor, unsteady gait, visual hallucinations, vertigo, vomiting, and weakness. The largest known ingestion of memantine worldwide was 2 grams in an individual who took memantine in conjunction with unspecified antidiabetic medications. This person experienced coma, diplopia, and agitation, but subsequently recovered. One patient participating in a NAMENDA XR clinical trial unintentionally took 112 mg of NAMENDA XR daily for 31 days and experienced an elevated serum uric acid, elevated serum alkaline phosphatase, and low platelet count. No fatalities have been noted with overdoses of memantine alone. A fatal outcome has very rarely been reported when memantine has been ingested as part of overdosing with multiple drugs; in those instances, the relationship between memantine and a fatal outcome has been unclear. Because strategies for the management of overdose are continually evolving, it is advisable to contact a poison control center to determine the latest recommendations for the management of an overdose of any drug. As in any cases of overdose, general supportive measures should be utilized, and treatment should be symptomatic. Elimination of memantine can be enhanced by acidification of urine. Manufactured for: Manufactured by: Forest Pharmaceuticals, Inc. Forest Laboratories Ireland Ltd Subsidiary of Forest Laboratories, Inc. St. Louis, MO 63045 Licensed from Merz Pharmaceuticals GmbH Revised: April 2013 62-12000315-BS-A-RMC8791-APR13 Please also see full Prescribing Information at www.namendaxr.com
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pharmacypractice feature
TECHNICIAN CE:
Specialty Pharmacy and the Role of the Pharmacy Technician by April Weaver, PharmD, Amy O’Kroley, CPhT, and Brandon Harkonen, CPhT
T
CE FOR TECHNICIANS
he terms “specialty pharmacy” and “specialty medications” have become increasingly prevalent in the pharmacy field within the last 5-10 years. Have you stopped to consider what this terminology means? Surprisingly, there is no standardized definition of a “specialty medication”. Generally speaking, however, these are medications which are difficult to manufacture or administer, may require specialized patient monitoring, and may have Food and Drug Administrative (FDA) mandated strategies in place to control and monitor their use.1 As you might expect, these medications tend to be expensive. For instance, Medicare Part D categorizes a medication as “specialty” if its negotiated allowed price is more than $600 per month.2 Specialty pharmacies have been developed as a way to ensure optimal management of the specialty pharmaceuticals. Per the Specialty Pharmacy Association of America, specialty pharmacies dispense FDA approved medications that are coupled with services
Objectives
COMPLETE ARTICLE AND CE EXAM AVAILABLE ONLINE: WWW.PSWI.ORG
• Describe common characteristics of specialty medications • Identify current trends in specialty pharmacy • Discuss opportunities for pharmacy technician contributions to specialty medication
designed to expedite therapy initiation, adherence, dosing, medication effectiveness and appropriateness.3
Specialty Medications
Specialty pharmaceuticals are used to treat chronic, serious or life-threatening disease ranging from cancer, multiple sclerosis and rheumatoid arthritis to rare genetic conditions such as hemophilia. They are formulated to be delivered orally, as a self-injection, or a physicianadministered infusion. Many of these medications are biologics derived from living cells cultured in a laboratory which contributes to the high cost and difficulty of manufacturing. Table 1 lists some of the
more common specialty medications by disease. Many of the current specialty medications do not have a low-cost generic equivalent available. In order to encourage the development of generic equivalents, the FDA has recently created a new approval pathway for clinically equivalent versions of biological therapies. Proponents of this idea hope that the clinically equivalent medications approved through this pathway (known as biosimilars) will drive down pricing for specialty medications. However, given the complexity involved in manufacturing biologics, price decreases are not likely to be of the same magnitude as that seen with current generics.
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Additionally, some health care providers are concerned biosimilars will not achieve the same results as the original product since the active ingredient may differ. Coverage of specialty medications can occur under the medical or pharmaceutical benefit of the health plan depending on whether the medication is administered in clinic or obtained through a pharmacy for self-administration. Express Scripts/ Medco and CVS/Caremark are among the top three companies that dispense and track specialty medications. The most recent Express Scripts drug trend report claims approximately half of the US specialty drug spending is currently billed through the pharmacy benefit.4 Specialty medications for inflammatory conditions, multiple sclerosis and cancer made up over 50% of the specialty spend for both CVS/Caremark and Express Scripts in 2013.4,5
Distribution and Access
Manufacturers or insurers can choose to limit which pharmacies can dispense their specialty medication which is why sometimes you are not able to fill a patient’s specialty medication at your pharmacy. In such situations, pharmacies must choose to negotiate for a signed contract in order to be allowed to dispense the medication. A signed contract can include information regarding: 1. Product pricing – the amount for which the pharmacy agrees to purchase the specialty product 2. Payment terms – agreement detailing when an invoice will be paid and any discounts or late fees the pharmacy may be subjected to 3. Data requirements – the pharmacy may be required to provide the manufacturer or insurer with information related to the dispensing of the product and/or clinical services provided as part of the agreement From the manufacturer or insurer’s perspective, limited distribution of a specialty medication can minimize or eliminate distribution costs while ensuring that patients on the medication are wellcared for and monitored. Therefore, a retail pharmacy may not be able to dispense a specialty medication until they prove they can meet the requirements of the manufacturer or insurer. From www.pswi.org
the pharmacy’s perspective, obtaining access to a specialty medication increases pharmacy profit and allows for a share in the growing specialty market. Not all specialty medications are subject to limited distribution. For example, many HIV medications are able to be dispensed by any pharmacy. Some of these medication names may be more familiar to you.
Monitoring
A lot of specialty medications require monitoring to achieve maximum benefit. Specialty pharmacies typically have medication management programs set up to provide patient education and answer questions. The education received through a specialty pharmacy may be more detailed than other pharmacies because the pharmacists and other health care professionals at the specialty pharmacy have received specialized training on the medications. Additionally, specialty pharmacies usually schedule periodic phone calls with patients to verify adherence and ensure effectiveness of the medication therapy. Through implementation
of these programs, patients are less likely to miss doses or misunderstand administration or storage requirements for their specialty medication. This leads to better management of the patient’s chronic condition and decreased costs for the insurer.
Specialty Medication Trends
Why is it so important to have a basic understanding of specialty pharmacy? According to IMS Health, specialty medications accounted for 69% of total spending on new brand name drugs in 2013 while overall specialty medications accounted for 30% of the consumer drug spending but only 2.3% of total prescriptions.6 In 2018 six of the ten bestselling drugs by revenue are projected to be specialty drugs, compared with five drugs in 2012 and three drugs in 2010.7 New developments in oncology, Hepatitis C, autoimmune diseases and HIV are expected to increase spending on specialty drugs up to 63% between 2014-2016.4 Generally speaking, CVS/Caremark predicts that specialty spending will quadruple by 2020 and account for about $402 billion a year in sales.5 Given these astronomical healthcare costs, it is imperative that specialty medication therapy is properly managed.
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Express Scripts predicts that the percentage of specialty medications billed through the pharmacy benefit will also increase over the next few years.4 This is especially relevant given that brand medications continue to increase in price, even after adjustment for inflation, as compared to generic medications which have decreased in price.4 Given that drug price is factored into the pharmacy’s reimbursement rate, pharmacy’s that dispense specialty medications and other brand name drugs will generate more profit than those pharmacies which do not.
TABLE 1. Clinical Trials of Blood Pressure Lowering Strategies in Patients with Diabetes Common Specialty Pharmaceutical Disease State
Common Specialty Pharmaceutical Agents
Copay Card/Program Options for Patient with Commercial Coverage
Inflammatory Conditions
Humira® (adalimumab) Enbrel® (etanercept) Stelera® (ustekinumab) Cimzia® (certolizumab) Simponi® (golimumab) Methotrexate
Humira Protection Plan® Enbrel Support® Stelara Support Program® CIMplicity Program® SimponiOne Program® Humira Protection Plan®
Multiple Sclerosis
Copaxone® (glatiramer) Avonex® (interferon beta-1a) Rebif® (interferon beta-1a) Gilenya® (fingolimod) Tecfidera® (dimethyl fumarate)
Shared Solutions® Active Access® MS Lifelines® Gilenya Co-Pay Support® Active Access®
Specialty Pharmacy – Role of the Pharmacy Technician
Cancer
Gleevec® (imatinib) Xeloda® (capecitabine) Revlimid® (lenalidomide)
Gleevec Co-Pay Assistance Program® Disease-specific® Celgene Co-Pay Program®
As specialty pharmacy products continue to become prominent players in the marketplace, opportunities for pharmacy staff to provide comprehensive patient services increase. Pharmacists are able to offer unparalleled services through comprehensive case management, patient education, and device training. Pharmacy technicians can complement pharmacists’ services and play a key role in expediting the Prior Authorization (PA) process by acting as an intermediary resource for clinic staff, insurance, and patients. This can be achieved by real-time benefits investigation, determining pharmacy preference (based on the insurance plan), and optimizing patient out-of-pocket cost.
HIV
Atripla® (efavirenz/emtricitabine/ tenofovir) Truvada® (emtricitabine/tenofovir) Norvir® (ritonavir) Isentress® (reltegravir) Viread® (tenofovir)
GILEAD Co-Pay Coupon® GILEAD Co-Pay Coupon® AbbVie Patient Assistance Foundation® Merck Multiuse savings Coupon® GILEAD Co-Pay Coupon®
Growth Deficiency
Norditropin Flexpro® (somatropin) Genotropin® (somatropin) Humatrope® (somatropin) Nutropin AQ® (somatropin) Omnitrope® (somatropin)
Nordisure® Pfizer Bridge Program® Humatrope Reimbursement Center® Nutropin GPS® OmniSource®
Hepatitis C
Olysio® (simperevir) Sovaldi® (sofosbuvir)
Olysio Savings Program® Sovaldi Co-Pay Coupon®
Prior Authorizations
Traditionally, the pharmacy technician has played little to no role in the PA process. He or she typically receives the prescription, processes and submits the claim to the insurer, and receives a PA requirement rejection. Each pharmacy has its own protocol thereafter, but typically, the pharmacy notifies the prescribing office that a PA is required and does not pursue the issue any further. However, with only one or two additional steps, pharmacy staff can ensure they have done everything possible to provide optimal service for their patients. For example, one way to expedite the PA process is to identify local commercial plans and become well-versed in their formulary. In doing so, once the pharmacy technician receives a prescription for a specialty product, he or she can efficiently process and submit the claim. If a PA is required,
the technician can contact the prescription benefit manager (PBM) and request that the correct PA form be sent to the provider’s office for completion. This facilitates the PBM and PA requirement for the clinic staff and also allows pharmacy staff to stay more up-to-date in the PA process and pass information along to the patient.
Copay Assistance
Many specialty products are derived from living cells which contributes to their unusually high cost. As such, despite insurance coverage, patients are often left with significant out-of-pocket costs. Fortunately, many specialty product manufacturers are aware of the financial impact on their patients and offer copay assistance which can be billed as secondary insurance. For example, the manufacturer of each medication listed in Table 1 offers some sort of copay assistance program to assist with out-of-pocket costs. While the programs vary in structure and enrollment, if the pharmacy technician becomes
well-versed in these programs, he or she can facilitate patient enrollment. These money-saving programs undoubtedly contribute to medication adherence and encourage positive therapeutic outcomes for patients. Pharmacy technician awareness and knowledge about these programs is a key first step! It is important to note that patients with Medicare or state coverage are not eligible for the copay assistance in Table 1. However, the manufacturers of the specialty medications listed in Table 1 have other available resources for these patients for which assistance depends on a variety of established eligibility criteria. These patients are best forwarded to the doctor’s office staff as a provider signature and private patient information are typically required.
Staying Up-to-Date
As the field of specialty pharmacy continues to expand, it is likely that demand for targeted disease-state management will result in subsets of
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specialty agents aimed at treating specific genetic variations of a disease. While personalized disease state management is exciting, a rapidly evolving subset of specialty medications presents a significant challenge to pharmacy staff. Pharmacists are required to maintain pace with new medications. Pharmacy technicians should also be aware of up and coming treatment regimens. The rapid evolution of specialty pharmacy products is best exemplified by recent developments in hepatitis C treatments. Hepatitis C virus (HCV) treatment prior to December 2013 was taxing on infected patients. FDA approval of the NS3/4A protease inhibitors boceprevir and telaprevir in combination with pegylated interferon and ribavirin resulted in significant side effects and was largely ineffective. The widely-publicized December 2013 approval of Gilead Science’s NS5B polymerase inhibitor sofosbuvir (Sovaldi) in combination with ribavirin and pegylated interferon for treatment of HCV genotypes 1 and 4, or in combination with ribavirin for the treatment of HCV genotypes 2 and 3 has been considered a game changer. Average treatment time is 12 weeks and comes with an $84,000 price tag but has a 90% sustained virologic response (SVR).8 Even more recently, in May 2014, Janssen filed for FDA-approval of an all-oral antiviral 12 week HCV genotype 1 treatment regimen available for the bargain price of $170,000 which would include Janssen’s NS3/4A protease inhibitor simeprevir (Olysio) plus Gilead’s sofosbuvir. This has been just the latest installment in a race to find the most efficacious treatment regimen with minimal side effects. Anticipated FDA approval of novel HCV antiviral therapies by the time this volume is published reinforces the importance of pharmacy staff’s pivotal role within the health care team. Antiviral HCV treatment is expected to continue to be based on strict daily regimens with high risk of treatment failure if patients are not compliant. Pharmacy technicians are well-positioned to take an active role in providing these and other specialty medications by means of proactive PA recognition, copay assistance programs, and drug ordering, thus contributing to increased patient compliance and improved patient outcomes. ● www.pswi.org
April Weaver PharmD, Amy O’Kroley CPhT, Brandon Harkonen, CPhT. References
1. Spatz I, McGee N. Health Policy Brief: Specialty Pharmaceuticals. Health Affairs. Nov 25 2013. 2. Milliman, Inc. Evaluation of Medical Specialty Medications: Utilization and Management Opportunities. http://info.cvscaremark.com/ insights2014/Singh06-Medical-SpecialtyUtilization-and-Management-Opportunities.pdf. Updated April 8, 2014. Accessed June 15, 2014. 3. Specialty Pharmacy Association of America. Specialty Pharmacy Key Terminology. http://www.spaarx.org/documents/SPAARX_ OVERVIEW_v5_aprvd.pdf. Updated April 2013. Accessed June 15, 2014. 4. Express Scripts. 2013 Drug Trend Report. http://lab.express-scripts.com/drugtrend-report/table-of-contents. Updated April 30, 2014. Accessed June 15, 2014. 5. 7 Sure Things to help you know where to go next with your prescription benefit. Insights (2014): Advancing the Science of Pharmacy Care. 2014. http:// info.cvscaremark.com/cvs-insights/prescription-drugtrend-increased-2013. Accessed June 15, 2014. 6. IMS Institute for Healthcare Informatics. Medicine Use and Shifting Costs of Healthcare: A Review of the Use of Medicines in the U.S. in 2013. http://www.imshealth.com/portal/site/ imshealth/uem.762a961826aad98f53c753c71ad8c22a /?vgnextoid=2684d47626745410VgnVCM10000076 192ca2RCRD&vgnextchannel=736de5fda6370410V gnVCM10000076192ca2RCRD&vgnextfmt=default. Updated April 9, 2014. Accessed June 15, 2014. 7. Robinson R. Specialty Drugs: An Evolving Commercial Model. PharmaVOICE. Feb 2014. http://www.imshealth.com/imshealth/Global/ Content/Corporate/Press%20Room/IMS_ Health_in_the_News/PharmaVOICE_2_2014_ SpecialtyDrugs.PDF. Accessed June 15, 2014. 8. U.S. Food and Drug Administration. FDA approves Sovaldi for chronic hepatitis C. http://www. fda.gov/newsevents/newsroom/pressannouncements/ ucm377888.htm. Accessed June 26, 2014. menuitem.762a961826aad98f53c753c71ad8c22a/?v gnextoid=2684d47626745410VgnVCM100000761 92ca2RCRD&vgnextchannel=736de5fda6370410Vg nVCM10000076192ca2RCRD&vgnextfmt=default. Updated April 9, 2014. Accessed June 15, 2014.
3. 4.
5.
6.
7. 8.
Assessment Questions
1.
9.
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Which of the following is true about specialty medications? a. They cost, on average, less than $600 per month b. There is no standardized definition for “specialty medication” c. They require no additional monitoring d. Many have a low-cost generic equivalent available Specialty medications are covered under
what type of benefit? a. Pharmacy b. Medical c. A or B d. None of the above All of the following are considered specialty medications except: a. Sofosbuvir b. Xeloda® c. Humira® d. Warfarin Which of the following is not usually included in a contract agreement for specialty medications? a. Price at which the pharmacy purchases the specialty medication b. Dispensing information for the specialty medication c. Name(s) of pharmacists trained to dispense specialty medication d. Invoice payment details True or False: Specialty pharmacies have medication management programs set up to provide patient education and monitor adherence. a. True b. False True or False: Generic equivalents of specialty medications will be formulated with the same active ingredient as the brand-name product. a. True b. False Which of the following are true regarding predicted trends in specialty pharmacy? a. Specialty drug spending is expected to increase over the next five years b. In 2018, six of the top ten best-selling medications will be specialty c. Transplant medications will contribute to increased spending d. All of the above e. A and B only As specialty pharmacy continues to grow it is of utmost importance that the pharmacy technician be knowledgeable about current specialty medication therapies. a. True b. False Mr. Smith is at the pharmacy pick up window for his Humira® prescription. His copay after commercial insurance is $200 and is not affordable based on his budget. Your best patient assistance option would include: a. Encourage Mr. Smith to call his doctor’s office b. Enroll Mr. Smith in the AbbVie Foundation Program®
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c. Coordination of benefits to the Humira Protection Plan® d. There are no copay reduction options for Mr. Smith’s Humira®
13. Identify current trends in specialty pharmacy a. Yes b. No
10. How can the pharmacy technician ensure that patients get their specialty medications in a timely manner? a. By becoming familiar with local PBM formularies b. Requesting that the correct PA form be sent to the physician’s office c. Knowledge of available copay assistance options for specialty medications d. All of the above e. None of the above 11. This activity met my educational needs. a. Met all educational needs related to the topic b. Met some educational needs related to the topic c. Did not meet my educational needs
18. Learning assessment questions were appropriate a. Yes b. No 19. Was/were the author(s) free of bias? a. Yes b. No
14. Discuss opportunities for pharmacy technician contributions to specialty pharmacy. a. Yes b. No
20. If you answered “no” to question 10, please comment. 21. Please indicate the amount of time it took you to complete the educational activity (including the assessment questions).
15. How would you rate the ability of the author(s) to provide a high-quality educational activity? a. Very capable, article was well-written and provided good information b. Somewhat capable, most information was presented well c. Needs improvement 16.
Did the activity meet the stated learning objectives?
How useful was the educational material? a. Very useful b. Somewhat useful c. Not useful
17. How effective were the learning methods used for this activity? a. Very effective b. Somewhat effective c. Not effective
12. Describe the common characteristics of specialty medications a. Yes b. No
COMPLETE ARTICLE AND CE EXAM AVAILABLE ONLINE: WWW.PSWI.ORG
CE FOR TECHNICIANS
Quiz Answer Form
Continuing Education Credit Information The Pharmacy Society of Wisconsin is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Continuing education credit can be earned by completing the self assessment questions. Questions may be completed online at www.pswi.org or by mailing completed answer form to PSW, 701 Heartland Trail, Madison, WI 53717.
circle one answer per question
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Specialty Pharmacy and the Role of the Pharmacy Technician - Technician CE
Name__________________________________________________________________________
ACPE Universal Activity Number: 0175-0000-14-072-H04-T
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Target Audience: Technicians Activity Type: Knowledge-based Release Date: September 1, 2014
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originalcontributions
An Integrated Care Approach to Specialty Pharmacy by Jason Rasoul, PharmD, Prati Wojtal, MS, FASHP and Jim Motz, BSPharm
A
s part of an Aurora Health Care strategic initiative in 2013, key departments integrated their resources to provide a new specialty pharmacy service for Aurora patients. The service involves Aurora physicians, nurses, financial counselors, pharmacists and pharmacy technicians working collaboratively to provide an integrated and connected approach specifically designed to provide pharmacy care for a number of chronic specialty disease states. Aurora Specialty Pharmacy (ASP) then provides timely and safe delivery of prescriptions for specialty medications directly to the patient. Specialty pharmacy is a term that best describes the delivery of high cost medications with unique storage or administration requirements, and the need for enhanced clinical care across a variety of disease states. The medications commonly include refrigerated medications, injectable drugs and an expanding group of high cost oral products. Patients being treated for the commonly described specialty disease states almost always require a level of care beyond “usual” pharmacy care. Consequently, specialty pharmacy care is referred to as a “high touch” service. The disease states most often managed at the Aurora Specialty Pharmacy (ASP) include hepatitis C, multiple sclerosis, auto-immune conditions (rheumatoid arthritis, ulcerative colitis, Crohn’s disease, ankylosing spondylitis, psoriasis and psoriatic arthritis), and oral therapies for cancer.
An Integrated Health Care System Makes the Difference With the development and release of new drug therapies, and the increase in revenue received by pharmacies for dispensing specialty items, the potential for growth across the specialty market is vast. It is forecast that the specialty drug market will grow at a rate of 20% annually for the next 3 years, and specialty drugs will www.pswi.org
account for at least 40% of all drug expenses by 2016.1 Competition is intensely growing between specialty pharmacies aiming to provide service to patients and capture resultant revenue. Unfortunately for some patients, pharmacy benefit administrators are also taking measures that cause specialty medications to be managed and dispensed via a pharmacy that has no connection to where the patient is receiving care. In many cases when specialty pharmaceuticals are mandated to be dispensed from a specific pharmacy, patients will become confused due a lack of coordination and unfamiliarity with the pharmacy. The health system integrated model provides an alternative to the potentially more disconnected mandated pharmacy approach. Within the integrated system, a specialty pharmacy team may be better able to document and measure and influence quality and patient outcomes. In an integrated delivery system the pharmacist is more accessible to patients, more effective in providing care in a timely fashion, and in achieving patient satisfaction. The Aurora integrated health system allows physicians, nurses, financial counselors, and pharmacists all to easily communicate directly with each other about the care plan for each patient. Every specialty pharmacy staff member utilizes the Aurora electronic medical record (EMR), allowing the patient’s care plan to be implemented quickly and efficiently. The ability to communicate easily and directly with physician offices and providers, and the opportunity to coordinate services and track patients across multiple health care settings are two distinct advantages of the Aurora Specialty Pharmacy.
Aurora Specialty Pharmacy - A Closer Look at Patient Management Every patient who sees an Aurora physician for one of the managed specialty disease states is eligible for the patient management services offered through the specialty pharmacy program. Physicians
and advanced practice providers begin the process with a referral to financial counselors, who provide a range of valuable patient care services. Financial counselors collect data, process prior authorizations, review insurance benefits and assist patients with enrolling in financial assistance programs. All these services are designed to direct the patient to the most economical way for that patient to receive and pay for their medication. Challenges arise when patients’ benefit plans do not allow the patient to use the services of an Aurora Pharmacy. If a patient is not allowed to use Aurora Specialty Pharmacy, the financial counselor works with the patient and physician to route the prescription to an appropriate in-network pharmacy. This ensures continuity of care, to the extent possible, and facilitates the patient initiation of therapy in a timely fashion. In those cases when a prescription is approved for dispensing at ASP the prescription is routed to the pharmacy and the specialty pharmacy coordinator then prepares to provide clinical support to the patient. The pharmacist first assures the medication is prescribed properly by assessing dosing with respect to an evaluation of patient characteristics (i.e. weight, renal function, hepatic impairment), determining clinical appropriateness, completing a full medication profile review, and referring to evidenced based treatment guidelines as necessary. The Aurora EMR is utilized and leveraged throughout this process, seamlessly delivering important patient information to the pharmacist. If the dose or frequency of a medication needs adjustment, the pharmacist will consult with the prescriber to make the proper modifications. After the clinical workup is completed the prescription is processed, the drug is procured if needed and prepared for delivery to the patient by certified pharmacy technicians. At the same time, the pharmacist provides patient education via a phone call to each patient. During the
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first encounter with patients, pharmacists will identify patients at high-risk for poor literacy and non-adherence through a series of validated questions. Those who are at risk will receive special consultation and follow up at each refill encounter. This ensures the best possible care for high-risk patients who may require more frequent or customized follow-up care. It also empowers patients to take charge of their own health care. Our experience shows that patients are more motivated and likely to adhere to their medication regimen when a pharmacist educates patients about their disease state and stresses the importance of their medication regimen. This personal touch helps to achieve better patient outcomes. Following the patient education session, medication is delivered directly to a place designated by the patient. ASP utilizes a national courier service to ensure overnight delivery of medications so patients quickly and conveniently, so they may begin or continue prescribed therapy without delay. Medications are either shipped at room temperature or via cold chain, depending on the manufacturer’s storage recommendation for that medication. Refrigerated items are shipped using sophisticated packaging and tested methods to ensure product quality and safety. Patients are aware of the shipping method and the delivery date of their medications throughout the process, and physicians are informed of when a patient will receive their medication and begin therapy. Ongoing management of specialty pharmacy patients is essential to achieving therapy goals. ASP handles the patient’s medication refills and monitors their therapy on a regular basis. Using a computer based program, anticipated refill dates are calculated and available to the pharmacy staff on a daily basis. Patients will be contacted three to five days prior to their next prescription refill date. During the refill process, the specialty pharmacist uses the EMR to assess necessary monitoring and provide further education as required. Should the need to communicate with the physician or nursing staff be determined following the patient consultation, ASP pharmacists will use the EMR to communicate any issues with drug therapy that have been detected. Pharmacists also utilize the EMR to track pertinent lab values
and office visits to ensure the prescription refill is medically necessary.
Measurement of Patient Outcomes and Quality In conjunction with Aurora Pharmacy’s quality improvement committee ASP has determined a set of measurements to identify and quantify the clinical and operational quality provided by the service. Patient outcome criteria have been determined and are routinely measured for each of the managed disease states. Prescribed medications are checked for clinical appropriateness, monitored for clinical effectiveness, and measured for cost effectiveness. Operational quality is continually monitored through a set of key quality indicators. In 2014, target quality levels are measured for indicators such as: • Financial services referral turnaround time • Telephonic access • Prescription delivery events/errors • Medication events/errors • Patient satisfaction • Provider satisfaction • Cold chain shipping management The anticipated result of quality indicator measurement and reporting is for documentation of best practices and improved clinical and operational quality of services provided to each patient.
Future Opportunities
The future of specialty pharmacy is robust, and presents an opportunity for pharmacies to grow clinically and financially. Drug manufacturers are devoting massive resources to research in specialty areas and are primed to release new drugs aiming to capture the revenue from this growing marketplace. A good example of the growth of specialty pharmacy was seen in 2012. The FDA approved 39 new drugs in 2012, of which 25 would be classified as specialty pharmaceuticals, and 13 of the 2012 approvals indicated for treatment of cancer.2 Product development for specialty drugs remains strong, with numerous reports indicating more than 600 specialty drugs in manufacturer’s product development pipelines. In particular, the transition from parenterally delivered therapies to oral therapies in many key areas (hepatitis C, oncology and neurology)
affords pharmacies the ability to more easily provide new medications to patients in the outpatient setting, and allows the patients to have an added measure of control over their own quality of life and health care. Our integrated system provides unique opportunities for pharmacists working in a specialty pharmacy. For example, Aurora Health Care has developed an Accountable Care Organization (ACO). Physicians, hospitals and other providers practicing in an ACO model coordinate care, and share financial risk to achieve high healthcare quality and reduce unnecessary spending. A population health approach is one management tool used by the ACO. Evidence based treatment protocols for a defined patient population, supported by the ASP pharmacists provide a new opportunity to demonstrate value and document treatment outcomes.
Challenges
Aurora’s specialty pharmacy program has certainly experienced barriers to implementing the specialty program. In a large system there are always competing priorities for resources. We addressed this by the development of a strong business plan to support our program, and by providing significant ongoing education to senior leadership on the growing importance of specialty pharmacy in our patient’s care. In addition, our specialty program faces many of the same challenges experienced by other pharmacies in the competitive specialty marketplace. Successfully addressing these challenges is a crucial next step in expanding our program and allowing the ASP team to provide specialty pharmacy services to a greater share of Aurora patients. Payers must be continually made aware of the value of our specialty program. As stated earlier, payers have an interest in directing patients to use a plan designated specialty pharmacy. This requirement is problematic for those patients who must receive pharmacy care outside our integrated system as a lack of care coordination may result - potentially limiting the quality of the medication therapy. Second, certain medications may have restricted distribution mandated by the manufacturer. In some instances distribution is restricted due to Risk
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Evaluation and Mitigation Strategies (REMS) program requirements. In other cases, manufacturers have selected limited pharmacy networks to keep better control over drug distribution, inventory and data collection. Additionally, some drug manufacturers and payers may require a specialty pharmacy to be accredited to procure their medications and process claims for their plans. This is a challenge that ASP is addressing, presently as an accreditation “in-process” pharmacy. Lastly, clinical challenges exist for the specialty pharmacists. As additional medications are released from the pipeline and approved, clinical pharmacists must be current with the latest updates to specialty pharmacy therapy and disease states. This requires continuing education on a regular basis within the specialty field to meet the knowledge base necessary to properly educate patients and maintain high clinical quality standards for the pharmacy.
Summary
Overall, specialty pharmacy is a rapidly growing field in the pharmacy
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world, and for integrated systems, one that is both clinically and financially rewarding. Overcoming the many barriers to entering the field may limit the ability for many pharmacies to develop such a program, but should those challenges be met, the potential for reward in the field is significant. Aurora Health Care’s strategic decision to utilize an integrated approach to specialty pharmacy provides our patients and clinical caregivers with certain advantages not possible at other pharmacies. For Aurora Specialty Pharmacy, the most valuable tool utilized is the ability to leverage a unified electronic medical record that can improve inter-professional communications, patient outcomes, and cost of care.●
Disclosure: The authors declare no real or potential conflicts or financial interest in any product or service mentioned in the manuscript, including grants, equipment, medications, employment, gifts, and honoraria.
References 1.
J Manag Care Pharm. 2013;19(1):42-48
2. 2012 FDA drug approvals. Nat Rev Drug Discov. 2013;12(2):87-90.
Jason Rasoul, PharmD, Specialty Pharmacy Coordinator, Aurora Health Care, Prati Wojtal, MS, FASHP, Director Ambulatory Pharmacy, Aurora Health Care and Jim Motz, B.S. Pharm., Specialty Pharmacy Program Manager, Aurora Health Care
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originalcontributions University of Wisconsin School of Pharmacy Student Writing Club:
Immunizing the Immunosuppressed: Recommendations for Vaccinating Patients on High-Level Immunosuppressive Therapy by Torie Grover, 2016 PharmD Candidate, Heather Hresko, 2016 PharmD Candidate, and Kristin Stawicki, 2016 PharmD Candidate
P
atients undergoing or anticipating treatment with high-dose immunosuppressive medications require special consideration when it comes to immunization.1 Due to diminished immune response and frequent contact with healthcare systems, morbidity and mortality from vaccine-preventable infections is high in this population.2 Despite this, vaccination rates for immunocompromised patients remain low, perhaps because there is limited information regarding the safety and efficacy of many vaccines in these patients.2,3 Nevertheless, guidelines for vaccinating immunocompromised patients are available, and pharmacists can work with these individuals and their physicians to decide which vaccinations should be given and determine an appropriate schedule for indicated vaccinations.1,3 Among the most common types of immunosuppressive medications are oral systemic corticosteroids, used to treat chronic autoimmune conditions such as rheumatoid arthritis (RA), systemic lupus erythematosusle, and inflammatory bowel diseases (IBD). High-level therapy is defined as treatment that exceeds 2 weeks in duration, at a prednisone dose greater than or equivalent to 20 mg/day in adults and 2 mg/kg/day in children.1 Antitumor necrosis factor alpha (anti-TNF) biologics are a newer class of high-level immunosuppressive drug therapy that is often used to treat RA and IBD. In either case, careful consideration must be taken when deciding which vaccines are safe and effective to administer before, during and after immunosuppressive therapy is initiated.
Vaccines to be Administered to Patients on High-Level Immunosuppressive Therapies The Infectious Diseases Society of America (IDSA) released guidelines in December 2013 offering evidence-based recommendations for vaccination in this
special population (Table 1.).3 In general live vaccinations pose a risk for infection in immunocompromised patients and are usually contraindicated while a patient is on high-level immunosuppressive therapy.1,3 Inactivated vaccines do not present a danger1,3, though an extra dose and/or alteration of vaccination schedule may be
TABLE 1. Recommendations for Vaccination of Patients Receiving High-level Immunosuppressive Medications* Planned High-level Immunosuppression Immunosuppression Haemophilus Influenzae Type B
U
U
Hepatitis A
U
U
Hepatitis B
U
U
Diphtheria, Tetanus, and Acellular Pertussis, Tetanus, Diphtheria, and Tetanus, Diphtheria, Pertussis (DTaP, Td, Tdap)
U
U
U: 11-26 y
U: 11-26 y
Inactivated Influenza Vaccine
U
U
Live Attenuated Influenza Vaccine
X
X
Measles, Mumps, and Rubella
U (a)
X
Measles, Mumps, Rubella, and Varicella
U (a)
X
U
U
R (b)
U: < 6 y R: ≥ 6 y (b)
R: ≥ 2 y
R: ≥ 2 y
Human Papillomavirus Vaccine
Meningococcal Conjugate Vaccine 13-Valent Pneumococcal Conjugate (PCV-13) 23-Valent Pneumococcal Polysaccharide Vaccine (PPSV23) Inactivated Polio Vaccine
U
U
Rotavirus
U
X
Varicella
U (a)
X
R: 50-59 y (c) U: ≥ 60 y
X
Zoster
(a) Administer only if patient is not severely immunosuppressed and timing is ≥ 4 weeks prior to starting immunosuppressive medications. (b) PCV13 should be administered ≥ 1 year after last PPSV23, if patient is ≥ 19 years old and previously received PPSV23. (c) Recommendation deviated from Centers for Disease Control and Prevention Advisory Committee on Immunization Practices. Key: U, Usual - immunize if not current; R, Recommended - immunize if not current, patient may be at increased risk for this vaccine-preventable disease; X, Contraindicated *Adapted from Rubin L, Levin M, Ljungman P, et. al. 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis. 2014;58(3):e44-100.
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indicated to induce immunity.1 For those beginning high-level immunosuppressive therapies, vaccination at least two to four weeks prior to initiation of treatment is preferable to allow time for optimal antibody development.1,3 Household and other close contacts should receive all ageappropriate vaccinations, with the exception of live oral polio and smallpox vaccines.1,3
Influenza
The inactivated influenza vaccine (IIV) should be given annually according to the Centers for Disease Control and Prevention Advisory Committee on Immunization Practices (CDC-ACIP). Recommendations for children and adults are updated annually.
PCV13 and PPSV23
Patients should receive all pneumococcal vaccines based on the CDC-ACIP annual schedule both PCV13 and PPSV23 are recommended for all adults on immunosuppressive therapy. Patients aged 2-5 years should receive one dose of 13-valent pneumococcal conjugate vaccine (PCV13) if they are up-to-date on their childhood vaccine schedule and two doses of PCV13 if they have an incomplete schedule (≤ 2 doses of PCV7 or PCV13 before age 24 months). For patients 2 years or older planning to initiate or currently on immunosuppressive medications, both the PCV13 and PPSV23 are indicated. If possible, patients should receive PCV13 first, followed by PPSV23 eight weeks later. If the patient has already received PPSV23, one year must elapse before receiving PCV13. A second dose of PPSV23 should be given five years later.1
Varicella
Varicella, a live vaccine, is contraindicated for patients currently receiving high-dose immunosuppressive medications. Vaccination can be given at least one month prior to initiation or one month after discontinuation of high-dose immunosuppressive therapy.1,3
Zoster
Zoster, a live vaccine, is indicated for patients two weeks (if possible) prior to initiation of high level immunosuppressive therapy.5 Administration to patients
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currently receiving high dose immunosuppressive medications should be considered based on the patient’s immune status and otherwise deferred for at least one month after discontinuing therapy.5
Hepatitis B
Concerns have been expressed that Hepatitis B vaccination may cause immune stimulation and subsequent flare of chronic inflammatory diseases like RA and SLE, but no evidence of exacerbation postvaccination has been reported.3 Therefore, this vaccination should be administered as a regularly recommended vaccine.
Role of the Pharmacist
Current rates of vaccination for patients receiving high-dose theraphy are inadequate. For example, immunization rates for persons treated for rheumatic diseases rarely surpass 30-40%.4 Rates among patients treated for IBD are similarly insufficient. Melmed et al6 assessed immunization status of patients in an IBD specialty clinic and found that 45% had received tetanus immunization in the past 10 years, 28% had received an annual influenza vaccine, 9% had received a pneumococcal vaccine, and only half of IBD patients at risk for Hepatitis B had been vaccinated against the infection. Pharmacists share responsibility with primary and specialty care providers to ensure all indicated vaccinations are administered. While many patients on anti-TNF therapy see physicians regularly, immunization counseling is often neglected in the clinical setting as more critical health concerns take priority.6 With the recent advent of immunization milestones in pharmacy practice, including the 1000th pharmacist trained by PSW in May of 2014, pharmacists are in a unique position to directly impact vaccination rates. Wisconsin pharmacists have the opportunity to identify unvaccinated individuals undergoing high-level immunosupressive treatment through the Wisconsin Immunization Registry, make immunization recommendations to providers, administer vaccines, and distribute oral and written vaccine information to atrisk patients. As advocates
for vaccination of immunosuppressed patients, pharmacists can consider offering immunization services to area internists and physicians who specialize in disease states associated with these medications. Alternatively, pharmacists can help reduce unnecessary long-term systemic steroid use and consequential adverse effects by decreasing doses and eliminating duplicate therapy whenever possible. Pharmacists should discuss with patients the risk of infection associated with immunosuppressive therapies, bearing in mind that while IDSA recommendations are a useful guide, the decision to vaccinate must ultimately result from clinical judgment on a case-by-case basis. ● by Torie Grover, 2016 PharmD Candidate, Heather Hresko, 2016 PharmD Candidate, and Kristin Stawicki, 2016 PharmD Acknowledgment: The authors would like to acknowledge Mary Hayney for her expert guidance in writing this article.
References
1. Centers for Disease Control and Prevention. General Recommendations on Immunization. MMWR. 2006;55(No. RR-15):26-31. 2. Aringer M. Vaccination under TNF blockade - less effective, but worthwhile. Arthritis Res Ther. 2012;14(3):117. 3. Rubin L, Levin M, Ljungman P, et al. 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis. 2014;58(3):e44-100. 4. Harpaz R, Ortega-sanchez IR, Seward JF. Prevention of herpes zoster: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2008;57(RR-5):1-30. 5. Gluck T, Muller-Ladner U. Vaccination in patients with chronic rheumatic or autoimmune diseases. Clin Infect Dis. 2008;46(9):1459-1465. 6. Melmed G, Ippoliti A, Papadakis K, et al. Patients with inflammatory bowel disease are at risk for vaccine-preventable illnesses. Am J Gastroenterol. 2006;101(8):1834-1840.
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originalcontributions
PSW Pharma-Athletes Part II Compiled by Emily Weisenbeck, Rebecca Augustine, and Tiffany Palm
T
he overwhelming response from pharmacists, pharmacy technicians, and students staying active around Wisconsin has inspired a second installment of PSW PharmaAthletes. Involvement in athletic endeavors continues to drive these individuals to achieve personal goals and connect them to their community and co-workers.
both the 2000 and 2004 Olympic Games. You may remember watching and cheering for him and his twin brother, natives of Wisconsin, in the Olympics. He and his twin brother, Paul, were the youngest competitors in the Sydney Games at 17 years of age. In the 2004 Olympic Games in Athens, Greece, Morgan won a Silver Medal with Team USA. The year before, he also won a silver medal with Team USA at the 2003 World Gymnastics Championships. Morgan is a multiple time National Floor Exercise Champion. With all of his success in such a rigorous sport, it would be surprising if he did not experience injuries along the way. In 2001, Morgan suffered a nerve injury that paralyzed his left shoulder for four to five months. He did not know if he would be able to return to gymnastics, but he continued to believe in his recovery. After about five months, his shoulder began to show improvement. Although, he did not receive a 100% recovery, he was able to return to the sport that he loves and compete for Team USA at the 2004 Olympic Games. Morgan believes that all of the lessons he learned in gymnastics about dedication, motivation, and overcoming adversity have
been instrumental in the path to becoming a pharmacist. He believes the profession is very rewarding but, at the same time, requires a huge time commitment to become proficient and capable of taking care of patients. Pharmacy school quickly requires students to become efficient with their time. Morgan has been able to manage his time to study while still maintaining a healthy social life outside of school. As Morgan finishes his final year of pharmacy school, he is looking forward to the new adventures and experiences that a career in pharmacy will bring. He plans to put as much effort into his pharmacy career as he did into his gymnastics.
Paul Lata, PharmD
Clinical Pharmacist, Madison VA Hospital For most of Paul’s life he has been involved in bicycling as a participant or as an organizer. He particularly enjoys long distance riding because of the escape it provides. His longest ride was a dawn to dusk ride from Marinette, WI to Sault Ste. Marie, Michigan in 1990. At the end of the day he had covered 260 miles. Recently he moved to Madison and discovered that, because of the topography, bicycle accomplishments there are measured vertically rather than horizontally. Last year he climbed 2.5 vertical miles in the 150 mile Dairyland Dare bicycle ride in Dodgeville.
Morgan Hamm, PharmD
2014 Graduate of Concordia University Wisconsin School of Pharmacy Morgan Hamm is a two time Olympian in the sport of men’s gymnastics attending
Todd Karpinski, PharmD, MS, FASHP
Executive Director - Chief Pharmacy Officer at Froedtert and the Medical College of Wisconsin Running has been a major part of both Todd’s professional and personal life for the past eight years. His running career started the day his wife told him she was running a 5K race in St. Louis. Being a competitive person, Todd decided that he would also run the race. When he finished the 5K in 25:55, he stated, “You gotta start somewhere”. Of the five marathons Todd has completed, the most satisfying race was the second Napa Valley marathon he ran in California last year. Todd had the opportunity to run with one of his best friends, Ryan Roux (Director of Pharmacy at MD Anderson). He was able to experience his friend completing his first
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ever marathon. It wasn’t his fastest time, finishing in 3:24; however, the race was Todd’s first long race after breaking his foot in 2012 when he questioned if he would ever be able to run a marathon again. Todd feels fortunate to be surrounded by many active individuals at Froedtert, many of whom are runners. Over the past five years, Todd has had the opportunity to run with many of his colleagues and share with them his joy of running. Todd states, “Running serves as an outlet for me to leave the stresses of the day behind and focus only on the road ahead”.
Nate Smith, Trevor Naleid, Ryan Stanke, Andrew Ensing, Thomy Singh, Lee Meredith, Bryant Schobert, Dominic Peeters, Nick Cox, John Folstad, Brent Anderson, Brian Teresinski, Kirby Palmquist, and Dan Ruhland
2014 PharmD Graduates of University of Wisconsin School of Pharmacy For the past three summers, The Drug Dealers, a group of recent pharmacy school graduates, have played together in the Madison School and Community Recreation (MSCR) Men’s Adult Slow Pitch softball league. Every Tuesday night from May to August the students came together after a long week of internships and rotations to play slow pitch softball against other city teams. As reigning, two-time champions, The Drug Dealers had a blast playing together, getting in some good exercise and fun.
www.pswi.org
Andrew Ensing, Nicholas Cox, Travis Tacheny, John Folstad, Emily Zimmerman, Brittany Schleicher, and Kerry Allen
2014 PharmD Graduates of University of Wisconsin School of Pharmacy Students from the University of Wisconsin-Madison School of Pharmacy gathered weekly at The Shell ice rink to take on teams from across campus in broomball, an adaptation of hockey without skates. The team, Lethal Dose, found the experience to be a great opportunity to bond outside of class, and to work off some steam. During the pictured season, Lethal Dose wore pink Team Erika shirts in support of their classmate, Erika Nelson who is currently battling breast cancer.
Dave Hager, PharmD UW Hospital and Clinics
While Dave claims “athlete” is a stretch, he has long enjoyed hiking as a chance to find peace, get a mental break, and recharge. As an Eagle Scout, Dave has made hiking a part of his life, from portaging canoes on Boy Scout trips to climbing alongside waterfalls during a 9 mile hike in Yosemite during his 10-year wedding anniversary. With this year’s seemingly never-ending cold winter, Dave jumped at the chance to hike alongside ice formations and caves at the Apostle Islands National Lakeshore. Dave and his wife took approximately
400 pictures along the hike and saw some amazing ice formations. In true athlete fashion, they headed back home through Stevens Point and stopped at O’so Brewing to rehydrate. Ever the pharmacist, Dave states, “I did not see many medication management needs while I was there, but being out in nature did seem to lower my blood pressure”. David Antoine, Brandon Patri, Paul Kolesar, Andria Mohr, Zakkary Scharp, Amanda Goodall, and Spencer Polaceck (not pictured) First-year Pharmacy Students at Concordia University Wisconsin School of Pharmacy
CUW’s Christian Pharmacy Fellowship International organization hosted a volleyball tournament this spring as a fundraiser for future mission trip opportunities. A group of first year pharmacy students headed to the championship round to battle the pharmacy faculty team. The students were able to claim victory and take home the trophy. Students and faculty alike agreed that this was a great way to promote fellowship between the different pharmacy classes, while having a great time playing volleyball. ●
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originalcontributions
What’s New in Pulmonary Hypertension in 2014? By Frank C. Spexarth, RPh, BCPS Abstract Macitentan (Opsumit®), riociguat (Adempas®) and oral treprostinil (Orenitram®) are new FDA- approved medications used to treat patients with pulmonary hypertension (PH). All three agents are distributed through a Specialty Pharmacy only. Macitentan is an once-a-day endothelial receptor antagonist (ERA), similar to bosentan and ambrisentan that is associated with less hepatic enzyme elevation than bosentan therapy. Riociguat is a direct-stimulator of the nitric oxide (NO) pathway and provides an oral option to treating WHO Group 4 PH (or chronic thromboembolic pulmonary hypertension). Oral treprostinil is the first marketed, orally administered prostacyclin. This agent offers a therapeutic option for PH patients unresponsive to oral ERAs and NO pathway medications. Although studies have not shown clinical benefit in studies, this agent may benefit patients who are not candidates for parenteral agents (epoprostenol, treprostinil) or intolerant to inhaled agents (iloprost, treprostinil).
P
ulmonary arterial hypertension (PAH) is a debilitating, progressive disease resulting in right heart failure and death. Idiopathic and familial forms of PAH (IPAH and FPAH, respectively, formerly known as primary pulmonary hypertension) has a median survival of 2.8 years if untreated.16 Long-term survival improved when epoprostenol was introduced in 1995 and has steady improved as new therapies have been introduced. Pharmacists play a key role in monitoring patient medication therapy. Most of the pulmonary hypertension medications are dispensed through the Specialty Pharmacy distribution system. However, pharmacist’s knowledge of these medications is essential to help them optimize patient medication therapy evaluations. There are three new pulmonary hypertension medications available in 2014 that will be reviewed: Macitentan (Opsumit®), riociguat (Adempas®) and oral treprostinil (Orenitram®).
Macitentan
Macitentan is a non-selective endothelial-receptor antagonist (ERA) that prevents endothelin-1, a potent vasconstrictor, binding to endothelin-A (ETA) and endothelin-B (ETB) receptors.
ETA receptor blockade causes vascular relaxation and has pulmonary artery antiproliferative effects. ETB receptor blockade causes vasoconstriction, pulmonary artery cell proliferation and inhibits endothelin-1 clearance. Despite potential differences in Clinical activity based on receptor selectively, the efficacy of selective ETA receptor blockers (ambrisentan) or nonselective receptor blockers (macitentan, bosentan) appear to be comparable.1 Macitentan was studied in SERAPHIN, a randomized, controlled trial comparing macitentan 3 mg daily, macitentan 10 mg daily and placebo in PAH patients (table 1).2 The study’s primary endpoint was the first occurrence of a composite endpoint of death, atrial septostomy, lung transplantation, initiation or treatment with IV or SQ prostacyclin (epoprostenol or treprostinil), or worsening of PAH symptoms. The primary endpoint event was reached in 46.4%, 38% and 31.4% of patients receiving placebo, macitentan 3 mg and 10 mg respectively. The hazard ratio for patients receiving 10 mg macitentan dose as compared with placebo was 0.55 (97.5% CI, 0.39 to 0.76; p<0.001). Side effects reported more frequently with macitentan compared to placebo included headache, nasopharyngitis and anemia. Peripheral edema and incidence of elevated alanine or aspartate aminotransferase levels that were
more than 3x upper limit of normal were similar amongst the groups. Macitentan is FDA approved for the treatment of PAH to delay disease progression. Macitentan 10 mg orally daily is the starting and maintenance dose. Macitentan has small volume of distribution, is highly protein bound and has an elimination half-life of 16 hours (with an active metabolite elimination half- life of 48 hours).17 Macitentan is metabolized by the CYP3A4 enzyme system, but there are no recommended dose adjustments for renal or hepatic dysfunction. Strong 3A4 inhibitors (ketoconazole, ritonavir) or inducers (rifampin) are not recommended for use with macitentan. Macitentan is contraindicated in pregnancy. All women, regardless of child-bearing age, must be entered into a Risk Evaluation and Mitigation Strategy REMS program to obtain medication. The opsumit REMS program requires baseline and monthly pregnancy tests. Prescribers and pharmacies must be certified with the Opsumit REMS program to prescribe and dispense macitentan. Unlike bosentan, liver function test monitoring is not required by the REMS program. Macitentan side effects include nasopharyngitis (20%), bronchitis (12%), headache (14%), liver enzyme elevation, hepatotoxicity, hemoglobin / hematocrit decreases early in therapy(13%) and pulmonary edema. Decreased sperm counts in males has been reported.5 Macitentan, bosentan, and ambrisentan are all Class I recommendations for the treatment of PAH patients with World Health Organization (WHO) functional class II-III symptoms according to recently published guidelines.1 These agents should also be considered for PAH patients with WHO functional class IV symptoms (Class IIa recommendation). Macitentan and ambrisentan may be preferred as these agents are less likely to cause a rise in liver function tests than seen in bosentan. Better patient compliance due to one-daily dosing may also favor these two medications. However, bosentan medication costs are significantly less than
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TABLE 1. Endothelial Receptor Antagonists (ERAs) Study Comparison Drug vs. Placebo
PH Med Therapy
PH Type
Therapy Length (weeks)
GMWD (meters)
Bosentan 125 mg BID
0%
Primary PAH or CTD
16
ARIES-14
Ambrisentan 5 or 10 mg QDay
0%
Idiopathic, CTD, HIV, anorexigens
ARIES-24
Ambrisentan 2.5 or 5 mg QDay
0%
SERAPHIN2
Macitentan 3 or 10 mg QDay
Baseline Data
WHO Functional Class I
II
III
IV
330 B 344 P
0
0
90%
10%
12
340
3%
32%
58%
7%
Idiopathic, CTD, HIV, anorexigens
12
355
2%
44%
52%
2%
63.7%
Idiopathic, heritable, CTD,HIV, anorexigens
24
360
0
52%
46%
2%
Drug vs. Placebo
6MWD* (meters)
WHO FC Decrease (Drug vs. P)
PVR* (olyn.sec. cm-5)
CI* L/hr/m2
mPAP mm Hg* (Drug vs. P)
NT-proBNP (Drug vs. P)
Bosentan 125 mg BID
125 mg + 35
42% vs. 30%
NA
NA
NA
NA
ARIES-14
Ambrisentan 5 or 10 mg QDay
5 mg + 31 10 mg + 51
NA
NA
NA
NA
5 mg â 30% 10 mg â 45%
ARIES-24
Ambrisentan 2.5 or 5 mg QDay
2.5 mg + 32 5 mg + 59
NA
NA
NA
NA
2.5 mg â 29% 5 mg â 30%
Macitentan 3 or 10 mg QDay
3 mg + 16.8 10 mg + 22
3 mg 20% vs. 13%. 10 mg 22% vs. 13%
3 mg -365 10 mg -383
3 mg + 0.69 10 mg + 0.63
NA
NA
BREATHE-13
Results BREATHE-13
SERAPHIN
2
6MWD= 6 minute walk distance, B= bosentan, CI = cardiac index, CTD= connective tissue disease, FC= functional class, HIV= human immunodeficiency virus, mPAP = mean pulmonary artery pressure, NA = not available, P= placebo, PAH= pulmonary arterial hypertension, PDE5= phosphodiesterase 5 inhibitors, PGE = prostacyclin (epoprostenol, treprostinil), PVR = pulmonary vascular resistance. *Difference comprared to placebo WHO= World Health Organization
these two agents (table 4). Macitentan has demonstrated reduced morbidity and mortality in PAH patients whereas earlier studies with bosentan and ambrisentan have only demonstrated improved 6 minute walk distance (6MWD). The 6MWD has not been validated as a surrogate marker of clinical efficacy.1
Riociguat
Riociguat a nitric oxide (NO) pathway stimulator by 1) directly stimulating soluble guanylate cyclase (sGC) which activates cGMP (cyclic guanosine monophosphate), and 2) sensitizes sGC- cGMP pathway to the effects of nitric oxide. cGMP stimulation causes pulmonary vasodilatation, and direct anti-proliferative and anti-fibrotic effects. Two randomized controlled studies have demonstrated that riociguat improves outcomes in patients with pulmonary hypertension (table 2). The CHEST-1 study compared riociguat to placebo in patients with chronic thromboembolic pulmonary hypertension (CTEPH, WHO Group 4 PH). Riociguat www.pswi.org
was found to significantly increase the 6 minute walk distance (6MWD) from baseline compared to placebo. Riociguat significantly improved WHO functional class status and cardiac index, while lowering pulmonary vascular resistance (PVR), mean pulmonary arterial pressure, and N-terminal pro-brain natriuretic peptide (NT-proBNP) compared to patients receiving placebo. The PATENT-1study compared riociguat to placebo in patients with PAH. The primary endpoint of 6MWD increased significantly from baseline after twelve weeks in patients receiving riociguat compared to placebo. There were also significant improvements in secondary endpoints of pulmonary vascular resistance (PVR), NT-proBNP, WHO functional class, time to clinical worsening and Borg dyspnea score from baseline in patients receiving riociguat compared to placebo. Riociguat is FDA-labeled for patients with 1) WHO Group 4 PH: Persistent/ recurrent chronic thromboembolic pulmonary hypertension (CTEPH) after
surgical treatment or inoperable CTEPH to improve exercise capacity, and 2) WHO Group 1 PH (PAH) as an alternative pulmonary arterial hypertension medication to improve exercise capacity, improve WHO functional class and to delay clinical worsening.11 Riociguat’s starting dose is 0.51 mg orally three times daily, with a target dose of 2.5 mg. Dose increases of 0.5 mg every 2 weeks are recommended if SBP>95 and the patient remains asymptomatic. Re-evaluate antihypertensive therapy when starting riociguat and consider dose reductions, especially arterial afterload medications (ACEI, ARBs, hydralazine, etc.). Riociguat has a small volume of distribution and is highly protein bound (95%). It is metabolized in the liver (CYP1A1, CYP3A, CYP2C8, and CYP2J2) and eliminated through the kidneys (40%). Riociguat’s elimination half-life is 12 hours.10 Avoid riociguat use in smokers and patients receiving strong CYP3A4 inducers. Riociguat and its active major active metabolite, M1, are
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TABLE 2. Nitric Oxide Pathway Study Comparisons Drug vs. Placebo
PH Group
PH Type
Length (weeks)
6MWD (meters)
PH Med Therapy
CHEST-16
Riociguat 2.5 mg TID
4
CTEPH
16
347
PATENT-17 PATENT-27
Riociguat 2.5 mg TID
1
Idiopathic/ inheritable 61%, CTD 25%
PATENT-1 12 wks PATENT-2 24 wks
PHIRST8
Tadalafil 40 mg QDay
1
Idiopathic, familial, CTD
SUPER9
Sildenafil TID
1
Idiopathic, CTD, shunt
Baseline Data
WHO Functional Class I
II
III
IV
0%
1%
31%
64%
4%
363
50%
3%
42%
53%
1%
16
352
Bosentan 53 %
1%
32%
65%
2%
12
339
0%
<19%
39%
58%
3%
NTproBNP* (Drug vs. P)
Drug vs. Placebo
6MWD* (meters)
WHO FC Decrease (Drug vs. P)
PVR*
CI* L/hr/m2
mPAP* mm Hg (Drug vs. P)
CHEST-16
Riociguat 2.5 mg TID
+ 46
33% vs. 15%
- 246
CO = + 0.9
-5
- 444
PATENT-17 PATENT-27
Riociguat 2.5 mg TID
+ 36
21% vs. 14%
- 226
CO = + 0.9
-4
- 432
+ 53
NA
NA
NA
NA
NA
Tadalafil 40 mg QDay
+ 33
Overall: No difference “No bosentan” group: 37 % vs. 16.2%
-209
+ 0.6
-4.3
NA
20 mg TID
+ 45
28% vs. 7%
-171
+0.23
-2.1 vs. 0.6
NA
40 mg TID
+ 46
36% vs. 7%
-192
+0.26
-2.6 vs. 0.6
NA
80 mg TID
+ 50
42% vs. 7%
-310
+0.39
-4.7 vs. 0.6
NA
Results
PHIRST8
SUPER9 (Sildenafil)
6MWD= 6 minute walk distance, B= bosentan, CI = cardiac index, CO=Cardiac Output, CTD= connective tissue disease, CTEPH = chronic thromboembolic pulmonary hypertension, FC= functional class, HIV= human immunodeficiency virus, mPAP = mean pulmonary artery pressure, NA = not available, P= placebo, PAH= pulmonary arterial hypertension, PDE5= phosphodiesterase 5 inhibitors, PGE = prostacyclin (epoprostenol, treprostinil), PVR = pulmonary vascular resistance. *Difference compared to placebo WHO = World Health Organization
catalyzed by cigarette smoke and strong CYP3A4 inducers (rifampin, phenytoin, carbamazepine, etc.), resulting in reduced plasma concentrations of both. These drug interactions significantly reduce the exposure to riociguat (e.g., 50%-60%) and require higher riociguat doses than recommended in the package insert. Strong CYP/P-gp/BCRP inhibitors (ketoconazole, itraconazole, protease inhibitors) increase exposure to riociguat and may lead to hypotension. Use lower initial riociguat doses (0.5 mg TID) when initiating therapy and monitor for hypotension. Avoid riociguat use if the patient has severe hepatic impairment (Child Pugh C) or has reduced renal function (CrCl< 15ml/min or if patient on dialysis). 11 Riociguat contraindications include pregnancy, mothers that are nursing and concurrent use of medications affecting the nitric oxide pathway. Nitric oxide pathway medications include nitrates (nitroglycerin)
and nitric oxide donors (nitroprusside), and phosphodiesterase type-5 (PDE5) inhibitors (i.e. sildenafil, vardenafil, tadalafil, dipyridamole, and theophylline). Riociguat is available in 0.5, 1, 1.5, 2 and 2.5 mg tablets. Riociguat requires enrollment into the Adempas REMS program for females, requiring pregnancy testing at baseline and monthly. Upon patient discharge from hospital, the hospital may dispense up to a 15-day patient supply to ensure continuity of therapy until medication can be obtained through a Specialty Pharmacy. Riociguat offers patients with chronic thromboembolic pulmonary hypertension (CTEPH) a convenient, oral treatment option. Previously, these patients were treated with intravenous epoprostenol. Riociguat is recommended (Class I recommendation) for patients with PAH with WHO functional class II-III symptoms according to recently published guidelines.1
Riociguat should also be considered for PAH patients with WHO functional class IV symptoms (Class IIa recommendation) in addition to parenteral prostacyclin therapy. Although riociguat studies have demonstrated that it significantly improves 6 minute walk distance (6MWD), this surrogate marker of efficacy has not been validated to improve long-term outcomes. Riociguat drawbacks include high cost (table 4) and potentially poorer patient compliance associated with three times daily dosing compared to other agents in this medication class (once-daily tadalafil).
Treprostinil Oral
Treprostinil is a stable, synthetic prostacyclin analog available in a parenteral (Remodulin® IV, SQ), inhalation (Tyvaso®) and newly approved oral (Orenitram®) dosage form. The parenteral dosage form requires an intravenous or subcutaneous catheter and is administered as a continuous
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infusion. The patient prepares the infusion every couple of days and catheter related complications are not uncommon (bloodstream infections, catheter occlusions, pain at administration site, etc.). The inhaled dosage form is administered four times daily and is usually well tolerated. However, the inhalation is limited by the number of puffs that can be administered as the disease progresses (up to 18 puffs). Intravenous treprostinil is usually prescribed for PAH patients with WHO functional class III-IV symptoms and not responding to less invasive PAH therapies (ERA, NO pathway, inhaled treprostinil). In theory, oral treprostinil offers patients a less invasive dosage form that is capable of achieving plasma treprostinil concentrations equivalent to the intravenous dosage form. Oral treprostinil studies are summarized in Table 3. In the FREEDOM-C study, patients
with PAH and on background ERA or PDE-5 inhibitor therapy were randomized to treprostinil 1 mg orally twice daily or placebo. A large number of treprostinil patients withdrew from the study compared to placebo (22% vs. 14%) due to intolerable prostacyclin excess side effects. As the study progressed, treprostinil 0.25 and 0.5 mg tablets became available which improved patient tolerability and reduced the patient dropout rate. Overall, due to the high dropout rate, this intent-to-treat study showed no significant changes in 6MWD with treprostinil compared to placebo.13 In the FREEDOM-M trial, patients with PAH and no current therapy for PAH, were randomized to treprostinil 1 mg orally twice daily or placebo. Based on the results of the previous study, FREEDOM-M was amended to start patient therapy at a lower treprostinil dose (0.25mg) and a modified intent-to-treat (mITT) cohort
was also reported in the study results. Patients started at the lower dose (the mITT cohort), showed a significant improvement in 6MWD at week 12 and better therapy tolerance. No other differences were found compared to placebo.12 In the FREEDOM-C2 study, patients on background ERA or PDE-5 inhibitor therapy were randomized to treprostinil 0.25 mg twice daily or placebo. The primary endpoint measured was 6MWD improvement from baseline. After 16 weeks of therapy, treprostinil treated group had similar 6MWD improvement compared to those receiving placebo. Secondary outcome measures showed no significant differences between treprostinil and placebo.14 This was the second study that demonstrated no apparent benefit from adding oral treprostinil to background PAH medication therapy. Based on the FREEDOM-M study
TABLE 3. Treprostinil ORAL Study Comparison Baseline Data
Drug vs. Placebo
PH Group
PH Type
Length (weeks)
6MWD (meters)
PH Meds
1
Idiopathic, familial or PAH associated with congenital heart disease or CTD or HIV.
16
346
1
Idiopathic or hereditary PAH (75%), congenital shunts, collagen vascular dx or HIV
12
Functional Class (FC) I
II
III
IV
PDE 25% ERA 30% Both 45%
1%
21%
76%
2%
T: 350 P: 339 (mITT)
0%
0
33%
67%
0%
16
T: 330 P: 337
PDE 43% ERA 17% Both 40%
0%
26%
73%
<1%
FREE-DOM-C
Treprostinil1 mg PO BID
FREE-DOM-M12
Treprostinil 0.25 mg PO BID
FREE-DOM-C214
Treprostinil 0.25 mg PO BID
1
Idiopathic, familial or PAH associated with congenital heart disease or CTD or HIV.
Results
Drug vs. Placebo
6MWD* (meters)
WHO FC Decrease (Drug vs. P)
Dyspnea fatigue index score*
Borg Dyspnea Index*
No Clinical Worsening*
Notes:
FREEDOM-C13
Treprostinil
+ 11 (+34 if T >3.5 mg)
18% vs. 15% (NS)
No significant difference
No significant difference
95% vs. 93%
Patient stopped therapy: Treprostinil 0.25 mg: 0% Treprostinil 0.5 mg: 12% Treprostinil 1 mg: 25%
FREEDOM-M12
Treprostinil
+ 23 (mITT)
No significant difference
No significant difference
No significant difference
90 % vs. 90%
Only 1 mg tablets available early in trial. mITT group had 0.25 mg tablets available.
FREEDOM-C214
Treprostinil
+ 10 (NS)
No significant difference
No significant difference
No significant difference
93% vs. 93%
If PAH diagnosis <1 year, 6MWD was +28 m. Longer study to detect difference?
13
6MWD= 6 minute walk distance, CI = cardiac index, CTD= connective tissue disease, ERA= endothelial receptor antagonists (bosentan, ambrisentan), FC= functional class, HIV= human immunodeficiency virus, mITT= modified intent to treat mPAP = mean pulmonary artery pressure, NA = not available, P= placebo, PAH= pulmonary arterial hypertension, PDE= phosphodiesterase 5 inhibitors, PGE = prostacyclin (epoprostenol, treprostinil), PVR = pulmonary vascular resistance, T = treprostinil. NS = Not Significant *Difference compared to placebo WHO = World Health Organization www.pswi.org
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TABLE 4. Pulmonary Hypertension Medication Costs (December 2013)
Generic Name
Dose
Medication
Yearly Costs
Bosentan
BID
Tracleer® 62.5 or 125 mg (60)
$49,932
Ambrisentan
Qday
Letairis® 5 or 10 mg (30)
$94,148
Macitentan
Qday
Opsumit® 10 mg tabs (30)
$94,039
Sildenafil
20 mg TID
Sildenafil 20 mg (generic) (100)
$ 658
Tadalafil
40 mg/day
Adcirca ® 20 mg
$ 19,881
Riociguat
TID
Adempas® (all 5 doses)
$ 91,250
Treprostinil
QID
Tyvaso® 1.74 mg/2.9 mL (4)
$202,233
6x/day
Ventavis® 20 mcg/1 mL
$202,356
Iloprost Epoprostenol
Drip
Veletri 1.5 mg vials
$ 82,344
Treprostinil
Drip
Remodulin® 1 mg/mL- 20 mL *
$242,063
Treprostinil
Drip
Remodulin® 10 mg/mL- 20 mL*
$242,063
Treprostinil
0.125 mg TID
Orenitram® 0.125 mg (100)
$ 6,406
Treprostinil
0.25 mg TID
Orenitram® 0.25 mg (100)
$ 12,812
Treprostinil
1 mg TID
Orenitram® 1 mg (100)
$ 51,246
Treprostinil
2.5 mg TID
Orenitram® 2.5 mg (100)
$128,115
* Calculation based on 70 kg patient receiving epoprostenol at 60 ng/kg/min (or treprostinil 90ng/kg/ min).
results, the FDA approved oral treprostinil for the treatment of PAH patients with functional class II-III symptoms to improve exercise ability and etiologies of idiopathic or heritable PAH or PAH associated with connective tissue disease. It is contraindicated in patients with severe hepatic impairment (Child-Pugh Class C) as the drug is eliminated by hepatic metabolism. Oral treprostinil is initiated at 0.25 mg orally twice daily with food/meal and titrated upward 0.25-0.5 mg every 3-4 days.15 Its elimination half-life is 4 hours and the drug is delivered in an extended release dosage form to decrease prostacyclin side effects associated with peak treprostinil serum concentrations. Treprostinil’ s oral absorption is only 17% and peak blood levels are obtained about 4 hours after ingestion.18 Three-times a day dosing may be preferable to avoid large peak to trough changes associated with oral dosage form and may improve patient tolerance. These doses are titrated by 0.125 mg increments every 3-4 days. There are no dosage adjustments necessary for patients with chronic kidney disease. Patients should not take Orenitram with alcohol, as alcohol alters the absorption characteristics of tablet. They should be instructed to not crush or split the tablet
as the drug is slowly released from the wax matrix during gastrointestinal transit. Patients may observe an insoluble shell eliminated in their stools which is normal. Blood pressure response with other antihypertensive agents that the patient is receiving should be monitored. Patients on oral treprostinil should be educated to monitor for signs/symptoms of insufficient prostacyclin or prostacyclin excess and report them to their physician: Insufficient prostacyclin: Hypotension, cool/clammy skin, SOB, hypoxia, fatigue, chest pain, syncope, palpitations, lower extremity edema. Prostacyclin excess: Hypotension, warm/ flushed skin, headache, jaw/leg/muscle pain, dizziness, nausea, vomiting, diarrhea, rash, restlessness/anxiety. Oral treprostinil is available in 0.125, 0.25, 1 and 2.5 mg extended release tablets. Patients should be instructed to bring this and all PAH medications with them to the hospital to avoid interruption in therapy. This agent may not be readily available at all hospitals due to cost or formulary issues. Upon discharge from the hospital, oral treprostinil is only available through a Specialty Pharmacy. There is no required REMS program for this medication. No PAH guideline recommendations are available for oral treprostinil since the
drug was marketed after the latest PAH guidelines were published in late 2013. Oral treprostinil may offer the patient an alternative to the more invasive therapies (prostacyclin IV or SQ) or an alternative if they are unable to tolerate other PAH therapies. Additional studies are needed to demonstrate that this expensive dosage form (table 4) is effective for patients already on dual PAH therapy (ERA plus NO pathway agent). In future studies, three times daily oral treprostinil may improve therapy tolerability by reducing peak treprostinil serum concentrations.
Summary
Macitentan, riociguat and oral treprostinil are new FDA-approved medications used to treat pulmonary hypertension. Macitentan offers a oncedaily ERA alternative proven to decrease morbidity and mortality in patients with PAH. Riociguat is a nitric oxide stimulator that significantly improves patient symptoms in patients with CTEPH and offers an oral dosage form for treatment of this disease. Oral treprostinil is commercially available for treatment of patients that are non-responsive to or intolerant to ERAs or NO pathway medications and are not candidates for parenteral epoprostenol or treprostinil. Additional studies are needed to support its role in treatment of pulmonary hypertension. ● Frank C Spexarth, RPh, BCPS, Pharmacy Clinical Coordinator—Cardiac Surgery Aurora Health Care Department of Pharmacy, Milwaukee, Wisconsin As part of his duties, he responsible for ensuring a smooth transition of care for hospitalized Aurora Medical Group Pulmonary Hypertension Clinic patients. Disclosure: The author declares no real or potential conflicts or financial interest in any product or service mentioned in the manuscript, including grants, equipment, medications, employment, gifts, and honoraria.
References
1. Galie N, Corris PA, Frost A, et al. Updated treatment algorithm of pulmonary arterial hypertension. J Am Coll Cardiol. 2013; 62: D60-D72. 2. Pulido T, Adzerikho I, Channick RN, et al, for the SERAPHIN Investigators. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013; 369:809-818.
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3. Rubin LJ, Badesch DB, Barst RJ, et al, for the BREATHE-1 Study Group. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002; 346:896-903. 4. Galie N, Olschewski H, Oudiz RJ, et al, for the ARIES Group. Ambrisentan for the treatment of pulmonary arterial hypertension. Circulation. 2008; 117:3010-3019. 5. Opsumit (macitentan) [package insert]. South San Francisco, CA: Actelion Pharmaceuticals US, Inc.; October 2013. 6. Ghofrani HA, D’Armini AM, Grimminger F, et al, for the CHEST-1 Study Group. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med. 2013; 369:319-329. 7. Ghofrani HA, Galie N, Grimminger F, et al, for the PATENT-1Study Group. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013; 369:330-340 8. Galie N, Brundage BH, Ghofrani HA, et al, for the PHIRST Study Group. Circulation. 2009; 119:2894-2903. 9. Galie N, Ghofrani HA, Torbicki A, et al, for the SUPER Study Group. N Engl J Med. 2005; 353:2148-2157. 10. Riociguat. In:DRUGDEX System (Micromedex 2.0). Greenwood Village, CO:
Truven Health Analytics; c1974-2014. http:// www.micromedexsolutions.com/micromedex2/ librarian#. Accessed July 25, 2014. 11. Adempas® (riociguat) [package insert]. Whippany, NJ: Bayer HealthCare Pharmaceuticals: October 2013. 12. Jing ZC, Parikh K, Pulido T, et al. Efficacy and safety of oral treprostinil monotherapy for the treatment of pulmonary arterial hypertension (the freedom-m study): a randomized, controlled study. Circulation. 2013; 127:624-633. 13. Tapson VF, Torres F, Kermeen F, et al. Oral treprostinil for the treatment of pulmonary arterial hypertension in patients on background endothelin receptor antagonist and/or phosphodiesterase type 5 inhibitor therapy (the freedom-c study): a randomized controlled trial. Chest. 2012; 142(6):1383-1390. 14. Tapson VF, Jing ZC, Xu KF, et al. Oral treprostinil for the treatment of pulmonary arterial hypertension in patients receiving background endothelin receptor antagonist and phosphodiesterase type 5 inhibitor therapy(the freedom-c2 study): a randomized controlled trial. Chest. 2013; 144(3):952-958. 15. Orenitram® (treprostinil extended-release tablets) [package insert]. Research Triangle Park, NC: United Therapeutics Corp.; December 2013. 16. D’Alonzo GE, Barst RJ, Ayres SM, et al.
THE PTCB
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Survival in patients with primary pulmonary hypertension: results from a national prospective registry. Ann Intern Med. 1991; 115:343–349. 17. Macitentan. In:DRUGDEX System (Micromedex 2.0). Greenwood Village, CO: Truven Health Analytics; c1974-2014. http:// www.micromedexsolutions.com/micromedex2/ librarian#. Accessed July 25, 2014. 18. Treprostinil. In:DRUGDEX System (Micromedex 2.0). Greenwood Village, CO: Truven Health Analytics; c1974-2014. http:// www.micromedexsolutions.com/micromedex2/ librarian#. Accessed July 25, 2014.
Certification by PTCB is the gold standard for pharmacy technicians. Many employers now require their employees to be PTCB-Certified Pharmacy Technicians (CPhTs). PTCB has a new website, a streamlined application process, sponsorships, and free verifications. The Pharmacy Technician Certification Exam (PTCE) reflects current knowledge areas demanded across all practice settings. PTCB’s requirements to become a CPhT include a high school diploma and a passing score on the PTCE. Learn more and apply at www.ptcb.org.
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originalcontributions
Human Papillomavirus: A Brief Overview and Recommendations for Pharmacists by Amy R. Nielsen and Mary S. Hayney, PharmD, MPH
H
uman papillomavirus (HPV) is a common sexually transmitted infection in the United States. Most infections are self-limiting and exhibit no symptoms, but persistent HPV infections can progress to precancerous lesions and cancer. HPV is known to cause cervical cancer as well as vaginal, vulvar, penile, anal, and oropharyngeal cancers.1,2 It is also a leading cause of genital warts.1 Currently two vaccines are available for primary prevention of HPV infection. The quadrivalent vaccine (HPV4, Gardasil®) and the bivalent vaccine (HPV2, Cervarix®) offer protection against HPV types 16 and 18, which cause 70% of cervical cancers and are associated with most other HPV-related cancers. HPV4 provides additional coverage against HPV types 6 and 11 that cause 90% of genital warts.1 Successful completion of the vaccine series decreases the risk of developing complications associated with HPV infection, namely cancers. As a result of the vaccine success and the implications it has for improving public health, the Centers for Disease Control and Prevention has made increasing HPV immunization rates among adolescents one of its top 5 priorities for 2014.3
HPV Vaccine History
The Advisory Committee on Immunization Practices (ACIP) currently recommends routine immunization of adolescents aged 11 or 12 years with either HPV4 (males and females) or HPV2 (females only).4 To be considered fully
immunized, individuals must complete a three-dose series. Either vaccine product series can be initiated in individuals as young as 9 years old; catch-up vaccination is indicated for females between the ages of 13 and 26 and males aged 13-21 years who have never received a dose or who have not yet completed the entire series.5 HPV vaccine-type prevalence has decreased by greater than 50% since the introduction of the quadrivalent vaccine in mid-2006, according to a study done by National Health and Nutrition Examination Surveys (NHANES).6 In addition to demonstrated efficacy, both vaccines have been shown to be safe. Adverse events are reported to the Vaccine Adverse Event Reporting System (VAERS); of the 56 million doses administered between June 2006 and March 2013, approximately 92% of the reported events were classified as nonserious.7
Wisconsin Coverage
Despite the evidence that supports safety and efficacy of the vaccines, immunization rates remain low both nationally and in the state of Wisconsin. According to data obtained from the Wisconsin Immunization Registry (WIR), only 34% of females and 11% of males received all three doses of the vaccine as of December 2013. When compared to other routine immunizations, this is significantly lower than the 92% of individuals that received the Tdap vaccine and the 75% of individuals that received the meningococcal conjugate vaccine in the state of Wisconsin. The discrepancy
among these immunization rates indicates that many opportunities to deliver HPV vaccines were missed. It is also interesting that approximately 55% of females and 29% of males between the ages of 13 and 17 in Wisconsin have received at least one dose of the HPV vaccine, but have yet to complete the series.8 Immunizers must implement strategies to assure completion of the series.
Barriers to HPV Vaccination
Several studies have examined the barriers that exist to HPV vaccination. The major obstacle that might be responsible for lack of immunization may originate from knowledge gaps from both the healthcare professional and the parent’s point of view. Healthcare professionals often fail to make a definitive recommendation for the HPV vaccine to adolescents and their parents. This may come from lack of understanding of the connection between HPV and genital warts and other noncervical cancers, causing the healthcare professional to underappreciate the true impact the vaccine may have, especially when it concerns immunizing males. Other evidence suggests that providing incomplete information about the risks and benefits of the HPV vaccine gives parents the impression that the vaccine series is more optional than necessary, leading them to forgo vaccination. Furthermore, healthcare providers may preferentially recommend the vaccine for older versus younger females rather than including it as a routine immunization for all adolescents as young as 9 years of age.9
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Parents and caregivers identified lack of awareness and information about the vaccine, childâ&#x20AC;&#x2122;s age, and not receiving a recommendation for the vaccine from a healthcare provider as the major barriers to immunizing their child. Social media may be increasing awareness that a vaccine is available, but many parents report that they need more information about use and safety before deciding to have their child immunized. Some studies found that parents believe that their child is too young to get vaccinated and are afraid that getting the vaccine will encourage sexual activity at a younger age. As a result, immunization is often delayed. Adolescents are more likely to receive the HPV vaccine if parents understand its use as a preventative tool or have a history of an HPV-related infection.9 Pharmacists are subject to a reimbursement barrier for provision of HPV vaccines. Private insurers make the decision regarding immunizer reimbursement individually so significant variability in coverage exists. Pharmacy staff or patients would have to contact their insurers to determine coverage. HPV vaccines are part of the Vaccines for Children program. The Vaccines for Children program makes vaccines available for children aged 0-18 years (9-18 years for HPV vaccines) who are not insured, underinsured, or Native American or Alaskan Native. No provision is made for payment of an administration fee. Medicaid does not reimburse pharmacy-based immunizers except for seasonal influenza vaccine. (See Immunization Update 2014 on pages 6-9 for a brief overview of the impact of the Affordable Care Act on pharmacy-based immunization services.)
Implications for Pharmacists
In an effort to increase the HPV immunization rate, it is important that healthcare professionals, including pharmacists, understand the importance of vaccinating adolescents before they begin sexual activity. Pharmacists should be prepared to discuss the HPV vaccine with parents and young adults for whom the vaccine is indicated, and should be sure to highlight the role of the vaccine in cancer prevention. Pharmacists are equipped with www.pswi.org
the knowledge to provide a definitive recommendation for HPV immunization. They should have a solid understanding of the vaccine indication and be confident when screening individuals to determine immunization status and eligibility. Although parents may wish to protect their children from the complications associated with HPV infections, most want more information about the vaccine before deciding to initiate the series. Pharmacists can help by having adequate and clear information readily accessible to parents. This information should address HPV infection, the risks and benefits of vaccination, safety, and the age at which the vaccine should be administered. Pharmacists should then conclude with a strong recommendation for vaccination. Parent beliefs that only sexually active individuals need the vaccine should be addressed. Pharmacists should be comfortable discussing the need to vaccinate at an age before sexual activity begins in order to provide the highest level of protection for the adolescent. A delay in immunization may mean a potentially missed opportunity for prevention. Furthermore, pharmacists can communicate the importance of vaccinating male patients. Finally, pharmacists should have a plan concerning completion of the entire three-dose series. If the vaccine series is initiated at the pharmacy, the date for the second dose should be scheduled before the patient leaves. The importance of receiving all three doses should be emphasized to the parents and the patient. Pharmacies should develop their own policies regarding reminders for upcoming doses in order to increase the number of adolescents that are fully immunized against HPV. For example, a pharmacy may decide to call patients, send an email or text message, or send a postcard reminding them of an upcoming appointment. Pharmacies may also consider contacting individuals that missed a vaccination appointment in order to encourage patients to return for overdue doses.
Conclusion
associated complications. By taking the time to address patient and parent concerns, pharmacists can help to clarify misconceptions about HPV and make a strong recommendation to vaccinate in an effort to increase immunization rates and ultimately improve public health outcomes. â&#x2014;? Amy R. Nielsen , Mary S. Hayney, PharmD, MPH. Parts of this manuscript are reprinted from JAPhA September/October 2014 issue Vaccine Update.
References
1. Humans IWGotEoCRt. Human papillomaviruses. IARC Monogr Eval Carcinog Risks Hum. 2007;90:1-636. 2. CDC. Quadrivalent human papillomavirus vaccine: recommendation of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep.2007; 56(RR02):1-24. 3. Centers for Disease Control and Prevention. CDC's top ten: five for 2013, five for 2014. http://stacks.cdc.gov/view/ cdc/21257. Accessed July 2, 2014. 4. CDC. Recommendation on the use of quadrivalent human papillomavirus vaccine in males- advisory committee on immunization practices (ACIP). MMWR Morb Mortal Wkly Rep 2011; 60(50):1705-1708. 5. CDC. FDA licensure of bivalent human papillomavirus vaccine (HPV2, Cervarix) for use in females and updated HPV vaccination recommendations for the advisory committee on immunization practices (ACIP). MMWR Morb Mortal Wkly Rep.2010;59(20):626-629. 6. Markowitz LE, Hariri S, Lin C, et al. Reduction in human papillomavirus (HPV) prevalence among young women following HPV vaccine introduction in the United States, National Health and Nutrition Examination Surveys, 20032010. J Infect Dis. Aug 2013;208(3):385-393. 7. CDC. Human papillomavirus vaccination coverage among adolescent girls, 2007-2012, and postlicensure vaccine safety monitoring, 2006-2013-United States. MMWR Morb Mortal Wkly Rep.2013;62(29):591-595. 8. Lazar KK, Imm P, Petit A, Conlon A, LoConte N. Human papillomavirus (HPV) related cancers and vaccination coverage in Wisconsin. Comprehensive Cancer Control Program (CCC) Issue Brief. 2014;10(3):1-4. 9. Holman DM, Benard V, Roland KB, Watson M, Liddon N, Stokley S. Barriers to human papillomavirus vaccination among US adolescents: a systematic review of the literature. JAMA Pediatr. Jan 2014;168(1):76-82.
HPV vaccination has been demonstrated to be safe and effective in primary prevention of HPV-
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In two 1-year pivotal studies: For patients with severe COPD associated with chronic bronchitis and a history of exacerbations
DALIRESP ® is the first and only selective PDE4 inhibitor to reduce the risk of COPD exacerbations1,2 • Reduces moderate or severe exacerbations by 17% vs placebo1,3,4 • Effective alone or in combination with a bronchodilator1,3 • Statistically significant increase in lung function (pre-bronchodilator FEV1) of 48 mL vs placebo1,4 – DALIRESP is not a bronchodilator; this increase was not clinically significant1,3
INDICATIONS AND USAGE DALIRESP is indicated as a treatment to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations. DALIRESP is not a bronchodilator and is not indicated for the relief of acute bronchospasm.
Reaching 1 million prescriptions and still going! IMPORTANT SAFETY INFORMATION Contraindications DALIRESP is contraindicated in patients with moderate to severe liver impairment (Child-Pugh B or C). Warnings and Precautions • DALIRESP is not a bronchodilator and should not be used for the relief of acute bronchospasm. • Prescribers should advise patients, their caregivers, and families to be alert for the emergence or worsening of insomnia, anxiety, depression, suicidal thoughts or other mood changes, and if such changes occur, to contact their healthcare provider. Prescribers should carefully evaluate the risks and benefits of continuing treatment if such events occur. Before using DALIRESP in patients with a history of depression and/or suicidal thoughts or behavior, prescribers should carefully weigh the risks and benefits of treatment with DALIRESP. – Treatment with DALIRESP is associated with an increase in psychiatric adverse reactions. In controlled clinical trials 5.9% of patients treated with DALIRESP reported psychiatric adverse reactions vs 3.3% treated with placebo. The most common psychiatric adverse reactions were insomnia (2.4% vs 1.0%), anxiety (1.4% vs 0.9%), and depression (1.2% vs 0.9%). Three patients treated with DALIRESP experienced suicide-related adverse reactions (one completed suicide and two suicide attempts) compared to one patient (suicidal ideation) treated with placebo. • Patients should have their weight monitored regularly. If unexplained or clinically significant weight loss occurs, weight loss should be evaluated and treatment discontinuation considered. – In addition to weight loss being reported as a common adverse reaction (7.5% of patients treated with DALIRESP vs 2.1% placebo), weight was prospectively assessed in two 1-year clinical trials. In these studies that compared DALIRESP to placebo, 20% vs 7% experienced moderate weight loss (5-10% of body weight) and 7% vs 2% experienced severe weight loss (>10% body weight). During the follow-up period after discontinuing DALIRESP, the majority of patients regained some of the weight they had lost. • Use with strong cytochrome P450 enzyme inducers (eg, rifampicin, phenobarbital, carbamazepine, phenytoin) is not recommended, as they decrease the exposure and may reduce the therapeutic effectiveness of DALIRESP. Adverse Reactions In clinical trials the most common adverse reactions (≥2% and greater than placebo) were diarrhea (9.5% vs 2.7%), weight loss (7.5% vs 2.1%), nausea (4.7% vs 1.4%), headache (4.4% vs 2.1%), back pain (3.2% vs 2.2%), influenza (2.8% vs 2.7%), insomnia (2.4% vs 1.0%), dizziness (2.1% vs 1.1%), and decreased appetite (2.1% vs 0.4%). Please also see Brief Summary of full Prescribing Information on reverse side. Source: Fingertip Formulary database, a registered trademark of Fingertip Formulary, LLC, as of [XX/XX/XX]. Data is subject to change. {INSERT If applicable [T3P=Preferred Brand; T4*=non-standard benefit design, with T3 being the preferred brand; PA=Prior Authorization; ST=Step Therapy.]} COPD=chronic obstructive pulmonary disease. PDE4=phosphodiesterase-4.
References: 1. DALIRESP (roflumilast) Prescribing Information. Forest Pharmaceuticals, Inc. St. Louis, MO. 2. US Food and Drug Administration. FDA news release. March 1, 2011. http://www.fda.gov/NewsEvents/newsroom/PressAnnouncements/ucm244989.htm. Accessed September 19, 2013. 3. Data on file. Forest Laboratories, Inc. 4. Calverley PMA, Rabe KF, Goehring U-M, Kristiansen S, Fabbri LM, Martinez FJ; for the M2-124 and M2-125 study groups. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet. 2009;374:685-694.
DALIRESP is a registered trademark of Takeda GmbH. © 2014 Forest Laboratories, Inc. DAL11614
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Pharmacist Involvement in Cardiac Rehabilitation Programs in Wisconsin: A Case Series by Laura M. Traynor, PharmD, BCPS and Kimberly D. Beyer, B.S., FAACVPR
C
ardiac rehabilitation (CR) is a structured program of cardiovascular risk reduction, including exercise, education, and psychosocial support, for patients who have recently had a major cardiac event including, but not limited to: myocardial infarction (MI), coronary artery stent placement, coronary artery bypass grafting, heart valve repair or replacement, heart transplant, and heart failure.1,2,3 Enrollment in CR programs has been shown to decrease mortality and recurrent nonfatal MI when employed after a cardiac event.4 Patients who are referred to CR are typically seen in the hospital by a cardiac rehabilitation professional for education related to risk factor modification prior to discharge. This is called inpatient CR.3 Early outpatient CR consists of outpatient exercise and education sessions, typically three times per week for six to twelve weeks. During these sessions, a program of gradually increasing exercise with telemetry monitoring is combined with education about risk factor modification and psychosocial support.2,3 After this program is completed, patients are encouraged to continue exercising on their own. Many programs offer a self-pay “maintenance” program which allow participants to continue to exercise in a medically supervised setting.3 CR programs typically employ registered nurses, exercise physiologists, and other qualified health care professionals to monitor patients during exercise and to provide education and support.2 A medical director, which may be a primary care physician or cardiologist, provides supervision of the program.4 Pharmacists are involved in CR programs to varying degrees. A review of pharmacist involvement in CR programs found instances of pharmacists who were
involved in the inpatient and outpatient phases of the program.5 Most of the reports in the literature are descriptive and not evaluative. The most common roles for pharmacists in CR programs are medication education, either individually or in the group setting; medication reconciliation; medication monitoring; evaluating and recommending changes to drug regimens; documenting involvement in the medical record; and acting as a medication resource for the other members of the CR interprofessional team.5
Cardiac Rehabilitation Programs in Wisconsin Cardiac rehabilitation programs have a strong history in Wisconsin. Some Wisconsin CR programs involve pharmacists, while others do not. In this article, the authors will discuss three programs that involve pharmacists; these programs vary in size and location: Edgerton Hospital Edgerton Hospital is a critical access hospital in the southern part of Wisconsin. It is an 18-bed facility with many outpatient services such as cardiac and pulmonary rehabilitation, diagnostic services, emergency and urgent care, outpatient rehabilitation services, sleep disorder evaluation and treatment, surgery, short-term rehabilitation and wound care. The CR program was started in May of 2008. It currently offers an early outpatient CR program and a maintenance program three days per week. This program has had a pharmacist involved with the program since its inception. Education is offered daily on an individual basis, and formalized education classes are offered on Mondays. A packet of educational materials is provided to the patients that
are not able to attend the educational offerings to ensure that the patients still receive the information. A pharmacist is involved in a medication class, which lasts 45 to 60 minutes and is on a scheduled rotating basis with other educational classes. The pharmacist is also available for 30-minute one-on-one appointments with the patients if needed. The pharmacist also serves as the medication resource contact for the staff of the CR program.6 Columbia St. Mary’s Hospital Ozaukee Columbia St. Mary’s Hospital Ozaukee is a 182-bed hospital in Mequon, Wisconsin located in the southeastern portion of Wisconsin. Columbia St. Mary’s Hospital Ozaukee is part of Columbia St. Mary’s Health System, which consists of a total of 5 hospitals and over 60 clinics serving Milwaukee, Ozaukee, Sheboygan and Washington Counties.7 The CR program has been in existence since the 1980’s with a pharmacist involved with the program since January 2011. Early outpatient CR is offered three times per week with five different classes per day. A maintenance program is offered the other two days per week. Education occurs once per week on Wednesdays and is built into the exercise session so all patients can attend. There are twelve classes in a rotation, and the pharmacist is responsible for a medication class that is about 20 to 30 minutes that covers cardiac medications (antiplatelet drugs, beta-blockers, ACE-inhibitors/ ARBs, and statins), medication adherence tips, and medication safety tips. The pharmacist works in CR one day per week on Wednesdays. The pharmacist meets with each patient who is enrolled in the CR program to perform medication reconciliation, discuss the purpose/benefit of each medication, discuss and evaluate
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for side effects, provide medication administration suggestions, and assess adherence to medications. The pharmacist also contacts the patient’s physician if needed for resolution of drug therapy problems. The pharmacist also assists in the CR classes by obtaining blood pressures and blood glucose readings. She enters data into the telemetry monitoring system and the electronic medical record. The pharmacist is certified in basic life support (BLS) and advanced cardiac life support (ACLS), and can provide assistance in emergencies should they arise. The pharmacist is available to the patients via email or phone if any questions arise outside of scheduled class times on Wednesdays. The pharmacist also provides educational in-services for the staff about new medications, new guidelines, and other related topics. The pharmacist precepts final-year Pharm.D students form Concordia University Wisconsin; these students are involved in the CR program as described above under the supervision of the preceptor. Funding for the pharmacist occurs through Concordia University of Wisconsin School of Pharmacy as the pharmacist holds a faculty position. University of Wisconsin Hospitals and Clinics The University of Wisconsin Hospitals and Clinics (UWHC) consists of a 592-bed hospital and 117 affiliated clinics located throughout southcentral Wisconsin.8 UWHC Preventive Cardiology program operates CR programs at two locations in Madison, WI. The early outpatient CR program is offered 3 times per week at three different times during the day. Education classes on various topics occur on Mondays. This CR program has been in existence for many years; a pharmacist joined the team in 2006. The pharmacist teaches two of the 12-week cycle of education classes for two of three CR cohorts. The first covers the ABCs of cardiac medications (A=antiplatelets, antianginals, ACE inhibitors/ARBs; B=beta-blockers, blood pressure; C=cholesterol, cigarettes; the second discusses safety concerns with using over-the-counter medications and dietary supplements in combination with heart medications. Each class lasts for 30 www.pswi.org
minutes. The pharmacist also meets with patients during their exercise sessions to discuss medication purpose, side effects, medication administration tips, and work with the patient to improve adherence. Individual one-hour brown-bag sessions are available for patients who demonstrate a need or desire for individual assessment and education. The pharmacist also provides monthly group education and individual appointments for participants in the CR program in Beaver Dam, WI. The pharmacist is available to patients through email or phone communication should any questions arise when the pharmacist is not physically present at both CR programs. The pharmacist also meets with patients in the maintenance program once per month if needed and provides an in-service at the Active Hearts support group affiliated with the program. The pharmacist has a relationship with the inpatient team who initially cares for these patients, so patients hear a consistent message regarding care after hospital discharge. The pharmacist precepts final-year Pharm.D. students from the University of Wisconsin, and these students are involved in the CR program as described above under the supervision of their preceptor. Pharmacy interns from UWHC also participate in the CR program during the summer months when final-year students are not available. Funding for the pharmacist occurs through the School of Pharmacy, as the pharmacist holds a faculty appointment.9
Benefits and Challenges of Pharmacist Involvement Although evaluative literature is scarce, some of the benefits of having a pharmacist involved in the CR are noted in table 1, as reported by the CR programs.7,9 The time period after a cardiac event can be a scary period for patients2; many patients have not taken daily medications before their cardiac event or procedure. Having a pharmacist involved in their cardiac recovery is a major benefit to the patients, as the pharmacist can provide education and support during this critical time. The biggest challenge for involving a pharmacist in a CR program may include the cost associated with adding another healthcare professional to the CR team. When embedded into a CR program, pharmacists are not able to bill for visits; the physician office or hospital receives a predetermined reimbursement for each CR session that a patient attends. Smaller facilities may have challenges scheduling the pharmacist if they do not have dedicated time devoted to the CR program. Pharmacists who provide care in CR should be well versed in cardiac procedures and diagnoses to ensure the most accurate information and recommendations are provided to patients and providers. Pharmacists who do not have previous knowledge of cardiovascular case may benefit from further education or training.
TABLE 1. Potential Benefits of Pharmacist Involvement in CR Programs
For patients
• • • • • •
Improved patient understanding of their medications Improved medication adherence Improved continuity and coordination of care Improved medication-related outcomes Correction of any misconceptions about their medications or disease Receipt of consistent messages regarding risk factor reduction from multiple members of the health care team • Availability of pharmacist experienced in cardiac care to assess medications and recommend adjustments when needed
For CR staff and administrators
• Improved quality of care for patients • Improved ability to meet programmatic outcomes • Improved understanding of medications, including specific indications, adverse reactions, and clinical effects due to staff education provided by the pharmacist • Improved understanding of new medications or new indications for existing medications due to staff education provided by the pharmacist
For the pharmacist
• Professionally rewarding role for the pharmacist • Improved perception of pharmacists as a source of information regarding cardiovascular health
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Get Involved!
There are many examples of pharmacist involvement in CR programs in the state of Wisconsin. We have chosen to highlight three different programs of varying sizes that have pharmacists involved to varying degrees. Getting involved in CR program can be possible with a time commitment as little as one hour every 12 weeks, but greater involvement can allow for a more expanded role and could involve a substantial FTE in a larger program. Pharmacists who are interested in getting involved with their community’s CR program can search the Wisconsin Society for Cardiac and Pulmonary Rehabilitation’s website at http://wiscphr. wisc.edu/Programs.aspx?cmspageid=729 or contact their hospital’s program director. Community pharmacists who are seeing patients who were recently discharged from the hospital after a cardiac event can encourage patients to enroll in cardiac rehabilitation programs, as both referral rates and enrollment rates BuySell_ads14_Layout 1 9,10 4:01 PM Page 4 can be improved. 1/25/14 ●
Laura M. Traynor, Pharm.D., BCPS, Associate Professor of Pharmacy Practice at Concordia University Wisconsin School of Pharmacy and Ambulatory Pharmacist at Columbia St. Mary’s Health System. and Kimberly D. Beyer, B.S., FAACVPR, Exercise Physiologist in Cardiopulmonary Rehabilitation and the Women’s Heart Secrets Program at Columbia St. Mary’s Health System. Conflicts of interest: The authors declare no real or potential conflicts or financial interest in any product or service mentioned in the manuscript, including grants, equipment, medications, employment, gifts, and honoraria. Acknowledgement: The authors would like to thank Karen J. Kopacek, RPh, Pharmacist in Preventive Cardiology at UW Hospitals and Clinics and Associate Dean for Student Affairs at the University of Wisconsin School of Pharmacy and Sue Kindschi, RN, BA, Cardiac Service Manager at Edgerton Hospital for providing information and insight about their programs.
References
1. Balady GJ, Williams MA, Ades PA, et al. AHA/AACVPR Scientific Statement-
Don’t leave money on the table when you transition the ownership of your business. Consider These Important Issues... • Reality-based valuation is critical to making a sale. • Exposure to the largest pool of buyers increases ability to get best price. • Chains are not your only option, there are many private buyers in the market today. • Confidentiality is critical to maintaining value. • There is financing available for qualified buyers of profitable businesses, including employees and children. • Transaction structure is the key to minimizing taxes upon sale. • Doing this alone is NOT a good idea.
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Core Components of Cardiac Rehabilitation/ Secondary Prevention Programs: 2007 Update. Circulation 2007;115:2675-2682 2. Guidelines for Cardiac Rehabilitation and Secondary Prevention Programs- Fifth Edition. Human Kinetics. American Assoication of Cardovascular and Pulmonary Rehabilitation. Champaign, IL. 2013. 3. What is cardiac rehab? Available at: http://wiscphr.wisc.edu/Content. aspx?cmspageid=698 Accessed 5/29/14 4. King M., Bittner V., Josephson R., et. al. Medical Director Responsibilities for Outpatient Cardiac Rehabilitation Programs/ Secondary Prevention Programs: 2012 Update. J Cardiopulm Rehabil Prev 32(6):410-419 5. White S, Anderson C. The involvement of pharmacists in cardiac rehabilitation: a review of the literature. Int J Pharm Pract 13:101-107. 6. Personal communication, Sue Kindschi, RN, BA 6/2/14 7. About Columbia St. Mary’s. Available at: http://www.columbia-stmarys.org/ Columbia_St_Marys Accessed 6/29/14. 8. UW Hospitals and Clinics Facts and Figures. Available at: http://www.uwhealth.org/files/uwhealth/ docs/pdf/uwhc_factsfigures.pdf Accessed 6/15/14 9. Personal communication, Karen Kopacek, R.Ph. 6/11/14 10. Balady GJ, Ades PA, Bittner VA, et al. Referral, Enrollment, and Delivery of Cardiac Rehabilitation/ Secondary Prevention Programs at Clinical Centers and Beyond. Circulation 2011;124:2951-2960
Your Local Specialist Larry Greenfield larryg@buy-sellapharmacy.com Tel: 1-(847)-949-2477
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“Our 14 year track record of successfully completing more than 400 independent pharmacy sales speaks for itself.” NOT FOR REPRODUCTION The Journal September/October 2014 www.pswi.org
originalcontributions
Specialty Pharmaceuticals: Oral Disease Modifying Agents for Multiple Sclerosis by Stephanie N. Davis, PharmD and Jamie Wong, PharmD
T
he treatment of multiple sclerosis (MS) is changing with earlier diagnosis resulting in earlier initiation of disease modifying therapy (DMT) and new oral agents. New oral DMTs, while providing additional treatment options, have the potential to drive up drug costs. In 2013 drug spend for MS ranked second only to that for rheumatoid arthritis for specialty drugs. Therefore, utilization management has been implemented by specialty pharmacy. The complex and highly individualized treatment of MS requires an understanding of MS and DMT for proper patient management. All efforts rely on the available evidence, which is summarized with a focus on oral DMT. Multiple sclerosis is a chronic, incurable, progressive, immune-mediated inflammatory and neurodegenerative disorder of the central nervous system (CNS) characterized by inflammation, demyelination and axonal degeneration. It affects approximately 400,000 people in the United States, predominantly in Caucasians, women, ages between 20 and 50 years and those residing in northern climates.1-3 More than 80% have relapsingremitting MS (RRMS) characterized by abrupt onset of symptoms followed by acute episodes of worsening and partial recovery. Primary progressive MS occurs
in 10% to 20% and is unresponsive to DMT.5 The goal of treatment in RRMS is to reduce the frequency of relapse and minimize or prevent neuronal destruction and progression of disability. As the immune response occurs early in MS and degeneration later, early treatment with DMTs, based on the individual’s stage of MS and treatment history, is recommended.4-6 Prior to 2010, MS treatment was limited to self-administered injectable beta interferons or Copaxone® (glatiramer acetate) (Teva Pharmaceutical Industries, LTD) that were associated with nonadherence in 25% of patients.7,8 Although parenteral agents continue to be first-line in therapy, up to 30% of patients are reported to have inadequate response at three years and require treatment with an alternative DMT.9,10 Oral DMTs approved for treatment of RRMS include Gilenya® (fingolimod) (Novartis), Aubagio® (teriflunomide) (Genzyme) and Tecfidera® (dimethyl fumarate or BG-12) (Biogen Idec) (see Table 1).11-13 Although distinct in their mechanism of action, they prevent migration of inflammatory T lymphocytes into the brain and spinal cord to reduce the frequency of relapse and diminish the immediate progression of disability (see Table 2). The oral DMTs have not been studied head-to-head and the superiority of one
TABLE 1. Oral disease-modifying therapy in MS11-13 Gilenya® (fingolimod)
Aubagio® (teriflunomide)
Tecfidera™ (dimethyl fumarate)
Dose (oral)
0.5 mg daily
7 or 14 mg daily
120 mg twice daily x 7 days then 240 mg twice daily
Protein binding
>99.7%
>99%
27% to 45%
T
6 to 9 days
18 to 19 days
1 hour
Pregnancy
Category C
Category X
Category C
Lactation
Discontinue breast feeding or drug
Discontinue breast feeding or drug
Use caution
1/2
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over another has not been established. Furthermore, results of trials with selfadministered injectable agents are not directly comparable to those of newer, oral agents in which patients studied were at an earlier stage of MS having been diagnosed and treated earlier than those in studies with injectable agents. The effectiveness of oral DMTs in preventing relapse has been demonstrated in clinical trials with reductions in the annualized relapse rate (ARR), the time to relapse, and in slowing the progression of disability as measured by changes in the Expanded Disability Status Scale (EDSS), an ordinal 10-point scale ranging from 0 (normal) to 10 (death) (see Table 3). A decrease in CNS inflammatory activity with DMT, as assessed by measures of gadolinium-enhancing T1 lesions, accumulating new T2 lesions and T1 hypointensities by magnetic resonance imaging (MRI) has also been documented. These short-term effects, however, are not predictive of long-term outcomes.14 Therapeutic choice is based on the DMT adverse effect profile, monitoring requirements and the individual’s response (see Table 3).
Gilenya® (fingolimod)
Fingolimod is metabolized to fingolimod-phosphate, a sphingosine-1phosphate (S1P) receptor modulator that acts to trap lymphocytes in the lymph nodes, preventing entry into the CNS and the development of MS lesions. It further binds to S1P receptors on CNS nerve cells resulting in astrocyte preservation and myelination and nervous system repair. Fingolimod 0.5 mg once daily is approved for treatment of RRMS. In clinical trials, fingolimod 0.5 mg daily for two years reduced the ARR and inflammatory lesion activity on MRI as compared to placebo in patients with mild-to-moderate RRMS.15,16 A reduction in the risk of progression of disability
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TABLE 2. Efficacy of oral disease-modifying therapy for MS 9 Oral DMT FDA approval
Aubagio® (teriflunomide)
Gilenya® (fingolimod)
Tecfidera™ (dimethyl fumarate)
2010
2012
2013
Relative RR
54%
31% (both doses)
51-53%
Absolute RR
0.18
0.37 (both doses)
0.17
NNT (2 years)
5
6 (both doses)
5
Relative RR
30%
7 mg (ns); 14 mg 26%
38%
Absolute RR
0.064
7 mg (ns); 14 mg 0.71
0.110
NNT (2 years)
14
14 mg 14
9
Clinical relapse
Disability progression
DMT = disease-modifying therapy; FDA = Food and Drug Administration; RR = risk reduction; NNT = number needed to treat; ns = not significant Note. Adapted from “Multiple Sclerosis: Current and Emerging Disease-Modifying Therapies and Treatment Strategies” by Dean Wingerchuk and Jonathan Carter, 2014, Mayo Clin Proc,89, p.228.
with fingolimod was significant in only one study.16 In a one-year comparative trial the ARR reduction and markers of inflammatory activity on MRI were greater with fingolimod than with Avonex® (IFN ®-1a) (Biogen Idec) in patients with RRMS.17 Modulation of the S1P receptors, present in the eyes, heart, lungs, and liver, with fingolimod results in adverse effects such as bradycardia, atrioventricular heart block, hypertension, hepatic enzyme elevations, respiratory changes, infections and macular edema.11 Fingolimod is contraindicated in patients with an existing or recent history of cardiac conditions and stroke and EKG, heart rate and blood pressure monitoring for six hours is required after the “first-dose” of fingolimod. Additional monitoring is required if abnormalities, symptomatic bradycardia or a high risk for cardiac events exist. Fingolimod may cause fetal harm and women of childbearing age should use contraception during treatment and for two months after discontinuation. Liver enzymes should be monitored and fingolimod discontinued if hepatotoxicity occurs. Those taking concurrent ketoconazole should be monitored due to inhibition of fingolimod metabolism. Live and attenuated vaccines should not be administered during and for two months after discontinuing fingolimod.
Aubagio® (teriflunomide)
Teriflunomide, the active metabolite of leflunomide, should not be given concurrently with leflunomide.12 Teriflunomide acts to inhibit dihydroorotate dehydrogenase and thereby pyrimidine synthesis resulting in slowed B and T lymphocyte proliferation and diminishing immune response in MS. In clinical trials, treatment of RRMS patients with teriflunomide 7 mg or 14 mg for two years resulted in a reduction in ARR and inflammatory lesion activity on MRI as compared to placebo.18,19 The risk of progression in disability was reduced only with 14 mg. In a comparative trial, there was no difference in time to relapse or discontinuation in those treated with teriflunomide or subcutaneous IFN®1a after 48 weeks. 20 The ARRs in the treatment groups were similar with the
exception of the teriflunomide 7 mg dose group in which the ARR was significantly higher than with IFN beta-1a. Teriflunomide carries a boxed warning for teratogenicity and hepatotoxicity.13 Prior to treatment, pregnancy must be ruled out and, because it is excreted in the semen, reliable contraception used by men and women. Teriflunomide levels may be detectable for eight months to two years after discontinuation due to the long halflife. Therefore, an 11-day rapid elimination procedure with cholestyramine must be performed if pregnancy occurs or if conception is planned. Those who become pregnant while taking teriflunomide must enroll in the pregnancy registry to monitor fetal outcomes. Baseline serum transaminase and bilirubin levels are required with monthly serum alanine aminotransferase levels for the first six months of treatment. If signs of hepatotoxicity occur or serum transaminases increase by more than three times the upper limits of normal, teriflunomide should be discontinued and a rapid elimination procedure employed. A baseline complete blood count (CBC) is required and tuberculosis must be ruled out and treated, if present, before teriflunomide is initiated due to potential bone marrow suppression. Blood pressure, serum potassium and renal function monitoring is recommended.
Tecfidera™ (Dimethyl Fumarate (BG-12) The exact mechanism of action of dimethyl fumarate (DMF) and its active metabolite, monomethyl fumarate, is
TABLE 3. Monitoring requirements for oral disease-modifying therapy11-13 Gilenya® (fingolimod)
Aubagio® (teriflunomide)
Baseline
CBC, LFTs, EKG, ophthalmologic exam
CBC, LFTs, blood pressure, pregnancy test, TB test
CBC
CBC
every 6 months
every 6 months
every 6 months
every 6 months
every month x 6 then every 6 months
LFT Blood pressure Ophthalmological exam
routine every 3 months
CBC = complete blood count, LFT = liver function tests, EKG = electrocardiogram Note. Adapted from “Multiple Sclerosis: Current and Emerging Disease-Modifying Therapies and Treatment Strategies” by Dean Wingerchuk and Jonathan Carter, 2014, Mayo Clin Proc,89, p.232.
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unknown.13 However, it is thought to protect neurons from oxidative stress through activation of the nuclear factor (erythroid-derived 2)-like transcriptional pathway involved in the cellular response to oxidative stress. In a placebo-controlled trial, patients with RRMS treated with DMF 240 mg twice daily had a significant reduction in the ARR and risk of progression of disability at two years. 21 In another trial, when glatiramer was added in a comparator arm, the ARR and CNS inflammation as measured by MRI was significantly reduced in both DMF and glatiramer arms, although there was no significant differences in the risk of progression of disability between the active treatment groups and placebo.22 To ameliorate flushing, which occurs in 40% of patients, DMF is initiated at half of the full dose for the first week and administration with food is recommended. Gastrointestinal symptoms such as diarrhea, nausea and upper abdominal pain may occur in 12% to 18% of patients. Lymphopenia, due to redistribution of lymphocytes, necessitates a baseline CBC with follow-up annually or as needed. Dose adjustments of DMF in renal or hepatic failure are unnecessary as the active metabolite is excreted through the lungs.
The Role of Specialty Pharmacy in the Treatment of MS The impact of specialty pharmacies and pharmacists on the treatment of MS is multifaceted and multi-layered, but should always be patient-focused. A management program of MS patients should include, treatment adherence monitoring, disease state management, patient education programs to include adverse effects and mitigation techniques, benefit investigation, and copay assistance/ patient assistance programs. Patient-focused goals include patient education to provide the “why” and “how” of treatment, motivation to achieve optimal adherence, and screening for co-morbid conditions such as depression. Collaboration with the prescriber is undertaken to assure the provision of fully encompassing, cost-efficient patient care. Set benchmarks for performance may www.pswi.org
include the maintenance of adherence rates of “X%” for all DMTs, consultations with “X%” of patients regarding adverse effects, and the provision of copay support to “X%” of patients. Methods for accomplishing the set goals are established and may include measures to promote adherence, research of published literature for established tools and programs, motivational techniques, proactive calls to patients with refill reminders, and the provision of positive reinforcement. Finally, outcomes must be collected and reported to showcase program successes or to identify areas for improvement. Reports may include the type of education and proportion of patients provided education, medication adherence rates and the proportion of patients referred to their health care provider for necessary followup.
Conclusion
Treatment of MS is rapidly evolving with newly developed oral DMTs, greater awareness of MS, and means of earlier diagnosis and treatment. With a focus on improving patient outcomes though specialty pharmacy management and collaboration with prescribers, further improvement is possible. ● Stephanie N. Davis is a Drug Information Specialist at Navitus Health Solutions, Madison, WI., Jamie Wong is a Pharmacy Manager at Lumicera Health Services, Madison, WI. Declaration of Conflicts of Interest: The authors declare no real or potential conflicts or financial interest in any product or service mentioned in the manuscript, including grants, equipment, medications, employment, gifts and honoraria
References
1. Pugliatti M, Sotgiu S, Rosati G. The worldwide prevalence of multiple sclerosis. Clin Neurol Neurosurg. 2002;104:182-91 2. Noseworthy JH, Lucchinetti C, Rodriguez M, et al. Multiple sclerosis. N Engl J Med. 2000;343:938-952. 3. Alonso A, Hernan MA. Temporal trends in the incidence of multiple sclerosis: a systematic review. Neurology. 2008;71:129-135. 4. Keegan BM. Therapeutic decision making in a new drug era in multiple sclerosis. Semin Neurol. 2013;33:5-12. 5. Freedman MS, Selchen D, Arnold DL, et al. Treatment optimization in MS: Canadian
MS Working Group updated recommendations. Can J Neurol Sci. 2013;40:307-323. 6. Lubin FD, Baier M, Cutter G. Effect of relapses on development of residual deficit in multiple sclerosis. Neurology. 2003;61:1528-1532. 7. Bandari DS, Sternaman D, Chan T, et al. Evaluating risks, costs, and benefits of new and emerging therapies to optimize outcomes in multiple sclerosis.J Manag Care Pharm.2012;18:S3-S16. 8. Devonshire V, Lapierre Y, Macdonell R, et al. The global adherence project (GAP): a multicenter observational study on adherence to disease-modifying therapies in patients with relapsing-remitting multiple sclerosis. Eur J Neurol. 2011;18:69-77. 9. Wingerchuk DM, Carter JL. Multiple sclerosis: current and emerging diseasemodifying therapies and treatment strategies. Mayo Clin Proc. 2014;89:225-240. 10. Gauthier SA, Glanz BI, Mandel M, et al. Incidence and factors associated with treatment failure in the CLIMB multiple sclerosis cohort study. J Neurol Sci. 2009;284:116-119. 11. Gilenya® [package insert]. East Hanover, NJ; Novartis; 2014. 12. Aubagio® [package insert]. Cambridge, MA; Genzyme Coporation;2012. 13. Tecfidera™ [package insert]. Cambridge, MA;Biogen Idec Inc;2013 14. Sormani MP, Bonzano L, Roccatagliata L, et al. Surrogate endpoints for EDSS worsening in multiple sclerosis. A metaanalytic approach. Neurol. 2010;75:302-309. 15. Kappos L, Radue EW, OpConnor P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010;362:387-401. 16. Calabresi PA, Radue EW, Goodin D, et al. Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomized, placebo-controlled, phase 3 trial. Lancet Neurol. 2014;13:545-556. 17. Cohen JA, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362:402-415. 18. O’Connor P, Wolinski JS, Confavreux C, et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med. 2011;365:1293-12303. 19. Confavreux C, O’Connor P, Comi G, et al. Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomized, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2014;13:247-256. 20. Vermersch P, Czlonkowska A, Grimaldi ME, et al. Teriflunomide versus subcutaneous interferon beta-1a inpatients with relapsing multiple sclerosis: a randomized, controlled phase 3 trial. Mult Scler. 2014;20:705-716. 21. Gold R, Kappos L, Arnold DL, et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012;367:1098-1107. 22. Linker RA, Lee DH, Ryan S, et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med. 2012;367:1087-1097.
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PSWnews Open Letter to the WI Pharmacy Community by Jeanette Roberts
Colleagues and Friends,
It’s impossible to believe that almost 11 years have gone by since Dave and I arrived in Madison. It has been an absolute privilege and honor to serve WI pharmacy as Dean of the fabulous University of Wisconsin School of Pharmacy. Did I mention we are ranked 5th in the country?! You may have heard me say that a time or two. I have so enjoyed getting to know many of you, UW alumni or not, and learning about the high level of pharmacy practice here and the spirit of innovation that drives so many things. I know you’ll welcome the new dean, Steve Swanson, with the same hospitality and friendship. He’s starting to get out there and meet people, so you’ll be seeing him at PSW events, UW alumni functions, and all the rest. Coming from Chicago, he does need a little help with his choice of NFL teams, but I leave that task in your very capable hands. So while I’m done being dean, I’m certainly not done. As we say in the business, I have “returned to the faculty.” Not that I ever left the faculty. Anyway, I am spending this academic year doing a sort of sabbatical and retooling for future teaching, research, and service. I will be traveling to South Africa a time or two to work with one of our international partners, the University of the Western Cape (UWC) School of Pharmacy in Capetown. UWC has served as one of our global health sites for fourth-year pharmacy students doing their advanced pharmacy practice experiences or APPEs. These are not short visits for superficial observation. They are clinically rigorous 7- or 8-week emersion experiences in the local pharmacy/health care systems. In addition, most agreements are exchanges, so we benefit from having students from abroad visit us in Madison. In my mind, there is no better learning experience than living and working in a culture very different from our own. These lessons are invaluable to inform what we do and how we serve “back home.” As an extension to our existing partnership, we proposed to cooperatively develop a post-PharmD pharmacy fellowship in comparative global health systems to the faculty at UWC. The idea is to design a 2-year experience that would allow the fellow to embark on a research project of importance to pharmacy and health care in South Africa. My job is to lay the groundwork for the fellowship by building relationships throughout pharmacy education and practice, public health, government, the pharmaceutical industry, and anyone else I can persuade to talk with me. I envision that an array of potential research projects will emerge all with the thread of enhancing pharmacy education and practice to allow pharmacists to better contribute to achieving the health care goals of South Africa. We hope to host a South African
fellow here in Madison as well. As you might imagine, infectious diseases are on the top of the list of challenges throughout Africa. Interestingly, South Africa is now coping with a whole new set of issues such as diabetes, obesity, heart disease, and all the rest. I believe there are limitless possibilities for pharmacists to make a huge impact on individual and public health challenges. That’s what the fellow will be studying. Allow me to take a moment to thank the committed faculty running our Office of Global Health that are making all this happen: Connie Kraus, Trisha Seys-Ranola, and Tom Thielke. The clinical rotations wouldn’t be possible without Marty Kieser. Karen Kopacek has been a big player in our global health work as well, and Mel de Villiers, a native of South Africa, was instrumental in our work with that country. I am also still interested in spending a year in Washington, DC as a Congressional or White House fellow working on US health care policy issues. These experiences require a rather involved application process and are quite competitive, so I’m not sure if that will come to pass. We’ll see. I hope to ultimately return to the classroom, teaching at the School of Pharmacy and perhaps at the La Follette School of Public Affairs, focused on biomedical ethics and state and national health care policy. As for the research side of things, I can’t really imagine re-starting an NIH-funded laboratory, but I guess it’s not impossible, and a lot more work needs to be done on the selenium project I had going on in cancer chemoprevention. There will be plenty of juicy topics for research in the policy world, I’m sure! And many ways to serve the School and the University that haven’t quite emerged yet. On another note, it still amazes me that a state like Wisconsin figured out long ago the value of investing in public higher education, allowing the blossoming of the University of Wisconsin that we see today. People from WI don’t seem to appreciate the absolute gem that resides here in Madison. Or maybe it’s the usual WI humility or “midwest nice” or something. Trust me, this University is a treasure and should not be taken for granted. One of the most compelling features to me is the commitment across campus to the Wisconsin Idea, our responsibility to take the expertise and knowledge from this great institution and apply them to real-world problems in the state, the country, and the world. Another compelling feature is the quality of the faculty here. You’ve probably heard me say that without the “A” faculty, nothing else matters. And it’s true. The same philosophy seems to apply to PSW as well. The state pharmacy organization in WI is another gem and also shouldn’t be taken for granted. Where ever I traveled as dean, PSW was admired and held up as an example. The very recent receipt of the Power of “A” Summit Award from ASAE, is another illustration of that. Straight “A” is for Wisconsin! So thanks for an incredible 11 years as dean! Take care and On Wisconsin!
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PMS 369
commentary The Price to Save a Life: Pharmacists’ Role in the Growing Area of Specialty Drugs by Nellie Jafari, PharmD Candidate 2015
A
ccording to PharmaVoice, specialty drugs are considered “typically high-cost, scientifically engineered drugs used to treat complex, chronic conditions that require special storage, handling, and administration, and involve a significant degree of patient education, monitoring, and management.”1 These medications can be oral, injectable, or biologic products. They can be used to treat a variety of diseases such as cancer, multiple sclerosis, rheumatoid arthritis, and rare genetic conditions.2 The exact definition of the term “specialty drugs” is a challenge to find as various stakeholders have their own definitions. The Center for Medicare and Medicaid Services specifically says that specialty drugs are those that cost more than $600/month.1 Regardless of the exact definition, these drugs are certainly going to have a huge impact on pharmacy practice and health care spending. Specialty medications are a continually growing portion of the prescription drug market. According to Express Scripts, there will be a 40% growth by 2014 and 67% by 2015 in the development of specialty drugs.1 Since 2010, specialty drugs have had a higher number of approvals than traditional drugs.3 Specialty drugs also have a disproportionate share of overall drug spending because each course of therapy is so expensive.4 In 2013, specialty drugs made up 25% of the $263.3 billion U.S prescription drug spending.3 It is projected that in 2018, 6 of the 10 best-selling drugs by revenue will be specialty drugs.1 These drugs provide hope in saving lives for diseases like cancer but at a cost that many cannot afford. It could cost almost $750,000 per year for a patient to be treated with some of the most expensive specialty drugs.3 Another example is the drug Sovaldi for hepatitis C. The treatment seems to be very effective, but one pill costs $1,000, totaling $84,000 for the entire treatment course.1 Due to these high costs, many exchange plans have decided that consumers will have to pay out of pocket costs.5 Although these innovative treatments
can be lifesaving for some patients, the costs overtime add financial stress on our health care system and patients. According to America’s Health Insurance Plans (AHIP), there are a number of reasons why these drugs are so expensive. A small percentage of patients utilize specialty medications, which drives up the cost per patient as manufacturers try to make up for the cost of developing the agents. Another contributing factor is the length of biologic drugs exclusivity period. Traditional medications are given a 5 year exclusivity during which other companies may not bring a similar drug, or generic, onto the market. Conversely, biologic drugs are given twelve years until other companies may bring a similar drug, in this case a biosimilar, to market.3 Although the Affordable Care Act did create a way for the FDA to approve interchangeable biosimilars, none have been approved. The lack of biosimilars on the market and a long exclusivity period mean that there are few or no lower cost alternatives for these medications.4 Pharmacists’ patient care services can help ensure that these high cost drugs are used safely and effectively and thus maximize their value. Pharmacists in all practice settings can counsel their patients taking specialty medications on proper administration, how to manage side effects, and the importance of adherence.6 Pharmacists that choose to specialize in these high cost medications may work in a specialty pharmacy that focuses on dispensing these products along with providing services such as medication therapy management, patient advocacy and treatment adherence.2 Health plans can contract with specialty pharmacies who focus on providing care to patients related to the complex medication deliveries and treatments associated with specialty medications.7 One way to reduce the cost impact of specialty drugs on overall health care spending is to implement policies to increase adherence. Studies have shown that adherence and persistence leads to better health outcomes which reduce
cost.8,9 According to WellPoint, “adherence for specialty drugs is critical to quality care, maybe more so than anywhere in medicine.”10 Complex diseases and medications lead to adherence challenges. This is an issue for specialty drugs since many of them have to be injected or require patient specific dosing and clinical management.8 To help improve patient adherence, pharmacists can provide education to patients about their disease state as well as how to administer or take the medication, offer emotional support, and follow up about their disease management.10 Pharmacists in all settings play a key role in reducing health care costs and ensuring quality by assisting patients and providers in the appropriate use, management, and administration of specialty drugs. ● Nellie Jafari, PharmD Candidate 2015, Virginia Commonwealth University. References
1. Specialty Drugs: An evolving commercial model. PharmaVoice. 2014; 14(2): 12-19. 2. American Pharmacist Associations. Accessed 27 May 2014. <http://www. pharmacist.com/specialty-pharmacy>. 3. AHIP. Specialty Drugs-Issues and Challenges. America’s Health Insurance Plans Issue Brief. 2014; 1-7. < http://www.ahip.org/IssueBrief/ Specialty-Drugs-Challenges-Issues/>. 4. AHIP Coverage. NYT: Specialty drug prices “soaring”. 18 April 2014. <http://www.ahipcoverage. com/2014/04/18/nyt-specialty-drug-prices-soaring/>. 5. Pearson CF. Consumers likely face high out of pocket costs for specialty drugs in exchange plans. Avalere Analysis. 20 February 2014. <http:// avalerehealth.net/expertise/managed-care/ insights/consumers-likely-face-high-out-ofpocket-costs-for-specialty-drugs-in-excha>. 6. NASP. Specialty pharmacy certification board recognizes first wave of certified specialty pharmacists. 11 November 2013.< http://www. spcboard.org/certification/eligibility-requirements/>. 7. Weingart SN, Brown E, Bach PB et al. NCCN Task Force Report: Oral chemotherapy. J Natl Compr Canc Netw. 2008; 6 Suppl 3: S1-14. 8. Ruddy K, Mayer E, Partridge A. Patient adherence and persistence with oral anticancer treatment. CA Cancer J Clin. 2009; 59(1): 56-66. 9. IMS Institute. “Avoidable Costs in U.S. Healthcare: The $200 Billion Opportunity from Using Medicines More Responsibly.” 19 June 2013. <http://www.theimsinstitute.org>. 10. Sipkoff M. Payers struggle to ensure high level of adherence to costly specialty drugs. Managed Care. 2008; 17(7):24-6, 29, 31.
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