September/October 2009, Vol 2, No 2

Covers_Cover 10/14/09 11:15 AM Page C1

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™ SEPTEMBER/OCTOBER 2009

VOLUME 2, NUMBER 6

COMMENTARY

Government Health Plans Always Ration Care Scott Gottlieb, MD

Cost-Sharing Enhances Cost Control H.E. Frech, III, PhD

REGULATORY

Predictive and Prognostic Models: Implications for Healthcare F. Randy Vogenberg, RPh, PhD

Stakeholder Perspective by Jason Roy, PhD ™

CLINICAL

Estimates of Commercial Population at High Risk for CV Events: Impact of Aggressive Cholesterol Reduction Kathryn Fitch, RN, MEd; Sara W. Goldberg, FSA, MAAA; Kosuke Iwasaki, FIAJ, MAAA; Bruce S. Pyenson, FSA, MAAA; Andreas Kuznik, PhD; Henry A. Solomon, FACP, FACC

Stakeholder Perspective by David Williams BUSINESS

Impact of Prescription Benefit Coverage Limits on Sevelamer Adherence for Patients with ESRD Bharati Bhardwaja, PharmD, BCPS; Nikki Carroll, MS; Eli Korner, PharmD; Kavita V. Nair, PhD

Stakeholder Perspective by Jack E. Fincham, PhD, RPh

Private Health Plans Perspectives on e-PHRs and e-Prescribing Nancy M. McGee, JD, MPH; Gene Reeder, RPh, PhD; Timothy S. Regan, BPharm, RPh; J.D. Kleinke; Steve Arnold, MD, MS

Stakeholder Perspective by Gary M. Owens, MD DEPARTMENTS ◆ Point and Counterpoint Healthcare Reform, Classicism, and How We Treat the Elderly End-of-Life Choices Are Necessary in Any Healthcare Reform ◆ Generic Drug Trends Can Generics Help Heal Our Ailing Healthcare System?

SUPPLEMENT

Savella: A New Option for the Management of Fibromyalgia Perspectives by Nirav R. Shah, MD, MPH; Gary M. Owens, MD; Philip Mease, MD

©2009 Engage Healthcare Communications, LLC www.AHDBonline.com

Covers_Cover 10/14/09 11:15 AM Page C2

This year, 1 in 5 Americans will have PHN pain after shingles 1

FOR RELIEF OF PAIN ASSOCIATED WITH PHN

A Custom Fit for Their Body Important Safety Information LIDODERM速 (lidocaine patch 5%) is indicated for relief of pain associated with post-herpetic neuralgia (PHN). Apply only to intact skin.

LIDODERM is contraindicated in patients with a history of sensitivity to local anesthetics (amide type) or any product component.

Even a used LIDODERM patch contains a large amount of lidocaine (at least 665 mg). The potential exists for a small child or a pet to suffer serious adverse effects from chewing or ingesting a new or used LIDODERM patch, although the risk with this formulation has not been evaluated. It is important to store and dispose of LIDODERM out of the reach of children, pets, and others.

Excessive dosing, such as applying LIDODERM to larger areas or for longer than the recommended wearing time, could result in increased absorption of lidocaine and high blood concentrations leading to serious adverse effects.

Avoid contact of LIDODERM with the eye. If contact occurs, immediately wash the eye with water or saline and protect it until sensation returns.

Patients with severe hepatic disease are at greater risk of developing toxic blood concentrations of lidocaine, because of their inability to metabolize lidocaine normally. LIDODERM should be used with caution in patients receiving Class I antiarrhythmic drugs (such as tocainide and mexiletine) since the toxic effects are additive and potentially synergistic. LIDODERM should also be used with caution in pregnant (including labor and delivery) or nursing mothers.

Allergic reactions, although rare, can occur.

During or immediately after LIDODERM treatment, the skin at the site of application may develop blisters, bruising, burning sensation, depigmentation, dermatitis, discoloration, edema, erythema, exfoliation, irritation, papules, petechia, pruritus, vesicles, or may be the locus of abnormal sensation. These reactions are generally

Covers_Cover 10/14/09 11:16 AM Page 205

A first-line therapy, alone or with oral analgesics 2,3

■ The first and only lidocaine-based topical medication for the treatment of PHN pain. Apply only to intact skin —More than a decade of use ■ Customized application for your patients with PHN pain —Patches can be cut to custom fit the areas of pain —Patients can wear up to 3 patches simultaneously for 12 hours, followed by 12 hours off4

mild and transient, resolving spontaneously within a few minutes to hours. Other reactions may include dizziness, headache, and nausea.

When LIDODERM is used concomitantly with local anesthetic products, the amount absorbed from all formulations must be considered.

Immediately discard used patches or remaining unused portions of cut patches in household trash in a manner that prevents accidental application or ingestion by children, pets, or others.

Before prescribing LIDODERM, please refer to the accompanying brief summary of full Prescribing Information.

References: 1. Cluff RS, Rowbotham MC. Pain caused by herpes zoster infection. Neurol Clin. 1998;16(4): 813-832. 2. Dworkin RH, O’Connor AB, Backonja M, et al. Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain. 2007;132(3):237-251. 3. Dubinsky RM, Kabbani H, El-Chami Z, Boutwell C, Ali H. Practice parameter: treatment of postherpetic neuralgia. An evidence-based report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2004;63(6):959-965.

4. Lidoderm Prescribing Information. Chadds Ford, PA: Endo Pharmaceuticals Inc; 2008.

LIDODERM® (Lidocaine Patch 5%) Rx only Brief Summary (For full Prescribing Information refer to package insert.)

INDICATIONS AND USAGE LIDODERM is indicated for relief of pain associated with post-herpetic neuralgia. It should be applied only to intact skin.

CONTRAINDICATIONS LIDODERM is contraindicated in patients with a known history of sensitivity to local anesthetics of the amide type, or to any other component of the product.

WARNINGS Accidental Exposure in Children Even a used LIDODERM patch contains a large amount of lidocaine (at least 665 mg). The potential exists for a small child or a pet to suffer serious adverse effects from chewing or ingesting a new or used LIDODERM patch, although the risk with this formulation has not been evaluated. It is important for patients to store and dispose of LIDODERM out of the reach of children, pets, and others. (See HANDLING AND DISPOSAL) Excessive Dosing Excessive dosing by applying LIDODERM to larger areas or for longer than the recommended wearing time could result in increased absorption of lidocaine and high blood concentrations, leading to serious adverse effects (see ADVERSE REACTIONS, Systemic Reactions). Lidocaine toxicity could be expected at lidocaine blood concentrations above 5 µg/mL. The blood concentration of lidocaine is determined by the rate of systemic absorption and elimination. Longer duration of application, application of more than the recommended number of patches, smaller patients, or impaired elimination may all contribute to increasing the blood concentration of lidocaine. With recommended dosing of LIDODERM, the average peak blood concentration is about 0.13 µg/mL, but concentrations higher than 0.25 µg/mL have been observed in some individuals.

PRECAUTIONS General Hepatic Disease: Patients with severe hepatic disease are at greater risk of developing toxic blood concentrations of lidocaine, because of their inability to metabolize lidocaine normally.

Allergic Reactions: Patients allergic to para aminobenzoic acid derivatives (procaine, tetracaine, benzocaine, etc.) have not shown cross sensitivity to lidocaine. However, LIDODERM should be used with caution in patients with a history of drug sensitivities, especially if the etiologic agent is uncertain.

Non-intact Skin: Application to broken or inflamed skin, although not tested, may result in higher blood concentrations of lidocaine from increased absorption. LIDODERM is only recommended for use on intact skin.

Eye Exposure: The contact of LIDODERM with eyes, although not studied, should be avoided based on the findings of severe eye irritation with the use of similar products in animals. If eye contact occurs, immediately wash out the eye with water or saline and protect the eye until sensation returns.

Drug Interactions Antiarrhythmic Drugs: LIDODERM should be used with caution in patients receiving Class I antiarrhythmic drugs (such as tocainide and mexiletine) since the toxic effects are additive and potentially synergistic.

Local Anesthetics: When LIDODERM is used concomitantly with other products containing local anesthetic agents, the amount absorbed from all formulations must be considered.

Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis: A minor metabolite, 2, 6-xylidine, has been found to be carcinogenic in rats. The blood concentration of this metabolite is negligible following application of LIDODERM. Mutagenesis: Lidocaine HCl is not mutagenic in Salmonella/mammalian microsome test nor clastogenic in chromosome aberration assay with human lymphocytes and mouse micronucleus test.

Impairment of Fertility: The effect of LIDODERM on fertility has not been studied.

Pregnancy Teratogenic Effects: Pregnancy Category B. LIDODERM (lidocaine patch 5%) has not been studied in pregnancy. Reproduction studies with lidocaine have been performed in rats at doses up to 30 mg/kg subcutaneously and have revealed no evidence of harm to the fetus due to lidocaine. There are, however, no adequate and well-controlled studies in pregnant women.

Because animal reproduction studies are not always predictive of human response, LIDODERM should be used during pregnancy only if clearly needed.

Labor and Delivery LIDODERM has not been studied in labor and delivery. Lidocaine is not contraindicated in labor and delivery. Should LIDODERM be used concomitantly with other products containing lidocaine, total doses contributed by all formulations must be considered.

Nursing Mothers LIDODERM has not been studied in nursing mothers. Lidocaine is excreted in human milk, and the milk: plasma ratio of lidocaine is 0.4. Caution should be exercised when LIDODERM is administered to a nursing woman.

Pediatric Use Safety and effectiveness in pediatric patients have not been established.

ADVERSE REACTIONS Application Site Reactions During or immediately after treatment with LIDODERM (lidocaine patch 5%), the skin at the site of application may develop blisters, bruising, burning sensation, depigmentation, dermatitis, discoloration, edema, erythema, exfoliation, irritation, papules, petechia, pruritus, vesicles, or may be the locus of abnormal sensation. These reactions are generally mild and transient, resolving spontaneously within a few minutes to hours.

Allergic Reactions Allergic and anaphylactoid reactions associated with lidocaine, although rare, can occur. They are characterized by angioedema, bronchospasm, dermatitis, dyspnea, hypersensitivity, laryngospasm, pruritus, shock, and urticaria. If they occur, they should be managed by conventional means. The detection of sensitivity by skin testing is of doubtful value.

Other Adverse Events Due to the nature and limitation of spontaneous reports in postmarketing surveillance, causality has not been established for additional reported adverse events including: Asthenia, confusion, disorientation, dizziness, headache, hyperesthesia, hypoesthesia, lightheadedness, metallic taste, nausea, nervousness, pain exacerbated, paresthesia, somnolence, taste alteration, vomiting, visual disturbances such as blurred vision, flushing, tinnitus, and tremor.

Systemic (Dose-Related) Reactions Systemic adverse reactions following appropriate use of LIDODERM are unlikely, due to the small dose absorbed (see CLINICAL PHARMACOLOGY, Pharmacokinetics). Systemic adverse effects of lidocaine are similar in nature to those observed with other amide local anesthetic agents, including CNS excitation and/or depression (light-headedness, nervousness, apprehension, euphoria, confusion, dizziness, drowsiness, tinnitus, blurred or double vision, vomiting, sensations of heat, cold, or numbness, twitching, tremors, convulsions, unconsciousness, respiratory depression, and arrest). Excitatory CNS reactions may be brief or not occur at all, in which case the first manifestation may be drowsiness merging into unconsciousness.

Cardiovascular manifestations may include bradycardia, hypotension, and cardiovascular collapse leading to arrest.

OVERDOSAGE Lidocaine overdose from cutaneous absorption is rare, but could occur. If there is any suspicion of lidocaine overdose (see ADVERSE REACTIONS, Systemic Reactions), drug blood concentration should be checked. The management of overdose includes close monitoring, supportive care, and symptomatic treatment. Dialysis is of negligible value in the treatment of acute overdose with lidocaine.

In the absence of massive topical overdose or oral ingestion, evaluation of symptoms of toxicity should include consideration of other etiologies for the clinical effects, or overdosage from other sources of lidocaine or other local anesthetics.

The oral LD50 of lidocaine HCl is 459 (346-773) mg/kg (as the salt) in nonfasted female rats and 214 (159-324) mg/kg (as the salt) in fasted female rats, which are equivalent to roughly 4000 mg and 2000 mg, respectively, in a 60 to 70 kg man based on the equivalent surface area dosage conversion factors between species.

DOSAGE AND ADMINISTRATION Apply LIDODERM to intact skin to cover the most painful area. Apply up to three patches, only once for up to 12 hours within a 24-hour period. Patches may be cut into smaller sizes with scissors prior to removal of the release liner. (See HANDLING AND DISPOSAL) Clothing may be worn over the area of application. Smaller areas of treatment are recommended in a debilitated patient, or a patient with impaired elimination.

If irritation or a burning sensation occurs during application, remove the patch (es) and do not reapply until the irritation subsides.

When LIDODERM is used concomitantly with other products containing local anesthetic agents, the amount absorbed from all formulations must be considered.

HANDLING AND DISPOSAL Hands should be washed after the handling of LIDODERM, and eye contact with LIDODERM should be avoided. Do not store patch outside the sealed envelope. Apply immediately after removal from the protective envelope. Fold used patches so that the adhesive side sticks to itself and safely discard used patches or pieces of cut patches where children and pets cannot get to them.

LIDODERM should be kept out of the reach of children.

Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). [See USP Controlled Room Temperature].

Manufactured for: Endo Pharmaceuticals Inc. Chadds Ford, Pennsylvania 19317 LIDODERM® is a Registered Trademark of Hind Health Care, Inc. Copyright© Endo Pharmaceuticals Inc. 2008 Rev. February, 2008 6524-11 E1 LD-1664 / December 2008

LIDODERM® is a registered trademark of Hind Health Care, Inc.

CHADDS FORD, PENNSYLVANIA 19317

© 2009 Endo Pharmaceuticals.

All Rights Reserved

LD-1652R/MARCH 2009

www.lidoderm.com

1-800-462-ENDO

SEPTEMBER/OCTOBER 2009

VOLUME 2, NUMBER 6

™

™

TABLE OF CONTENTS COMMENTARY

215 Government Health Plans Always Ration Care: Europe Offers a Glimpse of the Future If President Obama and Congressional Democrats Have Their Way Scott Gottlieb, MD

Publisher Nicholas Englezos nick@engagehc.com 732-992-1884 Associate Publisher Maurice Nogueira maurice@engagehc.com 732-992-1895

237 Cost-Sharing Enhances Cost Control H.E. Frech, III, PhD REGULATORY

218 Predictive and Prognostic Models: Implications for Healthcare Decision-Making in a Modern Recession F. Randy Vogenberg, RPh, PhD 222 Stakeholder Perspective by Jason Roy, PhD

Editorial Director Dalia Buffery dalia@AHDBonline.com 732-992-1889 Associate Editor Lara J. Reiman 732-992-1892 Senior Production Manager Lynn Hamilton

CLINICAL

224 Estimates of Commercial Population at High Risk for Cardiovascular Events: Impact of Aggressive Cholesterol Reduction Kathryn Fitch, RN, MEd; Sara W. Goldberg, FSA, MAAA; Kosuke Iwasaki, FIAJ, MAAA; Bruce S. Pyenson, FSA, MAAA; Andreas Kuznik, PhD; Henry A. Solomon, FACP, FACC

Business Manager Blanche Marchitto Editor-in-Chief Robert E. Henry rhenry@AHDBonline.com 732-992-1885

231 Stakeholder Perspective by David Williams

Mission Statement BUSINESS

242 Impact of Prescription Benefit Coverage Limits on Sevelamer Hydrochloride Adherence for Patients with ESRD Bharati Bhardwaja, PharmD, BCPS; Nikki Carroll, MS; Eli Korner, PharmD; Kavita V. Nair, PhD 250 Stakeholder Perspective by Jack E. Fincham, PhD, RPh 252 Private Health Plans Perspectives on Electronic Personal Health Records and Electronic Prescribing Nancy M. McGee, JD, MPH; Gene Reeder, RPh, PhD; Timothy S. Regan, BPharm, RPh, CPh; J.D. Kleinke; Steve Arnold, MD, MS, MBA, CPE 259 Stakeholder Perspective by Gary M. Owens, MD

Continued on page 208

American Health & Drug Benefits is included in the following indexing and database services: EMBASE/Elsevier Cumulative Index to Nursing and Allied Health Literature (CINAHL) EBSCO research databases Standard Periodical Directory

VOL. 2

NO. 6

American Health & Drug Benefits is founded on the concept that health and drug benefits have undergone a transformation: the econometric value of a drug is of equal importance to clinical outcomes as it is to serving as the basis for securing coverage in formularies and benefit designs. Benefit designs are greatly affected by clinical, business, and policy conditions.

This publication provides benefit design decision makers the integrated industry information they require to devise formularies and benefit designs that stand up to today’s special healthcare delivery and business needs.

Contact Information: For reprints, subscription information, and editorial queries, please contact: editorial@AHDBonline.com T: 732-992-1892 F: 732-992-1881

September/October 2009

www.AHDBonline.com

207

SEPTEMBER/OCTOBER 2009

VOLUME 2, NUMBER 6

™

TABLE OF CONTENTS

™

(Continued)

DEPARTMENTS

233 POINT AND COUNTERPOINT Healthcare Reform, Classicism, and How We Treat the Elderly: The Politics of Epidemiology Robert E. Henry 235 End-of-Life Choices Are Necessary in Any Healthcare Reform Gary M. Owens, MD 240 GENERIC DRUG TRENDS Can Generics Help Heal Our Ailing Healthcare System?

Dalia Buffery, MA, ABD

American Health & Drug Benefits, ISSN 19422962 (print); ISSN 1942-2970 (online), is published 6 times a year by Engage Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205A, Monroe Township, NJ 08831.

Copyright © 2009 by Engage Healthcare Communications, LLC. All rights reserved.

American Health & Drug Benefits and The Peer-Reviewed Forum for Evidence in Benefit Design are trademarks of Engage Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher. Printed in the United States of America.

SUPPLEMENT

S1

Savella (Milnacipran HCl): A New Option for the Management of Fibromyalgia

By Loretta Fala

S6

Stakeholder Perspectives Nirav R. Shah, MD, MPH; Gary M. Owens, MD; Philip Mease, MD

CAPTION CONTEST

Address all editorial correspondence to: editorial@AHDBonline. com, Telephone: 732-992-1889. Fax: 732-992-1881. American Health & Drug Benefits, 241 Forsgate Drive, Suite 205A, Monroe Township, NJ 08831.

Permission requests to reprint all or part of any article published in this journal should be addressed to PERMISSIONS DEPARTMENT. Fax: 732-992-1881.

The ideas and opinions expressed in American Health & Drug Benefits do not necessarily reflect those of the Editorial Board, the Editors, or the Publisher. Publication of an advertisement or other product mentioned in American Health & Drug Benefits should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturers about any features or limitations of products mentioned.

Neither the Editors nor the Publisher assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication.

238

WEB EXCLUSIVE www.AHDBonline.com

Meeting Highlights • Diabetes Pipeline: New Strategies Emerging for Glycemic Control • Vaccine Extends Life in Men with Prostate Cancer • SNM Image of the Year: Non-Hodgkin’s Lymphoma

208

AMERICAN HEALTH & DRUG BENEFITS

September/October 2009

POSTMASTER: CORRESPONDENCE REGARDING SUBSCRIPTIONS OR CHANGE OF ADDRESS should be directed to CIRCULATION DIRECTOR, American Health & Drug Benefits, 241 Forsgate Drive, Suite 205A, Monroe Township, NJ 08831.

Fax: 732-992-1881. YEARLY SUBSCRIPTION RATES: One year: $99.00 USD; Two years: $149.00 USD; Three years: $199.00 USD.

VOL. 2

NO. 6

KAPIDEX WORKS A

SECOND SHIFT TO HELP SHUT DOWN ACID PUMPS

KAPIDEX is the first and only PPI with a Dual Delayed Release™ (DDR) formulation, which provides a second release of drug Mean plasma concentration (in healthy subjects; day 5; ng/mL)1 1200 1000 800 600 400

KAPIDEX K KA A 60 mg 200

KA KA KAPIDEX 30 mg

0 0

6

12

18

24

Time (h)

• KAPIDEX 30 mg provided full 24-hour heartburn relief in a majority of symptomatic non-erosive gastroesophageal reflux disease patients at week 41 • KAPIDEX 60 mg provided consistently high erosive esophagitis healing rates at week 81 • KAPIDEX offers a safety and tolerability profile similar to lansoprazole1 • KAPIDEX can be taken without regard to food1 KAPIDEX should be swallowed whole. Alternatively, capsules can be opened, sprinkled on 1 tablespoon of applesauce, and swallowed immediately. While KAPIDEX can be taken without regard to food, some patients may benefit from administering the dose prior to a meal if post-meal symptoms do not resolve under post-fed conditions.

Conclusions of comparative efficacy cannot be drawn from this information.

Indications KAPIDEX is indicated for healing all grades of erosive esophagitis (EE) for up to 8 weeks, maintaining healing of EE for up to 6 months, and treating heartburn associated with symptomatic non-erosive gastroesophageal reflux disease (GERD) for 4 weeks.

Important Safety Information KAPIDEX is contraindicated in patients with known hypersensitivity to any component of the formulation. Hypersensitivity and anaphylaxis have been reported with KAPIDEX use. Symptomatic response with KAPIDEX does not preclude the presence of gastric malignancy. Most commonly reported treatment-emergent adverse reactions (≥2%): diarrhea (4.8%), abdominal pain (4.0%), nausea (2.9%), upper respiratory tract infection (1.9%), vomiting (1.6%), and flatulence (1.6%).

Do not co-administer atazanavir with KAPIDEX because atazanavir systemic concentrations may be substantially decreased. KAPIDEX may interfere with absorption of drugs for which gastric pH is important for bioavailability (e.g., ampicillin esters, digoxin, iron salts, ketoconazole).

Patients taking concomitant warfarin may require monitoring for increases in international normalized ratio (INR) and prothrombin time.

Increases in INR and prothrombin time may lead to abnormal bleeding, which can lead to serious consequences.

Please see adjacent brief summary of prescribing information for KAPIDEX.

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION KAPIDEXâ„¢ (dexlansoprazole) delayed release capsules INDICATIONS AND USAGE KAPIDEX is indicated for: s THE HEALING OF ALL GRADES OF EROSIVE ESOPHAGITIS %% FOR UP TO WEEKS

s MAINTAINING HEALING OF %% FOR UP TO MONTHS AND s THE TREATMENT OF HEARTBURN ASSOCIATED WITH NON EROSIVE GASTROESOPHAGEAL REmUX DISEASE '%2$ FOR WEEKS CONTRAINDICATIONS +!0)$%8 IS CONTRAINDICATED IN PATIENTS WITH KNOWN HYPERSENSITIVITY TO ANY COMPONENT OF THE FORMULATION (YPERSENSITIVITY AND ANAPHYLAXIS HAVE BEEN REPORTED WITH +!0)$%8 USE [see Adverse Reactions] WARNINGS AND PRECAUTIONS Gastric Malignancy 3YMPTOMATIC RESPONSE WITH +!0)$%8 DOES NOT PRECLUDE THE PRESENCE OF GASTRIC MALIGNANCY ADVERSE REACTIONS Clinical Trials Experience 4HE SAFETY OF +!0)$%8 WAS EVALUATED IN PATIENTS IN CONTROLLED AND UNCONTROLLED CLINICAL STUDIES INCLUDING PATIENTS TREATED FOR AT LEAST MONTHS AND PATIENTS TREATED FOR ONE YEAR 0ATIENTS RANGED IN AGE FROM TO YEARS MEDIAN AGE YEARS WITH FEMALE #AUCASIAN

"LACK !SIAN AND OTHER RACES 3IX RANDOMIZED CONTROLLED CLINICAL TRIALS WERE CONDUCTED FOR THE TREATMENT OF %% MAINTENANCE OF HEALED %% AND SYMPTOMATIC '%2$ WHICH INCLUDED PATIENTS ON PLACEBO PATIENTS ON +!0)$%8 MG PATIENTS ON +!0)$%8 MG AND PATIENTS ON LANSOPRAZOLE MG ONCE DAILY

DRUG REACTION ASTHENIA CHEST PAIN CHILLS FEELING ABNORMAL INmAMMATION

MUCOSAL INmAMMATION NODULE PAIN PYREXIA Hepatobiliary Disorders: BILIARY COLIC CHOLELITHIASIS HEPATOMEGALY Immune System Disorders: HYPERSENSI TIVITY Infections and Infestations: CANDIDA INFECTIONS INmUENZA NASOPHAR YNGITIS ORAL HERPES PHARYNGITIS SINUSITIS VIRAL INFECTION VULVO VAGINAL INFECTION Injury, Poisoning and Procedural Complications: FALLS FRACTURES

JOINT SPRAINS OVERDOSE PROCEDURAL PAIN SUNBURN Laboratory Investigations: !,0 INCREASED !,4 INCREASED !34 INCREASED BILIRUBIN DECREASED INCREASED

BLOOD CREATININE INCREASED BLOOD GASTRIN INCREASED BLOOD GLUCOSE INCREASED

BLOOD POTASSIUM INCREASED LIVER FUNCTION TEST ABNORMAL PLATELET COUNT DECREASED TOTAL PROTEIN INCREASED WEIGHT INCREASE Metabolism and Nutrition Disorders: APPETITE CHANGES HYPERCALCEMIA HYPOKALEMIA Musculoskeletal and Connective Tissue Disorders: ARTHRALGIA ARTHRITIS MUSCLE CRAMPS

MUSCULOSKELETAL PAIN MYALGIA Nervous System Disorders: ALTERED TASTE

CONVULSION DIZZINESS HEADACHES MIGRAINE MEMORY IMPAIRMENT PARES THESIA PSYCHOMOTOR HYPERACTIVITY TREMOR TRIGEMINAL NEURALGIA Psychiatric Disorders: ABNORMAL DREAMS ANXIETY DEPRESSION INSOMNIA LIBIDO CHANGES Renal and Urinary Disorders: DYSURIA MICTURITION URGENCY Reproductive System and Breast Disorders: DYSMENORRHEA DYSPAREUNIA MENORRHAGIA

MENSTRUAL DISORDER; Respiratory, Thoracic and Mediastinal Disorders: ASPI RA TION ASTHMA BRONCHITIS COUGH DYSPNOEA HICCUPS HYPERVENTILATION

RESPIRATORY TRACT CONGESTION SORE THROAT Skin and Subcutaneous Tissue Disorders: ACNE DERMATITIS ERYTHEMA PRURITIS RASH SKIN LESION URTICARIA Vascular Disorders: DEEP VEIN THROMBOSIS HOT mUSH HYPERTENSION

!DDITIONAL ADVERSE REACTIONS THAT WERE REPORTED IN A LONG TERM UNCONTROLLED STUDY AND WERE CONSIDERED RELATED TO +!0)$%8 BY THE TREATING PHYSICIAN INCLUDED ANAPHYLAXIS AUDITORY HALLUCINATION " CELL LYMPHOMA CENTRAL OBESITY CHOLECYSTITIS ACUTE DECREASED HEMOGLOBIN DEHYDRATION DIABETES MELLITUS DYSPHONIA EPISTAXIS FOLLICULITIS GASTROINTESTINAL PAIN GOUT HERPES !S CLINICAL TRIALS ARE CONDUCTED UNDER WIDELY VARYING CONDITIONS ADVERSE RE ZOSTER HYPERGLYCEMIA HYPERLIPIDEMIA HYPOTHYROIDISM INCREASED NEUTROPHILS

ACTION RATES OBSERVED IN THE CLINICAL TRIALS OF A DRUG CANNOT BE DIRECTLY COM -#(# DECREASE NEUTROPENIA ORAL SOFT TISSUE DISORDER RECTAL TENESMUS

PARED TO RATES IN THE CLINICAL TRIALS OF ANOTHER DRUG AND MAY NOT REmECT THE RESTLESS LEGS SYNDROME SOMNOLENCE THROMBOCYTHEMIA TONSILLITIS RATES OBSERVED IN PRACTICE /THER ADVERSE REACTIONS NOT OBSERVED WITH +!0)$%8 BUT OCCURRING WITH -OST #OMMONLY 2EPORTED !DVERSE 2EACTIONS THE RACEMATE LANSOPRAZOLE CAN BE FOUND IN THE LANSOPRAZOLE PACKAGE INSERT

4HE MOST COMMON ADVERSE REACTIONS r THAT OCCURRED AT A HIGHER !$6%23% 2%!#4)/.3 SECTION INCIDENCE FOR +!0)$%8 THAN PLACEBO IN THE CONTROLLED STUDIES ARE PRESENTED DRUG INTERACTIONS IN 4ABLE Drugs with pH-Dependent Absorption Pharmacokinetics Table 2: Incidence of Treatment-Emergent Adverse +!0)$%8 CAUSES INHIBITION OF GASTRIC ACID SECRETION +!0)$%8 IS LIKELY TO Reactions in Controlled Studies SUBSTANTIALLY DECREASE THE SYSTEMIC CONCENTRATIONS OF THE ()6 PROTEASE Placebo KAPIDEX KAPIDEX KAPIDEX Lansoprazole INHIBITOR ATAZANAVIR WHICH IS DEPENDENT UPON THE PRESENCE OF GASTRIC ACID FOR ABSORPTION AND MAY RESULT IN A LOSS OF THERAPEUTIC EFFECT OF ATAZANAVIR AND 30 mg 60 mg Total 30 mg THE DEVELOPMENT OF ()6 RESISTANCE 4HEREFORE +!0)$%8 SHOULD NOT BE (N=896) (N=455) (N=2218) (N=2621) (N=1363) Adverse Reaction % % % % % CO ADMINISTERED WITH ATAZANAVIR $IARRHEA

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&LATULENCE

)T IS THEORETICALLY POSSIBLE THAT +!0)$%8 MAY INTERFERE WITH THE ABSORPTION OF OTHER DRUGS WHERE GASTRIC P( IS AN IMPORTANT DETERMINANT OF ORAL BIOAVAILABILITY E G AMPICILLIN ESTERS DIGOXIN IRON SALTS KETOCONAZOLE Warfarin #O ADMINISTRATION OF +!0)$%8 MG AND WARFARIN MG DID NOT AFFECT THE PHARMACOKINETICS OF WARFARIN OR ).2 (OWEVER THERE HAVE BEEN REPORTS OF INCREASED ).2 AND PROTHROMBIN TIME IN PATIENTS RECEIVING 00)S AND WARFARIN CONCOMITANTLY )NCREASES IN ).2 AND PROTHROMBIN TIME MAY LEAD TO ABNORMAL BLEEDING AND EVEN DEATH 0ATIENTS TREATED WITH +!0)$%8 AND WARFARIN CONCOMITANTLY MAY NEED TO BE MONITORED FOR INCREASES IN ).2 AND PROTHROMBIN TIME

!DVERSE 2EACTIONS 2ESULTING IN $ISCONTINUATION )N CONTROLLED CLINICAL STUDIES THE MOST COMMON ADVERSE REACTION LEADING TO USE IN SPECIFIC POPULATIONS DISCONTINUATION FROM +!0)$%8 THERAPY WAS DIARRHEA Pregnancy /THER !DVERSE 2EACTIONS /THER ADVERSE REACTIONS THAT WERE REPORTED IN CONTROLLED STUDIES AT AN Teratogenic Effects 0REGNANCY #ATEGORY " 4HERE ARE NO ADEQUATE AND WELL CONTROLLED STUDIES INCIDENCE OF LESS THAN ARE LISTED BELOW BY BODY SYSTEM Blood and Lymphatic System Disorders: ANEMIA LYMPHADENOPATHY Cardiac WITH DEXLANSOPRAZOLE IN PREGNANT WOMEN 4HERE WERE NO ADVERSE FETAL EFFECTS Disorders: ANGINA ARRHYTHMIA BRADYCARDIA CHEST PAIN EDEMA MYOCARDIAL IN ANIMAL REPRODUCTION STUDIES OF DEXLANSOPRAZOLE IN RABBITS "ECAUSE ANIMAL INFARCTION PALPITATION TACHYCARDIA Ear and Labyrinth Disorders: EAR PAIN REPRODUCTION STUDIES ARE NOT ALWAYS PREDICTIVE OF HUMAN RESPONSE +!0)$%8 TINNITUS VERTIGO Endocrine Disorders: GOITER Eye Disorders: EYE IRRITATION SHOULD BE USED DURING PREGNANCY ONLY IF CLEARLY NEEDED EYE SWELLING Gastrointestinal Disorders: ABDOMINAL DISCOMFORT ABDOMINAL ! REPRODUCTION STUDY CONDUCTED IN RABBITS AT ORAL DEXLANSOPRAZOLE DOSES UP TENDERNESS ABNORMAL FECES ANAL DISCOMFORT "ARRETT S ESOPHAGUS BEZOAR TO MG PER KG PER DAY APPROXIMATELY FOLD THE MAXIMUM RECOMMENDED BOWEL SOUNDS ABNORMAL BREATH ODOR COLITIS MICROSCOPIC COLONIC POLYP HUMAN DEXLANSOPRAZOLE DOSE ; MG= BASED ON BODY SURFACE AREA ;"3!= CONSTIPATION DRY MOUTH DUODENITIS DYSPEPSIA DYSPHAGIA ENTERITIS ERUC REVEALED NO EVIDENCE OF HARM TO THE FETUS DUE TO DEXLANSOPRAZOLE )N ADDITION

TATION ESOPHAGITIS GASTRIC POLYP GASTRITIS GASTROENTERITIS GASTRO INTESTINAL REPRODUCTION STUDIES PERFORMED IN PREGNANT RATS WITH ORAL LANSOPRAZOLE AT DISORDERS GASTROINTESTINAL HYPERMOTILITY DISORDERS '%2$ ') ULCERS AND DOSES UP TO MG PER KG PER DAY TIMES THE RECOMMENDED HUMAN DOSE PERFORATION HEMATEMESIS HEMATOCHEZIA HEMORRHOIDS IMPAIRED GASTRIC BASED ON "3! AND IN PREGNANT RABBITS AT ORAL LANSOPRAZOLE DOSES UP TO MG EMPTYING IRRITABLE BOWEL SYNDROME MUCUS STOOLS NAUSEA AND VOMITING PER KG PER DAY TIMES THE RECOMMENDED HUMAN DOSE BASED ON "3! REVEALED ORAL MUCOSAL BLISTERING PAINFUL DEFECATION PROCTITIS PARESTHESIA ORAL RECTAL NO EVIDENCE OF IMPAIRED FERTILITY OR HARM TO THE FETUS DUE TO LANSOPRAZOLE HEMORRHAGE General Disorders and Administration Site Conditions: ADVERSE

Nursing Mothers )T IS NOT KNOWN WHETHER DEXLANSOPRAZOLE IS EXCRETED IN HUMAN MILK (OWEVER

LANSOPRAZOLE AND ITS METABOLITES ARE PRESENT IN RAT MILK FOLLOWING THE ADMINI S TRATION OF LANSOPRAZOLE !S MANY DRUGS ARE EXCRETED IN HUMAN MILK AND BECAUSE OF THE POTENTIAL FOR TUMORIGENICITY SHOWN FOR LANSOPRAZOLE IN RAT CARCINOGENICITY STUDIES [see Carcinogenesis, Mutagenesis, Impairment of Fertility] A DECISION SHOULD BE MADE WHETHER TO DISCONTINUE NURSING OR TO DISCONTINUE THE DRUG

TAKING INTO ACCOUNT THE IMPORTANCE OF THE DRUG TO THE MOTHER

WERE TREATED ORALLY WITH LANSOPRAZOLE AT DOSES OF TO MG PER KG PER DAY

ABOUT TO TIMES THE EXPOSURE ON A BODY SURFACE MG M BASIS OF A KG PERSON OF AVERAGE HEIGHT M "3! GIVEN THE RECOMMENDED HUMAN DOSE OF LANSOPRAZOLE MG PER DAY

OVERDOSAGE 4HERE HAVE BEEN NO REPORTS OF SIGNIlCANT OVERDOSE OF +!0)$%8 -ULTIPLE DOSES OF +!0)$%8 MG AND A SINGLE DOSE OF +!0)$%8 MG DID NOT RESULT IN DEATH OR OTHER SEVERE ADVERSE EVENTS $EXLANSOPRAZOLE IS NOT EXPECTED TO BE REMOVED FROM THE CIRCULATION BY HEMODIALYSIS )F AN OVERDOSE OCCURS TREATMENT SHOULD BE SYMPTOMATIC AND SUPPORTIVE

4HE POTENTIAL EFFECTS OF DEXLANSOPRAZOLE ON FERTILITY AND REPRODUCTIVE PERFORMANCE WERE ASSESSED USING LANSOPRAZOLE STUDIES ,ANSOPRAZOLE AT ORAL DOSES UP TO MG PER KG PER DAY TIMES THE RECOMMENDED LANSOPRAZOLE HUMAN DOSE BASED ON "3! WAS FOUND TO HAVE NO EFFECT ON FERTILITY AND REPRODUCTIVE PERFORMANCE OF MALE AND FEMALE RATS PATIENT COUNSELING INFORMATION

CLINICAL PHARMACOLOGY

[see FDA-Approved Patient Labeling in the full prescribing information]

Pharmacodynamics !NTISECRETORY !CTIVITY 4HE EFFECTS OF +!0)$%8 MG N OR LANSOPRAZOLE MG N ONCE DAILY FOR lVE DAYS ON HOUR INTRAGASTRIC P( WERE ASSESSED IN HEALTHY SUBJECTS IN A MULTIPLE DOSE CROSSOVER STUDY

Information for Patients 4O ENSURE THE SAFE AND EFFECTIVE USE OF +!0)$%8 THIS INFORMATION AND INSTRUCTIONS PROVIDED IN THE &$! APPROVED PATIENT LABELING SHOULD BE DISCUSSED WITH THE PATIENT )NFORM PATIENTS OF THE FOLLOWING

,ANSOPRAZOLE PRODUCED DOSE RELATED GASTRIC %#, CELL HYPERPLASIA AND %#, CELL CARCINOIDS IN BOTH MALE AND FEMALE RATS [see Clinical Pharmacology].

)N RATS LANSOPRAZOLE ALSO INCREASED THE INCIDENCE OF INTESTINAL METAPLASIA OF THE GASTRIC EPITHELIUM IN BOTH SEXES )N MALE RATS LANSOPRAZOLE PRODUCED A Pediatric Use 3AFETY AND EFFECTIVENESS OF +!0)$%8 IN PEDIATRIC PATIENTS LESS THAN YEARS DOSE RELATED INCREASE OF TESTICULAR INTERSTITIAL CELL ADENOMAS 4HE INCIDENCE OF THESE ADENOMAS IN RATS RECEIVING DOSES OF TO MG PER KG PER DAY TO OF AGE HAVE NOT BEEN ESTABLISHED TIMES THE RECOMMENDED LANSOPRAZOLE HUMAN DOSE BASED ON "3!

Geriatric Use EXCEEDED THE LOW BACKGROUND INCIDENCE RANGE TO FOR THIS STRAIN )N CLINICAL STUDIES OF +!0)$%8 OF PATIENTS WERE AGED YEARS AND OVER .O OVERALL DIFFERENCES IN SAFETY OR EFFECTIVENESS WERE OBSERVED BETWEEN OF RAT 4ESTICULAR INTERSTITIAL CELL ADENOMA ALSO OCCURRED IN OF RATS TREATED THESE PATIENTS AND YOUNGER PATIENTS AND OTHER REPORTED CLINICAL EXPERIENCE WITH MG LANSOPRAZOLE PER KG PER DAY TIMES THE RECOMMENDED LANSO HAS NOT IDENTIlED SIGNIlCANT DIFFERENCES IN RESPONSES BETWEEN GERIATRIC AND PRAZOLE HUMAN DOSE BASED ON "3! IN A YEAR TOXICITY STUDY YOUNGER PATIENTS BUT GREATER SENSITIVITY OF SOME OLDER INDIVIDUALS CANNOT BE )N A MONTH CARCINOGENICITY STUDY #$ MICE WERE TREATED ORALLY WITH RULED OUT] LANSOPRAZOLE DOSES OF MG TO MG PER KG PER DAY TO TIMES THE RECOMMENDED HUMAN DOSE BASED ON "3! ,ANSOPRAZOLE PRODUCED A DOSE Renal Impairment .O DOSAGE ADJUSTMENT OF +!0)$%8 IS NECESSARY IN PATIENTS WITH RENAL RELATED INCREASED INCIDENCE OF GASTRIC %#, CELL HYPERPLASIA )T ALSO PRODUCED IMPAIRMENT 4HE PHARMACOKINETICS OF DEXLANSOPRAZOLE IN PATIENTS WITH RENAL AN INCREASED INCIDENCE OF LIVER TUMORS HEPATOCELLULAR ADENOMA PLUS IMPAIRMENT ARE NOT EXPECTED TO BE ALTERED SINCE DEXLANSOPRAZOLE IS EXTENSIVELY CARCINOMA 4HE TUMOR INCIDENCES IN MALE MICE TREATED WITH MG AND METABOLIZED IN THE LIVER TO INACTIVE METABOLITES AND NO PARENT DRUG IS MG LANSOPRAZOLE PER KG PER DAY TO TIMES THE RECOMMENDED RECOVERED IN THE URINE FOLLOWING AN ORAL DOSE OF DEXLANSOPRAZOLE. LANSOPRAZOLE HUMAN DOSE BASED ON "3! AND FEMALE MICE TREATED WITH MG TO MG LANSOPRAZOLE PER KG PER DAY TO TIMES THE Hepatic Impairment .O DOSAGE ADJUSTMENT FOR +!0)$%8 IS NECESSARY FOR PATIENTS WITH MILD HEPATIC RECOMMENDED HUMAN DOSE BASED ON "3! EXCEEDED THE RANGES OF BACK IMPAIRMENT #HILD 0UGH #LASS ! +!0)$%8 MG SHOULD BE CONSIDERED FOR GROUND INCIDENCES IN HISTORICAL CONTROLS FOR THIS STRAIN OF MICE ,ANSOPRAZOLE PATIENTS WITH MODERATE HEPATIC IMPAIRMENT #HILD 0UGH #LASS " .O STUDIES TREATMENT PRODUCED ADENOMA OF RETE TESTIS IN MALE MICE RECEIVING TO HAVE BEEN CONDUCTED IN PATIENTS WITH SEVERE HEPATIC IMPAIRMENT #HILD 0UGH MG PER KG PER DAY TO TIMES THE RECOMMENDED LANSOPRAZOLE #LASS # .

HUMAN DOSE BASED ON "3!

3ERUM 'ASTRIN %FFECTS 4HE EFFECT OF +!0)$%8 ON SERUM GASTRIN CONCENTRATIONS WAS EVALUATED IN APPROX IMATELY PATIENTS IN CLINICAL TRIALS UP TO WEEKS AND IN PATIENTS FOR UP TO TO MONTHS 4HE MEAN FASTING GASTRIN CONCENTRATIONS INCREASED FROM BASELINE DURING TREATMENT WITH +!0)$%8 MG AND MG DOSES )N PATIENTS TREATED FOR MORE THAN MONTHS MEAN SERUM GASTRIN LEVELS INCREASED DURING APPROXIMATELY THE lRST MONTHS OF TREATMENT AND WERE STABLE FOR THE REMAINDER OF TREATMENT -EAN SERUM GASTRIN LEVELS RETURNED TO PRE TREATMENT LEVELS WITHIN ONE MONTH OF DISCONTINUATION OF TREATMENT

+!0)$%8 IS AVAILABLE AS A DELAYED RELEASE CAPSULE +!0)$%8 MAY BE TAKEN WITHOUT REGARD TO FOOD +!0)$%8 SHOULD BE SWALLOWED WHOLE

s !LTERNATIVELY +!0)$%8 CAPSULES CAN BE OPENED AND ADMINISTERED AS FOLLOWS n /PEN CAPSULE n 3PRINKLE INTACT GRANULES ON ONE TABLESPOON OF APPLESAUCE n 3WALLOW IMMEDIATELY

$ISTRIBUTED BY %NTEROCHROMAFlN ,IKE #ELL %#, %FFECTS Takeda Pharmaceuticals America, Inc. 4HERE WERE NO REPORTS OF %#, CELL HYPERPLASIA IN GASTRIC BIOPSY SPECIMENS $EERlELD ), OBTAINED FROM PATIENTS TREATED WITH +!0)$%8 MG MG OR MG FOR 5 3 0ATENT .OS

UP TO MONTHS

AND

$URING LIFETIME EXPOSURE OF RATS DOSED DAILY WITH UP TO MG PER KG PER DAY OF LANSOPRAZOLE MARKED HYPERGASTRINEMIA WAS OBSERVED FOLLOWED BY %#, +!0)$%8 IS A TRADEMARK OF 4AKEDA 0HARMACEUTICALS .ORTH !MERICA )NC AND CELL PROLIFERATION AND FORMATION OF CARCINOID TUMORS ESPECIALLY IN FEMALE RATS USED UNDER LICENSE BY 4AKEDA 0HARMACEUTICALS !MERICA )NC !LL OTHER TRADEMARK NAMES ARE THE PROPERTY OF THEIR RESPECTIVE OWNERS [see Nonclinical Toxicology ] Ú 4AKEDA 0HARMACEUTICALS !MERICA )NC %FFECT ON #ARDIAC 2EPOLARIZATION

! STUDY WAS CONDUCTED TO ASSESS THE POTENTIAL OF +!0)$%8 TO PROLONG THE 14 14c INTERVAL IN HEALTHY ADULT SUBJECTS +!0)$%8 DOSES OF MG OR MG DID NOT DELAY CARDIAC REPOLARIZATION COMPARED TO PLACEBO 4HE POSITIVE CONTROL MOXImOXACIN PRODUCED STATISTICALLY SIGNIlCANTLY GREATER MEAN MAXIMUM AND TIME AVERAGED 14 14c INTERVALS COMPARED TO PLACEBO

&OR MORE DETAILED INFORMATION SEE THE FULL PRESCRIBING INFORMATION FOR +!0)$%8 0) 2 *ANUARY OR CONTACT 4AKEDA 0HARMACEUTICALS !MERICA )NC AT

NONCLINICAL TOXICOLOGY

, ,0$

0) 2 "RF *ANUARY

Carcinogenesis, Mutagenesis, Impairment of Fertility 4HE CARCINOGENIC POTENTIAL OF DEXLANSOPRAZOLE WAS ASSESSED USING LANSOPRA ZOLE STUDIES )N TWO MONTH CARCINOGENICITY STUDIES 3PRAGUE $AWLEY RATS Reference: 1. KAPIDEX (dexlansoprazole) package insert, Takeda Pharmaceuticals America, Inc. KAPIDEX™ and Dual Delayed Release™ are trademarks of Takeda Pharmaceuticals North America, Inc., and are used under license by Takeda Pharmaceuticals America, Inc.

©2009 Takeda Pharmaceuticals North America, Inc. LPD-00256 6/09 Printed in U.S.A.

EDITORIAL BOARD

CLINICAL EDITOR

EPIDEMIOLOGY RESEARCH

PHARMACY BENEFIT DESIGN

Thomas G. McCarter, MD, FACP Chief Clinical Officer Executive Health Resources, PA

Joshua N. Liberman, PhD Vice President, Strategic Research CVS Caremark, Hunt Valley, MD

Joel V. Brill, MD Chief Medical Officer, Predictive Health, Phoenix, AZ

GOVERNMENT EDITOR

Kevin B. “Kip” Piper, MA, FACHE President, Health Results Group Sr. Counselor, Fleishman-Hillard Washington, DC

Nirav R. Shah, MD, MPH Assistant Professor of Medicine NYU School of Medicine, NYC Senior Investigator, Geisinger Health System, Danville, PA

Leslie S. Fish, PharmD Sr. Director of Pharmacy Services Fallon Community Health Plan, MA

ACTUARY

HEALTH INFORMATION TECHNOLOGY

David Williams Health Consultant Milliman, Windsor, CT

J. B. Jones, PhD, MBA Research Associate, Geisinger Health System, Danville, PA

CANCER RESEARCH

HEALTH OUTCOMES RESEARCH

Al B. Benson, III, MD, FACP Professor of Medicine Associate Director for Clinical Investigations Robert H. Lurie Comprehensive Cancer Center, Northwestern University Chair, Board of Directors, NCCN Samuel M. Silver, MD, PhD, FACP Professor, Internal Medicine Director, Cancer Center Network Division of Hematology/Oncology Assistant Dean for Research University of Michigan Health Systems CARDIOLOGY RESEARCH

Michael A. Weber, MD Professor of Medicine Department of Medicine (Cardiology) State University of New York ENDOCRINOLOGY RESEARCH

James V. Felicetta, MD Chairman, Dept. of Medicine Carl T. Hayden Veterans Affairs Medical Center, Phoenix, AZ EMPLOYERS

Alberto M. Colombi, MD, MPH Corporate Medical Director PPG Industries, Pittsburgh, PA Wayne M. Lednar, MD, PhD Global Chief Medical Officer Director, Integrated Health Services DuPont, Wilmington, DE Arthur F. Shinn, PharmD, FASCP President, Managed Pharmacy Consultants, Lake Worth, FL F. Randy Vogenberg, RPh, PhD Chief Strategy Officer Employer-based Pharmaceutical Strategies Senior Scholar, Department of Health Policy, Thomas Jefferson University

Gordon M. Cummins, MS Director, IntegriChain Kavita V. Nair, PhD Associate Professor, School of Pharmacy University of Colorado at Denver Gary M. Owens, MD President, Gary Owens Associates Glen Mills, PA Timothy S. Regan, BPharm, RPh Executive Director, Xcenda Palm Harbor, FL

AMERICAN HEALTH & DRUG BENEFITS

Scott R. Taylor, RPh, MBA Associate Director, Industry Relations Geisinger Health System, Danville, PA POLICY & PUBLIC HEALTH

Joseph R. Antos, PhD Wilson H. Taylor Scholar in Health Care Retirement Policy American Enterprise Institute Jack E. Fincham, PhD, RPh Professor of Pharmacy, School of Pharmacy University of Missouri, Kansas City, MO Alex Hathaway, MD, MPH, FACPM Senior Medical Policy Advisor Government Programs GlaxoSmithKline, Philadelphia, PA

Sharad Mansukani, MD Chief Strategic Officer, Nations Health Senior Advisor, Texas Pacific Group, FL

J. Warren Salmon, PhD Professor of Health Policy & Administration School of Public Health University of Illinois at Chicago

MANAGED MARKETS

REIMBURSEMENT POLICY

Jeffrey A. Bourret, MS, RPh, FASHP Executive Director, Customer-Centric Strategy and Innovation, Healthcare Systems Marketing Wyeth Pharmaceuticals, Collegeville, PA

Grant D. Lawless, BSPharm, MD, FACP Executive Director for Payor Relations Corporate Account Amgen, Thousand Oaks, CA

MANAGED CARE & GOVERNMENT AFFAIRS

Charles E. Collins, Jr, MS, MBA Associate Director, Managed Markets Marketing, Boehringer-Ingelheim Ridgefield, CT

Michael Schaffer, PharmD, MBA Director, Pharmacy Programs Sanovia Co., Philadelphia, PA RESEARCH & DEVELOPMENT

William E. Fassett, BSPharm, MBA, PhD Professor of Pharmacy Law & Ethics Vice Chair, Dept. of Pharmacotherapy College of Pharmacy, Washington State University, Spokane, WA

Michael F. Murphy, MD, PhD Chief Medical Officer and Scientific Officer Worldwide Clinical Trials Faculty, Center for Experimental Pharmacology and Therapeutics, HarvardMIT Division of Health Sciences and Technology, Cambridge, MA

PERSONALIZED MEDICINE

SPECIALTY PHARMACY

Wayne A. Rosenkrans, Jr, PhD Chairman and President, Personalized Medicine Coalition, Distinguished Fellow, MIT Center for Biomedical Innovation

Atheer A. Kaddis, PharmD Vice President, Managed Markets Diplomat Specialty Pharmacy Swartz Creek, MI

PHARMACOECONOMICS

James T. Kenney, RPh, MBA Pharmacy Operations Manager Harvard Pilgrim Health Care Wellesley, MA

PATIENT ADVOCACY

Jeff Jianfei Guo, BPharm, MS, PhD Associate Professor of Pharmacoeconomics & Pharmacoepidemiology, College of Pharmacy, University of Cincinnati Medical Center, OH

212

Paul Anthony Polansky, BSPharm, MBA Executive VP and Chief Pharmacy Officer Sanovia Corp., Philadelphia, PA

September/October 2009

VOL. 2

NO. 6

Gottlieb_Cover 10/14/09 12:22 PM Page 213

2.5 mg, 5 mg, 10 mg and 20 mg Rx Only Brief Summary: For complete details please see full Prescribing Information for BYSTOLIC. INDICATIONS AND USAGE BYSTOLIC is indicated for the treatment of hypertension. BYSTOLIC may be used alone or in combination with other antihypertensive agents.

CONTRAINDICATIONS BYSTOLIC is contraindicated in patients with severe bradycardia, heart block greater than first degree, cardiogenic shock, decompensated cardiac failure, sick sinus syndrome (unless a permanent pacemaker is in place), or severe hepatic impairment (Child-Pugh >B), and in patients who are hypersensitive to any component of this product.

WARNINGS Abrupt Cessation of Therapy Patients with coronary artery disease treated with BYSTOLIC should be advised against abrupt discontinuation of therapy. Severe exacerbation of angina and the occurrence of myocardial infarction and ventricular arrhythmias have been reported in patients with coronary artery disease following the abrupt discontinuation of therapy with β-blockers. Myocardial infarction and ventricular arrhythmias may occur with or without preceding exacerbation of the angina pectoris. Even patients without overt coronary artery disease should be cautioned against interruption or abrupt discontinuation of therapy. As with other β-blockers, when discontinuation of BYSTOLIC is planned, patients should be carefully observed and advised to minimize physical activity. BYSTOLIC should be tapered over 1 to 2 weeks when possible. If the angina worsens or acute coronary insufficiency develops, it is recommended that BYSTOLIC be promptly reinstituted, at least temporarily.

Cardiac Failure Sympathetic stimulation is a vital component supporting circulatory function in the setting of congestive heart failure, and β-blockade may result in further depression of myocardial contractility and precipitate more severe failure. In patients who have compensated congestive heart failure, BYSTOLIC should be administered cautiously.

If heart failure worsens, discontinuation of BYSTOLIC should be considered.

Angina and Acute Myocardial Infarction BYSTOLIC was not studied in patients with angina pectoris or who had a recent MI. Bronchospastic Diseases In general, patients with bronchospastic diseases should not receive β-blockers.

Anesthesia and Major Surgery If BYSTOLIC is to be continued perioperatively, patients should be closely monitored when anesthetic agents which depress myocardial function, such as ether, cyclopropane, and trichloroethylene, are used. If β-blocking therapy is withdrawn prior to major surgery, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.

The β-blocking effects of BYSTOLIC can be reversed by β-agonists, e.g., dobutamine or isoproterenol. However, such patients may be subject to protracted severe hypotension. Additionally, difficulty in restarting and maintaining the heartbeat has been reported with β-blockers.

Diabetes and Hypoglycemia β-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Nonselective β-blockers may potentiate insulin-induced hypoglycemia and delay recovery of serum glucose levels. It is not known whether nebivolol has these effects. Patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic agents, should be advised about these possibilities and nebivolol should be used with caution.

Thyrotoxicosis β-blockers may mask clinical signs of hyperthyroidism, such as tachycardia.

Abrupt withdrawal of β-blockers may be followed by an exacerbation of the symptoms of hyperthyroidism or may precipitate a thyroid storm.

Peripheral Vascular Disease β-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. Caution should be exercised in these patients.

Non-dihydropyridine Calcium Channel Blockers Because of significant negative inotropic and chronotropic effects in patients treated with β-blockers and calcium channel blockers of the verapamil and diltiazem type, caution should be used in patients treated concomitantly with these agents and ECG and blood pressure should be monitored.

PRECAUTIONS Use with CYP2D6 Inhibitors Nebivolol exposure increases with inhibition of CYP2D6 (see Drug Interactions).

The dose of BYSTOLIC may need to be reduced.

Impaired Renal Function BYSTOLIC should be used with caution in patients with severe renal impairment because of decreased renal clearance. BYSTOLIC has not been studied in patients receiving dialysis.

Impaired Hepatic Function BYSTOLIC should be used with caution in patients with moderate hepatic impairment because of decreased metabolism. Since BYSTOLIC has not been studied in patients with severe hepatic impairment, BYSTOLIC is contraindicated in this population (see CLINICAL PHARMACOLOGY, Special Populations and DOSAGE AND ADMINISTRATION).

Risk of Anaphylactic Reactions While taking β-blockers, patients with a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated challenge either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions.

In patients with known or suspected pheochromocytoma, an α-blocker should be initiated prior to the use of any β-blocker.

Information for Patients Patients should be advised to take BYSTOLIC regularly and continuously, as directed. BYSTOLIC can be taken with or without food. If a dose is missed, the patient should take the next scheduled dose only (without doubling it). Patients should not interrupt or discontinue BYSTOLIC without consulting the physician.

Patients should know how they react to this medicine before they operate automobiles, use machinery, or engage in other tasks requiring alertness.

Patients should be advised to consult a physician if any difficulty in breathing occurs, or if they develop signs or symptoms of worsening congestive heart failure such as weight gain or increasing shortness of breath, or excessive bradycardia.

Patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic agents, should be cautioned that β-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Nebivolol should be used with caution in these patients.

Drug Interactions BYSTOLIC should be used with care when myocardial depressants or inhibitors of AV conduction, such as certain calcium antagonists (particularly of the phenylalkylamine [verapamil] and benzothiazepine [diltiazem] classes), or antiarrhythmic agents, such as disopyramide, are used concurrently. Both digitalis glycosides and β-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.

BYSTOLIC should not be combined with other β-blockers. Patients receiving catecholamine-depleting drugs, such as reserpine or guanethidine, should be closely monitored, because the added β-blocking action of BYSTOLIC may produce excessive reduction of sympathetic activity. In patients who are receiving BYSTOLIC and clonidine, BYSTOLIC should be discontinued for several days before the gradual tapering of clonidine.

CYP2D6 Inhibitors: Use caution when BYSTOLIC is co-administered with CYP2D6 inhibitors (quinidine, propafenone, fluoxetine, paroxetine, etc.) (see CLINICAL PHARMACOLOGY, Drug Interactions).

Carcinogenesis, Mutagenesis, Impairment of Fertility In a two-year study of nebivolol in mice, a statistically significant increase in the incidence of testicular Leydig cell hyperplasia and adenomas was observed at 40 mg/kg/day (5 times the maximally recommended human dose of 40 mg on a mg/m2 basis). Similar findings were not reported in mice administered doses equal to approximately 0.3 or 1.2 times the maximum recommended human dose. No evidence of a tumorigenic effect was observed in a 24-month study in Wistar rats receiving doses of nebivolol 2.5, 10 and 40 mg/kg/day (equivalent to 0.6, 2.4, and 10 times the maximally recommended human dose). Co-administration of dihydrotestosterone reduced blood LH levels and prevented the Leydig cell hyperplasia, consistent with an indirect LH-mediated effect of nebivolol in mice and not thought to be clinically relevant in man.

A randomized, double-blind, placebo- and active-controlled, parallel-group study in healthy male volunteers was conducted to determine the effects of nebivolol on adrenal function, luteinizing hormone, and testosterone levels. This study demonstrated that 6 weeks of daily dosing with 10 mg of nebivolol had no significant effect on ACTH-stimulated mean serum cortisol AUC0-120 min, serum LH, or serum total testosterone.

Effects on spermatogenesis were seen in male rats and mice at ≥40 mg/kg/day (10 and 5 times the MRHD, respectively). For rats the effects on spermatogenesis were not reversed and may have worsened during a four-week recovery period. The effects of nebivolol on sperm in mice, however, were partially reversible.

Mutagenesis: Nebivolol was not genotoxic when tested in a battery of assays (Ames, in vitro mouse lymphoma TK+/-, in vitro human peripheral lymphocyte chromosome aberration, in vivo Drosophila melanogaster sex-linked recessive lethal, and in vivo mouse bone marrow micronucleus tests).

Pregnancy: Teratogenic Effects. Pregnancy Category C: Decreased pup body weights occurred at 1.25 and 2.5 mg/kg in rats, when exposed during the perinatal period (late gestation, parturition and lactation). At 5 mg/kg and higher doses (1.2 times the MRHD), prolonged gestation, dystocia and reduced maternal care were produced with corresponding increases in late fetal deaths and stillbirths and decreased birth weight, live litter size and pup survival. Insufficient numbers of pups survived at 5 mg/kg to evaluate the offspring for reproductive performance.

In studies in which pregnant rats were given nebivolol during organogenesis, reduced fetal body weights were observed at maternally toxic doses of 20 and 40 mg/kg/day (5 and 10 times the MRHD), and small reversible delays in sternal and thoracic ossification associated with the reduced fetal body weights and a small increase in resorption occurred at 40 mg/kg/day (10 times the MRHD). No adverse effects on embryo-fetal viability, sex, weight or morphology were observed in studies in which nebivolol was given to pregnant rabbits at doses as high as 20 mg/kg/day (10 times the MRHD).

Labor and Delivery Nebivolol caused prolonged gestation and dystocia at doses ≥5 mg/kg in rats (1.2 times the MRHD). These effects were associated with increased fetal deaths and stillborn pups, and decreased birth weight, live litter size and pup survival rate, events that occurred only when nebivolol was given during the perinatal period (late gestation, parturition and lactation).

No studies of nebivolol were conducted in pregnant women. BYSTOLIC should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers Studies in rats have shown that nebivolol or its metabolites cross the placental barrier and are excreted in breast milk. It is not known whether this drug is excreted in human milk.

Because of the potential for β-blockers to produce serious adverse reactions in nursing infants, especially bradycardia, BYSTOLIC is not recommended during nursing.

Geriatric Use Of the 2800 patients in the U.S.-sponsored placebo-controlled clinical hypertension studies, 478 patients were 65 years of age or older. No overall differences in efficacy or in the incidence of adverse events were observed between older and younger patients.

Pediatric Use Safety and effectiveness in pediatric patients have not been established. Pediatric studies in ages newborn to 18 years old have not been conducted because of incomplete characterization of developmental toxicity and possible adverse effects on long-term fertility (see Carcinogenesis, Mutagenesis, and Impairment of Fertility).

ADVERSE REACTIONS The data described below reflect worldwide clinical trial exposure to BYSTOLIC in 6545 patients, including 5038 patients treated for hypertension and the remaining 1507 subjects treated for other cardiovascular diseases. Doses ranged from 0.5 mg to 40 mg. Patients received BYSTOLIC for up to 24 months, with over 1900 patients treated for at least 6 months, and approximately 1300 patients for more than one year. In placebo-controlled clinical trials comparing BYSTOLIC with placebo, discontinuation of therapy due to adverse events was reported in 2.8% of patients treated with nebivolol and 2.2% of patients given placebo. The most common adverse events that led to discontinuation of BYSTOLIC were headache (0.4%), nausea (0.2%) and bradycardia (0.2%).

Adverse Reactions in Controlled Trials Table 1 lists treatment-emergent signs and symptoms that were reported in three 12week, placebo-controlled monotherapy trials involving 1597 hypertensive patients treated with either 5 mg, 10 mg or 20-40 mg of BYSTOLIC and 205 patients given placebo and for which the rate of occurrence was at least 1% of patients treated with nebivolol and greater than the rate for those treated with placebo in at least one dose group.

Table 1. Treatment-Emergent Adverse Events with an Incidence (over 6 weeks) ≥1% in BYSTOLIC-Treated Patients and at a Higher Frequency than PlaceboTreated Patients Placebo

Headache Fatigue Dizziness Diarrhea Nausea Insomnia Chest pain Bradycardia Dyspnea Rash Peripheral edema

(n = 205) (%) 6 1 2 2 0 0 0 0 0 0 0

Nebivolol 5 mg (n = 459) (%) 9 2 2 2 1 1 0 0 0 0 1

Nebivolol 10 mg (n = 461) (%) 6 2 3 2 3 1 1 0 1 1 1

Nebivolol 20-40 mg (n = 677) (%) 7 5 4 3 2 1 1 1 1 1 1

Other Adverse Events Observed During Worldwide Clinical Trials Listed below are other reported adverse events with an incidence of at least 1% in the more than 5300 patients treated with BYSTOLIC in controlled or open-label trials, whether or not attributed to treatment, except for those already appearing in Table 1, terms too general to be informative, minor symptoms, or events unlikely to be attributable to drug because they are common in the population.

These adverse events were in most cases observed at a similar frequency in placebo-treated patients in the controlled studies.

Body as a Whole: asthenia.

Gastrointestinal System Disorders: abdominal pain Metabolic and Nutritional Disorders: hypercholesterolemia and hyperuricemia Nervous System Disorders: paraesthesia Laboratory In controlled monotherapy trials, BYSTOLIC was associated with an increase in BUN, uric acid, triglycerides and a decrease in HDL cholesterol and platelet count.

Events Identified from Spontaneous Reports of BYSTOLIC Received Worldwide The following adverse events have been identified from spontaneous reports of BYSTOLIC received worldwide and have not been listed elsewhere. These adverse events have been chosen for inclusion due to a combination of seriousness, frequency of reporting or potential causal connection to BYSTOLIC. Events common in the population have generally been omitted. Because these events were reported voluntarily from a population of uncertain size, it is not possible to estimate their frequency or establish a causal relationship to BYSTOLIC exposure: abnormal hepatic function (including increased AST, ALT and bilirubin), acute pulmonary edema, acute renal failure, atrioventricular block (both second- and third-degree), bronchospasm, erectile dysfunction, hypersensitivity (including urticaria, allergic vasculitis and rare reports of angioedema), myocardial infarction, pruritus, psoriasis, Raynaud’s phenomenon, peripheral ischemia/claudication, somnolence, syncope, thrombocytopenia, various rashes and skin disorders, vertigo, and vomiting.

OVERDOSAGE In clinical trials and worldwide postmarketing experience there were reports of BYSTOLIC overdose. The most common signs and symptoms associated with BYSTOLIC overdosage are bradycardia and hypotension. Other important adverse events reported with BYSTOLIC overdose include cardiac failure, dizziness, hypoglycemia, fatigue and vomiting. Other adverse events associated with β-blocker overdose include bronchospasm and heart block.

The largest known ingestion of BYSTOLIC worldwide involved a patient who ingested up to 500 mg of BYSTOLIC along with several 100 mg tablets of acetylsalicylic acid in a suicide attempt. The patient experienced hyperhidrosis, pallor, depressed level of consciousness, hypokinesia, hypotension, sinus bradycardia, hypoglycemia, hypokalemia, respiratory failure and vomiting. The patient recovered.

Due to extensive drug binding to plasma proteins, hemodialysis is not expected to enhance nebivolol clearance.

If overdose occurs, BYSTOLIC should be stopped and general supportive and specific symptomatic treatment should be provided. Based on expected pharmacologic actions and recommendations for other β-blockers, the following general measures should be considered when clinically warranted: Bradycardia: Administer IV atropine. If the response is inadequate, isoproterenol or another agent with positive chronotropic properties may be given cautiously.

Under some circumstances, transthoracic or transvenous pacemaker placement may be necessary.

Hypotension: Administer IV fluids and vasopressors. Intravenous glucagon may be useful.

Heart Block (second or third degree): Patients should be carefully monitored and treated with isoproterenol infusion. Under some circumstances, transthoracic or transvenous pacemaker placement may be necessary.

Congestive Heart Failure: Initiate therapy with digitalis glycoside and diuretics.

In certain cases, consideration should be given to the use of inotropic and vasodilating agents.

Bronchospasm: Administer bronchodilator therapy such as a short-acting inhaled β2-agonist and/or aminophylline.

Hypoglycemia: Administer IV glucose. Repeated doses of IV glucose or possibly glucagon may be required.

In the event of intoxication where there are symptoms of shock, treatment must be continued for a sufficiently long period consistent with the 12-19 hour effective half-life of BYSTOLIC. Supportive measures should continue until clinical stability is achieved.

Call the National Poison Control Center (800-222-1222) for the most current information on β-blocker overdose treatment.

Forest Pharmaceuticals, Inc. Subsidiary of Forest Laboratories, Inc. St. Louis, MO 63045, USA Licensed from Mylan Laboratories, Inc. Under license from Janssen Pharmaceutica N.V., Beerse, Belgium

Rev. 08/08 © 2008 Forest Laboratories, Inc.

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For the treatment of hypertension

BYSTOLIC. Significant blood pressure reductions with a low incidence of side effects.1-3 www.BYSTOLIC.com Important Safety Information Patients being treated with BYSTOLIC should be advised against abrupt discontinuation of therapy. Severe exacerbation of angina and the occurrence of myocardial infarction and ventricular arrhythmias have been reported following the abrupt cessation of therapy with beta blockers. When discontinuation is planned, the dosage should be reduced gradually over a 1- to 2-week period and the patient carefully monitored.

BYSTOLIC is contraindicated in severe bradycardia, heart block greater than first degree, cardiogenic shock, decompensated cardiac failure, sick sinus syndrome (unless a permanent pacemaker is in place), severe hepatic impairment (Child-Pugh >B), and in patients who are hypersensitive to any component of this product.

BYSTOLIC should be used with caution in patients with peripheral vascular disease, thyrotoxicosis, in patients treated concomitantly with beta blockers and calcium channel blockers of the verapamil and diltiazem type (ECG and blood pressure should be monitored), severe renal impairment, and any degree of hepatic impairment or in patients undergoing major surgery. In patients who have compensated congestive heart failure, BYSTOLIC should be administered cautiously. If heart failure worsens, discontinuation of BYSTOLIC should be considered. Caution should also be used in diabetic patients as beta blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia.

Use caution when BYSTOLIC is co-administered with CYP2D6 inhibitors (quinidine, propafenone, fluoxetine, paroxetine, etc). When BYSTOLIC is administered with fluoxetine, significant increases in d-nebivolol may be observed (ie, an 8-fold increase in AUC).

In general, patients with bronchospastic disease should not receive beta blockers.

BYSTOLIC should not be combined with other beta blockers.

The most common adverse events with BYSTOLIC versus placebo (approximately ≼1% and greater than placebo) were headache, fatigue, dizziness, diarrhea, nausea, insomnia, chest pain, bradycardia, dyspnea, rash, and peripheral edema.

Please see brief summary of Prescribing Information on adjacent page. Š2009 Forest Laboratories, Inc

44-1014950

01/09

References: 1. BYSTOLIC [package insert]. St. Louis, Mo: Forest Pharmaceuticals, Inc.; 2008. 2. Data on file. Forest Laboratories, Inc. 3. Saunders E, Smith WB, DeSalvo KB, Sullivan WA. The efficacy and tolerability of nebivolol in hypertensive African American patients. J Clin Hypertens. 2007;9:866-875.

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COMMENTARY

Government Health Plans Always Ration Care: Europe Offers a Glimpse of the Future If President Obama and Congressional Democrats Have Their Way Scott Gottlieb, MD

O

nly by expanding government control of healthcare can we bring down its cost. That’s the faulty premise of the various proposals for health reform now being batted around Washington. The claimed cost control depends on politically safe ideas, such as preventive care or the adoption of electronic health records. And neither—even according to the Congressional Budget Office—will do much to reduce spending.

If these proposals are implemented and fail to produce savings, government will turn to a less appealing but more familiar tool to cut costs: the regulation of access to drugs and medical services. Medicare is already going down this path. What will be new about government-run healthcare is the instrument of regulatory control. There will be an omnipotent federal health board. Buried in current reform proposals, this board deserves closer scrutiny.

Our best look at this construct comes from a bill released by the Senate Committee on Health, Education, Labor, and Pensions (HELP). The bill calls for a “Medical Advisory Council” to determine what medical products and services are “essential benefits” and those that shouldn’t be covered by a public insurance plan.

The Senate Finance Committee turns to a “Federal Health Board” to compare similar medical treatments in order to steer reimbursement to lower-cost options.

Senate Finance also proposes a “sustainability commission” charged with finding automatic cuts to Medicare spending that would then pass Congress by a simple up or down vote.

Meanwhile, a draft healthcare reform proposal introduced in June 2009 in the House of Representatives by

Dr Gottlieb, a Practicing Physician and Resident Fellow at the American Enterprise Institute, was former Deputy Commissioner of the FDA from 2005 to 2007. He is partner in a firm that invests in healthcare companies Copyright © Scott Gottlieb. Reprinted with permission.

Originally printed in Opinion Journal. The Wall Street Journal.

June 25, 2009. All rights reserved.

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the three committees with jurisdiction over health policy set up an independent “advisory committee” that will “recommend a benefit package based on standards set in the law.” It also proposes a new “commission” that may, among other things, help develop treatment protocols based on government-directed research.

Congress, of course, can authorize the creation of panels and commissions to provide expert advice to the executive branch. But such bodies are typically advisory, and their advice is free to be rejected or modified by the president. Under the HELP Committee’s plan, the health board’s recommendations would be binding unless Congress acts within a brief period to pass a “joint resolution disapproving such report in its entirety.”

President Obama objects when people use the word “rationing” in regards to government-run healthcare.

But rationing is inevitable if we simply expand government control without fixing the way healthcare is reimbursed so that doctors and patients become sensitive to issues of price and quality.

Like Medicare’s recent decisions to curtail the use of virtual colonoscopies, certain wound-healing devices, and even a branded asthma drug, the board’s decisions will be one-size-fits-all restrictions. Such restrictions don’t respect variation in preferences and disease, which make costly products suitable for some, even if they are wasteful when prescribed to everyone.

Moreover, these health boards prove that policy makers know they’ll need to ration care but want to absolve themselves of responsibility. Some in Congress and the Obama administration recently tipped their hand on this goal by proposing to make recommendations of the current Medicare Payment Advisory Committee (MedPAC) legally binding rather than mere advice to Congress. Any new health board’s mission will also expand over time, just as MedPAC’s mandate grew to encompass medical practice issues not envisioned when it was created.

The idea of an omnipotent board that makes unpopular decisions on access and price isn’t a new construct.

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It’s a European import. In countries such as France and Germany, layers of bureaucracy-like health boards have been specifically engineered to delay the adoption of new medical products and services, thus lowering spending.

In France, assessment of medical products is done by the Committee for the Evaluation of Medicines.

Reimbursement rates are set by the National Union of Sickness Insurance Funds, a group that also negotiates pay to doctors.

In Germany, the Federal Joint Committee regulates reimbursement and restrictions on prescribing, while the Institute for Quality and Efficiency in Healthcare does formal cost-effectiveness analysis. The Social Insurance Organization, technically a part of the Federal Joint Committee, is in charge of setting prices through a defined formula that monitors doctors’ prescribing behavior and sets their practice budgets. In the past 12 months, the 15 medical products and services that cleared this process spent an average 35 months under review. (The shortest review was 19 months, the longest 51.)

In short, other countries where government plays a large role in healthcare aren’t shy about rationing.

President Obama’s budget director has acknowledged that rationing reduces costs. Peter Orszag told Congress last year when he headed the Congressional Budget Office that spending could be “moderated” if “diffusion of existing costly services were slowed.”

Medicare can already be painstakingly slow.

Appealing to it takes patients an average 21 months, according to a 2003 Government Accountability Office report (17 months involve administrative processing). Layers of commissions and health boards would delay access still further.

When asked to judge the constitutionality of the Senate HELP Committee proposal, there’s a reason why the nonpartisan Congressional Research Service said that the proposed Medical Advisory Council “raises potentially significant constitutional concerns.” Our Founders thought politicians should be accountable when it comes to citizens’ right to life, liberty, and the pursuit of heart surgery. ■

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Predictive and Prognostic Models: Implications for Healthcare Decision-Making in a Modern Recession F. Randy Vogenberg, RPh, PhD Various modeling tools have been developed to address the lack of standardized processes that incorporate the perspectives of all healthcare stakeholders. Such models can assist in the decision-making process aimed at achieving specific clinical outcomes, as well as guide the allocation of healthcare resources and reduce costs. The current efforts in Congress to change the way healthcare is financed, reimbursed, and delivered have rendered the incorporation of modeling tools into the clinical decision-making all the more important. Prognostic and predictive models are particularly relevant to healthcare, particularly in the clinical decision-making, with implications for payers, patients, and providers. The use of these models is likely to increase, as providers and patients seek to improve their clinical decision process to achieve better outcomes, while reducing overall healthcare costs. [AHDB. 2009;2(6):218-222.]

T

he decision-making process in many aspects of the healthcare delivery system is often complicated and detailed, requiring many considerations before arriving at a course of action in patient care. Increasingly today, the perspectives of each healthcare stakeholder should be considered, which often leads to confusion and controversy in decisionmaking. For example, what is of value to a patient may not be of value to a provider, and what medical evidence determines to be of value may be very limited or subject to interpretation because of the paucity of definitive evidence. These differences in the interpretation of a treatment value contribute to decision-making controversy and confusion among participating stakeholders, which is further inflamed by third-party coverage guidance. Inefficient decision-making is further compounded by a lack of standardized processes that fully address the perspectives of multiple stakeholders.

Various modeling tools have been devised to assist with the decision-making process. Some are aimed at predicting a clinical outcome, whereas others focus on identifying patients who may be at risk for the development of a particular condition.

There are usually no “general” models used; each desired result is obtained by the use of a modeling tool that is specifically tailored to the circumstance at

Dr Vogenberg is Principal, Institute for Integrated Healthcare, Sharon, MA, Adjunct Instructor, University of Rhode Island, College of Pharmacy, Kingston, RI, and Senior Fellow, Jefferson School of Population Health, Philadelphia, PA.

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hand.1 These prognostic and predictive mathematical camps, believers, or classes are created using formulas that are theoretically capable of assisting in the decision-making to achieve specific outcomes that could help guide allocation of resources in healthcare. Two such examples are prognostic and predictive models.1,2

Prognostic Modeling and Clinical Outcomes It is important to be able to predict future outcomes of diseases and/or treatments. In the past, such estimates were typically at the discretion of the clinician and were based on the provider’s individual experience and professional opinion. The prognostic model has been devised to assist clinicians and other providers in making more accurate predictions based on information garnered in the present. Prognostic models are statistical tools that predict a clinical outcome based on at least 2 points of patient data.2 Prognostic models are based on prognostic information that generally addresses the patient rather than the disease or treatment. Examples include statements that predict chance or duration of survival, progression of disease (how the patient is expected to progress in the scope of disease—from low- to high-risk group, not from precancer to cancer), and prediction of certain clinical events related to therapy or treatment response (eg, patient not likely to respond to a chosen treatment).3 Prognosis is heavily reliant on other inherent aspects of clinical management, including the initial diagnosis, as well as the prescribed therapy and skills of the clinician. Prognosis is driven by several character-

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istics: for example, a patient’s prognosis is strongly tied to the specific diagnosis (ie, benign prostatic hyperplasia vs prostate cancer), as well as to the therapeutic treatment decisions (watchful waiting vs surgery).

Prognostic models have many uses, including “guiding healthcare policy by generating global predictive scenarios; determining study eligibility of patients for new treatments; selecting appropriate tests and therapies in individual patient management including supporting decisions on withholding or withdrawing therapy.”4 The 2 main types of prognostic models are (1) those at the patient population level, and (2) those at the individual patient level. Patient population models focus on recognizing trends or discrepancies in groups of patients for a specific criterion, whereas individual patient models are used to govern treatment advice and provide patient-centered consultation.4 Prognostic models are normally used to make the best possible choices for a patient or group of patients with regard to a specific clinical scenario. Before a model is used in clinical practice, there must be sufficient evidence to ascertain that it is an appropriate tool applicable to the current situation. Therefore, evaluation of the model is important. The 2 main types include (1) laboratory evaluation, which is concerned with the statistical performance of the model, and (2) clinical evaluation, which aims to determine if the model can effectively address a clinical scenario (ie, if it is clinically effective, not just statistically effective— its “real-world” effectiveness).3 In addition, “For a prognostic model to be clinically useful, it should fulfill 2 requirements: it must be clinically valid and methodologically valid.”2 Many factors must be considered in the development of prognostic models to ensure their validity. The model should be user-friendly, so that a clinician can easily draw conclusions applicable to his/her patient’s situation. It should also include large sample sizes, to ensure precise measurements; and clinicians should be involved in a discussion of clinically relevant predictors that may affect prognosis.2 Prognostic models have evolved from the use of simple decision rules to guide therapy into complex mathematical formulas developed based on large population databases. For example, the pneumonia severity index (PSI) is a statistically derived prognostic model developed with patient database information.5,6 The PSI can be used by physicians to stratify patients with community-acquired pneumonia (CAP) as having a high risk or a low risk of death.5,6 The initial PSI model predicted 2.4 times more deaths from CAP than actually

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KEY POINTS u

The healthcare decision-making process is often complicated and inefficient, compounded by the need to consider a host of stakeholders. u The current efforts in Congress to change the way healthcare is financed, reimbursed, and delivered have rendered the use of the modeling tools all the more important for clinical decision makers. u Although often relegated to research only, applying prognostic and predictive models in the clinical process can enhance patients’ and providers’ ability to make the best clinical decisions. u With costs today heavily influencing benefit decisions of employers and other payers, the ability to predict outcomes becomes all the more important. occurred in practice.7 The model was recalibrated and has since been validated with the caveat that the PSI may not apply to all patients with CAP.7 Early experience with the PSI model alerted the medical community that statistically derived models are only as accurate as the data they are based on and may not apply to all institutions.

Concerns with published prognostic models include clinical credibility and evidence of accuracy, effectiveness, and generality.8 To ensure clinical credibility, certain criteria must be met8: • Clinicians should be able to easily obtain the data required in a matter timely enough to make their prediction • Calculations should be simple to allow the clinician to generate the prediction (algorithms are more useful than data entry) • Relevant patient data should have been tested for model inclusion.

The accuracy of the prognostic model should also be apparent, otherwise clinicians will have no confidence in using this tool; therefore, the model should have a low incidence of false-negative and false-positive results.8 The generality of the model should be readily discernible, to assure clinicians that it can be applied from one population to another. This entails that the model has been tested separately, at another time and place, on a different test set. Finally, there should be evidence of clinical effectiveness, perhaps from well-documented clinical trials that exhibit the accuracy of the model.5

Predictive Modeling and Cost Management Healthcare costs are increasing, a problem that is further compounded by our current economic crisis.6,7

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In response, employers and health plans alike are frantically searching for ways to reduce cost. Predictive modeling has become a popular way to assess and manage costs associated with healthcare. This modeling is used for the identification of patients at high risk for certain conditions and implementing interventions to prevent them from becoming high-cost.9 Predictive modeling is accomplished through risk assessment to determine susceptibility of a patient/ employee population to a specific condition.10 The value of such endeavors can be seen in successful identification of at-risk populations. This gives employers or health plans access to information that allows early identification of risk and appropriate and timely preventive actions.

Predictive modeling has been defined by Jonathan Weiner of Johns Hopkins Bloomberg School of Public Health as “a process that applies available data to identify persons who have high medical need and are ‘at risk’ for above-average future medical service utilization.”11 The availability of large amounts of data is critical for the development and effective implementation of a predictive model. These data are derived from pharmacy and medical claims and include diagnosis codes, demographic data, previous claim history, and laboratory results.

These information sets are analyzed by predictive models, which can use the data to identify cases that may move into a high-cost category in the future.11 Once the model does its job and identifies at-risk groups, action plans can be instituted by the employer or the health plan to manage their health.

The core “competency” of predictive modeling is its proactive nature; that is, not taking a reactive approach to disease management and cost containment but instead identifying trends and forecasting events that may have substantial implications for healthcare stakeholders. The 2 main categories of predictive modeling include (1) medical data–based models, and (2) prescription drug–based models. Medical data–based models contain clinical data from all sites of service; these are considered to have the highest predictive power of all models, meaning that they are most effective models for forecasting consumption of healthcare by a given population.12 The medical data that these models rely on, however, can take a substantial amount of time to become available electronically (12 months or more), whereas prescription drug–based data are available within 2 months.12 Generally speaking, the current disease burden of a population is most accurately represented by

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the most recent data. Prescription drug–based models are also advantageous in that prescription data are much easier to obtain than medical data from the exact same population, because of the variety of medical claims submitted for a patient each year, on both an inpatient and outpatient basis, whereas prescription drug data only require 1 database.12,13 The key principles that should be considered when implementing a predictive model include14: • A focus on total population and addressing of the entire spectrum of healthcare • Emphasis on behavioral change on a long-term scale • Creation of programs that are driven by data and aimed at addressing individual risk, learning, and health status • Supportive health plan designs with incentives.

When such criteria are met, predictive modeling is a valuable tool for employer plans in decreasing overall healthcare costs, while encouraging adherence to evidence-based medicine.

Predictive modeling has been successfully applied to identifying undiagnosed diabetes, predicting survival after in-hospital cardiopulmonary resuscitation, and determining which combat casualties are likely to require massive blood transfusions.15-17

Implications to Various Stakeholders The Regulatory Process In the current financial liquidity restraint and investment uncertainty, principally because of the economic recession, a volatile environment across stakeholders around the complexities of decision-making in the US healthcare has ensued. Congress passed funding for comparative effectiveness research in February 2009, has entered the healthcare reform debate in March 2009, and has begun the process to seek change in the way healthcare is financed, reimbursed, and delivered to the American public. This has made the choice of modeling tools all the more important for clinical decision makers.

The Patient’s Perspective From a patient point of view, tools that place an emphasis on health and outcomes are desirable. When diagnosed with a particular disease or disorder, questions of utmost importance spring to mind: How much time is left for me? How do I manage this condition?

What is my prognosis? Prognostic models can best address these concerns. This type of a model has become even more important in light of the economic recession, as patients are basing their treatment deci-

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sions more heavily on the cost that will be incurred.18 When used correctly, prognostic models can provide patients with more accurate and detailed information about their condition, allowing them to make more educated decisions about whether to undergo certain treatments or pursue other alternatives. For example, when a clinician uses a prognostic model and estimates a patient’s survival time as only 2 months, the patient may choose to forgo expensive chemotherapies and instead enroll in an end-of-life care program. Utilizing such effective tools to aid in clinical decision prognosticating, in combination with financial information, can result in a better-informed decision today about a treatment tomorrow.

The Payer’s Perspective What may be in the best interest of the patient is not necessarily viewed as the best course of action for an employer or a health plan. Cost, and the ability to recognize the potential for patients to move into a higher expense category, is a driving factor of significant influence to healthcare administrators.10,19 With such concepts heavily influencing the decisions of benefit providers, the ability to predict outcomes becomes all the more important, especially during the current economic downturn. Predictive models allow health plans and employers to identify at-risk patients and forecast their impact on health spending. This early recognition begets early action, so that data compiled and analyzed by the predictive model can serve as a catalyst for change and a basis for devising an action plan resulting in reduced expenditures.

The Provider’s Perspective Clinicians’ perspectives must also be considered.

The ability to properly diagnose and manage disease is an invaluable skill yet is not always held to a uniform standard.20 Differences in professional opinion among healthcare providers, as well as a general lack of trust in the applicability of current modeling tools, have created a barrier to a widespread use of clinical decisionmaking aids. Prognostic models, although often maligned, can be a valuable asset to clinicians when properly designed and implemented.

In the current economic climate, there is increasing pressure on providers to prescribe not only the most effective therapies but also to control costs for all stakeholders involved. Ideally, prognostic models can be of asset to clinicians and other healthcare providers by allowing them to recognize a specific disease or chart its course more accurately, enabling them to save valuable

time and money by selecting the appropriate treatments and action plans with more confidence, without wasting resources on testing procedures and therapies that have not been proved effective in evidence-based guidelines. If the design of prognostic models is streamlined so that their applicability and accuracy is more readily apparent to providers, their use may become more widespread, potentially decreasing total health expenditures through the use of more appropriate and cost-effective therapies.

From Research to Clinical Practice Prognostic and predictive models are primarily kept in the domain of research and only a handful have found wider acceptance for adoption to clinical practice. The adoption of a prognostic or a predictive model is largely dependent on the ease of use and generalizability of the model in terms of its clinical applicability or effectiveness.

There is danger in moving too quickly to use these models without appropriate validation and understanding of their limitations. As the public and clinical decision makers seek better tools to determine the relative value of a clinical choice, it is equally important to seek the use of reasonable tools that do not misrepresent the information needed to make an informed decision about their spending for medical care.

Conclusions Decision-making in healthcare is a confusing and involved process. This is compounded by the current condition of the US economy. Prognostic and predictive models have been devised to assist in the patient care decision-making. Each model has a particular purpose, strengths and weaknesses, and individual appeal to different healthcare stakeholders. A model is limited in its application in the way in which it can be used in clinical practice. In some cases, models may not be used for clinical practice directly; instead, they may be used indirectly to drive quality measures retrospectively. In light of the weakened economy, the implications of using either or both predictive and prognostic models have become all the more important. Their use, although still varied and controversial, may increase, as providers and patients alike seek to better understand clinical choices or options that may also reduce overall healthcare costs. ■ Acknowledgment The author wishes to acknowledge the editorial and literature research assistance provided by Stephen Cutts, PharmD, University of Rhode Island, College of Pharmacy.

Continued

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References 1. den Boer S, de Keizer NF, de Jonge E. Performance of prognostic models in critically ill cancer patients—a review. Crit Care. 2005;9:R458-R463.

2. Perel P, Edwards P, Wentz R, Roberts I. Systematic review of prognostic models in traumatic brain injury. BMC Med Inform Decis Mak. 2006;6:38.

3. Cook NR. Statistical evaluation of prognostic versus diagnostic models: beyond the ROC curve. Clin Chem. 2008;54:17-23.

4. Abu-Hanna A, Lucas PJ. Prognostic models in medicine: AI and statistical approaches. Methods Inf Med. 2001;40:1-5.

5. Fine JM, Hanusa BH, Lave JR, et al. Comparison of a disease-specific and a generic severity of illness measure for patients with communityacquired pneumonia. J Gen Intern Med. 1995;10:359-368.

6. Fine JM, Singer DE, Hanusa BH, et al. Validation of a pneumonia prognostic index using the MedisGroups Comparative Hospital Database. Am J Med. 1993;94:153-159.

7. Flanders WD, Tucker G, Krishnadasan A, et al. Validation of the pneumonia severity index. Importance of study-specific recalibration. J Gen Intern Med. 1999;14:333-340.

8. Wyatt JC, Altman DG. Prognostic models: clinically useful or quickly forgotten? BMJ. 1995;311:1539-1541 [Commentary].

9. Justice AC, Covinsky KE, Berlin JA. Assessing the generalizability of prognostic information. Ann Intern Med. 1999;130:515-524.

10. National Cancer Institute. Costs of Cancer Care. Cancer Trends Progress Report–2007 Update. http://progressreport.cancer.gov/doc_detail.asp? pid=1&did=2007&chid=75&coid=726&mid. Accessed November 21, 2008.

11. Fuhrmans V. Consumers cut health spending, as economic downturn takes toll. The Wall Street Journal. September 22, 2008. http://

online.wsj.com/article/SB122204987056661845.html. Accessed November 21, 2008.

12. HealthNEWS.Direct! Predictive modeling tools make further progress in healthcare. www.healthnewsdirect.com/?p=63. Accessed December 6, 2008.

13. Mahoney J. Value-based benefit design: using a predictive modeling approach to improve compliance. J Manag Care Pharm. 2008;14(6 suppl B):3-8.

14. Carlson B. Predictive modeling, sharp lens on near future. Manag Care. 2003;12:16-21.

15. Baan CA, Ruige JB, Stolk RP, et al. Performance of a predictive model to identify undiagnosed diabetes in a health care setting. Diabetes Care.

1999;22:213-219.

16. Danciu SC, Klein L, Hosseini M, et al. A predictive model for survival after in-hospital cardiopulmonary arrest. Resuscitation. 2004;62:35-42.

17. McLaughlin DF, Niles SE, Salinas J, et al. A predictive model for massive transfusion in combat casualty patients. J Trauma. 2008;64(2 suppl):S57-S63.

18. Noble L. Pros and cons of predictive modeling approaches. Healthc Financ Manage Assoc. November 3, 2004. www.hfma.org/publications/ know_newsletter/archives/110304.htm. Accessed November 21, 2008.

19. Silva C. “Employers investigating predictive models to cut health care costs.” Employee Benefit News. http://ebn.benefitnews.com/asset/ article/536761/employers-investigating-predictive-models-cut-health. html. Accessed November 21, 2008.

20. McAlister FA, Graham I, Karr GW, Laupacis A. Evidence-based medicine and the practicing clinician. J Gen Intern Med. 1999;14:236-242.

STAKEHOLDER PERSPECTIVE Potential Benefits of Prediction Models from Large Electronic Databases PAYERS/PROVIDERS: As discussed in the article, prediction modeling has the potential to benefit multiple stakeholders. With large electronic databases of clinical information now readily available, risk classification no longer needs to rely strictly on a single diagnostic test or summary score of a few key variables. Electronic health records (EHRs), for example, could be used as a source for building the models and for prospectively alerting physicians to high-risk individuals. Longitudinal data from EHRs include large amounts of information, such as demographics, health behaviors, clinical diagnoses and measures, laboratory results, prescriptions, and care utilization. Even skilled specialists may not have the time or ability to recognize signals from the collective risk factors. But as vast amounts of digital data have become available, powerful new classification techniques have been developed.

Prediction models from large clinical databases present an opportunity to move toward learning healthcare systems, where patient data contribute to evidence creation and individualized care. As this research area progresses, it is important to not just show the academic value of these models for predic-

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tive accuracy but also to provide evidence of benefit to the many healthcare stakeholders.

Consider the following example. Heart failure, a common and serious progressive illness, is often diagnosed at a relatively advanced stage, leaving few options to slow progression. If prediction models could successfully identify the disease earlier, these patients could be aggressively treated, potentially changing the course of the disease.

However, the true value of the model would need to be established, perhaps by randomizing physicians into intervention and control groups. The intervention group would receive an alert whenever one of their patients is classified as high risk based on the prediction model. Patient outcomes and costs could be compared between the groups, and physicians could be surveyed about their satisfaction with technology. If the results are favorable, the next step would be widespread implementation in the health system.

Jason Roy, PhD Department of Biostatistics and Clinical Epidemiology University of Pennsylvania, Philadelphia

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Estimates of Commercial Population at High Risk for Cardiovascular Events: Impact of Aggressive Cholesterol Reduction Kathryn Fitch, RN, MEd; Sara W. Goldberg, FSA, MAAA; Kosuke Iwasaki, FIAJ, MAAA; Bruce S. Pyenson, FSA, MAAA; Andreas Kuznik, PhD; Henry A. Solomon, FACP, FACC Objectives: To model the financial and health outcomes impact of intensive statin therapy compared with usual care in a high-risk working-age population (actively employed, commercially insured health plan members and their adult dependents). The target population consists of working-age people who are considered high-risk for cardiovascular disease events because of a history of coronary heart disease.

Study Design: Three-year event forecast for a sample population generated from the National Health and Nutrition Examination Survey data.

Methods: Using Framingham risk scoring system, the probability of myocardial infarction Kathryn Fitch or stroke events was calculated for a representative sample population, ages 35 to 69 years, of people at high risk for cardiovascular disease, with a history of coronary heart disease. The probability of events for each individual was used to project the number of events expected to be generated for this population. Reductions in cardiovascular and stroke events reported in clinical trials with aggressive statin therapy were applied to these cohorts. We used medical claims data to model the cohorts’ event costs. All results are adjusted to reflect the demographics of a typical working-age population.

Results: The high-risk cohort (those with coronary heart disease) comprises 4% of the 35- to 69-year-old commercially insured population but generates 22% of the risk for coronary heart disease and stroke. Reduced event rates associated with intensive statin therapy yielded a $58 mean medical cost reduction per treated person per month; a typical payer cost for a 30-day supply of intensive statin therapy is approximately $57.

Conclusions: Aggressive low-density lipoprotein cholesterol–lowering therapy for working-age people at high risk for cardiovascular events and with a history of heart disease appears to have a significant potential to reduce the rate of clinical events and is cost-neutral for payers. [AHDB. 2009;2(6):224-232.]

C

ardiovascular disease (CVD) is the leading cause of morbidity and mortality in the United States. The estimated direct and indirect cost of CVD for 2008 is $448.5 billion.1 CVD ranked highest among all disease categories for hospital discharges and was the most frequent primary diagnosis coded for physician, outpatient, and emergency department visits.1 Hypercholesterolemia, particularly elevated lowdensity lipoprotein cholesterol (LDL-C), is strongly

Ms Fitch is Principal and Healthcare Management Consultant, Ms Goldberg is Consulting Actuary, Mr Iwasaki is Consulting Actuary, and Mr Pyenson is Principal and Consulting Actuary, Milliman, New York, NY. Dr Kuznik is Associate Director of Outcome Research, and Mr Solomon is Medical Director, Pfizer Global Pharmaceuticals, New York, NY.

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associated with an increased risk of CVD, including coronary heart disease (CHD) events (ie, myocardial infarction [MI], angina, coronary revascularization) and stroke.2-4 Landmark statin studies targeting LDL-C lowering have shown dramatic reductions in heart attacks, stroke, and cardiac death.5-14 More recent studies have shown that intensive reduction of LDL-C levels in high-risk individuals with a history of CHD is associated with an even greater reduction in CVD events than conventional LDL-C lowering.7-9 Although aggressive LDL-C therapy resulting in positive patient outcomes has been well documented, reports continue to find inadequate LDL-C therapy and poor compliance with statin therapy.15-17 Employers and commercial insurers bear significant medical cost and productivity burdens associated with undertreat-

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ment of hypercholesterolemia and poor compliance with statins, particularly for the high-risk population.

Although studies have reported cost-effectiveness associated with statin therapy,18-23 none has reported the cost burden in terms relevant to an employer or a health plan, such as per member per month costs.

Specifically, reports lack outcomes adjusted to a working-age population. Many studies report cost-effectiveness utilizing quality-adjusted life-years, which provides information of limited utility for employers and payers.

A more meaningful approach may be to provide costeffectiveness in terms that would allow employers and payers to project short-term impact on medical utilization and costs for budgetary purposes. Other studies report cost-effectiveness using LDL-C reduction and unit drug costs across statins, without considering the impact of CVD event reduction cost offsets.

Our analysis models the cost impact of aggressive statin therapy for a commercially insured cohort of members at high risk for secondary events from CVD as a result of a history of CHD. This group represents an important subset of working-age health plan members for a commercial insurer. Using this newly developed model, we compare the CVD event and cost burden under conventional current therapy to represent the results of intensive statin therapy, which is the current standard of care for high-risk patients.

Disease management efforts by employers and other payers that are focused on commercial members with CHD can represent a substantial financial investment.

Such efforts seek to identify and provide early clinical intervention to improve outcomes in populations at risk for adverse events. Therefore, individuals with a history of CHD are targeted for disease management programs, because payers believe that such interventions can avoid various complications, including stroke and secondary events (eg, acute MI). However, the claims of improved outcomes of disease management vendors have received significant criticism.24,25 In particular, the range of improved outcomes demonstrated by applying the results of intensive statin therapy to this population can suggest plausible maximum improvements from disease management programs.

In addition, employers and insurers are experimenting with benefit designs, such as lower copayments or other financial incentives to maximize drug compliance for those with chronic diseases. Studies consistently report decreased statin compliance with higher copayments.26-29 The present article offers guidance to such experiments on the potential health and cost improvements possible through various initiatives.

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KEY POINTS u

u

u

u

u

This actuarial study highlights the potential costsavings for employers and payers with the use of intensive cholesterol-lowering therapy in people with coronary heart disease.

This study calculates cost-effectiveness in terms that facilitate projections of short-term impact on medical utilization and costs.

The target population is commercially insured people aged 35 to 69 years who have a high risk for cardiovascular/cerebrovascular events.

Results suggest that in these high-risk patients, intensive lipid-lowering therapy, would result in a 33% overall reduction in events.

This risk reduction would result in incremental average cost reductions of $58 per target patient per month, a $696 annual reduction per target patient.

Using the National Health and Nutrition Survey (NHANES) 2003-2004 and 2005-2006 survey data, we identified the target population of people at high risk for CVD who had a history of CHD. NHANES is a survey of healthcare information for US residents readily available from the National Center for Health Statistics and the Centers for Disease Control and Prevention. It is designed to provide reliable estimates of the health and nutritional status of the US civilian noninstitutionalized population.30

Target Population Our target population intentionally closely resembles the sample in the Treating to New Targets (TNT) study,8 which consisted of individuals with a history of CHD who are at high risk for CVD events. High risk for CVD as used here is based on the high-risk National Cholesterol Education Program (NCEP) III criteria,31 which include a history of CHD (ie, MI, unstable angina, stable angina, coronary artery procedures), diabetes, or stroke, and patients with >20% 10-year Framingham risk for CHD, combined with 2 or more of the following risk factors: • Cigarette smoking • Hypertension (blood pressure ≥140 mm Hg systolic or ≥90 mm Hg diastolic, or taking an antihypertensive medication) • High-density lipoprotein cholesterol <40 mg/dL • Men ≥45 years • Women ≥55 years • Family history of premature CHD.

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The Appendix (page 231) contains the NHANES survey examination fields used to identify individuals with high-risk criteria.

The population identified includes 2386 people aged 35 to 69 years in NHANES 2003-2006. Of these, 133 met TNT-like criteria for high CVD risk and a history of CHD. Because the NHANES data do not allow precise selection based on the TNT criteria, some NHANES participants who would have matched TNT criteria were likely omitted. We applied the NHANES portions of treatment target lives by quinquennial agegroups and sex to a population of 10,000 employees and 4721 spouses who had large employer-sponsored health coverage. The demographics of a working-age population are taken from Milliman’s 2008 Health Cost Guidelines,32 which is designed to represent the demographics of a typical large, employer-sponsored health benefit program.

Extrapolating this target population to an employer with 10,000 employees yields 256 men and 187 women (aged 35-69 years) at high risk for CVD who have a history of CHD. The Table in the Appendix displays the individual distributions by age and sex. The target population, with an average age of 53.5 years, is about 7 years older than the cohort of all 35- to 69-year-old persons in a working-age population (plus dependents).

The target population is more likely to have a history of diabetes (32% vs 9%) or hypertension (32% vs 18%) than the total population of that age-group. Of the target population, 55% was receiving statins according to the NHANES drug file.

Methods Using the Framingham risk scoring system,33-35 we calculated the probability of MI and stroke for each patient in the target population. The 3-year period used in this study reflects a compromise between a long-term study and the short-term horizon of many employee benefit managers.

To model the impact of intensive statin therapy for the target population, we applied the reduction in CHD and stroke events reported in the TNT study8 and in the Heart Protection Study (HPS).7 The TNT study compares the results of 80-mg and 10-mg atorva statin treatment arms. It was assumed that those in the target population who were receiving statin therapy were currently being treated with conventional statin therapy and were achieving outcomes similar to the 10mg atorvastatin arm. For those currently receiving statins, an additional event reduction shown for the 80-mg arm compared with the 10-mg arm was applied:

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22% (7%-34%, 95% confidence interval [CI]) for CHD and 25% (4%-41%, 95% CI) for stroke.

To model the impact of intensive statin therapy for those not receiving a statin, the event reduction of the 80-mg arm over the 10-mg arm in the TNT study was applied. In addition, the results of the HPS, which compared 40-mg simvastatin to placebo,7 was applied. The HPS reductions of 38% (30%-46%, 95% CI) for CHD and 25% (15%-34%, 95% CI) for stroke, combined with the TNT study reductions, produced reductions of 52% for CHD and 44% for stroke, and were applied for individuals not currently receiving statin therapy.

The HPS population closely resembled that of the TNT study, and we assumed that the event reductions in the TNT study for the 10-mg atorvastatin arm would be similar to the event reductions in the HPS 40-mg simvastatin arm, based on LDL-C reductions reported in each study, as well as other results.36 To quantify the cost impact of intensive statin therapy for a working-age population, we applied data queries to Medstat MarketScan 2003-2007 claims data.37 Medstat contains paid claims generated by more than 14 million commercially insured lives across the United States. Because our model uses the reduction in CVD events among target high-risk individuals as the driver of reduced costs, we identified costs of people with CVD events who also had diabetes, because other characteristics of the target population are not readily identifiable in claims. The following International Classification of Diseases, Ninth Revision (ICD-9) and Current Procedural Terminology (CPT-4) codes were used to identify individuals with a history of CVD events: stroke (ICD-9 code: 430.x, 431.x, 432.x, 433.x1, 434.x1); MI (ICD-9 code: 410.x0, 410.x2); coronary artery bypass graft (CPT code: 33510-33514, 33516-33519, 33521-33523); coronary angioplasty (CPT code: 33533-33536, 35600, 33572, and ICD-9 procedure code 36.1, 36.2x); and percutaneous transluminal coronary angioplasty (CPT code: 33140, 92980-92982, 92984, 92995, 92996, and ICD-9 procedure code: 36.01, 36.02, 36.05, 36.09).

Costs were applied to each individual based on average annual historic per-person medical claim costs, developed separately by sex by 5-year age bands for each CVD event. The event costs (costs during the year of an event) and costs incurred in the 2 years after an event populated a longitudinal cost model for people having an event. Baseline costs for individuals in the year before a CVD event served as a “background” cost. All costs were projected to 2008 levels, using industry trends from the 2008 Milliman Medical Index.38 Distinct costs were not applied to events that result-

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Table 1 LDL-C Goals and Number of Patients Not at Goal, by Risk Category Commercial Persons not at Risk level populationa LDL-C goal LDL-C goal 4.2% <100 mg/dL 73% High risk, (therapeutic (95%) history of option 70 mg/dL) CHD High risk, no history of CHD

9.4%

<100 mg/dL (therapeutic option 70 mg/dL)

70% (95%)

Moderately high risk

5%

<130 mg/dL

60%

Moderate risk

12%

<130 mg/dL

29%

Low risk

69%

<160 mg/dL

12%

NCEP guidelines applied to NHANES. CHD indicates coronary heart disease; LDL-C, low-density lipoprotein cholesterol; NCEP, National Cholesterol Education Program; NHANES, National Health and Nutrition Examination Survey.

ed in death. The costs include contributions from a small number of people with multiple events. However, the model assumes that a person could have, at most, one type of CVD event (ie, stroke, MI without revascularization, MI with revascularization, or revascularization without MI) over the 3-year model period.

Two distinct scenarios were modeled: a “current status” and a “therapy” scenario. The current status assumes that the current risk, treatment status, and costs continue throughout the 3-year time period modeled, while the therapy scenario assumes individuals with a history of CHD and a high risk for CVD events and receive the additional therapies specified in the TNT and HPS studies.

Results Analysis of the NHANES 2003-2006 data identifies 4.2% of patients in the 35- to 69-year-old age-group at high risk for CVD and with a history of CHD. Based on statin studies subsequent to the 2002 NCEP III guidelines, updated guidelines have set a therapeutic option of LDL-C <70 mg/dL for high-risk individuals, and some experts recommend the use of intensive statin therapy for all high-risk patients, even when LDL is <100 mg/dL.31 Only 55% of patients in the high-risk cohort with a history of CHD were taking a statin, although 95% were above LDL-C goal (considering the <70 mg/dL therapeutic option). Table 1 provides the distribution of 35 to 69 years old by risk category, NCEP III–updated

I

Risk level Patients, N Population 443 4.2% High risk, with CHD 985 9.4% High risk, no CHD 8998 86.3% Other than high risk 100% Total 10,426a

CHD/stroke CHD/stroke events, N events 49

22%

40

17%

138

61%

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Table 2 CHD/Stroke Risk Is Concentrated in High-Risk Patients with CHD

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Those aged 35-69 years, a subset of the total population of 10,000 employees and 4721 adult dependents.

CHD indicates coronary heart disease.

LDL-C goals, and portion of each cohort above NCEP III–updated goals.

Using the Framingham risk score and NHANES data, the probability of a CHD event or a stroke during 3 years was calculated for each patient. Table 2 presents the number of CHD events and strokes that occurred in the study cohort drawn from a typical working-age population of 10,000 employees and their 4721 dependents. The risk for CHD and stroke is concentrated disproportionately in the target population, which comprises just 4.2% of the 35- to 69-year-old commercial population but is responsible for 22% of the CHD and stroke risk.

Based on the Framingham risk scoring system, the 3year risk for stroke and CHD in the target population is 2.3% and 9.9%, respectively. If all high-risk patients with CHD were to receive intensive lipid-lowering therapy, stroke and CHD events in an employer population of 10,000 employees and 4721 dependents would be reduced from 49 events to 33 events, a 33% overall reduction. Table 3 illustrates the reduction under both current status and therapy scenarios and presents a range of event reduction based on the CIs reported in the TNT and HPS studies.

To estimate the cost impact of the reduced number of events, we applied event costs calculated from our Medstat analysis. The applied CHD costs used the database’s cost and distribution of MI with revascularization, MI without revascularization, and revascularization without MI identified in Medstat. Table 4 presents the costs in the year before the event, the event year, and the costs in the 2 years after the event. These costs reflect payer paid claims dollars and exclude member cost-sharing. Costs before the event vary by event type, which we postulate reflects differential patient risk characteristics.

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Table 3 Event Reduction with Aggressive Statin Therapy in Target Population Current status: no change Therapy scenario: from current intensive statin Events statin therapy therapy

Table 5 Medical Cost Reduction with Intensive Therapy CHD

Incremental cost per event Event reduction per 3 years, N Total cost reduction

Probability Strokea of an event during 3 years for target CHD events: population heart attack and revascularization Number of stroke + CHD events for target population

2.3%a

1.6% (95% CI, 1.3%-2.2%), a 30% reduction

Cost reduction per target person per month

(95% CI, 8%-47%) 9.9%

49

6.6% (5.4%-8.2%), a 33% reductionb (95% CI, 17%-45%)

$841,594 (95% CI, $442,000-$1,154,000)a $53 (95% CI, $28-$72)a $53,065

Events reduction per 3 years, N

1.6 (95% CI, 0.4-2.4)

Total cost reduction

$83,188 (95% CI, $22,000-$128,200)

Cost reduction per target person per month

Stroke reduction rate applies only to people aged 55-69 years, because Framingham stroke risk applies to people age ≥55 years. b Intensive statin therapy impact modeled using Treating to New Targets study and Heart Protection Study. Targeted population: high-risk patients with CHD aged 35-69 years, a subset of the total population of 10,000 employees and 4721 adult dependents.

14 (8-20)a

Stroke Incremental cost per event

33 (95% CI, 27-41)b

a

$58,077

CHD + Cost reduction per target stroke person per month

$5 (95% CI, $1-$8) $58 (95% CI, $29-$80)

a

95% confidence interval from Table 2 applied to events and costs.

CHD indicates coronary heart disease; CI, confidence interval.

CHD indicates coronary heart disease; CI, confidence interval.

Table 4 National Average Annual Cost of Events Per Patient, Projected to 2008 Before Event type event, $ Myocardial infarction 10,028 with revascularization Myocardial infarction, 24,634 no revascularization Revascularization, no 26,150 myocardial infarction 13,780 Stroke

Event 1 year after 2 years after year, $ event, $ event, $ 74,333

25,067

22,468

74,966

37,886

37,918

72,446

34,642

30,113

56,028

26,105

21,579

Costs in particular geographic regions vary from the national averages. Milliman’s 2008 Group Health Insurance Survey of preferred provider organization plans with highest and lowest cost regions vary by up to ± 11% to 12% from the national average.39 For a particular payer, costs can fall above or below this range, depending on negotiated reimbursement or local patterns, and costs for particular patients can be even more variable.

Incremental costs net the costs from the year before the event, from the year of the event, and the 2 subsequent years. Table 5 presents estimated incremental event costs for the 3 years after the events, based on

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Table 4, using equal probability of an event in all 3 years.

Incremental costs were applied to the number of events reduced over 3 years and calculated as an average $58 (95% CI, $29-$80) per target member per month reduction, or an annual cost reduction of $696 per target member, assuming intensive statin therapy. This cost reduction does not consider the cost of statin therapy, nor does it consider the potential impact on nonmedical costs, such as disability costs or lost work time.

To estimate how this cost reduction per target member compares against the cost of intensive statin therapy, Medstat 2006 and the first 3 quarters of Medstat 2007 were analyzed to identify claims for atorvastatin 80 mg/day, the dosage used in the TNT study. The average allowed cost for 2006 and for 2007 was $97 for a 30-day supply. Assuming a $25 copayment (2nd tier) and a 15% rebate to the payer/employer, the cost to a payer for a 30-day supply of intensive statin therapy with atorvastatin would be $57. Thus, compared with average medical cost reduction of $58 per target member per month, intensive statin therapy may be costneutral to the payer in this model (Table 5).

Discussion The literature on the cost–benefit relationship of statin therapy includes mention of some cost-effective nonstatin treatments to prevent CVD events, such as aspirin therapy.20,40 In addition, some critics of intensive

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statin treatment point out that the TNT study did not find a reduction in overall mortality in the higher-dose group, and did find persistent elevations in liver aminotransferase levels, raising questions about whether the side-effect risks exceed reported benefits of aggressive treatment for patients with stable CHD.41,42 Of note, potential risk reduction for individuals at low baseline risk may be necessarily small; however, the focus in this analysis is on patients at high CVD risk who have a history of CHD, which intends to provide additional perspective on this controversy.

In addition, the target population is defined by its CVD risk, not solely by its LDL-C level, suggesting a new perspective for consideration.

Patients with a history of CHD at high risk for CV events can be identified in claims data and frequently are identified through routine disease management algorithms. Specific strategies, including data such as dosage, patient prescription fills, and medication possession ratios, can be monitored through claims data and gaps targeted for intervention.

The reported medical cost reduction in our analysis is driven largely by fewer hospital admissions for stroke and CHD events. Disability, lost work time, and replacement costs for workers suffering from these events were not considered. According to the UnumProvident report, CVD was reported as the fifth leading cause of long-term disability, accounting for 8% of disability claims incidence.43 A 2007 report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee indicates that 15% to 30% of stroke patients become permanently disabled, and that stroke is a leading cause of long-term disability in the United States.44 By not considering disability costs, our modeling underestimates the potential cost-savings of intensive statin therapy for stroke prevention.

Landmark statin studies have shown that treatment of hypercholesterolemia with statin therapy significantly reduces the probability of a stroke or a CHD event. This report, although not the first to attempt to quantify the value of intensive therapy,18 presents this information in the context of employer-sponsored benefit plans.

This present analysis did not consider that some individuals in the model cohort generated from NHANES may already be receiving intensive statin therapy, and potential risk reduction would therefore be reduced.

But, this concern is at least partially offset by the assumption that patients in the modeled comparator group who were receiving lower-dose statin therapy were indeed compliant and received the full benefit of the HPS study, which is not likely to be the case.

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Limitations A challenge to the applicability of this model is whether clinical trial results can be replicated in the real-world setting of a health plan. Compliance in the real world may be lower and patients in a clinical trial may receive more attention and be managed more carefully than those enrolled in a health plan.

Another potential limitation is that the target population identified in NHANES may not precisely match the TNT population for characteristics such as age (our population was ages 35-69 years, while TNT was ages 35-75 years) or rates of comorbidities other than CHD. Consequently, this model may reflect the “upper limit” of various CVD event reductions associated with intensive statin therapy and may be used to estimate this maximum potential benefit, with the additional advantage of being practical to implement in the real world of health plan operations.

In addition, the present analysis did not consider that during the 3-year period modeled, aging would increase the size of the target population. Although the TNT and HPS outcomes were based on 4.9- and 5.0year treatment periods, respectively, our analysis uses a 3-year period. And whereas the TNT and HPS studies are well-regarded, our assumption that the results can be used in sequence and additively is not based on clinical trial results.

Finally, the cost figures presented in this article are point estimates of national average costs, although we offer ranges that indicate regional variation. However, a particular payer’s costs may fall outside this range, depending on contractual arrangements. This variation in business practices is distinct from random variation.

Conclusion The present analysis quantifies risk, events, and cost avoidance, with a focus on one of the widely and easily available tools—intensive statin therapy—that superior patient management efforts could bring to the population at high CVD risk. The range of improved outcomes demonstrated by applying intensive statin therapy to this population can suggest plausible maximum improvements in CVD risk reduction.

Information regarding specific program efforts (identification and therapies), outcomes (reduction in CVD events), and net costs (medical and prescription drugs) that can be measured demonstrates that intensive statin therapy for patients with established CHD may ultimately be cost-neutral to the payer. These results offer potential targets to determine the value of disease management programs aimed at populations at high CVD risk.

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Acknowledgment This research was supported by funding from Pfizer.

Disclosure Statement: Ms Fitch, Ms Goldberg, and Mr Pyenson are consultants to Pfizer.

Ms Fitch is also a consultant to Boehringer Ingelheim. Dr Kuznik and Mr Solomon are employed by Pfizer. ■

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Heart disease and stroke statistics—2008 update. Circulation. 2008;117: e25-e146.

2. Castelli WP. Epidemiology of coronary heart disease: the Framingham study. Am J Med. 1984;76:4-12.

3. Kurth T, Everett BM, Buring JE, et al. Lipid levels and the risk of ischemic stroke in women. Neurology. 2007;68:556-562.

4. Greenland P, Knoll M, Stamler J, et al. Major risk factors as antecedents of fatal and nonfatal coronary heart disease events. JAMA. 2003;290: 891-897.

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

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

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

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

9. Cannon CP, Braunwald E, McCabe CH, et al, for the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004; 350:1495-1504.

10. Shepherd J, Blauw GL, Murphy MB, et al, for the PROSPER Study Group. Pravastatin in elderly individuals at risk of vascular disease (PROSPER). Lancet. 2002;360:1623-1630.

11. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). JAMA. 2002;288:2998-3007.

12. Sever PS, Dahlöf B, Poulter NR, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the AngloScandinavian Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOTLLA). Lancet. 2003;361:1149-1158.

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

14. Pedersen TR, Faergeman O, Kastelein JJ, et al, for the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) Study Group. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction. JAMA. 2005;294:24372445.

15. Blackburn DF, Dobson RT, Blackburn JL, et al. Adherence to statins, beta-blockers and angiotensin-converting enzyme inhibitors following a first cardiovascular event. Can J Cardiol. 2005;21:485-488.

16. Parris ES, Lawrence DB, Mohn LA, Long LB. Adherence to statin therapy and LDL cholesterol goal attainment by patients with diabetes and dyslipidemia. Diabetes Care. 2005;28:595-599.

17. Ellis JJ, Erickson SR, Stevenson JG, et al. Suboptimal statin adherence and discontinuation in primary and secondary prevention populations. J Gen Intern Med. 2004;19:638-645.

18. Chan PS, Nallamothu BK, Gurm HS, et al. Incremental benefits and cost-effectiveness of high-dose statin therapy in high-risk patients with

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coronary artery disease. Circulation. 2007;115:2398-2409.

19. Ohsfeldt RL, Ghandi SK, Fox KM, et al. Effectiveness and costeffectiveness of rosuvastatin, atorvastatin, and simvastatin among highrisk patients in usual clinical practice. Am J Manag Care. 2006;12(15 suppl):S412-S423.

20. Armstrong EP, Zachry WM 3rd, Malone DC. Cost-effectiveness analysis of simvastatin and lovastatin/extended-release niacin to achieve LDL and HDL goal using NHANES data. J Manag Care Pharm. 2004;10: 251-258.

21. Lindgren P, Graff J, Olsson AG, et al. Cost-effectiveness of high-dose atorvastatin compared with regular dose simvastatin. Eur Heart J. 2007; 28:1448-1453.

22. Lindgren P, Buxton M, Kahan T, et al. Cost-effectiveness of atorvastatin for the prevention of coronary and stroke events: an economic analysis of the Anglo-Scandinavian Cardiac Outcomes Trial-lipid lowering arm (ASCOT-LLA). Eur J Cardiovasc Prev Rehabil. 2005;12:29-36.

23. Russell MW, Huse DM, Miller JD, et al. Cost effectiveness of HMGCoA reductase inhibition in Canada. Can J Pharmacol. 2001;8:9-16.

24. Motheral BR. 2008: A tipping point for disease management? J Manag Care Pharm. 2008;14:643-649.

25. Mattke S, Seid M, Ma S. Evidence for the effect of disease management: Is $1 billion a year a good investment? Am J Manag Care. 2007; 13:670-676.

26. Thiebaud P, Patel BV, Nichol MB. The demand for statin: the effect of copay on utilization and compliance. Health Econ. 2008;17:83-97.

27. Schneeweiss S, Patrick AR, Maclure M, et al. Adherence to statin therapy under drug cost sharing in patients with and without acute myocardial infarction: a population-based natural experiment. Circulation.

2007;115:2128-2135.

28. Goldman DP, Joyce GF, Karaca-Mandic P. Varying pharmacy benefits with clinical status: the case of cholesterol-lowering therapy. Am J Manag Care. 2006;12:21-28.

29. Gibson TB, Mark TL, Axelsen K, et al. Impact of statin copayments on adherence and medical care utilization and expenditures. Am J Manag Care. 2006;12:SP11-SP19.

30. Centers for Disease Control and Prevention. NHANES 2003-2006 public data release file documentation. www.cdc.gov/nchs/nhanes.htm.

Accessed October 17, 2008.

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

32. Milliman. Health Cost Guidelines: Commercial Rating Structures.

Seattle, WA; 2007.

33. D’Agostino RB, Wolf PA, Belanger AJ, Kannel WB. Stroke risk profile: adjustment for antihypertensive medication: the Framingham Study.

Stroke. 1994;25:40-43.

34. Wilson PW, D’Agostino RB, Levy D, et al. Prediction of coronary heart disease using risk factor categories. Circulation. 1998;97:1837-1847.

35. D’Agostino RB, Russell MW, Huse DM, et al. Primary and subsequent coronary risk appraisal: new results from the Framingham Study.

Am Heart J. 2000;139:272-281.

36. Rogers SL, Magliano DJ, Levison DB, et al. A dose-specific metaanalysis of lipid changes in randomized controlled trials of atorvastatin and simvastatin. Clin Ther. 2007;29:242-252.

37. Thompson Financial. Medstat MarketScan commercial claims database, 2003-2007. Licensed to Milliman, Inc. 38. Milliman. 2008 Milliman Medical Index. Seattle, WA; 2008. www. milliman.com/expertise/healthcare/products-tools/mmi/pdfs/millimanmedical-index-2008.pdf. Accessed August 6, 2009.

39. Milliman. Milliman’s 2008 Group Health Insurance Survey. www. milli man.com/expertise/healthcare/products-tools/group-health-insurancesurvey/. Accessed August 6, 2009.

40. Curtiss FR. Methods to attain optimal outcomes with lipid-lowering drug therapy. J Manag Care Pharm. 2004;10:251-258.

41. Pitt B. Low-density lipoprotein cholesterol in patients with stable coronary heart disease—is it time to shift our goals? N Engl J Med. 2005;352:1483-1484.

42. Auer J, Lamm G, Eber B. Intensive lipid lowering with atorvastatin in coronary disease [letter]. N Engl J Med. 2005;353:93.

43. UnumProvident Corp. Unum says cancer still no. 1 cause of disability, but survival and return-to-work rates are increasing. www.unum provident.com/newsroom/news/corporate/default.aspx. Accessed September 7, 2007.

44. American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics–2007 update.

Circulation. 2007;115:e69-e171.

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Commercial Population at High Risk for Cardiovascular Events

APPENDIX: Supplemental Materials 1. Demographics of Target Population and Standard Commercial Population Target Total population Age, y population, N (target + nontarget), N

Sex Men

Women

35-39 40-44 45-49 50-54 55-59 60-64 65-69 35-39 40-44 45-49 50-54 55-59 60-64 65-69

Total

13 8 46 18 62 66 32 11 47 24 55 27 17 16 443

1048 1122 1034 889 506 313 108 1072 1173 1124 982 562 372 121 10,426a

a

Those aged 35-69 years, a subset of the total population of 10,000 employees and 4721 adult dependents.

History of stroke MCQ160F Ever told you had a stroke History of cardiovascular disease Stroke (See above for NHANES item number) CHD (See above for NHANES item number) CHF MCQ160B Family history of premature CHD MCQ260GA Blood relative/myocardial infarction/ mother before age 50 years MCQ260GB Blood relative/myocardial infarction/ father before age 50 years Smoking SMQ040

Do you now smoke cigarettes?

Hypertension BPXSAR BPXDAR

Systolic blood pressure Diastolic blood pressure

High-density lipoprotein LBDHDL High-density lipoprotein Low-density lipoprotein LBDLDL Low-density lipoprotein Total cholesterol LBXTC Total cholesterol

2. Risk Factors in NHANES Were Identified Using: History of CHD MCQ160C Ever told you had CHD MCQ160D Ever told you had angina/angina pectoris MCQ160E Ever told you had a heart attack D0503 Drug file 0503 antianginals D0508 Drug file 0508 coronary vasodilators History of diabetes DIQ010 Doctor told you that you have diabetes DIQ050 Now taking insulin DIQ070 Now taking diabetic pills to lower blood sugar LBXGLU Blood glucose

CHD indicates coronary heart disease; CHF, congestive heart failure.

Drug File Data 0912 Hyperlipidemia 05100 Atorvastatin calcium 26500 Fluvastatin sodium 37200 Lovastatin 48400 Pravastatin sodium 53200 Simvastatin 70600 Cholesterol-lowering drug, unspecified 14100 Cholestyramine 24400 Fenofibrate 27000 Gemfibrozil

STAKEHOLDER PERSPECTIVE The 10,000-Life Measure Shows Real-World Costs of Disease Burden and Interventions on a Population PAYERS/EMPLOYERS: Although this study provides a significant contribution to the literature of diabetes and cholesterol management, it is the

authorsâ&#x20AC;&#x2122; use of the 10,000-life framework that should get the attention of various healthcare stakeholders for future research.

Continued next page

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CLINICAL

STAKEHOLDER PERSPECTIVE Continued from previous page The traditional use of quality-adjusted life-years (QALYs) as a measure of cost-effectiveness analysis has proved to be of little actionable use for health insurers, health plan decision makers, employers, and other payers. Although the QALY is a measure of social value, the concept is neither truly economics(cost-) nor population-based—2 strong components of today’s healthcare delivery system infrastructure.

Because some people may suggest that QALY is an economic construct, this point is worth clarifying.

QALY analysis does provide a means to evaluate the cost of a QALY. For example, incremental QALY values are often assigned to a specific technology, which is then accepted or rejected based on some hurdle. Missing from a QALY analysis, however, are concepts of affordability—population-based measures, such as how costs are spread across a population, productivity, and family/coworker impact.

By using a 10,000-life analytical framework, key stakeholders are provided with meaningful and practical information that can have a direct impact on people’s lives and the cost of healthcare. Although healthcare quality is a societal concern, healthcare

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management is a local activity. When stakeholders know how to identify individuals with specific diseases—as well as the real-world costs of those conditions and the costs of interventions—they can assess how these metrics affect the population they are responsible for, and set an agenda for change.

The appeal of the 10,000-life framework is that it can be scaled to any population size (the more local, the better), facilitate understanding of insurancerelated costs, and directly measure the impact of disease burden and interventions on the population.

The collaborative effort between clinical, actuarial, and disease experts, as evidenced in this article, is a model for healthcare stakeholders to encourage.

These experts’ training and experience, when combined, make cost-effectiveness analysis accessible to stakeholders closest to the patient. With further encouragement for these types of studies, much needed improvements in healthcare quality and cost reductions can be realized.

David Williams Health Consultant, Milliman Windsor, CT

FREE SUBSCRIPTION

September/October 2009

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POINT AND COUNTERPOINT

POINT

Healthcare Reform, Classicism, and How We Treat the Elderly: The Politics of Epidemiology Robert E. Henry Editor-in-Chief, American Health & Drug Benefits

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t wasn’t supposed to happen this way. The 1000-page House of Representatives healthcare reform bill, “America’s Affordable Health Choices Act,” was supposed to follow the new Congressional passage sequence: distribute it to all the usual suspects, read it on the cab ride to the hotel, and immediately sign it into law. So when Congressional members on both sides of the aisle started boring into the draft of the bill and came back with concern over language that only suggested a troubling threat to seniors, political veterans were caught off guard. Since then, with protests ringing across the country at town hall meetings and every other conceivable venue, it has become clear that Americans want a healthcare system bent on healing.

The immediate concern was over the now infamous end-of-life counseling provision, Section 1233, which would have authorized Medicare to pay for a consultation between a patient and doctor or nurse about how much or how little medical care is desired in the event of incapacitation, informing patients about the benefits of hospice and palliative care. At first blush, there was nothing alarming here. Providers and payers have been wrestling to draw the line between aggressive care for the terminally ill and the pointless, wasteful use of costly drugs that do little to improve or extend life in terminally ill patients. But there is an existing context for this language and the net effect of other provisions in the House bill that are intended to ration care, which would lead to the same result: an early and cost-effective death, all in the name of efficient healthcare resource allocation. (Note that there is all the difference in the world between a medically driven consultation with one’s doctor and an agenda-driven consultation designed a priori to discourage care.)

Concern arose immediately over end-of-life counseling and rationing for the elderly, with fears that it signaled the start of limiting access to healthcare for our sickest, usually oldest, patients. Fueling this fear is that a quarter of Medicare funds go to patients in the last year of their lives. Since policy must be drafted with an eye to clarity, the public wanted assurances that the government was not simply implementing a cost-saving measure designed to convince seniors to opt out of appropriate treatment when they are terminally ill. Evaluating the language within the context of

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political policy, the concern is that the bill is an incremental move toward replacing a progressive healthcare system with a regressive one, with the elderly as its first victims. The ensuing debate has helped to bring a central issue out in the forefront: will seniors receive the care they need?

As America stands on the brink of healthcare reform, it is important that we decide whether we are committed to a progressive healthcare system—one that aggressively pursues disease prevention, intervention, and innovation—or to a brave new world of limited healthcare resources, concluding that the best years of healthcare are behind us. If the latter, then we must become adept at rationing care for the elderly, ultimately endorsing euthanasia, assisted suicide, and rationing care as practical remedies. Society must choose sides; it cannot finesse both ends of the spectrum, because the war on disease takes all the resolve of a true all-out war. As healthcare reform takes shape, we must take stock of how we treat our elderly, a fundamental measure of the decency of our society. And as we look at new initiatives for dealing with end-of-life care, we must ask if the United States will follow the lead of Great Britain and provide coverage based on quality-adjusted life-years (QALYs), calculating coverage eligibility based on the cost of intervention measured against one’s age. By encouraging hospice-oriented care for the elderly and the rationing of care, is government embracing a regressive healthcare system? Is government’s healthcare vision one of reduced access to care for the elderly and infirmed, coupled with reduced development of new life-saving drugs because payer coverage strategies are skewed against coverage of branded medications, the profits of which are needed for innovation? If this is the picture, would the affluent consent to the terms that a regressive healthcare system proffers to the public at large? Would the wealthy accept a government mandate that says “it is your turn to die”?

Be it death counseling or rationing, the end goal is the same: death is good for the bottom line.

Before concluding that this cannot happen here, consider that fiercely pragmatic civilization, ancient Rome, which relied on the widespread use of death to achieve practical ends. Her brutal exaltation of the state over the individual was evident in its mass executions—Julius Caesar had his troops execute 50,000 Celtic soldiers

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taken prisoner in a single day following their surrender— and the systematic use of forced suicide for offenses against the state (by ending one’s life, the accused would not forfeit his property to the state but could have his heirs inherit it; suicide became regarded as the sensible thing to do, and citizens at all levels of society made use of it). Rome’s second emperor, Tiberius, ordered the execution of the inventor of a fabulous type of glass that was essentially unbreakable, because it was more valuable than gold and he feared it endangered the Roman economy. The culprit behind all this killing was classicism, a fixed mold for all actions within the state, with Draconian consequences for any who stressed the system. In principle, Roman classicism was state-ordered pessimism: there was no letting things work themselves out where state security, class system, or economy was at stake. Death was the neat, simple, pragmatic solution. By the end of the empire, Rome had devolved into a socialist nightmare of micromanagement and defeatism where death was sensible. The questions arise, is death becoming regarded as such now for seniors, and are Americans finding their depth by refusing to abandon them?

It has not escaped notice of policymakers that the major epidemiologic factor facing American healthcare is the aging of the baby boomers. The real crisis facing America’s healthcare system is what will happen 10 years from now when baby boomers begin contracting geriatric disease states and consuming vast healthcare resources, if nothing is done to improve current efficiencies to healthcare. But it is the nature of a free people to reorder their circumstances to overcome challenges to their survival. In the face of the graying of America, some policymakers would have us follow Rome and encourage the elderly and infirmed to die quickly and “will their estates” to the young. This is classical pessimism reincarnated 21st-century style under the guise of “death-with-dignity” allocation of resources. It is an easy guess that lawmakers and the wealthy endorsing this process for the public at large would exempt themselves from it. It is also an easy guess that most lawmakers do not want this to happen. If that is the case, it is imperative to insert language into the final healthcare bill that ensures the elderly have an “even playing field,” where healthcare eligibility is not driven by age or productivity.

Visit the National Museum of the Marine Corps and you see testimony to patriots who faced down seemingly invincible armies by an unshakable resolve to win. Their approach was simple: the enemy was out to annihilate America, and surrender was not an option. As politicians set out to assist the healthcare system, it is imperative that they adopt the same strategy. Disease is not

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something to run from, but to address head on. Ultimate solutions for solving the entire picture do not constitute reform, just utopianism. In a recent appearance on Charlie Rose, Mayo Clinic CEO and President Denis Cortese advised we undertake healthcare reform one chunk at a time, not all at once. He also faulted the bill for its emphasis on cost-containment instead of balancing this with quality; combine them and you have value, not just cost-savings, he warned.

The ultimate abdication from quality of care is the restriction of access to care for the oldest and sickest, the facilitation of death via dehydration, starvation, avoidance of cardiac resuscitation or ventilator usage, or simply rationing care. The concern over the aforementioned consultations in the healthcare reform bill stems from apprehension over realpolitik, where cost trumps quality and politics trumps cost. Is the bill the first stage of a strategy to entice seniors to sign boilerplate forms amounting to do not resuscitate (DNR)? If so, it is placing American healthcare on the slippery slope to icy utilitarianism. If not, then the language must clearly forbid it.

The American spirit of can-do that the Marines showed at Belleau Wood and Iwo Jima in World War II is the proper approach to American healthcare system reform. But first, government must stop trying to dominate the triangle of sectors (clinical, business, regulatory) and instead support the clinical and business systems.

Periodically, each of these 3 sectors regards itself as the one with the answers and seeks hegemony over the system, when it is balance of power that is needed.

Enlightened government is measured not by its power over citizens, but its protection of their liberty.

Government healthcare policy must avoid domination of the healthcare process and policies that encourage, and eventually mandate, terminally ill patients to die quickly and inexpensively. The language of the healthcare bill must be crafted to pursue healing, not dying. It must keep the emerging American healthcare system true to our positive core values—life, liberty, and pursuit of happiness—not QALYs. To be progressive and effective, the American healthcare system must embrace prevention, intervention, and innovation. Conspicuous by its absence is any fourth point called DNR. Instead of planning for an ultimate retreat from healthcare for seniors, policymakers should embrace strategies that encourage development of new drugs and devices that save lives and money spent when illness drives patients into nursing homes and hospitals. A society not committed to taking care of its elderly is essentially indecent and on its way out. We are better than that. We can and

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will take care of the sickest, not with foolhardy, reckless usage of costly medications that do little to prolong or improve life, but with new treatments and medications, and equally resourceful payer utilization processes that deliver quality on the high road of medicine.

We must continue to define our healthcare system as one befitting a free people, a system supportive of progress and the health of its citizens, a system confident

in the ability of science and physicians to find the cures needed to sustain our healthcare system. The best is yet to come if we remain positive and avoid surrendering up our sickest out of fear that we do not yet have all the resources to treat them. As we codify our healthcare system, let us retain its noblest elements and reward our oldest citizens with the resolve to heal, not abandon them in their last years. ■

COUNTERPOINT

End-of-Life Choices Are Necessary in Any Healthcare Reform Gary M. Owens, MD President, Gary Owens Associates, Philadelphia, PA

M

r Henry’s thoughtful comments raise serious concerns about the future of healthcare for the elderly. However, it is necessary to voice a response to some of these points.

I completely agree that we cannot allow ourselves to support a medical system that has the potential to abandon the elderly in time of need. We must be able to provide the necessary care for those individuals. However, I fully support efforts to have meaningful conversations with patients about their wishes at the end of their lives.

Death is inevitable for all of us. Many patients (my wife and I are 2 of them) have strong beliefs that when faced with some terminal illnesses, we would prefer to have minimal treatment, be kept comfortable, and, hopefully, spend our final days in relative dignity rather than submit to futile and possibly uncomfortable treatment.

Case in point: A close family member has advanced Alzheimer’s disease. This person has not known anyone in the family for more than 2 years. In essence, the “death of the person” we knew and loved has already occurred, and we have already gone through many of the grieving stages over that loss. Death for her would be a blessing, and although we have ensured that she receives good care, we do not intend to take action to prolong her physical existence if a life-threatening event happens.

In our current healthcare environment, meaningful discussions between patients and their physicians about end-of-life care rarely occur. These discussions are difficult, and in a busy medical practice, it is often easier to avoid such difficult conversations with patients.

However, an important aspect of care for patients with an end-stage illness is to discuss the level of care and intervention that such patients may want. Once that level of care is understood, the system must be poised to

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act according to those needs and wishes. On the one hand, if an elderly patient wants aggressive life-sustaining care, the system must be there to provide that care.

On the other hand, if the patient wants to be kept comfortable and have only palliative treatment, the system needs to be able to honor that request also.

This is a matter of choice. All too often, patients, their families, and the physicians who care for them are faced with decisions about treatment near the end of life, without that discussion having taken place. In such situations the physician, unaware of the patient’s choice and values, often must choose to act aggressively, because the wishes of that patient are not known. In my clinical career, I have witnessed too many situations where care provided to the elderly to prolong the inevitable end point has been simply futile. The system cannot afford, either morally or financially, to continue to function as it has in the past. We definitely need a system to allow choice, and the only way to do that is to have open and honest discussions about those end-of-life choices before the event happens.

I agree with your concluding statement, “We must continue to define our healthcare system as one befitting a free people, a system supportive of progress and the health of its citizens, a system confident in the ability of science and physicians to find the cures needed to sustain our healthcare system.” Such a system must make care available to those who need it, yet it must respect the values of those patients who are faced with end-oflife treatment choices. By having discussions about these needs in advance of a crisis situation, we can accomplish both goals.

I invite all readers to comment on Mr Henry’s interesting and thought-provoking points. ■

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COMMENTARY

Cost-Sharing Enhances Cost Control H.E. Frech, III, PhD

I

n their article published in the April/May issue of the journal (AHDB. 2009;2:70-77), Haren and McConnell report the results of a recent survey (conducted in 2008) of large employers, employee benefit consultants, and managed care executives. The survey was focused on recent and expected increases in patient cost-sharing, and the article provides the aggregated responses of those surveyed.

The survey results are fascinating, showing that most employers and health plans have increased both premiums and consumer copayments (of many types) in the past 12 months. A substantial minority of employers and health plans has also reduced copayments, strategically, on particular services, based on specific clinical considerations or chronic conditions. Of note, both groups, but especially the employers, report their high levels of satisfaction with the overall results of higher copayments.

One would think that this was a story of complex organizations positively adapting to changes in their environment as healthcare delivery becomes more costly.

Indeed, the survey results show the importance of health and drug benefit design.

Oddly, in their commentary on the results, the authors seem to take the trends revealed in their survey as bad news rather than good news. In part, this is the result of confounding cost-shifting (ie, raising premiums) with cost-sharing (ie, raising copayments). Cost-shifting only affects the consumerâ&#x20AC;&#x2122;s choice of whether to purchase insurance or which policy to purchase. It does not affect incentives to use more or less healthcare services.

Cost-sharing, however, strongly affects incentives to use more or less healthcare. Indeed, this effect, called â&#x20AC;&#x153;moral hazard,â&#x20AC;? is probably the best established empirical regularity in the entire field of health economics.

The concept of moral hazard originated in the insurance industry, where insurance that led to higher losses was generally viewed as a moral issue. (Dramatic examples, such as insurance-induced arson, fit this view fairly

Dr Frech is Professor of Economics, Department of Economics, University of California at Santa Barbara. He can be reached at frech@econ.ucsb.edu.

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well.) That moral hazard in healthcare, which was simply a demand response to lower out-of-pocket prices, was first clearly explained by Mark V. Pauly in 1968,1 and has since become a staple of health economics textbooks.2-4 The existence of moral hazard, of course, implies that more cost-sharing (higher copayments) will reduce the demand for healthcare services. As Pauly clearly showed, this is simply a result of movement up an ordinary demand curve. This concept lies at the heart of theoretical and empirical studies on demand for healthcare, which is probably the most carefully and completely studied demand topic in the entire field of economics, not merely in health economics. A recent survey done for the US Department of Defense lists 70 references on this topic, mostly empirical demand studies.5

Oddly, in their commentary on the results, the authors seem to take the trends revealed in their survey as bad news rather than good news. In part, this is the result of confounding cost-shifting (ie, raising premiums) with costsharing (ie, raising copayments).

The most famous research on healthcare demand sets the gold standard.6 This study, the RAND Health Insurance Experiment, which spanned the late 1970s through the early 1980s, randomly assigned consumers to different health plans, neatly (if expensively) side-stepping the statistical problem caused by the possibility of adverse selection (where sicker consumers choose more complete health insurance).6 The RAND study is one of the largest social science experiments ever conducted. It showed large and longlasting cost-savings from higher consumer copayments (and also from health maintenance organization utilization controls). Much of the savings, regardless of exactly how the copayments were designed and defined, occurred in hospitalization costs. For example, coinsur-

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COMMENTARY

ance imposed only on outpatient services reduced inpatient hospitalization expenses, as well as outpatient expenses. The effects on health status were nonexistent for most measures, small for correctable vision and periodontal health among the lowest-income consumers.6 Similar and consistent results are found in other studies, observational and natural experiments, in many countries, but no similar massive social experiments have been done.

This moral hazard, or demand effect, is well-known to insurers and actuaries. In a letter to Anthem Blue Cross/ Blue Shield of Maine, a Milliman actuary predicted the effect of various levels of copayments on utilization, ranging from 0.997 for the lowest cost-sharing to 0.730 for the highest cost-sharing—a 27% decrease from the least to the most cost-sharing.7 Even before the RAND study, actuaries and insurers took account of the costcontrolling effects of consumer copayments.8 There are only a few ways in which health insurers can control or influence costs: price bargaining with providers, utilization controls, and consumer copayments. It is well-established that employers and insurers believe that raising copayments reduces costs. The US healthcare system has well-known problems, such as the tax subsidy to employee health insurance and the

high percentage of the uninsured. But, one advantage of that system is that the degree of utilization control, aggressive price bargaining, and benefit design are determined by the competitive interaction of many well-informed buyers and competing insurers. Thus, the system is subject to experimentation, innovation, evolution, and consumer choice. ■ [Online first, July 8, 2009.]

References 1. Pauly MV. The economics of moral hazard: comment. Am Econ Rev. 1968;58:531-537.

2. Phelps C. Health Economics. 3rd ed. Boston, MA: Addison-Wesley; 2002:100-172.

3. Morrisey MA. Health Insurance. Chicago, IL: Health Administration Press; 2007:93-130.

4. Zweifel P, Manning WG. Moral hazard and consumer incentives in health care. In: Culyer AJ, Newhouse JP, eds. Handbook of Health Economics. Amsterdam: Elsevier; 2000:410-459.

5. Ringel JS, Hosek SD, Vollaard BA, Mahnovski S. The Elasticity of Demand for Health Care: A Review of the Literature and Its Application to the Military Health System. Santa Monica, CA: RAND Corp; 2002.

6. Newhouse JP. Free for All? Lessons from the RAND Health Insurance Experiment. Cambridge, MA: Harvard University Press; 1996.

7. Jack P. Burke. “Coverage Utilization Adjustments.” [Letter to Bill Whitmore.] August 15, 2005. www.maine.gov/pfr/insurance/bluecross_ anthem/2009_rate_filing/pdf/4_W1250035_AppE_Milliman_Letter.pdf.

Accessed June 22, 2009.

8. Phelps CE, Newhouse JP. Coinsurance, the price of time, and the demand for medical services. Rev Econ Stat. 1974; 56:334-342.

Submit your caption at www.AHDBonline.com

CAPTION CONTEST Winners Receive $50 Submission deadline: November 30, 2009 Winners’ names posted: December 3, 2009

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Partnership. People.

Programs. Passion.

The Flexibility You Need. The Integrity You Deserve.

| MANAGED MARKETS

Leaders in Business. Partners in Care.

Visit Takeda on the Web at www.tpna.com.

Generics_Cover 10/14/09 11:25 AM Page 240

GENERIC DRUG TRENDS

Can Generics Help Heal Our Ailing Healthcare System?

Dalia Buffery, MA, ABD

W

ith cost becoming a major obstacle in any potential healthcare reform, the role of generic drugs is gaining even greater popularity than before among policymakers as a cost-saving feature in the attempt to overhaul our healthcare system. The tension between the makers of generic drugs and brandname manufacturers notwithstanding, there is a general agreement in government that increased use of generics can substantially reduce overall healthcare costs, especially during the current economic environment.

According to the Generic Pharmaceutical Association (GPhA), the rise in the use of generic medicines in past decades has saved the healthcare system “more than $734 billion in the last decade alone.”1 Because more generics are being approved by the FDA each month, the potential for even greater future savings is real.

In early July 2009, as part of the House of Agriculture Appropriation bill, the House approved an increase in the funding for the US Food and Drug Administration (FDA)’s Office of Generic Drugs But by mid-July, the Senate Committee on Health, Education, Labor, and Pensions (HELP) defeated Rep Henry Waxman’s proposal of a 5-year exclusivity period for a new biosimilars (generic version of biologics) pathway in favor of a 12-year exclusivity period proposed by Rep Anna Eshoo. The 47 to 11 vote in favor of the longer period signals strong support for the biotechnology industry and a delay in the potential financial benefits to consumers and to the healthcare system as a whole. President Obama and the AARP are among those who are favoring a shorter period, with the President supporting a 7-year exclusivity period.

The fight, however, is not over.

In mid-September, Sen Orrin G. Hatch and Rep Waxman—the “fathers” of the Hatch-Waxman Act that led to the current generics pathway (and the creation of the generic industry)—addressed the GPhA’s Annual Policy Conference, advocating for generics and biosimilars as a cost-saving mechanism that can improve our ailing healthcare system, noting that generics have saved the US healthcare system much more money than was initially anticipated.

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Sen Hatch reiterated that generics reduce consumer costs, hence the goal is to provide incentives to get high-quality generics to market early, “especially as we consider healthcare reform legislation.”2 But it was Sen Hatch who introduced the 12-year biosimilar exclusivity period amendment at the HELP Committee markup of its healthcare reform bill.

In contrast, Rep Waxman was focused the ongoing fight for biosimilar legislation. When it comes to the future of biosimilars pathway, he emphasized, the “war is not over,” adding that if the 12-year exclusivity amendment becomes law, it would “impose almost insurmountable barriers to real competition in the biopharmaceutical marketplace….The Eshoo amendment is everything a monopolist could hope for.”2 Health and Human Services Secretary Kathleen Sebelius also attended the GPhA conference. She stressed that President Obama is committed to the 7year biosimilar exclusivity period as part of a general healthcare reform, while also cognizant of the need to promote and encourage innovation.3 So in the struggle to introduce a biosimilar pathway, just as is the case with the “wars” on healthcare reform, everyone agrees on the need to enhance cost-saving mechanisms, while also acknowledging that unlike some areas in which innovation is a goal unto itself (eg, education, science), innovation in healthcare requires incentives beyond the reward of improving health. It was not always like that in medicine. ■ References 1. Generic Pharmaceutical Association. GPhA applauds house action to increase funding for FDA’s Office of Generic Drugs. July 9, 2009. www.gphaonline.org/media/press-releases/2009/gpha-applauds-houseaction-increase-funding-fda%E2%80%99s-office-generic-drugs. Accessed September 29, 2009.

2. Generic Pharmaceutical Association. Senator Hatch and chairman Waxman stress important role generic medicines play in strengthening health care system on 25th anniversary of Hatch-Waxman Act. September 18, 2009. www.gphaonline.org/media/press-releases/2009/ gpha-senator-hatch-and-chairman-waxman-stress-important-role-generic -medic. Accessed September 29, 2009.

3. Generic Pharmaceutical Association. Obama administration says it will continue to push for seven years of market exclusivity for biogenerics.

September 17, 2009. www.gphaonline.org/media/press-releases/2009/gpha -obama-administration-says-it-will-continue-push-seven-years-market-ex.

Accessed September 29, 2009.

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Q. Which Global Generics Company Filled More

Than 70% of its Capsules in the U.S. Last Year?

A . Mylan Pharmaceuticals.* With global resources and one of the largest pharmaceutical manufacturing facilities in the United States—brand or generic—Mylan is committed to bringing Americans the medicine they need. In fact, last year we filled more than 70% of our capsules in the U.S.* This year, we expect to introduce an unprecedented number of new products, all reflecting the standards that have earned us the trust and respect of pharmacists, who rank our generics highest in quality.† That’s why our products will continue to offer quality and affordability for the patients who need them and peace of mind for the pharmacists who dispense them. *Data on file. Mylan Pharmaceuticals Inc. † Drug Topics Generic Company Survey. November 2008.

©2009 Mylan Pharmaceuticals Inc.

MYNMKT307

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Impact of Prescription Benefit Coverage Limits on Sevelamer Hydrochloride Adherence for Patients with ESRD Bharati Bhardwaja, PharmD, BCPS; Nikki Carroll, MS; Eli Korner, PharmD; Kavita V. Nair, PhD Objective: To assess the impact of prescription benefit coverage on medication adherence in Medicare-eligible members diagnosed with end-stage renal disease taking sevelamer hydrochloride.

Methods: This pilot study involved a retrospective analysis of patients with end-stage renal disease taking sevelamer, with an annual cap on brand prescription drug spending compared with those without a cap. We compared sevelamer adherence and discontinuation proportions between the 2 groups of Medicare patients in 2003 and 2004.

Medication adherence was calculated based on the proportion of available days covered Bharati Bhardwaja in relationship to capped versus noncapped pharmacy benefit.

Results: Rate ratios showed that in 2003, the patients taking sevelamer under a capped benefit (N = 43) had 27% fewer days of drug use compared with those (N = 88) without a capped benefit (relative risk, 0.73; 95% CI, 0.58-0.93). Similarly, in 2004, those taking sevelamer under the capped benefit (N = 21) had 33% fewer days of drug use compared with those (N = 117) without a capped benefit (relative risk, 0.67; 95% CI, 0.46-0.96).

Conclusions: Medication adherence was significantly lower for patients with a capped brand-name drug benefit. These findings provide insight into potential drug utilization patterns, including for sevelamer, under the Medicare Part D benefit, where members could face significant out-of-pocket expenditures once coverage limits are reached. [AHDB. 2009;2(6):242-250.]

H

yperphosphatemia is prevalent among patients with end-stage renal disease (ESRD) and continues to be an important and challenging area for drug therapy. The kidneys play a key role in maintaining normal serum phosphorus levels, which is impaired at an estimated glomerular filtration rate (GFR) of 50 mL/min to 60 mL/min.1,2 An adaptive process by the kidneys, which involves an increase in circulating parathyroid hormone (PTH) with normal calcitriol levels, helps to control phosphorus at this low

Dr Bhardwaja is a Nephrology Clinical Pharmacy Specialist, Kaiser Permanente, Department of Nephrology/Renal Care Program, Denver, and Clinical Assistant Professor, University of Colorado Denver School of Pharmacy; Ms Carroll is Biostatistician, Institute for Health Research, Kaiser Permanente Colorado, Denver; Dr Korner was Research Investigator, Kaiser Permanente Colorado, Institute for Health Research, Denver, during this study and is currently Medical Liaison, Virology & Hepatology, Roche Laboratories; Dr Nair is Associate Professor, School of Pharmacy, University of Colorado at Denver.

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GFR value.1,2 Once the GFR decreases to 25 mL/min to 30 mL/min, the PTH elevation and low levels of calcitriol cannot maintain a normal phosphorus level, leading to hyperphosphatemia.1,2 Hyperphosphatemia, in addition to elevated calcium phosphorus product and elevated PTH, is associated with significant morbidity and mortality.1 Failure to adequately control elevated serum phosphorus levels can result in cardiovascular events, including coronary artery disease (CAD), uncontrolled hyperparathyroidism, and fractures.1 These complications carry a significant economic burden and untoward personal costs associated with hospitalization, increased higher healthcare resource utilization, decreased quality of life, and premature death.3-7 The Kidney Disease Outcomes Quality Initiative (K/DOQI) clinical practice guidelines published by the National Kidney Foundation emphasize the importance of serum phosphorus control in patients with ESRD.8 The K/DOQI guidelines recommend the initiation of oral phosphate binders when serum phosphorus and intact PTH levels cannot be kept within the

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target range with dietary phosphorus restriction alone.

Calcium-containing phosphate-binding medications are effective; however, they carry the risk of elevating serum calcium levels above the target range in patients with ESRD.8,9 Hypercalcemia has been linked to increased mortality risk in patients with ESRD.5,10-14 The K/DOQI guidelines suggest a preference for phosphate bindersâ&#x20AC;&#x201D;which are noncalcium, nonmagnesium, and nonaluminum, such as sevelamer hydrochloride (Renagel; henceforth sevelamer)â&#x20AC;&#x201D;in patients on dialysis with severe vascular and/or other soft-tissue calcifications. The guidelines also suggest the use of these agents in patients with hypercalcemia to control phosphorus levels.8,11 A recent study showed that 53% of patients with advanced chronic kidney disease fulfilled at least 1 criterion for the use of sevelamer.15 Sevelamer is a polymeric compound that binds phosphate within the intestinal lumen, limiting absorption of and decreasing serum phosphate concentrations without altering calcium, aluminum, or bicarbonate concentrations.16 It is not currently available as a generic product.

For some patients, its use may be limited by its high cost.17 In addition, reduced adherence to sevelamer in patients with ESRD because of financial barriers can significantly increase utilization of high-cost drivers of healthcare, such as hospitalizations and outpatient visits.

In 2003, the average wholesale price (AWP) for sevelamer was $1.31/tablet or between $2832 and $8484 per year.18 In 2004, the AWP increased to $1.42/tablet or between $3072 and $9204 annually for an individual19 (based on a dosing frequency of 2-6 tablets/meal and 3 meals/day). Limitations with prescribing a phosphorus-restricted diet in addition to limitations in phosphorus removal by conventional dialysis, make the use of a noncalcium-based phosphate binder, such as sevelamer, the option to managing hyperphosphatemia without increasing the risk for hypercalcemia.5 Patients who are unable to comply with sevelamer therapy because of cost constraints are often left with the alternative of calcium-based phosphate binders and may be at risk for subsequent complications secondary to hypercalcemia.

In one study, patients treated with sevelamer had a 50% lower likelihood of hospitalization and had lower overall annual costs by more than $16,500 per patient than patients not receiving this drug.20 However, nonadherence to drug therapy has been a significant problem in the ESRD population.21-23 Nonadherence to hemodialysis treatment, as assessed by the number of missed dialysis sessions and hyperphosphatemia, has been associated with increased mortality.6 In that study,

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KEY POINTS u

Previous studies have shown that drug benefit coverage design can affect patient medication adherence. u Putting a cap on total drug spending has been associated with decreased medication adherence, resulting in poor clinical outcomes. u Results of this study showed that sevelamer hydrochloride adherence was significantly lower for Medicare patients with end-stage renal disease with a capped brand-name drug benefit compared with those without a capped benefit. u Reduced drug utilization may likely have been the result of greater patient cost-sharing. This utilization pattern has ramifications on biochemical outcomes in this patient population and potentially in other patients using brand-name medications. the relative risk for skipping 1 or more dialysis treatments per month was 1.30, and the mortality risk for serum phosphorus >6.5 mg/dL was 1.27 relative to a serum phosphorus of 2.4 mg/dL to 6.5 mg/dL.6,7 The direct cost-related nonadherence rate in the United States for patients with ESRD is 29%.24

Drug Benefit and Adherence Caps on total drug spending have been associated with decreased medication adherence and reduced control of systolic blood pressure, low-density lipoprotein (LDL) cholesterol, and glycosylated hemoglobin in patients with hypertension, hyperlipidemia, and diabetes, respectively.25 Patients with drug coverage limits have increased emergency department visits and hospitalizations, which may have a direct impact on total healthcare spending.25-27 There is limited research examining the impact of sevelamer adherence within a capped drug benefit for patients with ESRD. An appropriate way to measure sevelamer adherence within a Medicare managed care population is by using the proportion of days covered (PDC).28,29 PDC is the number of days in the measurement period covered by prescription claims for the same medication or another in its therapeutic category as defined by the Pharmacy Quality Alliance.30 The PDC threshold is the level (typically 80%) above which the medication has a reasonable likelihood of achieving most of its potential clinical benefit.

Patients with ESRD are eligible for prescription drug coverage under Medicare Part D. The standard Part D benefit includes limits on total drug spending. For

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Table 1 Copays for Sevelamer in the Capped Group, 2003 and 2004 2003 2004 $30 copay, $50 copay, $30 copay, $50 copay, Cap N (%) N (%) N (%) N (%) $500

2 (4.7)

14 (32.6)

NA

NA

$1000

NA

NA

NA

9 (42.9)

$1500

0

27 (62.8)

NA

12 (57.1)

example, in 2006 the total drug spending limit was $2250, after which patients enter a coverage gap and are responsible for 100% of the cost of all medications until catastrophic coverage takes effect. The total drug spending limit for Medicare Part D increased to $2400 and $2510, respectively, in 2007 and 2008.31,32 Sevelamer is a tier 2 (preferred brand-name) drug in most Medicare Part D plans.33 Patients with ESRD taking sevelamer could be particularly vulnerable to spending limits in the Part D benefit, because they may be responsible for 100% of medication costs once they reach the coverage gap threshold.

The primary objective of this pilot study was to compare adherence and discontinuation proportions in patients with ESRD receiving sevelamer under a capped brand-name prescription benefit in Medicare plans and in retiree patients who have no caps in nonMedicare plans offered by Kaiser Permanente Colorado. Secondary end points included specific biochemical outcomes for patients with ESRD within a capped and a noncapped prescription benefit.

Methods Kaiser Permanente Colorado is an integrated healthcare delivery system for more than 400,000 members in the Denver-Boulder metropolitan area. The physicians of the Colorado Permanente Medical Group contract exclusively with the Kaiser Foundation Health Plan to provide comprehensive healthcare services. Medicareeligible members represent approximately 15% of Kaiser Permanente Colorado membership.

In 2003 and 2004, Medicare patients in a Medicare+Choice plan had a $30 or $50 copay for brand-name medications, with a $500 (2003 and 2004), $1000 (2004), or $1500 (2003) capped benefit.

Members paid their copays until the prescription drug cap was met each year. At that point, they were responsible for 100% of the cost of all brand-name prescription drugs. The capped benefit differed slightly between 2003 and 2004. In 2004, patients with a Medicare+Choice plan also had a $300 deductible for

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Table 2 Distribution of Copays for Sevelamer in the Noncapped Group, 2003 and 2004 Prescription drug 2003 2004 copay, $ N (%) N (%) 3 5 7 10 15 20 25 30 40 50

3 (3.4) 5 (5.7) 1 (1.1) 16 (18.2) 6 (6.8) 24 (27.3) 2 (2.3) 19 (21.6) 1 (1.1) 11 (12.5)

3 (2.6) 4 (3.4) 0 20 (17.1) 5 (4.3) 34 (29.1) 9 (7.7) 23 (19.7) 5 (4.3) 14 (12.0)

brand-name medications, after which they faced a cap on brand-name drug spending.

The annual copay distribution for sevelamer in the capped group is shown in Table 1. A large proportion of patients in 2003 (95%) and 2004 (100%) had prescription copays of $50 for this medication.

The noncapped prescription benefit did not have any limits on prescription drug spending and represented a retiree Medicare population with employer-sponsored coverage. Retiree-based Medicare patients in the noncapped group typically paid a copay for brand-name medications ranging from $5 to $40. Table 2 shows the annual distribution of copays for sevelamer in the noncapped group. In 2003 and 2004, a large proportion of patients in the noncapped group had copays of $20 (27% and 20%, respectively) or $30 (15% and 20%, respectively).

All patients with documented ESRD receiving sevelamer during the first 6 months of 2003 and 2004 were identified using pharmacy claims data. Inclusion criteria were continuous dialysis (peritoneal or hemodialysis) between January 1, 2003, and December 31, 2004, and continuous health plan membership with pharmacy benefits for this period. Because of a lack of awareness of the Medicare drug discount card (instituted in 2004), and the difficulty in identifying patients who had the card, the potential impact of the discount was excluded.34 The sevelamer index date was defined as the first sevelamer dispensed in each calendar year. All dispensing events were captured through the end of each calendar year. Patients were stratified into groups according to type of Medicare drug coverage (capped or noncapped). The 2 groups were kept separate, because the capped benefits changed from 2003 to 2004.

Sevelamer adherence was defined as the PDC during

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Table 3 Characteristics of Patients with Sevelamer Dispensing in the First 6 Months of 2003 and 2004

Characteristic Age at first dispensing Distinct oral medications, Na Sex Female Male Comorbid conditions CAD Diabetes mellitus MDD CHF Atrial fibrillation Hypertension Parathyroidectomy

2003 (N = 131) Capped (n = 43) Noncapped (n = 88) (5th, 95th (5th, 95th Median percentile) Median percentile) P 62 yr

(33, 85 yr)

61 yr

(34, 78 yr) .644

6 N

(2, 15) %

7 N

(2, 15) %

16

37.2

40

27

62.8

29

2004 (N = 138) Capped (n = 21) Noncapped (n = 117) (5th, 95th (5th, 95th Median percentile) Median percentile) P 69 yr

(49, 88 yr)

62 yr

6 N

(3, 12) %

7.5 N

(2, 16) %

45.4

8

38.1

50

42.7

48

54.6

13

61.9

67

57.3

67.4

28

31.8

.001

11

52.4

47

40.2

.296

37

86.1

78

88.6

.670

20

95.2

100

85.5

.307

0

0.0

4

4.6

NA

0

0.0

2

2.3

NA

8

18.6

22

25.0

.413

7

33.3

24

20.5

.254

.245

(27, 81 yr) .014 .134

8

18.6

6

6.8

.067

6

28.6

8

6.8

.008

32

74.4

66

75.0

.942

15

71.4

92

78.6

.569

5

11.6

11

12.2

.921

1

4.8

8

6.7

.735

a

Distinct medications calculated by medications with a total of at least 90-day supply over the year summed up by the first 8 digits in the generic product identifier code (down to the drug name level).

CAD indicates coronary artery disease; CHF, chronic heart failure; MDD, major depressive disorder.

calendar years 2003 and 2004. The PDC was measured as a continuous variable and was calculated by dividing the total number of days supply of sevelamer dispensed by the total number of days between the index dispensing of sevelamer and the end of both calendar years.27-30 Patients were considered to have discontinued the use of sevelamer if they only had 1 prescription of the drug filled in each calendar year. Discontinuation proportions were calculated by dividing the number of patients who discontinued sevelamer by the total number of patients receiving a sevelamer prescription in the capped and noncapped group for each year.

Laboratory test results were obtained through a review process of each patientâ&#x20AC;&#x2122;s charts. The last measured values for the relevant clinical markers were collected each month for each patient, and the average of these values was used as the outcome measure.

Medical and pharmacy data from administrative sources and patient chart reviews were used to identify patient age (based on the index date for a sevelamer dispensing); sex; comorbid conditions (major depressive disorder, atrial fibrillation, chronic heart failure [CHF], hypertension, CAD, diabetes mellitus); procedure for parathyroidectomy; pharmacy benefit structure (capped vs noncapped); concurrent drug use (calcimimetics; cal-

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cium-, aluminum-, or magnesium-containing phosphate binders; and vitamin D analog therapy); associated laboratory test results (corrected calcium-phosphorus product; and corrected serum calcium, serum phosphorus, and intact PTH).

For both calendar years, comorbid conditions of interest were identified by the codes of the International Classification of Diseases, 9th Revision, and procedures of interest were identified by the Current Procedural Terminology, 4th Edition. Although beneficiaries have the ability to change coverage during the year, pharmacy benefit structure at the index sevelamer prescription was assumed to continue during each calendar year. Concurrent drug use was primarily identified using National Drug Codes.

Statistical significance of differences for the descriptive variables noted above was tested using the Wilcoxon rank sum or chi-square tests for continuous and categorical variables, respectively. Associations between pharmacy benefit coverage and medication adherence and discontinuation were evaluated using Poisson regression modeling with the canonical loglink function and an offset parameter to accommodate the effect of unequal length of the individual follow-up period.35 The model was fit with a correction for

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Table 4 Characteristics Associated with Medication Adherence for Sevelamer Users 2003 Variable characteristics Noncapped benefit referent No parathyroidectomy referent Continuous number of medications Continuous age at first dispensing Male referent No depression referent No atrial fibrillation referent No hypertension referent No CHF referent No CAD referent No metoprolol/atenolol use referent No calcimimetics use referent Corrected Ca  P product ≤55 mg2/dL2 referent No concurrent calcium-based phosphate binder referent

2004

Adjusted rate Adjusted rate ratios (95% CI) ratios (95% CI) 0.73 (0.58-0.93)a 0.67 (0.46-0.96)a 0.50 (0.33-0.76)b 0.65 (0.37-1.17) 0.99 (0.98-1.00) 1.00 (0.99-1.02) 1.00 (0.99-1.01) 1.00 (0.99-1.01) 1.14 (0.94-1.39) 1.02 (0.82-1.27) 0.88 (0.50-1.55) 0.59 (0.21-1.67) 0.84 (0.59-1.19) 0.93 (0.62-1.40) 1.02 (0.81-1.29) 0.87 (0.66-1.14) 1.14 (0.90-1.45)

NA NA 0.99 (0.79-1.25) 1.05 (0.85-1.29) 1.20 (0.95-1.53) NA 0.98 (0.72-1.34) 1.16 (0.87-1.55) 1.01 (0.74-1.38) 0.91 (0.72-1.15) 0.78 (0.58-1.05)

a

P <.05 (significant difference).

P <.01 (significant difference).

Ca  P indicates calcium-phosphorus product; CAD, coronary artery disease; CHF, chronic heart failure; CI, confidence interval.

b

overdispersion. Rate ratios were tabulated to compare the capped and noncapped groups. Logistic regression analysis was used to determine the relationship between pharmacy benefit coverage discontinuation proportions for sevelamer. Analyses were conducted using SAS 9.1 (SAS Institute; Cary, NC).

Results Table 3 describes the characteristics of patients with ESRD receiving sevelamer during the first 6 months of 2003 and 2004. In 2003, 131 patients met the eligibility criteria: 43 (32.8%) patients were in the capped group and 88 (67.2%) in the noncapped group. In 2004, 138 patients met the eligibility criteria: 21 (15.2%) patients in the capped group and 117 (84.8%) in the noncapped group. The top 3 diagnoses for patients in the capped group in 2003 were diabetes mellitus, atrial fibrillation, and hypertension, and in 2004 diabetes mellitus, hypertension, and CAD. Similar trends were observed in the noncapped group.

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In 2003, the capped and noncapped groups were similar in most characteristics, except CAD, where the capped group had a higher percentage of members than the noncapped group (P = .001). In 2004, the noncapped group was younger than the capped group and had a lower percentage of members with atrial fibrillation.

The capped-group patients faced greater cost-sharing for sevelamer after they reached their cap (results not shown). In 2003, the mean copay for patients taking sevelamer in the capped group was $50 before the cap was reached and $395 after the cap was reached. In 2004, the mean copay was $160 before the cap was reached and $264 after. In 2003, the unadjusted median PDC was 40.0% for the capped group and 66.3% for the noncapped group; in 2004 the unadjusted median PDC for the capped group was 40.4% compared with 59.2% for the noncapped group. In 2003 and 2004, 60.5% of the patients in the capped group had PDCs <50% compared with 33% in the noncapped group. The unadjusted proportion of patients who discontinued sevelamer was 28% in 2003 and 19% in 2004 in the capped group and 15% in 2003 and 17% in 2004 in the noncapped group. None of these differences were significant.

Adjusted rate ratios are shown in Table 4. Adjusted analysis showed that factors influencing the PDC in 2003 included pharmacy benefit group and presence of the parathyroidectomy procedure. Adjusted rate ratios reveal that in 2003 patients with a capped benefit had 27% fewer days of sevelamer use compared with the noncapped benefit (odds ratio [OR], 0.73; 95% confidence interval [CI], 0.58-0.93). The 2004 adjusted rate ratios showed those with a capped benefit have 33% fewer days of sevelamer use compared with the noncapped benefit (OR, 0.67; 95% CI, 0.46-0.96).

None of the variables, including the type of pharmacy benefit, were associated with discontinuation of sevelamer in 2003 and 2004 (Table 5).

In 2003, there was a significant difference in the corrected serum calcium level, serum phosphorus level, and the corrected calcium-phosphorus product in patients with ESRD in the capped group compared with those in the noncapped group (Table 6). The intact PTH values did not differ significantly between the capped and noncapped groups.

Patients with ESRD in the noncapped group had slightly lower corrected serum calcium and serum phosphorus values but much lower corrected calcium-phosphorus product values (a difference of 4.7 mg/dL). In 2004, results were similar to 2003, except that the corrected calcium-phosphorus product was not significantly different between the 2 groups.

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Discussion Although the ESRD population accounts for less than 1% of the entire US population, it continues to increase at a rate of 3% annually across all races and agegroups.36 Total Medicare spending in 2006 was nearly $355 billion; ESRD costs rose to $23 billion (6.4% of the total Medicare budget).36 Patients with ESRD have many comorbidities, and a majority of the older patients take 5 or more medications.36 The leading cause of ESRD is diabetes (44.8%), followed by hypertension (26.8%) and glomerulonephritis (12.8%).36 Drug therapy for patients with ESRD is complex, requiring many oral and injectable medications, some of which require multiple doses each day. Attempts to use behavioral models to predict medication nonadherence have suggested complex interrelationships between psychologic factors and adherence in this patient population.21 A recent review suggests health beliefs (eg, perceptions of self-efficacy with regard to taking medication), social support (eg, support of friends, family, and renal staff), family dynamics (eg, family problems caused by the patient’s illness), and personality traits (eg, low conscientiousness) as significant predictors of nonadherence to phosphate-binding medications in these patients.37 Results of our analysis show that adherence to sevelamer treatment was 27% lower in the capped group in 2003 and 33% lower in 2004 compared with the noncapped group. Patients with ESRD were taking an average of 10 to 12 medications in both years. The total annual out-of-pocket (OOP) expenses for sevelamer were 26% and 57% higher for patients in the capped group compared with patients in the noncapped group in 2003 and 2004, respectively.

These rates of adherence are higher than those reported in a previous study, although that study only examined patient self-reports of cost-related nonadherence, which are typically lower than what is examined in claims data, because of recall bias issues.24 In addition, our small sample size did not allow us to examine whether the use of sevelamer was influenced by members reaching the capped portion of their prescription benefit.

However, despite the generosity of the noncapped benefit, median adherence rates were only 40.4% in 2003 and 59.2% in 2004. Thus, although cost is a factor that may affect adherence, other factors not examined in this pilot study may affect adherence as well.

Our findings also suggest that lower adherence to sevelamer treatment may have been associated with less desirable biochemical outcomes. The K/DOQI guidelines recommend a serum phosphorus level of 3.5

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Table 5 Characteristics Associated with Discontinuation of Sevelamer 2003 2004 Variable characteristics Adjusted odds Adjusted odds ratios (95% CI) ratios (95% CI) Noncapped benefit referent 0.50 (0.20-1.27) 1.31 (0.41-4.16) No parathyroidectomy referent 1.83 (0.54-6.18) 0.48 (0.07-3.16) 0.98 (0.92-1.04) 1.00 (0.95-1.05) Continuous number of medications 0.99 (0.96-1.02) 1.01 (0.99-1.04) Continuous age at first dispensing 0.99 (0.44-2.19) 1.21 (0.55-2.65) Male referent No atrial fibrillation referent 2.36 (0.61-9.14) 0.73 (0.18-2.88) 1.13 (0.43-2.96) 1.16 (0.42-3.21) No hypertension referent 0.79 (0.29-2.18) No CHF referent NA 0.69 (0.31-1.55) No CAD referent NA 1.76 (0.75-4.10) 1.26 (0.54-2.94) No metoprolol or atenolol use referent 3.11 (1.09-8.86) No calcimimetics use referent NA 0.39 (0.14-1.08) 2.56 (0.90-7.24) Corrected Ca  P product ≤55 mg2/dL2 referent No concurrent calcium-based 1.63 (0.66-4.02) 1.54 (0.60-3.96) phosphate binder referent Ca  P indicates calcium-phosphorus product; CAD, coronary artery disease; CHF, chronic heart failure; CI, confidence interval.

mg/dL to 5.5 mg/dL for patients with ESRD, a corrected serum calcium level of 8.4 mg/dL to 9.5 mg/dL, and a goal for corrected calcium-phosphorus product of 55 mg2/dL2.8 The corrected serum calcium values were above K/DOQI targets in the capped group in both years. The serum phosphorus values and corrected calcium–phosphorus product were at the high end of the target goal range in the capped group in 2003.

Although this pilot study was not designed to evaluate the clinical significance of the biochemical values, results from previous studies have identified significant morbidity and mortality risks associated with hyperphosphatemia and hypercalcemia.3-6,10-14 Because there are no generic alternatives to sevelamer hydrochloride, its use in this population and the impact of cost-sharing on adherence could have implications in the current healthcare environment.

The impact of sevelamer adherence on health plan resource utilization and total healthcare costs is an area for further research. Medicare+Choice beneficiaries with a capped annual drug benefit were found to have higher odds of nonadherence to antihypertensive, lipid-lowering, and diabetes medications (30%, 27%, 33%, respec-

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Table 6 Clinical Marker Differences between Capped/Noncapped Groups

Characteristic Corrected calcium values Serum phosphorus values Corrected calciumphosphorus product Intact PTH values

Capped (n = 32) (5th, 95th Median percentile)

2003 Noncapped (n = 60) (5th, 95th Median percentile) P

Capped (n = 20) (5th, 95th Median percentile)

2004 Noncapped (n = 96) (5th, 95th Median percentile) P

9.7

(8.5, 10.8)

9.6

(8.0, 10.7) .022

9.7

(8.4, 10.7)

9.5

(8.2, 10.5) .003

5.5

(3.3, 7.8)

5.1

(3.4, 8.1)

4.8

(3.0, 7.5)

4.9

(3.2, 7.9)

53.5

(30.9, 74.9)

48.8

45.6

(28.8, 73.7)

46.5

(30.6, 74.0) .433

299.5

(53.5, 1603.5)

300

391

(100, 2186)

421

(98, 1449) .369

.015

(31.9, 74.7) <.001 (90.0, 1003.0)

.089

.097

PTH indicates parathyroid hormone.

tively).25 Furthermore, patients with a capped benefit were more likely to have elevated systolic blood pressure (OR, 1.05; 95% CI, 1.00-1.09), LDL cholesterol (OR, 1.13; 95% CI, 1.03-1.25), and glycosylated hemoglobin (OR, 1.23; 95% CI, 1.03-1.46).25 Finally, patients with a capped benefit had 28% lower pharmacy costs, 4% lower office visit costs, but 13% higher hospital costs and 9% higher emergency department costs.25 Sokol and colleagues examined the relationship between medication adherence for diabetes, hypertension, dyslipidemia, and CHF on the risk of hospitalizations and total healthcare expenditures.38 Using diabetes as an example, they found that diabetic patients with adherence levels between 80% and 100% had a 13% risk of hospitalizations compared with 26% risk for those with adherence levels <40%. In patients with schizophrenia, 17% of adherent patients (>80% adherence) had a psychiatric hospitalization compared with 30% of nonadherent patients (<80% adherence).39 In another study of patients with type 2 diabetes, adherence remained the strongest predictor for annual healthcare costs, where a decrease of between 8.6% and 28.9% was observed for every 10% increase in adherence.40 Therefore, nonadherence has been associated with greater utilization of high-cost drivers of healthcare expenditures, such as inpatient visits and emergency department visits, which ultimately results in increased medical costs and the subsequent economic implications of medication nonadherence.

What are the implications of the lower adherence for sevelamer we found in our study on overall healthcare utilization and costs? It was beyond the scope of our study to directly examine this impact, but we conducted an estimation of the impact of lower adherence on total

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healthcare costs for patients with ESRD using published literature estimates for patients with diabetes who could be at risk for chronic kidney disease and ESRD. The recent US Renal Data System (USRDS) reported an overall 50% change in new ESRD cases due to diabetes between 1996 and 2006.36 Balkrishnan and colleagues found that a 10% decrease in medication adherence for diabetes can lead to an 8.6% to 28.9% increase in total healthcare costs.40 We found that in 2003, patients with ESRD with a capped benefit had 27% lower adherence compared with those without a noncapped benefit. In 2004, those with a capped benefit had 33% lower adherence compared with those with a noncapped benefit. The USRDS 2008 annual data report for ESRD show that the per-member per-month (PMPM) cost of treating a patient with ESRD under Medicare in 2006 was $6266.36 Moreover, Medicare expenditures were approaching $72,000 per patient annually in 2006 and inpatient/outpatient costs of $4300 PMPM for patients with ESRD.36 Using the conservative estimate of 8.6%40 to extrapolate the impact of reduced adherence for sevelamer on healthcare costs, we can estimate that in 2003, patients with a capped benefit taking sevelamer potentially could have had 2.7-fold greater healthcare costs or a potential increase of $1454 PMPM in healthcare costs compared with patients with a noncapped benefit in 2003. Using the high-end estimate of 28.9%, we can estimate that patients taking sevelamer with a capped benefit could potentially experience an increase of $4889 PMPM in healthcare costs compared with patients with a noncapped benefit. Similarly, in 2004 the conservative estimate can potentially yield an increase of $1778 PMPM in total healthcare costs for

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patients who were taking sevelamer with a capped benefit compared with those with a noncapped benefit.

The high-end estimate can potentially yield an increase of $5975 PMPM in total healthcare costs in 2004 for patients taking sevelamer with a capped benefit compared with a noncapped benefit.

What are the implications of our findings for the Medicare Part D benefit? Using the Medicare Current Beneficiary Survey data between 1997 and 2001, Patel and Davis estimate that under the current Part D benefit, patients with ESRD will have mean annual OOP drug costs that are twice those of non-ESRD Medicare patients ($2329 vs $1331, respectively).41 Approximately 54% of the patients with ESRD were taking more than 10 medications, and the majority of patients with ESRD reached the benefit gap (70% vs 43%, respectively) and the catastrophic coverage (39% vs 14%, respectively).41 Patients with ESRD approached the benefit gap and catastrophic coverage earlier (June vs July and July vs September, respectively).41 With a majority of patients with ESRD expected to reach prescription drug coverage limits by midyear and have significant OOP costs, our findings provide evidence of a negative impact of increased cost-sharing on sevelamer adherence.

Limitations The small sample size was a limitation of this study, which may limit the generalizability of the findings, although the characteristics of the patients examined are similar to national estimates.36 We compared retirees to Medicare members in this study and were unable to measure important variables, such as income, that could affect the ability to purchase prescription medications. It is possible that the retiree population in the noncapped group had higher income levels than the Medicare beneficiaries in the capped group, which might have influenced their adherence behavior as well.

We were also not able to measure whether the impact of a potential selection bias of patients with ESRD in a Medicare+Choice plan versus retirees in an employersponsored plan influenced the use of sevelamer.

Conclusion Our pilot study revealed that patients with ESRD taking sevelamer under a capped benefit for brandname coverage had lower levels of adherence compared with those who did not face such a restriction. These results provide preliminary evidence of how ESRD beneficiaries may fare under the current Part D benefit.

With escalating inpatient and outpatient costs for patients with ESRD, research on medication adherence

and its impact on healthcare costs will be beneficial. ■ Disclosure Statement Dr Korner is currently an employee at Roche Pharmaceuticals.

References 1. Moe SM, Sprague AM. Mineral and bone disorders in chronic kidney disease. In: Brenner BM. Brenner & Rector’s The Kidney. Philadelphia, PA: Saunders Elsevier; 2008.

2. Delmez JA, Slatopolsky E. Hyperphosphatemia: its consequences and treatment in patients with chronic renal disease. Am J Kidney Dis. 1992; 4:303-317.

3. Ganesh SK, Stack AG, Levin NW, et al. Association of elevated serum PO(4), Ca ✕ PO(4) product, and parathyroid hormone with cardiac mortality risk in chronic hemodialysis patients. J Am Soc Nephrol. 2001;12:21312138.

4. Block GA, Klassen PS, Lazarus JM, et al. Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. J Am Soc Nephrol. 2004; 15:2208-2218.

5. Block GA, Danese M, Kim K, et al. Elevated PTH and Ca ✕ P levels are associated with increased hospitalization in hemodialysis patients. Am J Kidney Dis. 2003;41:A3. Abstract 15.

6. Block GA, Hulbert-Shearon TE, Levin NW, Port FK. Association of serum phosphorus and calcium ✕ phosphate product with mortality risk in chronic hemodialysis patients: a national study. Am J Kidney Dis. 1998;31: 607-617.

7. Saran R, Bragg-Gresham JL, Rayner HC, et al. Nonadherence in hemodialysis: associations with mortality, hospitalization, and practice patterns in the DOPPS. Kidney Int. 2003;64:254-262.

8. National Kidney Foundation. K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis. 2003;42(4 suppl 3):S1-S201.

9. Bleyer AJ, Burke SK, Dillon M, et al. A comparison of the calcium-free phosphate binder sevelamer hydrochloride with calcium acetate in the treatment of hyperphosphatemia in hemodialysis patients. Am J Kidney Dis. 1999;33:694-701.

10. Block GA, Klassen P, Danese M, et al. Relationship between serum calcium and mortality risk in hemodialysis patients. Am J Kidney Dis. 2003;41:A3. Abstract 16.

11. Chertow GM, Burke SK, Raggi P, for the Treat to Goal Working Group. Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients. Kidney Int. 2002;62:245-252.

12. Goldberg DI, Dillon MA, Slatopolsky EA, et al. Effect of RenaGel, a non-absorbed, calcium- and aluminum-free phosphate binder, on serum phosphorus, calcium, and intact parathyroid hormone in end-stage renal disease patients. Nephrol Dial Transplant. 1998;13:2303-2310.

13. Slatopolsky EA, Burke SK, Dillon MA; the RenaGel Study Group.

RenaGel, a nonabsorbed calcium- and aluminum-free phosphate binder, lowers phosphorus and parathyroid hormone. Kidney Int. 1999;55:299-307.

14. Chertow GM. Slowing the progression of vascular calcification in hemodialysis. J Am Soc Nephrol. 2003;14(9 suppl 4):S310-S314.

15. White CA, Jaffery J, Magner P. Cost of applying the K/DOQI guidelines for bone metabolism and disease to a cohort of chronic hemodialysis patients. Kidney Int. 2007;71:312-317.

16. Goodman WG. Medical management of secondary hyperparathyroidism in chronic renal failure. Nephrol Dial Transplant. 2003;18(suppl 3):iii2-iii8.

17. Amin N. The impact of improved phosphorus control: use of sevelamer hydrochloride in patients with chronic renal failure. Nephrol Dial Transplant. 2002;17:340-345.

18. 2003 Drug Topics Red Book. Montvale, NJ: Medical Economics; 2003.

19. 2004 Drug Topics Red Book. Montvale, NJ: Medical Economics; 2004.

20. Collins AJ, St. Peter WL, Dalleska FW, et al. Hospitalization risks between Renagel phosphate binder treated and non-Renagel treated patients. Clin Nephrol. 2000;54:334-341.

21. Loghman-Adham M. Medication noncompliance in patients with chronic disease: issues in dialysis and renal transplantation. Am J Manag Care. 2003;9:155-171.

22. Bame SI, Petersen N, Wray NP. Variation in hemodialysis patient compliance according to demographic characteristics. Soc Sci Med. 1993; 37:1035-1043.

23. Cleary DJ, Matzke GR, Alexander AC, Joy MS. Medication knowledge and compliance among patients receiving long-term dialysis. Am J Health Syst Pharm. 1995;52:1895-1900.

Continued

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24. Hirth RA, Greer SL, Albert JM, et al. Out of pocket spending and medication adherence among dialysis patients in 12 countries. Health Aff (Millwood). 2008;27:89-102.

25. Hsu J, Price M, Huang J, et al. Unintended consequences of caps on Medicare drug benefits. N Engl J Med. 2006;354:2349-2359.

26. Tamblyn R, Laprise R, Hanley JA, et al. Adverse events associated with prescription drug cost-sharing among poor and elderly persons.

JAMA. 2001;285:421-429.

27. Ho PM, Rumsfeld JS, Masoudi FA, et al. Effect of medication nonadherence on hospitalization and mortality among patients with diabetes mellitus. Arch Intern Med. 2006;166:1836-1841.

28. Patel BV, Remigio-Baker RA, Thiebaud P, et al. Improved persistence and adherence to diuretic fixed-dose combination therapy compared to diuretic monotherapy. BMC Fam Pract. 2008;9:61.

29. Doshi JA, Zhu J, Lee BY, et al. Impact of a prescription copayment increase on lipid-lowering medication adherence in veterans. Circulation.

2009;119:390-397.

30. The Pharmacy Quality Alliance. Proportion of days covered: antidepressant continuation phase. www.pqaalliance.org/files/Nov2008Meeting Materials/MENTALHEALTHAntidepressContinuationPDCMeasure Concept.doc. Accessed February 20, 2009.

31. Centers for Medicare & Medicaid Services. Medicare Part D benefit parameters for standard benefit: annual adjustments for 2007. May 22, 2006. www.cms.hhs.gov/MedicareAdvtgSpecRateStats/Downloads/2007_ Part_D_Parameter_Update.pdf. Accessed September 8, 2009.

32. Centers for Medicare & Medicaid Services. Notification of changes in Medicare Part D payment for calendar year 2008. www.cms.hhs.gov/ MedicareAdvtgSpecRateStats/Downloads/PartDannouncement2008.pdf.

April 2, 2007. Accessed September 8, 2009.

33. Biotechnology Industry Organization. Medicare Part D plans deliver significant savings on innovative, breakthrough medicines. www.bio.org/ healthcare/medicare/BIOPricingSurvey.pdf. Accessed February 20, 2009.

34. Nayeem AI, Chertow GM. Lessons for Medicare Part D in the hemodialysis community. BMC Nephrol. 2006;7:11.

35. Zou G. A modified Poisson regression approach to prospective studies with binary data. Am J Epidemiol. 2004;159:702-706.

36. US Renal Data System. USRDS 2008 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States. 2008. www.usrds.org/2008/pdf/V2_11_2008.pdf. Accessed January 21, 2009.

37. Karamanidou C, Clatworthy J, Weinman J, Horne R. A systematic review of the prevalence and determinants of nonadherence to phosphate binding medication in patients with end-stage renal disease. BMC Nephrol. 2008;9:2.

38. Sokol MC, McGuigan KA, Verbrugge RR, Epstein RS. Impact of medication adherence on hospitalization risk and healthcare costs. Med Care.

2005;43:521-530.

39. Svarstad BL, Shireman TI, Sweeney JK. Using drug claims data to assess the relationship of medication adherence with hospitalization and costs. Psychiatr Serv. 2001;52:805-811.

40. Balkrishnan R, Rajagopalan R, Camacho FT, et al. Predictors of medication adherence and associated health care costs in an older population with type 2 diabetes mellitus. Clin Ther. 2002;25:2958-2971.

41. Patel UD, Davis MM. Falling into the doughnut hole: drug spending among beneficiaries with end-stage renal disease under Medicare Part D plans. J Am Soc Nephrol. 2006;17:2546-2553.

STAKEHOLDER PERSPECTIVE Balancing Horizontal and Vertical Equity within Managed Health Plans Drug Benefit PHARMACY/MEDICAL DIRECTORS: This study by Bhardwaja and colleagues once again highlights effects of prescription benefit coverage limitations on medication adherence in managed care drug programs. Providing coverage for beneficiaries reflects horizontal equity in that coverage is available for many members within a plan. Subsequently, very difficult decisions must be made concerning vertical equityâ&#x20AC;&#x201D;what will the scope of the benefit be for varying beneficiaries? Standardizing care coverage at different levels is a challenge for those involved in benefit design. Through a capped drug benefit, more coverage may be available for a broad base of enrollees, but such a capped benefit as was shown in this study decreased patientsâ&#x20AC;&#x2122; compliance, which can lead to downstream costs that result from the negated beneficial aspect of enhanced compliance.

This study preceded the implementation of the Medicare Part D program, a market-based model of a government-subsidized health insurance program component that began on January 1, 2006. This program also provides a capped benefit with the coverage gap (doughnut hole). During 2006-2009, the median Medicare Part D premiums paid by beneficiaries increased by 35%; between 2008 and 2009 alone, premiums increased by 17%.1 Cost-sharing requirements for recipients also increased by 35%

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over the 3-year period.1 The release of the latest Medicare Annual Report indicates that the Medicare hospital insurance (HI) trust fund is projected to be exhausted by the year 2017.2 The annual updating report from 1 year ago indicated solvency of the HI trust fund through 2019, so in a 1-year period, a 2-year decrease has now been projected. Medicare Part D (and Part B) is funded through a supplementary medical insurance (SMI) fund, which is separate from HI, and SMI is projected to be solvent over the same time period. However, the state of the economy, increased demand for services, and looming healthcare reform could change the SMI metrics very quickly. How these economic challenges within the cacophony of the debates about healthcare reform influence drug benefit design programs will be important to observe in the coming months and years.

References 1. Hargrave E, Haodley J, Cubanski J, Neuman T. New Analysis Reveals Rising Costs for Medicare Part D Enrollees Over Time. Washington, DC: Kaiser Family Foundation. www.kff.org/medicare/upload/7917.pdf.

Accessed June 11, 2009.

2. Centers for Medicare & Medicaid Services. 2009 Annual Report of the Boards of Trustees of the Federal Hospital Insurance and Federal Supplementary Medical Insurance Trust Funds. www.cms.hhs.gov/reports trustfunds/downloads/tr2009.pdf. May 2009. Accessed June 18, 2009.

September/October 2009

Jack E. Fincham, PhD, RPh Professor, University of Missouri School of Pharmacy, Kansas City

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We focus on the human in human health care

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Private Health Plans Perspectives: Electronic Personal Health Records and Electronic Prescribing Nancy M. McGee, JD, MPH; Gene Reeder, RPh, PhD; Timothy S. Regan, BPharm, RPh, CPh; J.D. Kleinke; Steve Arnold, MD, MS, MBA, CPE Background: Patients, payers, public health researchers, medical economists, and policymakers have all called for aggressive deployment of information technologies to support the management of health records and prescriptions. In response, payers of all types have been making investments in electronic systems.

Objectives: To understand, analyze, and quantify current private payer involvement in electronic personal health records and electronic prescribing development and implementation.

Gene Reeder Nancy McGee Methods: A web-based survey involving 62 private commercial payer respondents representing more than 80 million covered lives and 16 national plans.

Results: Responses showed relatively high rates of implementation of electronic personal health records among respondents (20 currently and 9 in the next 24 months), but a unanimity of agreement of disappointing plan members’ utilization of these systems. Implementation rates of electronic prescribing systems are even higher.

More than half of the respondents reported utilization rates below 10%.

Conclusion: The disappointing results with the implementations of electronic systems are most likely the result of variables exogenous to the technologies themselves. The low utilization of electronic prescribing is most likely related to the general lack of penetration of information technology into the work flow of most prescriber offices.

[AHDB. 2009;2(6):252-259.]

A

cross socioeconomic strata, American households are adopting an increasingly electronic way of life. Bills are routinely paid online, bank balances are tracked, goods are purchased, and music is downloaded at record consumer adoption rates.1 Income levels, bank balances, and consumer preferences are routinely shared and stored in the electronic ether. There is a unity of confidence and comfort on behalf of the consumer and the vendor that these personal pieces of information are safe and secure.

Why, then, does healthcare continue to lag behind in the development of electronic solutions, despite a potential to make strides in patient quality of care?2 Are payers being proactive in embracing electronic solu-

Ms McGee is Senior Vice President and Chief Operating Officer, Lash Group, San Bruno, CA. Dr Reeder is Director, Xcenda, Columbia, SC. Mr Regan is Executive Director, Customer Insights, Xcenda, Palm Harbor, FL. Mr Kleinke is Chief Executive Officer, Mount Tabor Online Services, Portland, OR. Dr Arnold is Vice President and Chief Medical Officer, Touchstone Health Plan, LaGrangeville, NY.

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tions to improve healthcare? Are they offering tools for their members to track personal health and solutions for providers to quickly submit drug prescriptions? We know that these tools and solutions exist, but are they being actively developed and adopted by health plans and other payers to create opportunities for more effective and efficient management of member health? This article examines whether payers are adopting electronic personal health records (e-PHRs) to help patients manage their healthcare, as well as electronic prescribing (ePrescribing) technologies to help physicians in prescribing medications for their patients.

Electronic Personal Health Records e-PHRs allow patients to capture, view, store, and share information about their healthcare. In addition, e-PHRs are “more than just static repositories for patient data; they combine data, knowledge, and software tools, which help patients to become active participants in their own care.”3 In December 2006, the Markle Foundation issued a press release with the results of a survey showing that consumers perceive e-PHRs as

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important tools in decreasing medical errors and costly repeat procedures that result in increased quality of patient care.4 The survey also showed that 8 of 10 Americans are concerned about their health data being used in inappropriate ways without their permission.

Ultimately, survey results suggested that while Americans are enthusiastic about e-PHRs, security concerns must be addressed for such technologies to be adopted by consumers.4 These findings from the Markle Foundation set the stage for the current study.

Services related to e-PHRs are continuing to emerge in the market. The primary reason is the growing healthcare consumer demand for connectivity, information access, and electronic communications that are currently standard offerings in many other sectors of the economy.5 In addition, patient financial exposure to an increasing share of medical costs is expanding.6 As a result, these increased costs to the patient are driving the demand for access to information about the comparative cost and quality of care.5 A call by both presidential candidates to decrease the overall cost of healthcare to Americans by adopting technologies to realize savings was a key issue in the 2008 presidential elections. Further, the launch by health plans of online PHR systems, and their promotion of these systems for member retention and as marketing tools, has motivated commercial payers to begin to invest and innovate in this area. Finally, the launch

by Google Health and Microsoft Health Vault of competing personal health information systems that allow consumers to manage their own health data, independent of the systems available from their health plans, have brought additional demand from consumers to have access to e-PHR technologies and services.

Electronic Prescribing e-Prescribing involves technologies that allow prescribers to electronically send prescriptions directly to a pharmacy. The Centers for Medicare & Medicaid Services defines e-Prescribing as, “the transmission, using electronic media, of prescription or prescriptionrelated information between a prescriber, dispenser, pharmacy benefit manager, or health plan, either directly or through an intermediary, including an e-Prescribing network. e-Prescribing includes, but is not limited to, 2way transmissions between the point of care and the dispenser.”7 This definition has provided guidance to payers as they continue to develop, adopt, and implement ePrescribing technologies for prescribers.

To learn more about how private payers are participating in the development and implementation of e-

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KEY POINTS u

Investing in e-Prescribing and e-PHR systems is costly but has the potential to improve the delivery of care and reduce healthcare costs. u This survey of 62 commercial payers representing >80 million covered lives investigated payers’ current and potential level of implementation of these electronic systems in their respective plans. u Responses showed relatively high rates of implementation of health information technology: 20 payers have already implemented such systems and 9 payers will be doing so in the next 24 months. u However, this survey also reveals a unanimously low level of plan members’ utilization of these systems.

More than half of the respondents reported utilization rates below 10%.

PHRs and e-Prescribing technologies, Lash Group, a firm focused on patient access issues, commissioned Xcenda, a healthcare consulting firm, to conduct a web-based survey with members of Managed Care Network (MCN) in October 2008. MCN is composed of more than 100 key medical and pharmacy directors from national and regional managed care organizations across the United States. More than 100 MCN members were invited via an e-mail to participate in the survey created by the authors of this article. The response rate was approximately 62%. Data from the online survey were analyzed by consultants at Xcenda. These data form the basis for this article.

Participant Demographics A total of 62 (of more than 100) private payers representing more than 80 million covered lives and 16 national plans responded to the survey. Although respondents could select more than 1 response to characterize their health plan, the plans with the highest representation were: • Commercial (33) • Medicare Advantage (23) • Managed Medicaid (16).

The remaining participants described themselves as integrated healthcare (13); Medicare prescription drug plan (13); pharmacy benefit manager (5); and traditional Medicaid (4).

Figure 1 represents the geographic coverage of the plan participants.

Nearly 94% (58) of the respondents indicated that they were members of the health plan’s P&T Committee. Additional job functions included pharmacy

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Figure 1 Plan Participant Geographic Coverage

Table 1 Potential Risks of Health Plan–Implemented e-PHRs, Perceived by Payers (n = 62)

Northeast

34

National

26

Midwest

Geographic region

Potential risks

21

West

13

Southwest

10

Southeast

Respondents % (N)

Liability for privacy and security breaches

48 (30)

Increased liability if network providers fail to access or use the information in a member’s e-PHR

40 (25)

Increased liability for missing information that adversely affects a member’s medical care

37 (23)

Increased conflict with network providers because of the release of the information to their patients

32 (20)

None

16 (10)

Othera

7 (4)

7

Other

3

Northwest

3

North

2 0

South

0

5

10

15 20 25 30 Surveyed payers (n = 62), %

35

40

Note: Total is more than 100% because some plans cover multiple geographic areas.

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operations (38); medical management (16); policy development (3); provider relations (2); and other, including pharmaceutical managed care consultants and formulary management (3).

Other responses included: miscoded data that labels a patient to have a condition that they do not; risk of “down time”—if member or doctor is not able to access the information when needed; fewer gaps in care of patients; and high resource need for only a small percentage of population use.

Results Respondents were asked to think about any type of e-tool currently in use by their health plan members.

The survey question was worded as follows: “Think for a moment about any type of ‘e-tool’ currently in use by your health plan members. Please estimate the percentage of current members who use any type of health plan ‘e-tool’ that might be available to them.” In this context, “e-tool” was defined as any health plan educational tool that is available in electronic form to the members of the plan. They were then asked to estimate the percentage of current members who use any type of health plan e-tool that might be available to them. Of the 62 respondents, 32 estimated that between 1% and 25% of their current members used some type of health plan e-tool that was available to them, while 13 participants estimated that between 26% and 50% of participants use some type of e-tools. Eleven participants estimated that between 51% and 100% of their members used e-tools, while 6 plans estimated that there was no use of any e-tools by their members.

The survey reflected that 59 payers (95%) felt that the overall effect of a member’s use of e-PHRs would be positive for both the member and for the health plan.

In addition, 46 payers agreed or strongly agreed that

e-PHRs can be effective in managing plan members’ medical treatment and overall health status. Fortyeight of the payers in the survey felt that e-PHRs provided improvements in 2 key areas: (1) the overall quality of the member’s medical care, and (2) the ability to communicate with providers. In addition, 26 payers also felt that improvements in the overall health status of the member could be realized.

Payers also perceived risks associated with health plan implementation of e-PHRs. Table 1 sets forth a summary of these potential risks. Specifically, 30 payers were concerned with liability for privacy and security breaches. Other areas of concern included the potential for increased risk of liability if network providers fail to access or use the information in a member’s ePHR, increased risk of liability for missing information that adversely affects a member’s medical care, and increased conflict with network providers as a result of the release of information to their patients.

Currently, 20 of the respondent’s plans offer some form of e-PHR access to their members. Of the remaining 42 plans, 9 indicated that they planned to do so within the next 24 months. The major factors that are motivating payer decision-making in providing e-PHR tools to members include benefits related to quality of

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Figure 2 Rating of Most Important Factors for Implementing/ Promoting e-Prescribing: Comparing Plans with (cohort 1) and without (cohort 2) e-Prescribing Systems 60

52% 50% (24) (8)

50 Respondents, %

care and preventive health.

For the 20 payers that do offer e-PHRs, the cost of implementing e-PHR access was not a major factor.

These payers also answered a question related to whether their health plan implemented an e-PHR as a part of its marketing and member retention strategy, 10 payers agreed; however, adoption rates were relatively low, with 2 payers indicating that 31% or more of their current members access their e-PHR at least once every 60 days. As may be expected, all 20 payers who provided e-PHR access were disappointed by the low amount of member use of the e-PHR system.

The total group of 62 respondents divided into 2 cohorts. The first cohort, consisting of 46 payers, included plans that support or promote e-Prescribing directly or indirectly. The second cohort, consisting of 16 payers, included plans that do not currently support or promote e-Prescribing. Taken collectively, these results indicate that payer adoption of e-Prescribing is further along than e-PHRs. Many of the plans that had more than 300,000 covered lives have already funded and implemented e-Prescribing systems. The major reasons for implementing e-Prescribing included improved formulary compliance and reduced medication errors. These improvements translate into a high return on investment for payers that implement e-Prescribing platforms.

Of plans in the first cohort with e-Prescribing platforms, 37 primarily used the system to direct providers to preferred drugs within the therapeutic class. In addition, 29 plans with e-Prescribing platforms use the system to check for potential drug contraindications.

Of the 16 plans in the second cohort that currently do not offer e-Prescribing, 6 payers plan to do so in the next 24 months. Within this cohort, 8 payers rated the most important reason for implementing e-Prescribing as reduced medication errors, followed by improved formulary compliance (3 payers) and increased therapeutic and/or generic substitution rates (3 payers).

Direction of a greater percentage of total prescriptions to preferred fulfillment channels, such as mail-order or network pharmacies, was rated as being most important for 2 payers in this subset. Figure 2 compares the importance ratings for e-Prescribing of the 2 cohorts.

Both cohorts were asked what effect an ePrescribing system would have on the reimbursement status of drugs currently covered under the medical benefit (Table 2). Of the 46 payers with e-Prescribing systems, 31 felt that the system allows them to narrow coverage for drugs within a class. For example, this may occur because of the opportunity to more closely mon-

Cohort 1 (n = 46) Cohort 2 (n = 16)

40 30 20

22% (10) 19% (3)

15% (7)

19% (3)

10

13% (2)

11% (5)

0 Improved formulary compliance

Reduced medication errors

Increased Direction of greater therapeutic percentage of total and/or generic prescriptions to substitution rates preferred fulfillment channels (eg, mailorder, network pharmacies)

Most important factors

Note: Cohort 1 consists of 46 payers that support or promote e-Prescribing either directly or indirectly. Cohort 2 consists of 16 payers that do not support e-Prescribing either directly or indirectly.

itor utilization of these types of drugs. Similarly, of the 16 payers without an e-Prescribing system, 13 felt that an e-Prescribing system would allow them to narrow coverage for drugs. Conversely, when both cohorts were asked if an e-Prescribing system might expand coverage for more drugs within a class because of the automation of prior authorization and greater opportunities with exceptions documentation, the percentages were smaller. In the first cohort, 6 payers thought that coverage might expand, and in the second cohort only 3 payers thought that an e-Prescribing system would allow for an expansion of coverage.

In addition, the cohort without e-Prescribing was asked what effect an e-Prescribing system might have on the utilization of specialty drugs covered under the pharmacy benefit. For this question, respondents were permitted to check all answers that applied to their plan. Of the 16 payers in this cohort, 14 believed that the system would be used to direct providers to the preferred drugs within the therapeutic class; 12 suggested that the e-Prescribing system would be used to automate prior authorization and other administrative processes; 11 thought the system would be used to check for potential contraindications for these and other drugs that the patient is taking; and 9 said that the system would be used to channel fulfillment to preferred distributors.

The 46 payers with e-Prescribing were asked about

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Table 2 Effect of e-Prescribing on Reimbursement of Drugs under Medical Benefit Effects of e-Prescribing system

Cohort 1 (n = 46)

Cohort 2 (n = 16)

The system would allow us to narrow coverage for drugs within a class (eg, because of the ability to closely monitor drug utilization)

31

13

I do not know

9

0

The system would allow us to expand coverage for more drugs within a class (eg, because of automation of prior authorization and more opportunities for exceptions documentation)

6

3

the impact of the system from a technologic, economic, and provider relations standpoint (Table 3). Results of the respective ratings of the technologic impact of implementing and/or promoting an e-Prescribing system to their organization were bimodal; 22 payers (48%) reported a significant impact and 16 payers (35%) reported a minor impact. Similarly, the implementation of the technology was viewed as largely positive to their organizations, with 19 payers reporting positive or very positive effects. Finally, payers reported that the effect of the technology implementation to

Some of the most successful examples of implemented e-PHRs have occurred in group practices where patients have access to e-PHRs that mirror their physician’s electronic medical records. their organization was as anticipated, with the same 19 payers reporting expected effects or just as expected effects, and only a few unexpected. Economic impacts were minor and as expected. Only 6 payers indicated an unexpected or minor influence. The impact on the health plan provider relations varied, with plans reporting major and minor influences; however, the

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impact was positive and in line with plan expectations.

Although most respondents were neutral about goal achievement for their e-Prescribing initiative, 32 indicated that implementation or promotion of an ePrescribing system had helped their health plan achieve its pharmacy management goals.

Although the survey responses from both cohorts indicated that e-Prescribing is viewed as a valued resource by 46 (74%) of the payers, the frequency of prescriber use of a plan’s e-Prescribing capabilities was relatively low. More than 50% of respondents indicated that less than 10% of prescribers accessed the ePrescribing system at least once every 60 days. Data reflected an overall disappointment by payers relative to the low prescriber use of e-Prescribing in their plans.

Discussion Payers responding to our survey indicated that the greatest perceived benefit of e-PHR was improvements in the quality of members’ medical care. In addition, they recognized the benefit for members to be able to communicate with their providers and participate in the management of their overall health status. Quality of care and preventive health benefits were the major factors in payers’ decisions to provide e-PHR to members.

Cost was not a major factor in the decision-making process; however, utilization of these tools remains low.

The findings related to low member utilization are consistent with the Markle Foundation’s survey that was conducted in 2006. That survey highlighted the concern of Americans about the possible inappropriate use of their health information.4 Based on the data from our survey, one explanation for the low utilization is a continued concern by members about the privacy of their health records. Despite optimism that e-PHR could give physicians access to a more complete picture of the patient’s health, it is not clear what type of ePHR will be accepted by the public as a standard.8 Although some forms of e-PHR are populated by the patient, others integrate with claims data from the health plan. In either case, many argue that it is necessary for the government to set standards for privacy and data standards before the public will have sufficient trust in using e-PHR as a tool.8 In addition, there continues to be limited access to computers and the Internet by the patients that could benefit the most from an e-PHR, including Medicareaged patients. Programs are under way to ameliorate this problem through the use of improved connectivity and accessibility, such as the use of cell phones for ePHR and disease management, decisions regarding

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Table 3 Technologic, Economic, and Provider Relations Impact Implementation of e-Prescribing 1. Technologic Impact

1

2

3

4

5

Description (n = 46)

1a. On a scale of 1-5, with 5 representing a very major impact, how would you rate the technologic impact of implementing and/or promoting an e-Prescribing system on your organization?

22% (10)

13% (6)

17% (8)

39% (18)

9% (4)

Impact was bimodal: 48% reported significant impact, 35% reported minor influence; mean = 3.0

1b. On a scale of 1-5, with 5 representing a very positive impact, how would you rate the technologic impact of implementing and/or promoting an e-Prescribing system on your organization?

0% (0)

9% (4)

50% (23)

33% (15)

9% (4)

Impact mostly positive: 40% reported positive/very positive effects, few negatives; mean = 3.4

1c. On a scale of 1-5, with 5 representing the exact impact you expected, how would you rate the technologic impact of implementing and/or promoting an e-Prescribing system on your organization?

0% (0)

11% (5)

48% (22)

33% (15)

9% (4)

Impact was largely as anticipated: 40% reported expected/just as expected effects, a few unexpected; mean = 3.4

2a. On a scale of 1-5, with 5 representing a major impact, how would you rate the economic impact of implementing and/or promoting an e-Prescribing system on your organization?

24% (11)

17% (8)

33% (15)

20% (9)

7% (3)

Economic impact on health plan largely mild or minor influence; mean = 2.7

2b. On a scale of 1-5, with 5 representing a very positive impact, would you rate the economic impact of implementing and/or promoting an e-Prescribing system to your organization?

0% (0)

15% (7)

63% (29)

22% (10)

0% (0)

Economic impact on health plan close to neutral; mean = 3.1

2c. On a scale of 1-5, with 5 representing the exact impact you expected, how would you rate the economic impact of implementing and/or promoting an e-Prescribing system on your organization?

0% (0)

13% (6)

52% (24)

30% (14)

4% (2)

Economic impact on health plan largely as expected, only 13% indicated unanticipated minor influence; mean = 3.3

3a. On a scale of 1-5, with 5 representing a very major impact, how would you rate the impact of implementing and/or promoting an ePrescribing system on provider relations for your organization?

13% (6)

17% (8)

39% (18)

26% (12)

4% (2)

Impact on the health plan provider relations was varied with plans reporting both major and minor influence; mean = 2.9

3b. On a scale of 1-5, with 5 representing a very positive impact, how would you rate the impact of implementing and/or promoting an ePrescribing system on provider relations for your organization?

0% (0)

9% (4)

52% (24)

35% (16)

4% (2)

Impact on health plan provider relations mostly positive, few negative impacts; mean = 3.3

3c. On a scale of 1-5, with 5 representing the exact impact you expected, how would you rate the impact of implementing and/or promoting an e-Prescribing system on provider relations for your organization?

0% (0)

17% (8)

41% (19)

37% (17)

4% (2)

Impact on health plan provider relations in line with plan expectations, only 17% reported somewhat unexpected effects; mean = 3.3

2. Economic Impact

3. Provider Relations Impact

what elements should be part of an e-PHR, and how this can relate to improved compliance and utilization.9 Some of the most successful examples of implemented e-PHRs have occurred in group practices where patients have access to e-PHRs that mirror their physi-

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cianâ&#x20AC;&#x2122;s electronic medical records.8 Payers had a greater adoption rate of e-Prescribing systems than e-PHRs. Respondents believed that the benefits of e-Prescribing include fewer medication errors, better control of possible contraindications,

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improved medication management, and compliance with payer formularies. All these benefits relate to improved member health, as well as the potential for cost-savings to the payer by enforcing utilization controls. Data showed that whereas channel management is important, it is not as compelling to payers as formulary compliance and increased substitution rates.

Because channel fulfillment can be a contract issue with specialty pharmacies or brown-bagging out of the pharmacy, it is possible that providing tools to prescribers to use the recommended drug is the primary reason that payers want to implement e-Prescribing platforms within their plans. This finding could be explained by some of the respondents being integrated with specialty pharmacies, while others may not have as much connectivity to distribution. As a result, the interest in fulfillment is higher with specialty products than with products currently covered under the medical benefit.

Although incentives are one way of encouraging a specific behavior, assistance with education and integration with office workflows should be considered as additional means to help providers adopt e-Prescribing technologies.

As with e-PHR utilization, payers were similarly disappointed that the frequency of prescriber use of their plan’s e-Prescribing capabilities was relatively low. It is foreseeable that as plans begin to manage drugs covered under the pharmacy and medical benefits with greater scrutiny, prescribers will adopt this technology at a greater rate.

Currently, low adoption of e-Prescribing by prescribers may be explained by the significant financial burden of investing in the necessary hardware and software to integrate e-Prescribing with their existing practice management systems. Examples of additional costs to prescribers include training costs, maintenance fees, and upgrade costs.10 Another barrier involves prescriptions for controlled substances, which may not be transmitted electronically.10 As a result of these barriers, adoption rates currently appear to be low among survey respondents.

Both the government and private insurers have put a plan in place to create incentives for e-Prescribing adoption and use. Under the Medicare Improvements for Patients and Providers Act of 2008, “Medicare will

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provide incentive payments to eligible physicians who meet an annual threshold of e-Prescribing and patient volume.”11 Private insurers are giving away e-Prescribing software to encourage provider uptake and use.11 Although incentives are one way of encouraging a specific behavior, assistance with education and integration with office workflows should be considered as additional means to help providers adopt e-Prescribing technologies.11 Ultimately, as technology becomes more affordable, and the ability to integrate existing systems becomes easier, it is foreseeable that workflows will change, the adoption rates will increase, and prescriber utilization of e-Prescribing systems will likely improve.

Conclusion There is no doubt that healthcare consumer demand is growing for connectivity, information access, and electronic communications. Similarly, payers are looking for ways to improve formulary compliance and reduce medication errors. e-PHR is an example of a technology that plans are developing to help patients make decisions about their healthcare based on cost and quality measures. Similarly, e-Prescribing technologies are being developed by payers to help physicians send prescriptions electronically to pharmacies.

The intent of these technologies is positive for patients, physicians, and payers, but hurdles related to data security remain. It will be important for payers to provide confidence to plan members that their data will not be shared inappropriately. Similarly, the cost to providers of implementing new systems will need to be managed carefully to encourage adoption and routine utilization of the technology. ■ References 1. Gonsalves A. Digital downloads rise as music CD sales fall. Information Week. December 19, 2008. www.informationweek.com/news/personal_tech/ music/showArticle.jhtml;jsessionid=ON3YXGG2HVP0IQSN DLPCKH0CJUNN2JVN?articleID=212501299&_requestid=59385 Accessed January 2, 2009.

2. Poon EG, Jha AK, Christino M, et al. Assessing the level of healthcare information technology adoption in the United States: a snapshot.

BMC Med Inform Decis Mak. 2006;6:1.

3. Tang PC, Ash JS, Bates DW, et al. Personal health records: definitions, benefits, and strategies for overcoming barriers to adoption. J Am Med Inform Assoc. 2006;13:121-126.

4. Americans see access to their medical information as a way to improve quality, reduce health care costs. Markle Foundation press release.

December 7, 2006. www.markle.org/resources/press_center/press_releases/ 2006/press_release_12062006.php. Accessed December 29, 2008.

5. Krohn R. The consumer-centric personal health record—it’s time.

J Healthc Inf Manag. 2007;21:20-23.

6. Bodenheimer T. High and rising health care costs. Part 1: seeking an explanation. Ann Intern Med. 2005;142:847-854.

7. Department of Health and Human Services. Centers for Medicare &

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Medicaid Services. Rules and Regulations. 42 CFR Part 423 Medicare Program. E-Prescribing and the Prescription Drug Program; Final Rule.

Fed Reg. 2005;70(214):67,593.

2006/press_release_12062006.php. Accessed December 29, 2008.

8. Terry K. Will PHRs rule the waves or roll out with the tide? Hosp Health Netw. 2008;82:36-39,1.

9. Blake H. Mobile phone technology in chronic disease management.

Nurs Stand. 2008;23:43-46.

10. Electronic prescribing becoming mainstream practice. The Center for Improving Medication Management. eHealth Initiative Report. June 8, 2008. www.ehealthinitiative.org/e-Prescribing/. Accessed December, 29, 2008.

11. Freidman M, Schueth A, Bell DS. Interoperable electronic prescribing in the United States: a progress report. Health Aff (Millwood). 2009; 28:393-403.

STAKEHOLDER PERSPECTIVE Electronic PHRs and e-Prescribing: Not Quite There Yet MEDICAL DIRECTORS: The use of health information technology (HIT) is definitely being embraced by health plans. In this article, we learn that a significant number of health plans have made major investments in electronic personal health records (e-PHRs) and electronic (e-Prescribing).

Plans recognize that this costly investment has the potential to improve the delivery of healthcare and are willing to underwrite the cost of these systems as an investment in the future. e-PHRs have the potential to allow members to view and share their records with multiple providers, allowing members to interact more effectively and more accurately with providers. Yet, from the survey in this article we learn that the utilization of these systems by plan members remains relatively low, at less than 10%. Although the reasons for this low utilization may vary from lack of connectivity for some population segments to lack of interest by others, privacy is still a major concern for the public.

Patients are concerned about who can access their records, and for what purposes. However, privacy concern is not the sole reason for slow adoption of these records. In the past, medical record keeping has been viewed as a process external to the patient; the doctor or hospital has been responsible for managing these records. Until patients understand the value of having access to medical information, and until that value is demonstrated to them by improved encounters with the system, patients are

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unlikely to take an active interest in e-PHRs. The survey also shows that despite almost universal availability of e-Prescribing in major health plans, providers have been slow to adopt this technology. Like the patients they serve, doctors have not yet learned how to incorporate this technology into their practice routines effectively. They, too, will need to better understand the benefits of this technology, and how it can improve care by reducing errors and minimizing drug窶電rug interactions before adopting e-Prescribing into their daily routine.

The intent is clearly to move the healthcare system toward increased use of HIT, and the benefits are obvious. What is not yet clear is how to get providers and patients to adopt these systems. Plans will need to actively promote the benefits and outcomes of using HIT to their members and providers to ultimately reap the benefits of this technology. Like all new things, change often comes slowly; sometimes the pace of that change is frustrating to its leaders. But we have crossed the bridge to the electronic era in medicine, and we now will need to continue to find innovative ways to increase adoption of these systems.

Although we are not quite there yet, continued investment in HIT, coupled with reassurance about its benefits, will allow us to continue to move forward Gary M. Owens, MD Gary Owens Associates Philadelphia, PA

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Savella (Milnacipran HCl): A New Option for the Management of Fibromyalgia Stakeholder Perspectives

By Nirav R. Shah, MD, MPH; Gary M. Owens, MD; Philip Mease, MD

Forest Pharmaceuticals, Inc, provided funding for this publication.

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Savella (Milnacipran HCl): A New Option for the Management of Fibromyalgia

By Loretta Fala, Medical Writer

F

ibromyalgia (FM) is a condition characterized by chronic, widespread soft-tissue pain with tender points along with other symptoms, often resulting in functional impairment. Affecting an estimated 2% to 4% of the US population, generally first diagnosed between the ages of 20 and 50 years, FM is about 7 times more common in women than in men.1 The incidence of FM rises with age. By age 80 years, approximately 8% of adults meet the classification of FM set forth by the American College of Rheumatology (ACR).2 Patients with lupus, rheumatoid arthritis (RA), or ankylosing spondylitis are at risk for FM.1

Burden of Illness FM is costly to the individual patient and to society.

In the United States, costs attributed to FM are estimated at $12 billion to $14 billion annually and are associated with a loss of 1% to 2% of the nationâ&#x20AC;&#x2122;s overall productivity.3 According to a 2007 study, 34% of patients with FM spend between $100 to $1000 monthly above their insurance coverage to visit a clinician.3 The mean annual healthcare costs are approximately 3 times higher among patients with FM than those without FM.3 Pain-related medication costs account for about 11% of the total costs.3 In addition, twice as many patients with FM use nonpain medications, including antibiotics, cough and cold medications, and ulcer drugs.3 Employees with FM incur total annual costs nearly twice as high as other employees.4 They also incur medical and drug costs that are a staggering 86% higher than costs incurred by others.4 Moreover, based on a multicenter survey designed to assess the work and disability status of 1604 patients with FM, an estimated 26.5% of workers receive some form of disability payment.5 For employees with FM, the prevalence of disability is estimated to be twice as high as that of all employees.2 Failure to diagnose a true case of FM is costly in terms of medical resources and can result in excess visits to a general practitioner, as well as excess prescriptions, referrals, and diagnostics.2,6 Conversely, diagnosed cases of FM lead to savings and a decrease in resource utilization, particularly for tests and imaging studies.6 Fibromyalgia Diagnosis FM may be accompanied by many symptoms, including fatigue, sleep disturbances, morning stiffness,

cognitive difficulties, headaches and migraines, irritable bowel syndrome, mood disturbances, temporomandibular joint dysfunction, and environmental sensitivities.2,7,8 Often diagnosed by primary care physicians, FM accounts for an estimated 15% to 20% of visits to rheumatologists, second only to osteoarthritis as the most common presenting factor.7,9 Although FM is not life threatening,10 it can have a significant impact on a patientâ&#x20AC;&#x2122;s quality of life (QoL) and daily functioning.11 Based on a study comparing QoL of women with FM with that of women with RA, osteoarthritis, permanent ostomies, insulin-dependent diabetes, and healthy controls, women with FM consistently scored lowest in all categories.12 FM is recognized as a legitimate clinical entity by the American Medical Association, National Institutes of Health, World Health Organization, ACR, and the US Food and Drug Administration (FDA).11,13 Recent studies suggest that patients with FM have a generalized disturbance in pain processing and an amplified response to stimuli.2 Alterations occurring in the central nervous system (CNS) and at the periphery may contribute to the sensation of pain.14 The perception of pain involves a complex interaction between the ascending and descending pathways, with the ability to change the dynamic between stimulus and response.14 Moreover, the descending pathway systems may have an important role in central sensitization.14 Neurotransmitter defects in ascending and descending CNS pathways contribute to the pain associated with FM.15,16 The neurotransmitters serotonin and norepinephrine play a role in descending pain-inhibiting pathways.14,15 Another neurotransmitter, substance P, is an 11 amino acid neuropeptide being studied for its presumed role in pain transmission.14 Substance P coexists with glutamate in afferent terminals of the spinal cord.14 Abnormalities associated with norepinephrine and serotonin have been seen in patients with FM.14,15 Data suggest a potential decrease in serotonin- and norepinephrine-related activity in patients with FM.14 Conversely, increased levels of substance P and glutamate have been seen in these patients.14-16 Against this background, increasing attention is focused on the CNS and aberrant pain processing as the underlying mechanism of FM.2 Despite increasing recognition, FM continues to be overlooked and misdiagnosed, and its diagnosis is often

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delayed.7,11 Because its symptoms are similar to other disorders, FM is difficult to diagnose.7 Conditions that must be ruled out before FM diagnosis include RA, polymyalgia rheumatica, hypothyroidism, and lupus.17,18 If compelling evidence exists, other tests, such as a Lyme antibody, may be warranted.18 The diagnostic criteria for FM established by the ACR include a history of widespread pain in all 4 quadrants of the body for more than 3 months, and pain in a minimum of 11 of the 18 designated tender spots when pressure is applied.18,19 Although no cure is available, treatment can provide symptom relief and function improvement.10 The therapeutic goals of medication include the management of pain, fatigue, and reduced function, and improving other FM-associated symptoms.20 Nonpharmacologic approaches to FM include patient education, exercise, alternative therapies, and self-management.1

Drug Therapy In January 2009, milnacipran HCl (Savella), a dual serotonin-norepinephrine reuptake inhibitor (SNRI), was approved for the management of FM. It is a welcome addition to the limited arsenal of agents available for FM. The 2 other FDA-approved drugs are the anticonvulsant Lyrica (pregabalin), and the SNRI Cymbalta (duloxetine hydrochloride).

Pregabalin is indicated for the management of FM, pain associated with diabetic peripheral neuropathy (DPN), postherpetic neuralgia, and partial-onset seizures.21 Duloxetine is indicated for the management of FM, depression, generalized anxiety disorder, and DPN.22 Milnacipran is currently the only agent approved solely for the management of FM.23 Milnacipran is available in 4 tablet strengths.23 Based on findings from 2 pivotal phase 3 clinical trials, treatment with milnacipran 100 mg/day (50 mg twice daily) or 200 mg/day (100 mg twice daily) showed significant and clinically meaningful concurrent improvements across 3 measures of FM—pain reduction, patient global assessment, and physical function.9,24 Milnacipran is the first and only product approved to treat the symptoms of FM using a composite responder analysis as the primary end point.21-24 Clinical Pharmacology Milnacipran is indicated for the management of FM in adults (≥18 years old). It is not approved for use in patients younger than age 18. The exact mechanism of milnacipran’s central pain inhibitory action is unknown.23 In preclinical studies, milnacipran has been shown to inhibit neuronal norepinephrine and serotonin reuptake, demonstrating a 3-fold more potent inhibition of norepinephrine uptake in vitro than sero-

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tonin, without directly affecting the uptake of dopamine or other neurotransmitters.23 In in vitro studies, milnacipran was distinguished from other dual reuptake inhibitors, including duloxetine and venlafaxine, by its selectivity for norepinephrine over serotonin, whereas duloxetine and venlafaxine are more selective for serotonin reuptake inhibition over norepinephrine.24 Because milnacipran shows an affinity for the norepinephrine and serotonin receptors, without binding to dopamine, histamine, or muscarinic receptors, it is not associated with many of the side effects of tricyclic antidepressants.8,23 Milnacipran is well absorbed, with an absolute bioavailability of approximately 85% to 90%, reaching maximum concentrations within 2 to 4 hours.23 Absorption is not affected by food. Excreted primarily unchanged in urine (55%), milnacipran has a terminal elimination half-life of 6 to 8 hours. Steady-state levels are reached in 36 to 48 hours. Milnacipran has a low degree of binding to plasma proteins (13%).23

Results from Clinical Trials At the Outcomes Measures in Rheumatology 8 (OMERACT 8) meeting, 23 clinicians with expertise in FM convened to reach consensus on core symptom domains, evaluate outcome measures in clinical trials, and define research agenda. During the meeting, physicians and patients were asked to rank 40 FM-specific domains in relative importance.25 The top 4 core criteria rated as “essential,” in order of importance, were25: • Pain • Fatigue • Patient global status • Multidimensional function.

OMERACT 8 participants agreed that “the ability to measure clinically meaningful change in multiple dimensions of fibromyalgia utilizing a composite responder index is desirable.”25 This formed the clinical end point framework for the milnacipran clinical studies.

The FDA approval of milnacipran was based on the results of 2 randomized, multicenter, double-blind, placebo-controlled US studies that used a composite responder analysis.9,24 The 2 primary end points were rates of FM composite responders (3-measure composite) and pain responders (2-measure composite). Threemeasure composite responders were defined as patients concurrently experiencing clinically meaningful improvements in 3 domain criteria—pain (30% or more improvement in pain), patient global status (rating of very much improved, a score of 1, or much improved, a score of 2, on the patient global impression of change [PGIC] scale), and physical function, defined as a 6point or more improvement in the Short-Form 36 physical component summary score. Two-measure composite

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Table 1 Milnacipran Multimeasure Responder Analysis Demonstrating Significant Fibromyalgia Relief Threshold for response ≥30% reduction from baseline score

Area of improvement Pain relief

Measure VAS pain

Global improvement

PGIC

Score of 1 or 2: “very much improved” or “much improved”

Physical functional improvement

SF-36 PCS

≥6 point improvement

2-Measure composite respondersa √

3-Measure composite respondersb √

√

√

√

a2-measure

composite responders were required to demonstrate simultaneous pain relief and global improvement versus placebo. composite responders were required to demonstrate simultaneous pain relief, global improvement, and physical function versus placebo.

PGIC indicates patient global impression of change; SF-36 PCS, Short-Form 36 physical component survey; VAS, visual analog scale. b3-measure

responders were defined as those who met the pain and the PGIC criteria.9,24 Pain data for the milnacipran trials were captured via an electronic patient diary that measured pain from a scale of 0 (no pain) to 100 (worst possible pain).9,24 Patients reported their current level of pain at specific intervals. Data collections were taken in the morning, at 3 to 5 random prompts throughout the day, and in the evening. In the morning report, patients rated their average level of pain in the previous 24 hours; and at the end of a 7-day period, patients rated their average level of pain for the previous 7 days.9,24 Milnacipran is the only agent approved for the management of FM that collected pain data with the help of an electronic patient diary, which allows for capturing real-time pain data, as well as 24-hour and 7-day pain recall.

The first study included 86 centers and 1196 patients who were randomized to 15 weeks of treatment with milnacipran 100 mg/day, milnacipran 200 mg/day, or to placebo.9 The second study included 59 centers and 888 patients randomized to 15 weeks of milnacipran 100 mg/day, milnacipran 200 mg/day, or to placebo.24 Although the primary end point was 3 months, this trial also included a 27-week end point.24 Findings from both studies showed that milnacipran achieved a significant response rate compared with placebo in the 2-measure and 3-measure composite at 3 months (Table 1).9,24 In both studies, a significant decrease in pain was reported as early as week 1 of treatment with a stable dose of milnacipran in patients who reported themselves globally very much or much improved.9,23,24

Adverse Reactions Milnacipran was found to be safe and generally well tolerated in clinical trials. The most common adverse event (AE) was nausea (37% vs 20% for placebo).19,22 Other AEs more common (≥5% and greater than

placebo) with milnacipran include headache, constipation, dizziness, insomnia, hot flushes, hyperhidrosis, vomiting, palpitations, heart rate increase, dry mouth, and hypertension.23 Overall, premature treatment discontinuation in clinical trials because of AEs was 23% in patients treated with milnacipran 100 mg/day and 26% with milnacipran 200 mg/day compared with 12% of placebotreated patients.23 Milnacipran is not associated with a significant incidence of fatigue or somnolence and does not cause weight gain.23 Patients treated with milnacipran for up to 3 months in both the 100 mg/day and the 200 mg/day treatment groups experienced a weight loss of approximately 0.8 kg, compared with a mean weight loss of approximately 0.2 kg in placebotreated patients.23

Contraindications Like other dual reuptake inhibitors, milnacipran’s label includes a black box warning about the risk for increased suicidal ideation or behavior in children, adolescents, and young adults with major depressive disorder and other psychiatric disorders.1 Milnacipran is not approved for use in pediatric patients.23 The development of a potentially life-threatening serotonin syndrome or neuroleptic malignant syndrome (NMS)-like reactions have been reported with SNRIs and selective serotonin reuptake inhibitors (SSRIs) alone, including milnacipran, but particularly with concomitant use of serotonergic drugs (including triptans), with drugs that impair metabolism of serotonin, including monoamine oxidase inhibitors (MAOIs), or with antipsychotics or other dopamine antagonists. In its most severe form, serotonin syndrome can resemble NMS. Patients should be monitored for the emergence of serotonin syndrome or NMS-like signs and symptoms.

Milnacipran is also contraindicated for use within

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MAOIs concomitantly, or within 14 days of discontinuing an MAOI. A minimum of 5 days should be allowed between discontinuing milnacipran and starting an MAOI.23 The SNRIs, including milnacipran, have been associated with reports of an increase in blood pressure (BP). In the 3-month placebo-controlled FM clinical trials, milnacipran treatment was associated with mean increases of up to 3.1 mm Hg in systolic BP and diastolic BP. Sustained increases in BP could have adverse consequences. BP should be measured before initiating milnacipran treatment and measured periodically throughout the treatment. Preexisting hypertension and other cardiovascular conditions should be treated before starting therapy with milnacipran. Dose reduction or discontinuation should be considered for patients with a sustained increase in BP while taking milnacipran.23 Reports of increases in heart rate have been associated with SNRIs, including milnacipran. In clinical trials, relative to placebo, milnacipran treatment was associated with mean increases in pulse rate of approximately 7 to 8 beats per minute.23 Heart rate should be measured before initiating milnacipran treatment and measured periodically throughout treatment. Preexisting tachyarrhythmias and other cardiac conditions should be treated before starting therapy with milnacipran. Dose reduction or discontinuation should be considered for patients who experience a sustained increase in heart rate while taking milnacipran.23 Withdrawal symptoms have been observed in clinical trials following discontinuation of milnacipran, as with other SNRIs and SSRIs. Patients should be monitored for these symptoms when discontinuing treatment with milnacipran. Milnacipran should be tapered and not discontinued abruptly after extended use.23 SSRIs and SNRIs, including milnacipran, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, and other anticoagulants may contribute to this risk. Patients should be cautioned about the risk of bleeding associated with the concomitant use of milnacipran and NSAIDs or other anticoagulants.23 Milnacipran should not be used in patients with uncontrolled narrow-angle glaucoma. An increased risk of mydriasis was associated with milnacipran, as has been reported with other dual reuptake inhibitors of norepinephrine and serotonin. Milnacipran should be used cautiously in patients with controlled narrowangle glaucoma.23 Mild elevations in liver enzymes have been reported with milnacipran, and in rare instances, fulminant hepatitis.23 Increased rates of genitourinary AEs have been reported in male patients with a history of obstructive uropathies.23

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Exercise caution in patients with substantial alcohol use or chronic liver disease, patients with mania or a history of seizure disorder, and in those with significant hypertension or cardiac disease.

Consult the prescribing information for additional safety information.23

Drug–Drug Interactions Milnacipran is unlikely to result in clinically significant pharmacokinetic drug interactions because it undergoes minimal CYP450-related metabolism, is predominantly excreted unchanged in urine, and has a low degree of plasma protein binding.8,23 However, pharmacodynamic interactions may occur with lithium, epinephrine and norepinephrine, serotonergic drugs, digoxin, clonidine, clomipramine, CNS-active drugs, and MAOIs. As noted, concomitant use of NSAIDs and other anticoagulants with SSRIs or SNRIs, including milnacipran, may increase the risk of bleeding events.23 Dosing and Administration Milnacipran is available in 12.5-mg, 25-mg, 50-mg, and 100-mg tablet strength. Except for the first-day dose of 12.5 mg, milnacipran is administered in 2 divided doses/day, with a recommended dose of 100 mg/day (or 50 mg twice daily) after day 7. For initial dosing, milnacipran is titrated according to a specified schedule (Table 2) and is available in 2 titration pack options.

The dose may be increased to 200 mg/day (or 100 mg twice/day), based on patient response. Doses above 200 mg/day have not been studied.23 Milnacipran can be taken with or without food; however, when taken with food, it may improve tolerability in patients who experience nausea. After extended use, milnacipran should be reduced gradually rather than discontinued abruptly. The maintenance dose should be reduced by 50% in patients whose creatinine clearance is <30 mL/min. No dosage adjustment is indicated for mild renal impairment or for patients with hepatic insufficiency.

Milnacipran is nonnarcotic and is not categorized as a scheduled substance by the US Drug Enforcement Administration.23 Milnacipran use in specific population is as follows23: • As a pregnancy category C agent it should only be used in pregnant women if the potential benefit justifies potential risks to the fetus. Because it is not known if milnacipran is excreted in human milk and its safety in infants is not known, nursing while taking this agent is not recommended.

• It is not recommended in pediatric patients; its safety and effectiveness in patients younger than age 17 years have not been established.

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Table 2 Initial Dosing and Titration for Savella Timing Dose titration Day 1 12.5 mg Days 2, 3 25 mg/d or 12.5 mg bid Days 4-7 50 mg/d or 25 mg bid After day 7 100 mg/d or 50 mg bid Start-up titration pack options 2-wk titration pack Includes 1-wk titration and 1 wk of 100 mg/d dose 4-wk titration pack Includes 1-wk titration and 3 wks of 100 mg/d dose Note: Although Savella is nonnarcotic, prescription should be written for the smallest quantity of tablets consistent with good patient management to reduce the risk of overdose.

• Because milnacipran is primarily excreted unchanged through the kidneys, with an expected decrease in renal function associated with age, renal function should be considered before prescribing milnacipran in elderly patients. It has been associated with hyponatremia in elderly patients, who are at increased risk for this.

• This medication is not recommended in patients with end-stage renal disease, and should be used with caution in those with moderate renal impairment or severe hepatic impairment.

Cost The cost of Savella is $3.38/day. In comparison, Lyrica costs $4.28/day, and Cymbalta $4.00/day. These costs reflect wholesale acquisition cost per labeled daily dose. Net costs varies by health insurance plan.

Conclusion Patients with FM have many comorbidities and high levels of healthcare utilization and costs. Increased education and awareness about FM, earlier diagnosis, and improved management approaches, including effective new treatments, may lead to improved patient outcomes and subsequent reductions in utilization and costs.

Milnacipran is the most recent addition to the limited number of FDA-approved drugs for the management of FM. Milnacipran is an SNRI that blocks reuptake of norepinephrine with approximately 3 times greater potency in vitro than serotonin.

Milnacipran delivers simultaneous improvements on 3 key aspects of FM, has a low potential for pharmacoki-

netic drug–drug interactions, and is not associated with a significant incidence of fatigue or somnolence, or weight gain. It offers economic value compared with other agents approved for the management of FM. ■ References 1. American College of Rheumatology. Fibromyalgia. www.rheumatology. org/public/factsheets/diseases_and_conditions/fibromyalgia.asp?aud=pat.

Accessed August 11, 2009.

2. National Fibromyalgia Association. About fibromyalgia. www.fmaware. org/site/PageServer?pagename=fibromyalgia. Accessed April 15, 2009.

3. Berger A, Dukes, E, Edelsberg J, Oster G. Characteristics and healthcare costs of patients with fibromyalgia syndrome. Int J Clin Pract. 2007; 61:1498-1508.

4. White LA, Birnbaum HG, Kaltenboeck A, et al. Employees with fibromyalgia: medical comorbidity, healthcare costs, and work loss. J Occup Environ Med. 2008;50:13-24.

5. Wolfe F, Anderson J, Harkness D, et al. Work and disability status of persons with fibromyalgia. J Rheumatol. 1997;24:1171-1178.

6. Annemans L, Wessely S, Spaepen E, et al. Health economic consequences related to the diagnosis of fibromyalgia syndrome. Arthritis Rheum.

2008;58:895-902.

7. Johns Hopkins Medicine. Fibromyalgia syndrome—common and difficult to diagnose. Health Alerts. www.johnshopkinshealthalerts.com/ alerts/arthritis/JohnsHopkinsHealthAlertsArthritis_427-1. Accessed August 7, 2009.

8. Cios DA, Kim JE. Milnacipran: a serotonin and norepinephrine reuptake inhibitor for the management of fibromyalgia syndrome. Formulary.

2009;44:197-202.

9. Clauw DJ, Mease P, Palmer RH, et al. Milnacipran for the treatment of fibromyalgia in adults: a 15-week, multicenter, randomized, doubleblind, placebo-controlled, multiple-dose clinical trial. Clin Ther. 2008; 30:1988-2004.

10. Arthritis Foundation. Fibromyalgia. What is it? www.arthritis.org/ disease-center.php?disease_id=10. Accessed August 10, 2009.

11. Navarro RP. Contemporary management strategies for fibromyalgia.

Am J Manag Care. 2009;15(7 suppl):S197-S218.

12. Burckhardt CS, Clark SR, Bennett RM. Fibromyalgia and quality of life: a comparative analysis. J Rheumatol. 1993;20:475-479.

13. Gilliland RP. Fibromyalgia. Emedicine. January 5, 2009. http:// emedicine.medscape.com/article/312778-print. Accessed August 9, 2008.

14. Rao SG, Gendreau JF, Kranzler JD. Understanding the fibromyalgia syndrome. Psychopharmacol Bull. 2007;40:24-67.

15. Dadabhoy D, Clauw DJ. Therapy insight: fibromyalgia—a different type of pain needing a different type of treatment. Nat Clin Pract Rheumatol.

2006;2:364-372.

16. Harris RE, Sundgren PC, Pang Y, et al. Dynamic levels of glutamate within the insula are associated with improvements in multiple pain domains in fibromyalgia. Arthritis Rheum. 2008;58:903-907.

17. Johns Hopkins Medicine. Fibromyalgia: understanding a mysterious ailment. Health Alerts. www.johnshopkinshealthalerts.com/reports/ arthritis/2130-1.html. Accessed August 7, 2009.

18. Fontaine K. Fibromyalgia: diagnosis. www.hopkins-arthritis.org/ arthritis-info/fibromyalgia/diagnosis.html. Accessed April 15, 2009.

19. Wolfe F, Smythe HA, Yunus MB, et al, for the Multicenter Criteria Committee. The American College of Rheumatology 1990 criteria for the classification of fibromyalgia. Arthritis Rheum. 1990;33:160-172.

20. Fontaine KE. Fibromyalgia: treatment. www.hopkins-arthritis.org/ arthritis-info/fibromyalgia/treatment-info.html. Accessed April 15, 2009.

21. Lyrica (pregabalin). Prescribing information. New York, NY: Pfizer; April 2009.

22. Cymbalta (duloxetine HCl). Prescribing information. Indianapolis, IN: Eli Lilly; February 16, 2009.

23. Savella (milnacipran HCl). Prescribing information. St. Louis, MO: Forest Pharmaceuticals; March 2009.

24. Mease PJ, Clauw DJ, Gendreau RM, et al. The efficacy and safety of milnacipran for treatment of fibromyalgia: a randomized, double-blind, placebo-controlled trial. J Rheumatol. 2009;36:398-409.

25. Mease P, Arnold LM, Bennett R, et al. Fibromyalgia syndrome. J Rheumatol. 2007;34:1415-1425.

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Composite Outcomes for Fibromyalgia Nirav R. Shah, MD, MPH Assistant Professor of Medicine, NYU School of Medicine, and Senior Investigator, Geisinger Health System

RESEARCHERS: Fibromyalgia (FM) is a complicated disease. Until the American College of Rheumatology came up with standardized criteria on its classification, it has been very difficult to study. These common criteria were created from the perspective of care providers to facilitate identifying patients, not from a patient perspective. To evaluate clinical benefit, however, a patient perspective is central, and a composite outcome measure incorporating patient-centered outcomes was used in 2 milnacipran registration trials.

Composite measures are appropriate when it is not clear what end point is most important or if more than 1 is thought to be important, and individual outcomes selected to be a part of the composite are related across a spectrum of benefit. For milnacipran, the composite outcome measure used met this standard and consisted of 3 measures: (1) an improvement in pain from baseline, (2) a global rating scale, and (3) an improvement in physical function.

Composite measures are often used when individual ones are insufficient to determine effects of importance.

For example, if events are rare, a composite of several different measures or events can be used to best capture the effects of an intervention.1 Composites are frequently used in cardiology, where composites of individual components such as cardiovascular mortality, revascularization, and myocardial infarction are lumped together into a single measure.2 Several guiding principles are paramount when using and designing good composite measures for efficacy and effectiveness. First, individual components of a composite outcome should be similar in importance when considered from a patient perspective.1 Interpreting a composite outcome is difficult enough, so that mixing “apples and oranges” in terms of clinical importance only further complicates their use. Often death is included in a composite measure. This practice is widespread, but a patient dying, by definition, disallows any subsequent events of different measures within a composite to occur. In the case of milnacipran, the 3 outcomes chosen are of similar importance, and rather

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than arbitrarily selecting only 1 outcome of interest, the composite facilitates use of all 3.

A second principle in using a composite measure is to increase power and ability to examine differences between the intervention and the control groups.3 If individual events are infrequent, for example, a composite measure composed of several related individual measures may increase statistical efficiency. Although not necessarily the case for FM, the measures chosen can be considered a form of “hedging bets,” so that the trial will be adequately powered.

A final principle relates to the magnitude of each individual measure’s effect size. These should be similar; otherwise 1 measure may drive results in a composite.4 For example, if the pain improvement criteria were met in 80% of patients, and the functional status criteria in only 20%, the overall composite would be unbalanced and would not truly reflect functional status. For milnacipran, improvements had to occur in at least 2 measures for a given patient, further ensuring that no single component could drive the results.

The composite measure for FM effectiveness represents a good application of the principles of composite design and of criteria selection. In the future, as our understanding of the disease process evolves and new types of drugs are developed, new composite measures will be required. It is hoped that they would live up to the standard set with milnacipran. ■ Disclosure Statement: Dr Shah receives unrestricted research grants from AstraZeneca, Merck, Pfizer, Roche, and has received honoraria from Takeda.

References 1. Ferreira-González I, Busse JW, Heels-Ansdell D, et al. Problems with use of composite end points in cardiovascular trials: systematic review of randomised controlled trials. BMJ. 2007;334:786.

2. Lim E, Brown A, Helmy A, Mussa S, Altman DG. Composite outcomes in cardiovascular research: a survey of randomized trials. Ann Intern Med. 2008;149:612-617.

3. Freemantle N, Calvert M, Wood J, et al. Composite outcomes in randomized trials: greater precision but with greater uncertainty? JAMA. 2003;289:2554-2559.

4. Ross S. Composite outcomes in randomized clinical trials: arguments for and against. Am J Obstet Gynecol. 2007;196:119.e1-e6.

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Management of Fibromyalgia Gary M. Owens, MD President, Gary Owens Associates, Philadelphia, PA

PAYERS: Fibromyalgia is a complex syndrome that is characterized by diffuse pain associated with a host of other symptoms, including fatigue, sleep disturbances, morning stiffness, cognitive dysfunction, headaches, and feelings of anxiety and depression. This syndrome is far more prevalent in women and may affect up to 4% of the US population.

Fibromyalgia often presents with vague complaints and is often incorrectly diagnosed by clinicians. This may lead patients with fibromyalgia to seek care from multiple physicians; these patients often undergo a significant number of diagnostic tests before a correct diagnosis is reached. Data have shown that patients with fibromyalgia, on average, spend more than 3 times as much money and time on healthcare as do matched populations without this condition. A significant amount of spending for these patients is for diagnostic studies and for medications, often targeted at the relief of pain. Despite this cost and the use of healthcare resources, patients with fibromyalgia often suffer a reduced quality of life, and their ability to be productive members of the workforce is affected.

The present article describes a new medication, milnacipran HCl (Savella), a serotonin-norepinephrine reuptake inhibitor (SNRI), which has been shown in clinical trials to improve many of the symptoms associated with fibromyalgia. Most important, this agent demonstrated significant improvement in fibromyalgia composite responders (defined as those with meaningful improvements in 3 clinical domains—pain, patient global assessment, and physical function)—as well as fibromyalgia pain responders (defined as the patient meeting both pain and global change criteria).

Although this agent is not a cure for fibromyalgia, it does add an additional tool for the clinician to use in the treatment of this complex syndrome. Milnacipran joins pregabalin (Lyrica) and duloxetine HCl (Cymbalta) as the only agents FDA-approved for the management of fibromyalgia. In addition to these 3

agents, a broad range of medication classes—anticonvulsants, antidepressants, anti-inflammatory drugs, as well as pain relievers that include opioids— are used “off-label” for the treatment of fibromyalgia.

With the approval of a new SNRI for the management of fibromyalgia, P&T Committees will be asked to review the treatment options for fibromyalgia, which will include a review of the 3 FDA-approved agents and of agents frequently used “off label” for the treatment of fibromyalgia. In the absence of head-to-head data comparing the 3 FDA-approved agents, and with virtually no data to compare these agents to the many drugs that are currently used “off label” for the treatment of fibromyalgia symptoms, it will be a challenge for P&T Committees to assess this category. P&T Committees therefore must consider differences in mechanisms of action, pharmacokinetic profiles, efficacy outcomes, as well as the criteria for determining such outcomes, safety, and tolerability, when making their decisions. It is likely that we shall continue to see significant variability of formulary tier-placement decisions made by different P&T Committees. Similarly, some committees may choose to implement clinical management programs, for this agent, much as we have seen for the other agents in the class.

P&T Committees will continue to be challenged in this category to provide the right balance of patient access, clinical outcomes, and cost management.

Having comparative clinical trial data and outcome studies would certainly help facilitate these decisions, but this information is generally not available in the early post-approval phase. Without that information, P&T Committees will need to carefully evaluate new treatment options based on existing data to make appropriate treatment options available for this complex and costly illness. ■ Disclosure Statement: Dr Owens is a consultant to Amgen, AstraZeneca, Genentech, Novartis, and Schering-Plough.

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Composite End Points and the Impact of Milnacipran on Patients with Fibromyalgia Philip Mease, MD Chief, Rheumatology Research, Swedish Medical Center, Clinical Professor, University of Washington School of Medicine, and is in clinical practice, Seattle Rheumatology Associates, Seattle, Washington

PROVIDERS: The recent approval of milnacipran hydrochloride (Savella) for the management of fibromyalgia (FM) was based on clinical trials showing that a significantly greater proportion of patients taking milnacipran compared with those taking placebo met the prespecified criteria for being a responder based on a composite end point. Of the drugs approved for the management of FM, only clinical trials of milnacipran incorporated a composite end point to establish efficacy.

Composite end points have been used to evaluate the clinical efficacy of several therapies for the treatment of asthma,1 migraine,2 organ transplantation,3 myocardial infarction,4 and diabetes,5 exemplifying a growing trend in the use of this type of end point. Moreover, several expert panels, such as the Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) group, have encouraged the use of composite end points in the evaluation of new medicines. What is the relevance of composite end points when trying to understand the impact of milnacipran on patients with FM? Clinically, composite end points are considered to be more robust and meaningful than analyses of group mean changes on a single, continuous end point such as pain for several reasons. First, assessing milnacipran’s composite end points—pain,6 the patient global impression of change (PGIC),7 and physical functioning8—ensures that the therapy is producing clinically significant improvements in multiple domains simultaneously, in the same patient. In contrast, a continuous analysis of change in pain reflects only group mean differences, which may not necessarily reflect the actual change observed for any given patient. In addition, relying on multiple group-level comparisons across different end points does not ensure that reductions in pain and improvements in functioning, for example, are occurring in the same group of patients.

Second, estimates of efficacy derived from composite end points reflect a conservative, worst-case profile of a drug’s efficacy. This is because patients who fail to meet the composite responder threshold may have experienced clinically meaningful changes in 1 or more domains but fail to qualify as a responder because of their response on a single domain.

Third, because PGIC ratings are thought to reflect each patient’s global evaluation of the balance of the efficacy of a drug against its tolerability, incorporating PGIC ratings in the composite end point broadens the evaluation beyond efficacy to include tolerability as well.

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Fourth, by incorporating a measure of function, the ability of the therapy to not only treat symptoms but also help to return the patient toward more normal functioning is assessed. Therefore, the composite end points used in milnacipran’s clinical development program speak to a more comprehensive analysis of its efficacy and tolerability from the individual patient’s perspective.

Composite end points also have shortcomings. While composite end points have the potential to increase the statistical power of clinical trials by elevating the observed event rate through aggregating multiple end points, the converse can be true if the various domains are not all equally responsive to therapy.9 For example, if improvements in physical functioning are harder to achieve than reductions in pain, which is potentially the case for patients with FM, then the percentage of patients reporting improvements in physical functioning sets a ceiling for the maximum percentage of patients who can qualify as composite responders. Composite end points can only be as robust as the end point most difficult to change, and they require that the therapy produces clinically significant changes in multiple domains in the same patient. As such, they can set a high hurdle for success.

The use of composite end points in drug development is likely to increase. In the case of milnacipran, the use of composite end points provides a conservative estimate of the rates of clinically meaningful, multidimensional change in patients with FM. ■ Disclosure Statement: Dr Mease receives grant research from and is a consultant to Boehringer Ingelheim, Cypress Pharmaceuticals, Eli Lilly, Forest, Fralex Therapeutics, Pfizer, and Wyeth. He is on the Speaker’s Bureau of Cypress Pharmaceuticals, Eli Lilly, Forest, Pfizer, and Wyeth.

References 1. Bateman ED. Measuring asthma control. Curr Opin Allergy Clin Immunol.

2001;1:211-216.

2. Antonaci F, Sances G, Guaschino E, et al. Meeting patient expectations in migraine treatment: what are the key endpoints? J Headache Pain. 2008;9:207-213.

3. Washburn K. Endpoints in trials for clinical liver transplantation. Curr Opin Organ Transplant. 2008;13:252-256.

4. Cannon CP. Clinical perspectives on the use of composite endpoints. Control Clin Trials. 1997;18:517-529.

5. Betteridge DJ, DeFronzo RA, Chilton RJ. PROactive: time for a critical appraisal. Eur Heart J. 2008;29:969-983.

6. Farrar JT, Young JP Jr, LaMoreaux L, et al. Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale.

Pain. 2001;94:149-158.

7. Dworkin RH, Turk DC, Wyrwich KW, et al. Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations. J Pain. 2008;9:105-121.

8. Glassman SD, Copay AG, Berven SH, et al. Defining substantial clinical benefit following lumbar spine arthrodesis. J Bone Joint Surg Am. 2008;90: 1839-1847.

9. Ferreira-González I, Permanyer-Miralda G, Busse JW, et al. Methodologic discussions for using and interpreting composite endpoints are limited, but still identify major concerns. J Clin Epidemiol. 2007;60:651-657.

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Brief Summary of Prescribing Information Brief Summary of USAGE Prescribing Information INDICATIONS AND ® (aspirin/extended-release AGGRENOX dipyridamole) is indicated to reduce the risk of stroke in patients who have had transient ischINDICATIONS AND USAGE ® emia of the brain or completed ischemicdipyridamole) stroke due to is thrombosis.

AGGRENOX (aspirin/extended-release indicated to reduce the risk of stroke in patients who have had transient ischemia of the brain or completed ischemic stroke due to thrombosis.

CONTRAINDICATIONS CONTRAINDICATIONS AGGRENOX is contraindicated in patients with hypersensitivity to dipyridamole, aspirin or any of the other product components.

AGGRENOX (aspirin/extended-release is contraindicated in patients with hypersensitivity drug to dipyridamole, aspirin or any with of the Allergy: Aspirin is contraindicated in dipyridamole) patients with known allergy to nonsteroidal anti-inflammatory products and in patients other product of components. the syndrome asthma, rhinitis, and nasal polyps. Aspirin may cause severe urticaria, angioedema or bronchospasm (asthma).

Allergy: Aspirin is contraindicated in patients with known allergy to nonsteroidal anti-inflammatory drug products and in patients with Reye’s Syndrome: Aspirin should not be used in children or teenagers for viral infections, with or without fever, because of the riskthe of asthma,with rhinitis, and nasaluse polyps.

Aspirin may cause urticaria, angioedema or bronchospasm (asthma). ofsyndrome Reye’s syndrome concomitant of aspirin in certain viralsevere illnesses.

Reye’s Syndrome: Aspirin should not be used in children or teenagers for viral infections, with or without fever, because of the risk of Reye’s WARNINGS syndrome with concomitant use of aspirin in certain viral illnesses.

Alcohol Warning: Patients who consume three or more alcoholic drinks every day should be counseled about the bleeding risks WARNINGS involved with chronic, heavy alcohol use while taking aspirin.

Alcohol Warning: Patients who consume three or more alcoholic drinks every day should be counseled about the bleeding risks involved Coagulation Abnormalities: Eventaking low doses of aspirin can inhibit platelet function leading to an increase in bleeding time. This can with chronic, heavy alcohol use while aspirin. adversely affect patients with inherited or acquired (liver disease or vitamin K deficiency) bleeding disorders.

Coagulation Abnormalities: Even low doses of aspirin can inhibit platelet function leading to an increase in bleeding time. This can Gastrointestinal (GI)with Side Effects: GI side effects includeorstomach heartburn, nausea, vomiting, and gross GI bleeding. adversely affect patients inherited or acquired (liver disease vitamin Kpain, deficiency) bleeding disorders.

Although minor upper GI symptoms, such as dyspepsia, are common and can occur anytime during therapy, physicians should remain Gastrointestinal (GI) Side GI even side effects pain,GIheartburn, nausea, vomiting, and gross bleeding.

Although alert for signs of ulceration andEffects: bleeding, in the include absencestomach of previous symptoms.

Physicians should informGIpatients about the minorand upper GI symptoms, sucheffects as dyspepsia, common can occur signs symptoms of GI side and whataresteps to takeand if they occur.anytime during therapy, physicians should remain alert for signs of ulceration and bleeding, even in the absence of previous GI symptoms. Physicians should inform patients about the signs and symptoms Peptic Ulcer Disease: Patients with a history of active peptic ulcer disease should avoid using aspirin, which can cause gastric of GI side effects and what steps to take if they occur. mucosal irritation, and bleeding.

Peptic Ulcer Disease: Patients with a history of active peptic ulcer disease should avoid using aspirin, which can cause gastric mucosal Pregnancy: irritation, and AGGRENOX bleeding. can cause fetal harm when administered to a pregnant woman. Maternal aspirin use during later stages of pregnancy may cause low birth weight, increased incidence for intracranial hemorrhage in premature infants, stillbirths and neonatal Pregnancy: fetalof harm wheneffects administered to a pregnant woman. Maternal aspirin useonduring stages of death.

BecauseAGGRENOX of the abovecan andcause because the known of nonsteroidal anti-inflammatory drugs (NSAIDs) the fetallater cardiovaspregnancy causeoflow weight, increasedAGGRENOX incidence for intracranial hemorrhage in premature stillbirths and neonatal death. cular systemmay (closure thebirth ductus arteriosus), should be avoided in the third trimesterinfants, of pregnancy.

Because of the above and because of the known effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on the fetal cardiovascular system Aspirin been shown to be teratogenic in rats (spina bifida, exencephaly, microphthalmia and coelosomia) and rabbits (congested (closurehas of the ductus arteriosus), AGGRENOX should be avoided in the third trimester of pregnancy. fetuses, agenesis of skull and upper jaw, generalized edema with malformation of the head, and diaphanous skin) at oral doses of Aspirin has beenand shown be teratogenic in rats (spina bifida, exencephaly, and resorption coelosomia)rate andinrabbits (congested fetuses, 330 mg/kg/day 110 to mg/kg/day, respectively.

These doses, which alsomicrophthalmia resulted in a high rats (63% of implantaagenesis of skull and upper jaw, generalized edema with malformation of the head, and diaphanous at oralcontained doses of 330 mg/kg/day and 2 tions versus 5% in controls), are, on a mg/m basis, about 66 and 44 times, respectively, the doseskin) of aspirin in the maximum 110 mg/kg/day,daily respectively.

These which also resulted instudies a high resorption rate in rats (63% of performed implantations versusrabbits 5% in and controls), recommended human dose of doses, AGGRENOX. Reproduction with dipyridamole have been in mice, rats 2 a mg/m basis, about 66 and times,and respectively, the dose of aspirin contained the25 maximum recommended daily human dose atare, oralondoses of up to 125 mg/kg, 4044 mg/kg 1000 mg/kg, respectively (about 11⁄2, 2inand times the maximum recommended dailyof AGGRENOX. Reproduction studies with dipyridamole haverevealed been performed in mice, rabbits ratsdue at tooral doses of upWhen to 125 mg/kg, 2 basis) and have human oral dose, respectively, on a mg/m no evidence of harm to theand fetus dipyridamole.

330 mg 40 mg/kg and was 1000combined mg/kg, respectively 1 1⁄2, 2 and 25 times therat, maximum recommended daily human oralindicating dose, respectively, on a aspirin/kg/day with 75 mg(about dipyridamole/kg/day in the the resorption rate approached 100%, potentiation 2 basis) andfetal havetoxicity. revealed no are evidence of harmand to well-controlled the fetus due tostudies dipyridamole.

Whenwomen.

330 mg aspirin/kg/day was combined with ofmg/m aspirin-related There no adequate in pregnant If AGGRENOX is used during preg75 mg dipyridamole/kg/day in the rat, the resorption rate approached 100%, indicating potentiation of aspirin-related fetal toxicity.

There nancy, or if the patient becomes pregnant while taking AGGRENOX, the patient should be apprised of the potential hazard to the fetus. are no adequate and well-controlled studies in pregnant women. If AGGRENOX is used during pregnancy, or if the patient becomes pregnant while PRECAUTIONS taking AGGRENOX, the patient should be apprised of the potential hazard to the fetus.

General PRECAUTIONS AGGRENOX General is not interchangeable with the individual components of aspirin and Persantine® Tablets.

AGGRENOX (aspirin/extended-release dipyridamole) not and interchangeable individual components aspirin Coronary Artery Disease: Dipyridamole has a vasodilatoryiseffect should be usedwith with the caution in patients with severe of coronary and Persantine artery disease (e.g.,® Tablets. unstable angina or recently sustained myocardial infarction). Chest pain may be aggravated in patients with underlying coronaryArtery artery Disease: disease who are receiving Coronary Dipyridamole hasdipyridamole. a vasodilatory effect and should be used with caution in patients with severe coronary artery disease (e.g., unstable angina or recently sustained myocardial infarction).

Chest pain mayinfarction be aggravated underlying coronary For stroke or TIA patients for whom aspirin is indicated to prevent recurrent myocardial (MI) inorpatients angina with pectoris, the aspirin in artery disease whonotareprovide receiving dipyridamole. this product may adequate treatment for the cardiac indications.

For strokeInsufficiency: or TIA patients for whom aspirin is indicated to prevent recurrent myocardial infarction (MI) in or angina pectoris, aspirin in this Hepatic Elevations of hepatic enzymes and hepatic failure have been reported association withthedipyridamole product may not provide adequate treatment for the cardiac indications. administration.

Hepatic Insufficiency: Elevations hepatic and hepatic failure have been reported in association withperipheral dipyridamole administration.

Hypotension: Dipyridamole shouldofbe usedenzymes with caution in patients with hypotension since it can produce vasodilation.

Hypotension: be used caution patients(glomerular with hypotension since can than produce peripheral vasodilation.

Renal Failure:Dipyridamole Avoid aspirinshould in patients withwith severe renalinfailure filtration rateitless 10 mL/minute).

RenalofFailure: Avoid withofsevere renal failurebleeding (glomerular rate less thanin10themL/minute).

Risk Bleeding: In aspirin ESPS2 inthepatients incidence gastrointestinal wasfiltration 68 patients (4.1%) AGGRENOX group, 36 patients (2.2%) the extended-release dipyridamole group, 52 patientsbleeding (3.2%) inwas the68 aspirin group, andin34thepatients (2.1%)group, in the36 placebo groups.

Risk ofinBleeding: In ESPS2 the incidence of gastrointestinal patients (4.1%) AGGRENOX patients (2.2%) in the extended-release dipyridamole group,was 52 9patients (3.2%) in the aspirin group, andgroup, 34 patients (2.1%) in theinplacebo groups.

The incidence of intracranial hemorrhage patients (0.6%) in the AGGRENOX 6 patients (0.5%) the extended-release dipyridamole group, 6 patients (0.4%) in the aspirin group and 7 patients (0.4%) in the placebo groups.

The incidence of intracranial hemorrhage was 9 patients (0.6%) in the AGGRENOX group, 6 patients (0.5%) in the extended-release dipyridamoleTests group, 6 patients (0.4%) in the aspirin group and 7 patients (0.4%) in the placebo groups.

Laboratory Aspirin has been associated with elevated hepatic enzymes, blood urea nitrogen and serum creatinine, hyperkalemia, proteinuria and Laboratory Tests prolonged time.

Aspirin hasbleeding been associated with elevated hepatic enzymes, blood urea nitrogen and serum creatinine, hyperkalemia, proteinuria and prolonged bleeding time.associated with elevated hepatic enzymes.

Dipyridamole has been Dipyridamole has been associated with elevated hepatic enzymes.

Drug Interactions Drug Interactions drug-drug interaction studies were conducted with the AGGRENOX formulation. The following information was No pharmacokinetic No pharmacokinetic drug-drug interaction studies were conducted with the AGGRENOX formulation. The following information was obtained obtained from the literature. from the literature.

Adenosine: Dipyridamole has been reported to increase the plasma levels and cardiovascular effects of adenosine. Adjustment of Adenosine:dosage Dipyridamole been reported to increase the plasma levels and cardiovascular effects of adenosine. Adjustment of adenosine adenosine may behas necessary. dosage may Converting be necessary.

Angiotensin Enzyme (ACE) Inhibitors: Due to the indirect effect of aspirin on the renin-angiotensin conversion pathway, the Angiotensin Converting Enzymeeffects (ACE)ofInhibitors: Due to thebeindirect effectby of concomitant aspirin on the renin-angiotensin conversion pathway, the hyponatremic and hypotensive ACE inhibitors may diminished administration of aspirin. hyponatremic and hypotensive of ACE may becan diminished by concomitant administration of aspirin. (and toxicity) due Acetazolamide: Concurrent useeffects of aspirin andinhibitors acetazolamide lead to high serum concentrations of acetazolamide use offor aspirin and acetazolamide can lead to high serum concentrations of acetazolamide (and toxicity) due to toAcetazolamide: competition atConcurrent the renal tubule secretion. competition atTherapy the renal(heparin tubule forand secretion.

Anticoagulant warfarin): Patients on anticoagulation therapy are at increased risk for bleeding because of drugAnticoagulant Therapy (heparin warfarin): Patients on anticoagulation therapy are binding at increased for bleeding because of drug-drug drug interactions and effects on and platelets.

Aspirin can displace warfarin from protein sites,risk leading to prolongation both the interactions and onbleeding platelets. time.

Aspirin can displace warfarin protein binding sites, leading toincreasing prolongation of bothrisk. the prothrombin prothrombin timeeffects and the Aspirin can increase thefrom anticoagulant activity of heparin, bleeding time and the bleeding time.acid Aspirin increase the anticoagulant activity heparin,acid, increasing bleeding risk. in the total concentration Anticonvulsants: Salicylic can can displace protein-bound phenytoin andofvalproic leading to a decrease Salicylic acidincan displace protein-bound ofAnticonvulsants: phenytoin and an increase serum valproic acid levels. phenytoin and valproic acid, leading to a decrease in the total concentration of phenytoin andThe an increase in serum valproic levels.may be diminished by the concomitant administration of aspirin due to inhibition Beta Blockers: hypotensive effects of betaacid blockers Blockers: The hypotensive of beta renal blockers mayflow be and diminished the retention. concomitant administration of aspirin due to inhibition of ofBeta renal prostaglandins, leading effects to decreased blood salt andbyfluid renal prostaglandins, leading to decreasedmay renalcounteract blood flowthe andanticholinesterase salt and fluid retention.

Cholinesterase Inhibitors: Dipyridamole effect of cholinesterase inhibitors, thereby potentially Cholinesterase Inhibitors: Dipyridamole may counteract the anticholinesterase effect of cholinesterase inhibitors, thereby potentially aggravating myasthenia gravis. aggravating myasthenia gravis.

Diuretics: The effectiveness of diuretics in patients with underlying renal or cardiovascular disease may be diminished by the conDiuretics:administration The effectiveness of diuretics in inhibition patients with underlying renal or cardiovascular disease may beblood diminished by the comitant of aspirin due to of renal prostaglandins, leading to decreased renal flow and saltconcomitant and fluid administration of aspirin due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention. retention.

Methotrexate:Salicylate Salicylate can inhibit methotrexate, leading to bone marrow toxicity, especially in the elderly or renal or impaired.

Methotrexate: inhibitrenal renalclearance clearanceof of methotrexate, leading to bone marrow toxicity, especially in the elderly renal impaired.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): The concurrent use of aspirin with other NSAIDs may increase bleeding or lead to decreased renal function.Anti-Inflammatory Drugs (NSAIDs): The concurrent use of aspirin with other NSAIDs may increase bleeding or lead to Nonsteroidal decreased renal function.

Oral Hypoglycemics: Moderate doses of aspirin may increase the effectiveness of oral hypoglycemic drugs, leading to hypoglycemia.

Oral Hypoglycemics: Moderateand doses of aspirin maySalicylates increase the effectiveness of oral hypoglycemic drugs,agents. leading to hypoglycemia.

Uricosuric Agents (probenecid sulfinpyrazone): antagonize the uricosuric action of uricosuric Uricosuric Agents (probenecid and sulfinpyrazone): Carcinogenesis, Mutagenesis, Impairment ofSalicylates Fertility antagonize the uricosuric action of uricosuric agents.

Carcinogenesis, of the Fertility In studies in which Mutagenesis, dipyridamole wasImpairment administered in feed to mice (up to 111 weeks in males and females) and rats (up to 128 weeks in andinupwhich to 142dipyridamole weeks in females), there was noinevidence The highest dose administered studies Inmales studies was administered the feedoftodrug-related mice (up to carcinogenesis.

111 weeks in males and females) and rats (up in to these 128 weeks 2 mg/kg/day) on aweeks mg/min basis, aboutthere equivalent the maximum recommended daily human oral (MRHD) mice and about in(75males and upwas, to 142 females), was notoevidence of drug-related carcinogenesis.

The dose highest dose in administered in twice studies the MRHD rats. these (75inmg/kg/day) was, on a mg/m2 basis, about equivalent to the maximum recommended daily human oral dose (MRHD) inCombinations mice and about twice the MRHD rats. (1:5 ratio) tested negative in the Ames test, in vivo chromosome aberration tests (in mice and of dipyridamole and in aspirin hamsters), oralofmicronucleus mice(1:5 andratio) hamsters) oral dominant lethaltest, testin(invivo mice).

Aspirin, alone, induced chromosome Combinations dipyridamoletests and (in aspirin testedand negative in the Ames chromosome aberration tests (in mice aberrations in cultured human fibroblasts. tests of dipyridamole alone with bacterial mammalian systems werechromonegative. and hamsters), oral micronucleus tests (inMutagenicity mice and hamsters) and oral dominant lethal test (inand mice).

Aspirin,cell alone, induced some aberrations cultured human fibroblasts. tests offordipyridamole alone with bacterial andperformance. mammalian cell systems Combinations of in dipyridamole and aspirin have Mutagenicity not been evaluated effects on fertility and reproductive There was no were negative. evidence of impaired fertility when dipyridamole was administered to male and female rats at oral doses up to 500 mg/kg/day (about 12 times 2 the MRHD on of a mg/m basis). Aand significant in number of corpora lutea with consequent reduction in performance. implantations There and livewas fetuses Combinations dipyridamole aspirin reduction have not been evaluated for effects on2 fertility and reproductive no was, however, observed at 1250 mg/kg (more thanwas 30 times the MRHD a mg/m basis).rats Aspirin inhibits in rats. evidence of impaired fertility when dipyridamole administered to on male and female at oral dosesovulation up to 500 mg/kg/day (about 12 times the MRHD on a mg/m2 basis). A significant reduction in number of corpora lutea with consequent reduction in implantations Pregnancy 2 and live fetuses was, however, observed at 1250 mg/kg (more than 30 times the MRHD on a mg/m basis).

Aspirin inhibits ovulation in rats.

Teratogenic Effects: Pregnancy Category D (see WARNINGS) Labor and Delivery Pregnancy Aspirin can Effects: result inPregnancy excessive Category blood lossD at(see delivery as well as prolonged gestation and prolonged labor. Because of these effects on the Teratogenic WARNINGS) mother and because of adverse fetal effects seen with aspirin during the later stages of pregnancy (see WARNINGS, Pregnancy), Labor and Delivery AGGRENOX should be avoided in the third trimester of pregnancy and during labor and delivery.

Aspirin canMothers result in excessive blood loss at delivery as well as prolonged gestation and prolonged labor. Because of these effects on Nursing the mother and because of adverse fetal effects seenmilk. withCaution aspirin should during be theexercised later stages of AGGRENOX pregnancy (see WARNINGS, Pregnancy), Both dipyridamole and aspirin are excreted in human when is administered to a nursing woman.

AGGRENOX should be avoided in the third trimester of pregnancy and during labor and delivery.

Pediatric Use Nursing Mothers Safety and effectiveness of AGGRENOX in pediatric patients have not been studied. Due to the aspirin component, use of this product in the pediatric populationand is not recommended Both dipyridamole aspirin are excreted(see in CONTRAINDICATIONS). human milk. Caution should be exercised when AGGRENOX is administered to a nursing woman.

ADVERSE REACTIONS Pediatric Usemulticenter, double-blind, randomized study (ESPS2) was conducted to compare the efficacy and safety of AGGRENOX A 24-month, (aspirin/extended-release placebo, extended-release dipyridamole alone aspirin component, alone. The study wasthis conducted Safety and effectiveness ofdipyridamole) AGGRENOX inwith pediatric patients have not been studied. Due to and the aspirin use of product in a totalpediatric of 6602population male and female who had(see experienced a previous ischemic stroke or transient ischemia of the brain within three months the is notpatients recommended CONTRAINDICATIONS). prior to randomization.

ADVERSE REACTIONS 1 presents the incidence of adverse events that occurred in 1% orwas moreconducted of patientstotreated with the AGGRENOX the incidence was also ATable 24-month, multicenter, double-blind, randomized study (ESPS2) compare efficacy where and safety of AGGRENOX greater than in those patients treateddipyridamole with placebo. alone There isand no clear benefit of the dipyridamole/aspirin combination overofaspirin to safety. with placebo, extended-release aspirin alone.

The study was conducted in a total 6602with malerespect and female patients who had experienced a previous ischemic stroke or transient ischemia of the brain within three months prior to randomization.

Table 1 presents the incidence of adverse events that occurred in 1% or more of patients treated with AGGRENOX where the incidence was also greater than in those patients treated with placebo. There is no clear benefit of the dipyridamole/aspirin combination over aspirin with respect to safety.

Table Adverse Events in in ESPS2* Table1:1:Incidence Incidenceofof Adverse Events ESPS2* Individual Treatment GroupTreatment Group Individual BodySystem/Preferred System/Preferred Term ER-DP Alone Alone Placebo Body Term AGGRENOXAGGRENOXER-DP Alone ASAASA Alone Placebo Total Number of Patients 1650 1654 1649 Total Number of Patients 1650 1654 16491649 1649 Total Number of Patients at Least Total Number (%)(%) of Patients WithWith at Least One Adverse Event (80.2%) 1304 (79.1%) OneOn-Treatment On-Treatment Adverse Event 1319 (79.9%) 1319 (79.9%)1305 (78.9%) 1305 (78.9%) 13231323 (80.2%) 1304 (79.1%) Central Peripheral Nervous System Disorders Central& & Peripheral Nervous System Disorders Headache 647 (39.2%)647 (39.2%)634 (38.3%) 558 558 (33.8%) 543 (32.9%) Headache 634 (38.3%) (33.8%) 543 (32.9%) Convulsions 28 (1.7%)28 (1.7%) 15 (0.9%) 28 28(1.7%) 2626 (1.6%) (1.6%) Convulsions 15 (0.9%) (1.7%) Gastro-Intestinal System Disorders Gastro-Intestinal System Disorders Dyspepsia 303 (18.4%) 299 299 (18.1%) 275 (16.7%) Dyspepsia 303 (18.4%)288 (17.4%) 288 (17.4%) (18.1%) 275 (16.7%) Abdominal Pain 255 (15.4%) (15.9%) 239 (14.5%) Abdominal Pain 289 (17.5%)289 (17.5%)255 (15.4%) 262 262 (15.9%) 239 (14.5%) Nausea 264 (16.0%)254 (15.4%) 254 (15.4%) (12.7%) 232 (14.1%) Nausea 264 (16.0%) 210 210 (12.7%) 232 (14.1%) Diarrhea 257 (15.5%) (6.8%) 161 (9.8%) Diarrhea 210 (12.7%)210 (12.7%)257 (15.5%) 112 112(6.8%) 161 (9.8%) Vomiting 138 (8.4%)129 (7.8%) 129 (7.8%) (6.1%) 118 (7.2%) Vomiting 138 (8.4%) 101 101(6.1%) 118 (7.2%) Hemorrhage Rectum 22 (1.3%) (1.0%) Hemorrhage Rectum 26 (1.6%)26 (1.6%) 22 (1.3%) 16 16(1.0%) 1313 (0.8%) (0.8%) Melena 10 (0.6%) (1.2%) Melena 31 (1.9%)31 (1.9%) 10 (0.6%) 20 20(1.2%) 1313 (0.8%) (0.8%) Hemorrhoids 13 (0.8%) (0.6%) Hemorrhoids 16 (1.0%)16 (1.0%) 13 (0.8%) 10 10(0.6%) 1010 (0.6%) (0.6%) Hemorrhage 5 (0.3%) (0.9%) GIGIHemorrhage 20 (1.2%)20 (1.2%) 5 (0.3%) 15 15(0.9%) 77 (0.4%) (0.4%) Bodyasas a Whole - General Disorders Body a Whole - General Disorders Pain 105 (6.4%) 88 (5.3%) 88 (5.3%) 103 (6.2%) 99 (6.0%) Pain 105 (6.4%) 103 (6.2%) 99 (6.0%) Fatigue 95 (5.8%) 93 (5.6%) 97 (5.9%) 90 (5.5%) Fatigue 95 (5.8%) 93 (5.6%) 97 (5.9%) 90 (5.5%) Back Pain 76 (4.6%) 77 (4.7%) 74 (4.5%) 65 (3.9%) Back Pain 76 (4.6%) 77 (4.7%) 74 (4.5%) 65 (3.9%) Accidental Injury 42 (2.5%) 24 (1.5%) 51 (3.1%) 37 (2.2%) Accidental Injury 42 (2.5%) 24 (1.5%) 51 (3.1%) 37 (2.2%) Malaise 27 (1.6%) 23 (1.4%) 26 (1.6%) 22 (1.3%) Malaise 27 (1.6%)29 (1.8%) 23 (1.4%) 26 17(1.6%) 2218 (1.1%) (1.3%) Asthenia 19 (1.1%) (1.0%) Asthenia 29 (1.8%)17 (1.0%) 19 (1.1%) 17 16(1.0%) 188 (0.5%) (1.1%) Syncope 13 (0.8%) (1.0%) Syncope 17 (1.0%) 13 (0.8%) 16 (1.0%) 8 (0.5%) Psychiatric Disorders Psychiatric Disorders Amnesia 39 (2.4%) 40 (2.4%) 57 (3.5%) 34 (2.1%) Amnesia 39 (2.4%)18 (1.1%) 40 (2.4%) 57 22(3.5%) 3415 (0.9%) (2.1%) Confusion 9 (0.5%) (1.3%) Confusion 18 (1.1%)19 (1.2%) 9 (0.5%) 22 10(1.3%) 1515 (0.9%) (0.9%) Anorexia 17 (1.0%) (0.6%) Anorexia 19 (1.2%)20 (1.2%) 17 (1.0%) 10 18(0.6%) 159 (0.5%) (0.9%) Somnolence 13 (0.8%) (1.1%) Somnolence 13 (0.8%) 18 (1.1%) 9 (0.5%) Musculoskeletal System Disorders 20 (1.2%) Musculoskeletal System Disorders Arthralgia 91 (5.5%) 75 (4.5%) 91 (5.5%) 76 (4.6%) Arthralgia 91 (5.5%)34 (2.1%) 75 (4.5%) 91 17(5.5%) 7619 (1.2%) (4.6%) Arthritis 25 (1.5%) (1.0%) Arthritis 34 (2.1%)18 (1.1%) 25 (1.5%) 17 13(1.0%) 1914 (0.8%) (1.2%) Arthrosis 22 (1.3%) (0.8%) Myalgia 16 (1.0%) (0.7%) Arthrosis 18 (1.1%)20 (1.2%) 22 (1.3%) 13 11(0.8%) 1411 (0.7%) (0.8%) Respiratory System Disorders Myalgia 20 (1.2%) 16 (1.0%) 11 (0.7%) 11 (0.7%) CoughingSystem Disorders 25 (1.5%) 18 (1.1%) 32 (1.9%) 21 (1.3%) Respiratory Upper Respiratory Tract Infection 9 (0.5%) (1.0%) Coughing 25 (1.5%)16 (1.0%) 18 (1.1%) 32 16(1.9%) 2114 (0.8%) (1.3%) Cardiovascular Upper Respiratory Disorders, Tract InfectionGeneral 16 (1.0%) 9 (0.5%) 16 (1.0%) 14 (0.8%) Cardiac Failure 26 (1.6%) 17 (1.0%) 30 (1.8%) 25 (1.5%) Cardiovascular Disorders, General Platelet, Bleeding & Clotting Disorders Cardiac Failure 26 (1.6%) 17 (1.0%) 30 (1.8%) 25 (1.5%) Hemorrhage NOS 52 (3.2%) 24 (1.5%) 46 (2.8%) 24 (1.5%) Platelet, Bleeding & Clotting Disorders Epistaxis NOS 16 (1.0%) (2.7%) Hemorrhage 52 (3.2%)39 (2.4%) 24 (1.5%) 46 45(2.8%) 2425 (1.5%) (1.5%) Purpura 23 (1.4%) 8 (0.5%) 9 (0.5%) Epistaxis 39 (2.4%) 16 (1.0%) 45 (2.7%) 257 (0.4%) (1.5%) Neoplasm Purpura 23 (1.4%) 8 (0.5%) 9 (0.5%) 7 (0.4%) Neoplasm NOS 28 (1.7%) 16 (1.0%) 23 (1.4%) 20 (1.2%) Neoplasm Red Blood Cell Disorders Neoplasm NOS 28 (1.7%) 16 (1.0%) 23 (1.4%) 20 (1.2%) Anemia 27 (1.6%) 16 (1.0%) 19 (1.2%) 9 (0.5%) Red Blood Cell Disorders *Reported treatment where the treated with placebo.

Anemia by ≥1% of patients during AGGRENOX 27 (1.6%) 16incidence (1.0%)was greater than 19in those (1.2%) 9 (0.5%) Note: ER-DP = extended-release dipyridamole 200 mg; ASA = aspirin 25 mg. The dosage regimen for all treatment groups is BID. *Reported of patients during AGGRENOX treatment where the incidence was greater than in those treated with placebo.

NOS =bynot≥1% otherwise specified.

Note: ER-DP = extended-release 200 mg; aspirin 25 mg. The dosage regimen for all treatment groups19% is BID. Discontinuation due to adversedipyridamole events in ESPS2 wasASA 25%= for AGGRENOX, 25% for extended-release dipyridamole, for aspirin, otherwise specified. and NOS 21% =fornotplacebo (refer to Table 2).

Discontinuation due to adverse events in ESPS2 was 25% for AGGRENOX, 25% for extended-release dipyridamole, 19% for aspirin, and Table 2: Incidence Adverse 21% for placebo (refer toofTable 2). Events that Led to the Discontinuation of Treatment: Adverse Events with an Incidence of ≥1% in the AGGRENOX group Table 2: Incidence of Adverse Events that Led to the Discontinuation of Treatment: Treatment Groups Adverse Events with an Incidence of ≥ 1% in the AGGRENOX group AGGRENOX ER-DP ASA Placebo Treatment Total Number of Patients 1650 1654 Groups 1649 1649 AGGRENOX ER-DP ASA Placebo Patients with at least one Adverse Event Total of Patientsdiscontinuation 1650 417 (25%) 1654 419 (25%) 1649 thatNumber led to treatment 318 (19%) 3521649 (21%) Patients with at least one Adverse Event Headache 165 (10%) 166 (10%) 57 (3%) 69 (4%) thatDizziness led to treatment discontinuation 417 (25%) 85 (5%) 419 (25%)97 (6%) 318 69 (19%) 352 (21%) (4%) 68 (4%) Headache 165 (10%) 91 (6%) 166 (10%)95 (6%) 57 51 (3%)(3%) 69 (3%) (4%) Nausea 53 Dizziness 85 (5%) 74 (4%) 97 (6%) 64 (4%) 69 56 (4%)(3%) 68 (3%) (4%) Abdominal Pain 52 Nausea 91 (6%) 59 (4%) 95 (6%) 61 (4%) 51 49 (3%)(3%) 53 (3%) (3%) Dyspepsia 46 Abdominal 74 (4%) 53 (3%) 64 (4%) 52 (3%) 56 28 (3%)(2%) 52 (1%) (3%) Vomiting Pain 24 Diarrhea 9 (<1%) 16 Dyspepsia 59 (4%) 35 (2%) 61 (4%) 41 (2%) 49 (3%) 46 (<1%) (3%) Stroke 73 Vomiting 53 (3%) 39 (2%) 52 (3%) 48 (3%) 28 57 (2%)(3%) 24 (4%) (1%) Transient Ischemic Attack (2%) 48 Diarrhea 35 (2%) 35 (2%) 41 (2%) 40 (2%) 9 26 (<1%) 16 (3%) (<1%) Angina Pectoris 26 Stroke 39 (2%) 23 (1%) 48 (3%) 20 (1%) 57 16 (3%)(<1%) 73 (2%) (4%) Note: ER-DP = extended-release dipyridamole 35 200 (2%) mg; ASA = aspirin 2540 mg.(2%) The dosage regimen for26all treatment groups is BID. Transient Ischemic Attack (2%) 48 (3%) Angina Pectoris 23 (1%) 20 (1%) 16 (<1%) 26 (2%) Other adverse events: Adverse reactions that occurreddipyridamole in less than 200 1% mg; of patients treated 25 withmg.

AGGRENOX the ESPS2 study and that were ismedically Note: ER-DP = extended-release ASA = aspirin The dosageinregimen for all treatment groups BID. judged to be possibly related to either dipyridamole or aspirin are listed below (see WARNINGS). Body as a Whole: Allergic reaction, fever.

Other adverse events: Cardiovascular: Hypotension. Central Nervous System: Coma, dizziness, paresthesia, cerebral hemorrhage, intracranial hemorrhage, Adverse reactions that occurredGastrointestinal: in less than 1%Gastritis, of patientsulceration treated with the ESPS2 and that were medically judged be subarachnoid hemorrhage. andAGGRENOX perforation.inHearing andstudy Vestibular Disorders: Tinnitus, and to deafpossibly related with to either dipyridamole or aspirin arehave listeddifficulty below (see WARNINGS). a Whole: Allergic reaction, fever. ness. Patients high frequency hearing loss may perceiving tinnitus. InBody theseaspatients, tinnitus cannot be used as Cardiovascular: Hypotension.

Central dizziness, paresthesia, cerebralarrhythmia, hemorrhage, intracranial hemorrhage, a clinical indicator of salicylism.

HeartNervous Rate andSystem: RhythmComa, Disorders: Tachycardia, palpitation, supraventricular tachycardia. subarachnoid hemorrhage.

Gastrointestinal: Gastritis, ulceration and perforation.

Hearing and Vestibular Disorders: Tinnitus, and deafness.

Liver and Biliary System Disorders: Cholelithiasis, jaundice, hepatic function abnormal. Metabolic & Nutritional Disorders: HyperglyPatients frequency hearing may Disorders: have difficulty perceiving tinnitus.

In thesePsychiatric patients, tinnitus cannot be usedReproductive: as a clinical cemia, with thirst.high Platelet, Bleeding andloss Clotting Hematoma, gingival bleeding.

Disorders: Agitation. indicator salicylism. Heart Rate andHyperpnea, Rhythm Disorders: palpitation, arrhythmia, supraventricular tachycardia.

Liver and Biliary Uterine ofhemorrhage.

Respiratory: asthma,Tachycardia, bronchospasm, hemoptysis, pulmonary edema. Special Senses Other DisorSystem Disorders: Cholelithiasis, jaundice,Disorders: hepatic function & Nutritional Disorders:and Hyperglycemia, thirst. Vascular Platelet, ders: Taste loss. Skin and Appendages Pruritus,abnormal. urticaria.Metabolic Urogenital: Renal insufficiency failure, hematuria.

Bleeding and Clotting Disorders: (Extracardiac) Disorders: Flushing.Hematoma, gingival bleeding. Psychiatric Disorders: Agitation. Reproductive: Uterine hemorrhage.

Respiratory: Hyperpnea, asthma, bronchospasm, hemoptysis, pulmonary edema. Special Senses Other Disorders: Taste loss. Skin and The following is a list Pruritus, of additional adverse reactionsRenal that insufficiency have been reported eitherhematuria. in the literature or (Extracardiac) are from postmarketing Appendages Disorders: urticaria.

Urogenital: and failure, Vascular Disorders:spontaneFlushing. ous reports for either dipyridamole or aspirin. Body as a Whole: Hypothermia, chest pain. Cardiovascular: Angina pectoris. Central The following is a list of additional reactions that have been reported either inacidosis, the literature or are from postmarketing spontaneous Nervous System: Cerebral edema.adverse Fluid and Electrolyte: Hyperkalemia, metabolic respiratory alkalosis, hypokalemia.

Gastroreports for either dipyridamole or aspirin.

Body as a Whole: Hypothermia, chest pain.

Cardiovascular: Angina pectoris.

Central Nervous System: intestinal: Pancreatitis, Reye’s syndrome, hematemesis. Hearing and Vestibular Disorders: Hearing loss. Hypersensitivity: Acute anaphyCerebral edema. Fluid andLiver Electrolyte: Hyperkalemia, metabolicHepatitis, acidosis, hepatic respiratory alkalosis, hypokalemia.Rhabdomyolysis.

Gastrointestinal: Metabolic Pancreatitis,& laxis, laryngeal edema. and Biliary System Disorders: failure.

Musculoskeletal: Reye’ s syndrome, hematemesis.

Hearing and Vestibular Disorders: Hearing loss.

Hypersensitivity: Acute anaphylaxis, laryngeal edema.

Nutritional Disorders: Hypoglycemia, dehydration. Platelet, Bleeding and Clotting Disorders: Prolongation of the prothrombin time,Liver disand Biliary System Disorders: Hepatitis, coagulopathy, hepatic failure. thrombocytopenia.

Musculoskeletal: Rhabdomyolysis.

Metabolic &pregnancy Nutritionaland Disorders: Hypoglycemia, seminated intravascular coagulation, Reproductive: Prolonged labor, stillbirths, lower dehydration. andand Clotting Disorders: Prolongation of the prothrombin time, Skin disseminated intravascular coagulation, birth weightPlatelet, infants, Bleeding antepartum postpartum bleeding.

Respiratory: Tachypnea, dyspnea. and Appendages Disorders: Rash, coagulopathy, thrombocytopenia.

Reproductive: Prolonged pregnancy and labor, stillbirths, lower birth weight infants, antepartum and alopecia, angioedema, Stevens-Johnson syndrome, pruritus, urticaria, skin hemorrhages such as bruising, ecchymosis, and hematoma. postpartum Tachypnea, dyspnea.

Skin and Vascular Appendages Disorders:Disorders): Rash, alopecia, angioedema, Urogenital:bleeding.

InterstitialRespiratory: nephritis, papillary necrosis, proteinuria.

(Extracardiac Allergic vasculitis. Stevens-Johnson syndrome, pruritus, urticaria, skin hemorrhages such as bruising, ecchymosis, and hematoma. Urogenital: Interstitial nephritis, papillary The following is a list of additional adverse events that have been reported either in the literature or are from postmarketing spontaneous necrosis, proteinuria. Vascular (Extracardiac Disorders): Allergic vasculitis. reports for either dipyridamole or aspirin. The causal relationship of these adverse events has not been established: anorexia, aplastic The following is a list of thrombocytosis. additional adverse events that have been reported either in the literature or are from postmarketing spontaneous anemia, pancytopenia, reports for either dipyridamole or aspirin. The causal relationship of these adverse events has not been established: anorexia, aplastic anemia, Laboratorythrombocytosis.

Changes pancytopenia, Over the course of the 24-month study (ESPS2), patients treated with AGGRENOX showed a decline (mean change from baseline) in Laboratory Changes 3. hemoglobin of 0.25 hematocrit 0.75%, and erythrocyte 0.13x106/mm Over the course of theg/dL, 24-month studyof(ESPS2), patients treatedcount with of AGGRENOX showed a decline (mean change from baseline) in OVERDOSAGE hemoglobin of 0.25 g/dL, hematocrit of 0.75%, and erythrocyte count of 0.13x106/mm3.

Because of the dose ratio of dipyridamole to aspirin, overdosage of AGGRENOX is likely to be dominated by signs and symptoms of OVERDOSAGE dipyridamole of real or to suspected medical attention or contact a Poison dipyridamole) Control Centerisimmediately.

Because of the overdose. dose ratioInofcase dipyridamole aspirin, overdose, overdosageseek of AGGRENOX (aspirin/extended-release likely to be Careful medical management is essential. dominated by signs and symptoms of dipyridamole overdose. In case of real or suspected overdose, seek medical attention or contact a Poison Control Center immediately. Careful medical management is essential.

DOSAGE AND ADMINISTRATION The recommended dose of AGGRENOX capsules is one capsule given orally twice daily, one in the morning and one in the evening. The DOSAGE AND ADMINISTRATION ® capsules should be swallowed whole without chewing. AGGRENOX capsulescapsules may be administered or without food.daily, one in the (aspirin/extended-release dipyridamole) is one capsulewith given orally twice The recommended dose of Aggrenox morning and one in the evening.

The capsules should be swallowed whole chewing.

AGGRENOX capsules be administered with Alternative Regimen in Case of Intolerable Headaches: In thewithout event of intolerable headaches duringmay initial treatment, switch ortowithout food. at bedtime and low-dose aspirin in the morning. Because there are no outcome data with this regimen and headaches one capsule become lessRegimen of a problem as treatment continues, patients should returnoftointolerable the usualheadaches regimen as sooninitial as possible, within Alternative in Case of Intolerable Headaches: In the event during treatment,usually switch to one one week. capsule at bedtime and low-dose aspirin in the morning. Because there are no outcome data with this regimen and headaches become less of a problem as treatment patients should the usual regimen as soonof asaspirin possible,and usually within one®week.

AGGRENOX is notcontinues, interchangeable withreturn the to individual components Persantine Tablets.Rx only AGGRENOX not interchangeable with the individual aspirin and Persantine® Tablets.

Marketed by:isBoehringer Ingelheim Pharmaceuticals Inc., components Ridgefield, CTof06877 USA Marketed by: Boehringer IngelheimIngelheim Pharmaceuticals Ridgefield, CT 06877 USA Germany Manufactured by: Boehringer PharmaInc., GmbH & Co. KG, Biberach, Manufactured by: Boehringer Pharma GmbH &GmbH Co. KG, © Biberach, Germany Licensed from: BoehringerIngelheim Ingelheim International Copyright Boehringer Ingelheim International GmbH 2007 Licensed from: Boehringer Ingelheim International GmbH © Copyright Boehringer Ingelheim International GmbH 2007 ALLRIGHTS RIGHTS RESERVED PatentPatent No. 6,015,577 42633/US/7 AG/BS/42633 AG49262 ALL RESERVED No. 6,015,577 42633/US/7 AG/BS/42633 AG49265 Rx only

Covers_Cover 10/14/09 11:17 AM Page C4

Pick the TIA or ischemic stroke patients out of the crowd.

AGGRENOX may be right for many of them.

AGGRENOX has been shown to be twice as effective as low-dose aspirin when compared to placebo.1 • In ESPS 2, relative risk reductions were 37.0% for AGGRENOX vs placebo; 18.1% for aspirin vs placebo; 23.1% for AGGRENOX vs aspirin alone ESPS 2 = European Stroke Prevention Study 2.

CHOOSE AGGRENOX FOR SECONDARY STROKE RISK REDUCTION THAT MAY BE RIGHT FOR MANY PATIENTS. Important Safety afety Information Aggrenox® (aspirin/extended-release dipyridamole) 25 mg/200 mg capsules is indicated to reduce the risk of stroke in patients who have had transient ischemia of the brain or completed ischemic stroke due to thrombosis.

In ESPS 2, the most common adverse event with AGGRENOX was headache (39.2% vs. 32.9% with placebo), which was more frequent at the onset of therapy but diminished over time. Bleeding (including GI and intracranial bleeding) was comparable to aspirin (8.7% vs. 8.2%) and higher than placebo (8.7% vs. 4.5%). GI side effects (such as dyspepsia, stomach pain, heartburn, nausea, and vomiting) were other common adverse events.

AGGRENOX contains aspirin. Patients who consume three or more alcoholic drinks every day should be counseled about the bleeding risks associated with chronic, heavy alcohol use while taking aspirin. Even low doses of aspirin can increase bleeding time, which can adversely affect patients with bleeding disorders. Patients with a history of active peptic ulcer disease should avoid using aspirin. Aspirin should be avoided in the third trimester of pregnancy. Aspirin is contraindicated in patients with known allergy to nonsteroidal anti-inflammatory drug products and in patients with the syndrome of asthma, rhinitis, and nasal polyps occurring in combination.

Reference: 1. Diener H-C, Cunha L, Forbes C, et al. European Stroke Prevention Study 2: dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci. 1996; 143:1-13.

Please see reverse side for Brief Summary of Prescribing Information.

Copyright © 2009, Boehringer Ingelheim Pharmaceuticals, Inc. All rights reserved.

Printed in the U.S.A.

(08/09)

AG66794

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