May/June 2012, Vol 5, No 3

EDITORIAL

“SCOTUS”: Will They or Won’t They?David B. Nash, MD, MBA

CLINICAL

Managing Hypertension in the Elderly: A Common Chronic Disease withIncreasing AgeQuang T. Nguyen, DO, FACE; Scott R. Anderson, MS IV; Lindsay Sanders, DO, MPH; Loida D. Nguyen, PharmD, BCPS

Stakeholder Perspective by Katrina Moore, PharmD

BUSINESS

Utilization of Anticoagulation Therapy in Medicare Patients with Nonvalvular Atrial FibrillationKate Fitch, RN, MEd; Jonah Broulette; Bruce Pyenson, FSA, MAAA; Kosuke Iwasaki, FIAJ, MAAA; Winghan Jacqueline Kwong, PharmD, PhD

Stakeholder Perspective by Michael F. Murphy, MD, PhD

Recent Developments, Utilization, and Spending Trends for Pompe Disease TherapiesJing Guo, BPharm; Christina M.L. Kelton, PhD; Jeff J. Guo, PhD

Stakeholder Perspective by Albert Tzeel, MD, MHSA, FACPE

AMCP 2012 HIGHLIGHTS

™

©2012 Engage Healthcare Communications, LLCwww.AHDBonline.com

MAY/JUNE 2012 VOLUME 5, NUMBER 3

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN™

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

is a registered trademark of Incyte Corporation.© 2012, Incyte Corporation. All rights reserved.R

Indications and UsageJaka� is indicated for treatment of patients with intermediate or high-risk myelo� brosis, including primary myelo� brosis, post–polycythemia vera myelo� brosis and post–essential thrombocythemia myelo� brosis.

Important Safety Information• Treatment with Jaka� can cause hematologic adverse

reactions, including thrombocytopenia, anemia and neutropenia, which are each dose-related effects, withthe most frequent being thrombocytopenia and anemia.A complete blood count must be performed before initiating therapy with Jaka� . Complete blood counts should be monitored as clinically indicated and dosingadjusted as required

• The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache

• Patients with platelet counts <200 × 109/L at the start of therapy are more likely to develop thrombocytopenia

during treatment. Thrombocytopenia was generally reversible and was usually managed by reducing the dose or temporarily withholding Jaka� . If clinically indicated, platelet transfusions may be administered

• Patients developing anemia may require blood transfusions. Dose modi� cations of Jaka� for patients developing anemia may also be considered

• Neutropenia (ANC <0.5 × 109/L) was generally reversible and was managed by temporarily withholding Jaka�

• Patients should be assessed for the risk of developing serious bacterial, mycobacterial, fungal and viral infections. Active serious infections should have resolved before starting Jaka� . Physicians should carefully observe patients receiving Jaka� for signs and symptoms of infection (including herpes zoster) and initiate appropriate treatment promptly

• A dose modi� cation is recommended when administeringJaka� with strong CYP3A4 inhibitors or in patients with

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Prescribing Information. Incyte Corporation. November 2011. 1

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has shown that with the right process, manufacturers can successfully collaborate with regulatory agencies and academic

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may provide a model for the future use of PROs in marketing applications.8

How PROs were successfully integrated into the Jaka� ® (ruxolitinib) drug development program1

A novel approach to engage clinicians and FDA

PROs are an important means to demonstrate treatment

bene� ts in clinical trials.2,3 Use of a PRO instrument can

evaluate symptoms best judged by the patient, whether

caused by the disease or treatment toxicity. Assessment

of symptom burden is important because it can be a major

indicator of disease severity, progression or improvement.

Incorporating PROs into a clinical trial program provides a

means for evaluating the impact of therapy from the patient’s

perspective and helps patients and clinicians make better-

informed decisions.4

TAILORING a PRO tool for myelo� brosis

Myelo� brosis (MF) is a life-threatening, progressive disease

characterized by splenomegaly, debilitating symptoms and

cytopenias.5-7 Measures to assess both the splenomegaly

and core symptoms of MF were incorporated into the phase III,

double-blind placebo-controlled study, COMFORT-I, for Jaka� .

Spleen reduction, as measured by imaging (MRI or CT), was the

primary and biologic endpoint, and a reduction in total symptom

score (TSS), the PRO measure, was a key secondary endpoint.8,9

The TSS encompassed the following symptoms: abdominal

discomfort, pain under left ribs, early satiety, pruritus, night

sweats and bone/muscle pain.9

To include PROs in the trial, a novel instrument had to be

speci� cally developed. After patient interviews, advice from

clinical experts and extensive input from the FDA, the

modi� ed Myelo� brosis Symptom Assessment Form, version

2.0 (modi� ed MFSAF v2.0) was � nalized as part of the Special

Protocol Assessment prior to the initiation of COMFORT-I.

Ultimately, Jaka� was approved by the FDA for the treatment

of intermediate or high-risk MF.1,8 This became Incyte’s � rst

approved drug and also the � rst oncology medicine approved

with symptom data in its label since the FDA ’s draft guidance on

PROs was � nalized in 2009.2,4

gresswith patient-reported outcomes

Making

PRO

P

Placebo (n = 145)Jaka� (n = 145)

COMFORT-I: Percent Change in TSS in Individual Patients From Baseline to Week 24 or Last Observation9,a,b

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Upper 50th Percentile Upper 50th Percentile

Each bar represents an individual patient’s response. Worsening of TSS is truncated at 150%.

Placebo (n = 153)Jaka� (n = 155)

COMFORT-I: Percent Change in Spleen Volume in Individual Patients From Baseline to Week 24 or Last Observation9,a

Upper 50th Percentile Upper 50th Percentile

80

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35% Reduction

Each bar represents an individual patient’s response.

Jaka� is a registered trademark of Incyte Corporation.© 2012, Incyte Corporation. All rights reserved.RUX-1130 05/12

I is indicated for treatment of patients with intermediate

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for patients developing anemia

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a As studied in COMFORT-I, a randomized, double-blind, placebo-controlled phase IIIstudy with 309 total patients (United States, Canada, Australia). The primary endpoint was the proportion of subjects achieving a ≥35% reduction in spleen volume frombaseline to Week 24 as measured by MRI or computed tomography (CT). A secondary endpoint was the proportion of subjects with a ≥50% reduction in TSS from baseline to Week 24 as measured by the daily patient diary, the modi� ed MFSAF v2.0.9,10

b Symptom scores were captured by a daily patient diary recorded for 25 weeks. TSS encompasses debilitating symptoms of MF: abdominal discomfort, pain under left ribs, early satiety, pruritus, night sweats and bone/muscle pain. Symptom scores ranged from 0 to 10 with 0 representing symptoms “absent” and 10 representing “worst imaginable” symptoms. These scores were added to create the daily total score, which has a maximum of 60. At baseline, mean TSS was 18.0 in the Jaka� group and 16.5 in the placebo group.9,10

References: 1. McCallister E, et al. BioCentury. Reprint from December 5, 2011. 2. Haley S.The Pink Sheet. November 21, 2011;73:47. Symptom Measurement in Clinical Trials. 3. US Department of Health and Human Services Guidance for Industry: Patient-reported outcome measures: Use in medical product development to support labeling claims. December 2009. 4. Basch E, et al. Issue brief from Conference on ClinicalCancer Research, November 2011. 5. Cervantes F, et al. Blood. 2009;113:2895-2901.6. Mesa RA, et al. Leuk Res. 2009;33:1199-1203. 7. Verstovsek S, et al. N Engl J Med.2012;366:799-807. 8. Deisseroth AB, et al. Clin Cancer Res. 2012 Apr 27. (Epubahead of print). 9. Jaka� Prescribing Information. Incyte Corporation. November 2011. 10. Data on File, Incyte Corporation.

renal or hepatic impairment [see Dosage and Administration]. Patients should be closely monitored and the dose titrated based on safety and ef� cacy

• There are no adequate and well-controlled studies of Jaka� in pregnant women. Use of Jaka� during pregnancy is not recommended and should only be used if the potential bene� t justi� es the potential risk to the fetus

• Women taking Jaka� should not breast-feed. Discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother

PROVIDING proof of patient bene� t

MF is progressive, and spleen size and symptoms can become increasingly burdensome to patients over time.5-7 Jaka� is

proven to decrease total symptom score in patients with intermediate or high-risk MF—this is an important consideration when

evaluating and treating patients.9 The FDA approval included patients with intermediate-2 risk and high risk, as well as patients

with intermediate-1 risk, since intermediate-1 patients may also have symptoms that require treatment. Clinical experience with

Jaka� has shown that with the right process, manufacturers can successfully collaborate with regulatory agencies and academic

experts to develop relevant and validated PRO instruments that can be incorporated into clinical trials.1,8 The approval of Jaka�

marks a signi� cant milestone in which validated PRO instruments can provide symptom data and demonstrate clinical bene� t.

The experience with Jaka� may provide a model for the future use of PROs in marketing applications.8

JAKAFI endpoints included both biologic and patient-reported outcomes8,9

T

Please see Brief Summary of Full PrescribingInformation on the following page.

Table 2: Worst Hematology Laboratory Abnormalities in the Placebo-controlled Studya

Jakafi Placebo (N=155) (N=151)Laboratory All All Parameter Gradesb Grade 3 Grade 4 Grades Grade 3 Grade 4 (%) (%) (%) (%) (%) (%)Thrombocytopenia 69.7 9.0 3.9 30.5 1.3 0Anemia 96.1 34.2 11.0 86.8 15.9 3.3Neutropenia 18.7 5.2 1.9 4.0 0.7 1.3

a Presented values are worst Grade values regardless of baselineb National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0Additional Data from the Placebo-controlled Study 25.2% of patients treated with Jakafi and 7.3% ofpatients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine trans-aminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 1.9% for Jakafi with 1.3%Grade 3 and no Grade 4 ALT elevations. 17.4% of patients treated with Jakafi and 6.0% of patients treatedwith placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase(AST). The incidence of Grade 2 AST elevations was 0.6% for Jakafi with no Grade 3 or 4 AST elevations.16.8% of patients treated with Jakafi and 0.7% of patients treated with placebo developed newly occurring orworsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was 0.6% forJakafi with no Grade 3 or 4 cholesterol elevations.DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinibis predominantly metabolized by CYP3A4. Strong CYP3A4 inhibitors: The Cmax and AUC of ruxolitinibincreased 33% and 91%, respectively, with Jakafi administration (10 mg single dose) following ketoconazole200 mg twice daily for four days, compared to receiving Jakafi alone in healthy subjects. The half-life was alsoprolonged from 3.7 to 6.0 hours with concurrent use of ketoconazole. The change in the pharmacodynamicmarker, pSTAT3 inhibition, was consistent with the corresponding ruxolitinib AUC following concurrent admin-istration with ketoconazole. When administering Jakafi with strong CYP3A4 inhibitors a dose reduction isrecommended [see Dosage and Administration (2.4) in Full Prescribing Information]. Patients should beclosely monitored and the dose titrated based on safety and efficacy. Mild or moderate CYP3A4 inhibitors:There was an 8% and 27% increase in the Cmax and AUC of ruxolitinib, respectively, with Jakafi administration(10 mg single dose) following erythromycin, a moderate CYP3A4 inhibitor, at 500 mg twice daily for 4 days,compared to receiving Jakafi alone in healthy subjects. The change in the pharmacodynamic marker, pSTAT3inhibition was consistent with the corresponding exposure information. No dose adjustment is recommendedwhen Jakafi is coadministered with mild or moderate CYP3A4 inhibitors (eg, erythromycin). CYP3A4inducers: The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, with Jakafi administration(50 mg single dose) following rifampin 600 mg once daily for 10 days, compared to receiving Jakafi alone inhealthy subjects. In addition, the relative exposure to ruxolitinib’s active metabolites increased approximately100%. This increase may partially explain the reported disproportionate 10% reduction in the pharmaco-dynamic marker pSTAT3 inhibition. No dose adjustment is recommended when Jakafi is coadministered witha CYP3A4 inducer. Patients should be closely monitored and the dose titrated based on safety and efficacy.USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no adequate and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment withruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses.Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at dosesof 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of terato-genicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest andmaternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 timesthe clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weightsof approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. Ina pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implan-tation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups forfertility indices or for maternal or embryofetal survival, growth and development parameters at the highestdose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily).Nursing Mothers It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or itsmetabolites were excreted in the milk of lactating rats with a concentration that was 13-fold the maternalplasma. Because many drugs are excreted in human milk and because of the potential for serious adversereactions in nursing infants from Jakafi, a decision should be made to discontinue nursing or to discontinuethe drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effec-tiveness of Jakafi in pediatric patients have not been established. Geriatric Use Of the total number ofmyelofibrosis patients in clinical studies with Jakafi, 51.9% were 65 years of age and older. No overall differ-ences in safety or effectiveness of Jakafi were observed between these patients and younger patients. RenalImpairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study inhealthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)],moderate [CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8)additional subjects with end stage renal disease requiring hemodialysis were also enrolled. The pharmaco-kinetics of ruxolitinib was similar in subjects with various degrees of renal impairment and in those withnormal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasingseverity of renal impairment. This was most marked in the subjects with end stage renal disease requiringhemodialysis. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removalof some active metabolites by dialysis cannot be ruled out. When administering Jakafi to patients withmoderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet countbetween 100 X 109/L and 150 X 109/L and patients with end stage renal disease on dialysis a dose reductionis recommended [see Dosage and Administration (2.5) in Full Prescribing Information]. HepaticImpairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study inhealthy subjects (N=8) and in subjects with mild [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], orsevere hepatic impairment [Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28%and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patientswith normal hepatic function. The terminal elimination half-life was prolonged in patients with hepaticimpairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). The change in the pharmaco-dynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in ruxolitinib exposureexcept in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity wasmore prolonged in some subjects than expected based on plasma concentrations of ruxolitinib. When administering Jakafi to patients with any degree of hepatic impairment and with a platelet count between 100 X 109/L and 150 X 109/L, a dose reduction is recommended [see Dosage and Administration (2.5) inFull Prescribing Information].

BRIEF SUMMARY: For Full Prescribing Information, see package insert.INDICATIONS AND USAGE Jakafi is indicated for treatment of patients with intermediate or high-riskmyelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essentialthrombocythemia myelofibrosis.CONTRAINDICATIONS None.WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatmentwith Jakafi can cause hematologic adverse reactions, including thrombocytopenia, anemia and neutropenia.A complete blood count must be performed before initiating therapy with Jakafi [see Dosage andAdministration (2.1) in Full Prescribing Information]. Patients with platelet counts of less than 200 X 109/Lat the start of therapy are more likely to develop thrombocytopenia during treatment. Thrombocytopenia wasgenerally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi. If clinically indicated, platelet transfusions may be administered [see Dosage and Administration (2.2) in FullPrescribing Information, and Adverse Reactions]. Patients developing anemia may require blood trans-fusions. Dose modifications of Jakafi for patients developing anemia may also be considered. Neutropenia(ANC less than 0.5 X 109/L) was generally reversible and was managed by temporarily withholding Jakafi[see Adverse Reactions]. Complete blood counts should be monitored as clinically indicated and dosingadjusted as required [see Dosage and Administration (2.2) in Full Prescribing Information, and AdverseReactions]. Infections Patients should be assessed for the risk of developing serious bacterial, mycobac-terial, fungal and viral infections. Active serious infections should have resolved before starting therapy withJakafi. Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection andinitiate appropriate treatment promptly. Herpes Zoster Physicians should inform patients about early signsand symptoms of herpes zoster and advise patients to seek treatment as early as possible [see AdverseReactions].ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted underwidely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directlycompared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Thesafety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase 3 studies,patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 88.7% ofpatients treated for more than 6 months and 24.6% treated for more than 12 months. One hundred andeleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. Ina double-blind, randomized, placebo-controlled study of Jakafi, 155 patients were treated with Jakafi. Themost frequent adverse drug reactions were thrombocytopenia and anemia [see Table 2]. Thrombocytopenia,anemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactionswere bruising, dizziness and headache [see Table 1]. Discontinuation for adverse events, regardless ofcausality, was observed in 11.0% of patients treated with Jakafi and 10.6% of patients treated with placebo.Following interruption or discontinuation of Jakafi, symptoms of myelofibrosis generally return topretreatment levels over a period of approximately 1 week. There have been isolated cases of patients discon-tinuing Jakafi during acute intercurrent illnesses after which the patient’s clinical course continued to worsen;however, it has not been established whether discontinuation of therapy contributed to the clinical course inthese patients. When discontinuing therapy for reasons other than thrombocytopenia, gradual tapering of thedose of Jakafi may be considered [see Dosage and Administration (2.6) in Full Prescribing Information].Table 1 presents the most common adverse reactions occurring in patients who received Jakafi in the double-blind, placebo-controlled study during randomized treatment.Table 1: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlledStudy During Randomized Treatment

Jakafi Placebo (N=155) (N=151)Adverse All All Reactions Gradesa Grade 3 Grade 4 Grades Grade 3 Grade 4 (%) (%) (%) (%) (%) (%)Bruisingb 23.2 0.6 0 14.6 0 0Dizzinessc 18.1 0.6 0 7.3 0 0Headache 14.8 0 0 5.3 0 0Urinary Tract Infectionsd 9.0 0 0 5.3 0.7 0.7Weight Gaine 7.1 0.6 0 1.3 0.7 0Flatulence 5.2 0 0 0.7 0 0Herpes Zosterf 1.9 0 0 0.7 0 0

a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0b includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site

hematoma, increased tendency to bruise, petechiae, purpurac includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitisd includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria

urine, bacteria urine identified, nitrite urine presente includes weight increased, abnormal weight gainf includes herpes zoster and post-herpetic neuralgiaDescription of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies, mediantime to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (0.3%)discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobinreached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and thengradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This patternwas observed in patients regardless of whether they had received transfusions during therapy. In therandomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receivingplacebo received red blood cell transfusions during randomized treatment. Among transfused patients, themedian number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebotreated patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia wasgenerally reversible with dose reduction or dose interruption. The median time to recovery of platelet countsabove 50 X 109/L was 14 days. Platelet transfusions were administered to 4.7% of patients receiving Jakafiand to 4.0% of patients receiving control regimens. Discontinuation of treatment because of thrombo-cytopenia occurred in 0.7% of patients receiving Jakafi and 0.9% of patients receiving control regimens.Patients with a platelet count of 100 X 109/L to 200 X 109/L before starting Jakafi had a higher frequency ofGrade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 109/L (16.5%versus 7.2%). Neutropenia In the two Phase 3 clinical studies, 1.0% of patients reduced or stopped Jakafibecause of neutropenia. Table 2 provides the frequency and severity of clinical hematology abnormalitiesreported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study.

Jakafi is a trademark of Incyte Corporation. All rights reserved.U.S. Patent No. 7,598,257© 2011 Incyte Corporation. All rights reserved.Issued: November 2011 RUX-1040

133www.AHDBonline.com l American Health & Drug Benefits lVol 5, No 3 l May/June 2011

TABLE OF CONTENTS

Continued on page 136

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EDITORIAL

141 “SCOTUS”: Will They or Won’t They?David B. Nash, MD, MBA

CLINICAL

146 Managing Hypertension in the Elderly: A Common Chronic Disease withIncreasing AgeQuang T. Nguyen, DO, FACE; Scott R. Anderson, MS IV; Lindsay Sanders, DO, MPH;Loida D. Nguyen, PharmD, BCPS

153 Stakeholder Perspective by Katrina Moore, PharmD

BUSINESS

157 Utilization of Anticoagulation Therapy in Medicare Patients with NonvalvularAtrial FibrillationKate Fitch, RN, MEd; Jonah Broulette; Bruce Pyenson, FSA, MAAA; Kosuke Iwasaki,FIAJ, MAAA; Winghan Jacqueline Kwong, PharmD, PhD

167 Stakeholder Perspective by Michael F. Murphy, MD, PhD

PublisherNicholas [email protected] PublisherMaurice [email protected] DirectorDalia [email protected] EditorLara J. Lorton732-992-1892Editorial AssistantJennifer [email protected] AssistantZach CeretelleSenior Production ManagerLynn HamiltonQuality Control DirectorBarbara MarinoBusiness ManagerBlanche Marchitto

Founding Editor-in-ChiefRobert E. Henry

American Health & Drug Benefits isfounded on the concept that health anddrug benefits have undergone a transfor-mation: the econo metric value of a drugis of equal importance to clinical out-comes as it is to serving as the basis forsecuring coverage in formularies andbenefit designs. Because benefit designsare greatly affected by clinical, business,and policy conditions, this journal offersa forum for stakeholder integration andcollaboration toward the improvementof healthcare.This publication further provides benefitdesign de cision makers the integratedindustry information they require to deviseformularies and benefit designs that standup to today’s special healthcare deliveryand business needs.Contact Information:For subscription information and edi torial queries, please contact: [email protected]: 732-992-1892F: 732-992-1881

Mission Statement

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ent

Cir

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tin

g In

flu

enza

Vir

us

(%)

2002-03 2004-05 2006-07 2009-10 2010-11

A strain

2001-02 2003-04 2005-06 2007-08 2008-09

B strain

Influenza B Strain Prevalence Is Variable3

B strain mismatch occurred in this year’s flu vaccine

It’s fl u season. Which one’s the culprit?

DATA INDICATE IT MAY BE THE B STRAIN

Many of your members may be vaccinated against infl uenza, yet still may not be protected against all circulating strains this coming season. Why? There are different strains of infl uenza—A strains and B strains. Protecting against infl uenza depends, in part, on predicting the circulating strains each season, and then ensuring the vaccination covers those strains.1

Infl uenza B causes fl u morbidity every season, yet predicting the dominant circulating B strain is not an exact science. Current fl u vaccines protect against two A strains, and one of the two B strain lineages.2

In 5 out of 10 infl uenza seasons (2001-2011), the predominant circulating B strain was different from the one included in the infl uenza vaccine.3 When the incorrect B strain is predicted in an annual vaccine, the mismatch can leave a portion of your membership unprotected.

V

References: 1. World Health Organization. Infl uenza (Seasonal) Fact Sheet No 211, April 2009. http://www.who.int/mediacentre/factsheets/fs211/en/#. Accessed January 4, 2012. 2. Centers for Disease Control and Prevention. Seasonal Infl uenza (Flu). 2011-2012 Infl uenza Vaccine Information. http://www.cdc.gov/fl u/fl u_vaccine_updates.htm. Accessed January 4, 2012. 3. Centers for Disease Control and Prevention. Seasonal Infl uenza (Flu). Past Weekly Surveillance Reports. http://www.cdc.gov/fl u/weekly/pastreports.htm. Accessed January 4, 2012. 4. Thompson WW, Shay DK, Weintraub E, et al. Infl uenza-associated hospitalizations in the United States. JAMA. 2004;292(11):1333-1340. 5. Molinari NA, Ortega-Sanchez IR, Messonnier ML, et al. The annual impact of seasonal infl uenza in the US: measuring disease burden and © 2012 MedImmune. All rights reserved.

VACCINATED, YET NOT OPTIMALLY PROTECTED

What does this mean for your health plan?

• In seasons where mismatched circulating B strains predominate, your vaccinated members may be more susceptible to infl uenza illness

POTENTIAL IMPACT OF PROTECTION

Protecting against both infl uenza B strain lineages avoids the challenge of predicting which one will predominate in upcoming infl uenza seasons. In fact, a recent CDC model§ estimated that protecting against both B strains may have helped avoid 2.7 million cases of infl uenza illness over ten fl u seasons.7

© 2012 MedImmune. All rights reserved. 10116-22956

costs. Vaccine. 2007;25:5086-5096. 6. Adams PF, Hendershot GE, Marano MA. Current estimates from the National Health Interview Survey, 1996. Vital Health Stat 10. 1999;(200):1-203. 7. Reed C, Meltzer MI, Finelli L, Fiore A. Public health impact of including two lineages of infl uenza B in a quadrivalent seasonal infl uenza vaccine. [Published online ahead of print January 4, 2012.] Vaccine. (2012),doi:10.1016/j.vaccine.2011.12.098.

§ The model used in the analysis is dependent on variables such as overall burden of infl uenza, annual vaccine capacity and coverage, and proportion of infl uenza burden due to circulating B strains.

ESTIMATED ANNUAL IMPACT OF INFLUENZA A AND B

• 200,000 hospitalizations4*

• 31 million outpatient visits5†

• 44 million lost working days5†

• 38 million lost school days in one year6‡

*Based on 2003 population demographics.† Estimated annual average based on data from infl uenza seasons from 1979-1980 through 2000-2001.

‡Estimated figure pertains to 1996 only.

B

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136 l American Health & Drug Benefits l www.AHDBonline.com May/June 2012 l Vol 5, No 3


American Health & Drug Benefits, ISSN1942-2962 (print); ISSN 1942-2970(online), is published 8 times a year byEngage Healthcare Communications,LLC, 241 Forsgate Drive, Suite 205A,Monroe Township, NJ 08831. Copyright © 2012 by Engage HealthcareCommunications, LLC. All rightsreserved. American Health & Drug Benefitsand The Peer-Reviewed Forum for Evidencein Benefit Design are trademarks of EngageHealthcare Communications, LLC. Nopart of this publication may be repro-duced or transmitted in any form or byany means now or hereafter known, elec-tronic or mechanical, including photo-copy, recording, or any informationalstorage and retrieval system, without written permission from the Publisher.Printed in the United States of America.

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TABLE OF CONTENTS (Continued)



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BUSINESS

182 Recent Developments, Utilization, and Spending Trends for Pompe Disease TherapiesJing Guo, BPharm; Christina M.L. Kelton, PhD; Jeff J. Guo, PhD

188 Stakeholder Perspective by Albert Tzeel, MD, MHSA, FACPE

DEPARTMENTS

168 Correction

175 AMCP Highlights

Electronic Service Alerts Providers of Low-Cost Drugs, Shows Significant Cost-Savings

Consumer-Directed Health Plans’ Impact on Medication Adherence in Chronic Conditions

High-Deductible Health Plans: Mixed Results in Clinical Outcomes,Associated Costs

Pharmacists’ Knowledge Gap about Oncology Genetic Testing, Benefit Design

EDITORIAL BOARD


EDITOR-IN-CHIEFDavid B. Nash, MD, MBA Dean, the Dr Raymond C. and Doris N.Grandon Professor, Jefferson School ofPopulation Health

DEPUTY EDITORSJoseph E. Couto, PharmD, MBAAssistant Professor, Jefferson School of Population HealthDirector, Health Economics andOutcomes Research Fellowship Program

Laura T. Pizzi, PharmD, MPH, RPhAssociate Professor, Department ofPharmacy Practice, Jefferson School of Pharmacy

ACTUARY David WilliamsMilliman Health ConsultantWindsor, CT

AGING AND WELLNESSEric G. Tangalos, MD, FACP, AGSF,CMDProfessor of MedicineMayo Clinic, Rochester, MN

CANCER RESEARCHAl B. Benson, III, MD, FACPProfessor of MedicineAssociate Director for ClinicalInvestigationsRobert H. Lurie Comprehensive CancerCenter, Northwestern UniversityImmediate Past President, ACCCPast Chair, NCCN Board of Directors

Samuel M. Silver, MD, PhD, FACPProfessor, Internal MedicineDirector, Cancer Center NetworkDivision of Hematology/OncologyAssistant Dean for ResearchUniversity of Michigan Health Systems

CARDIOLOGY RESEARCH Michael A. Weber, MDProfessor of MedicineDepartment of Medicine (Cardiology)State University of New York

EMPLOYERSArthur F. Shinn, PharmD, FASCPPresident, Managed Pharmacy Consultants, Lake Worth, FL

F. Randy Vogenberg, RPh, PhDPrincipal, Institute of IntegratedHealthcare, Sharon, MA

ENDOCRINOLOGY RESEARCHJames V. Felicetta, MD Chairman, Dept. of Medicine Carl T. Hayden Veterans AffairsMedical Center, Phoenix, AZ

EPIDEMIOLOGY RESEARCHJoshua N. Liberman, PhDVice President, Research OperationsCenter for Health ResearchGeisinger Health System, Danville, PA

GOVERNMENTKevin B. “Kip” Piper, MA, FACHEPresident, Health Results Group, LLCWashington, DC

HEALTH INFORMATION TECHNOLOGY J. B. Jones, PhD, MBAResearch Investigator, Geisinger Health System, Danville, PA

Victor J. Strecher, PhD, MPHProfessor and Director, Center for HealthCommunications ResearchUniversity of Michigan Schools of PublicHealth and Medicine, Ann ArborFounder and Chief Visionary OfficerHealthMedia, Johnson & Johnson

HEALTH OUTCOMES RESEARCH Diana Brixner, RPh, PhDProfessor and ChairDepartment of PharmacotherapyExecutive Director, Outcomes ResearchCenter, University of Utah College ofPharmacy, Salt Lake City

Kavita V. Nair, PhDAssociate Professor, School of PharmacyUniversity of Colorado at Denver

Gary M. Owens, MDPresident, Gary Owens AssociatesGlen Mills, PA

Timothy S. Regan, BPharm, RPhExecutive Director, XcendaPalm Harbor, FL

HEALTH & VALUE PROMOTION Thomas G. McCarter, MD, FACPChief Clinical OfficerExecutive Health Resources, PA

Albert Tzeel, MD, MHSA, FACPENational Medical DirectorHumanaOne, Milwaukee

MANAGED MARKETS Jeffrey A. Bourret, RPh, MS, FASHPSenior Director, Branded SpecialtyPharmacy Programs, US SpecialtyCustomers, Pfizer, Specialty Care Business Unit, PA

Charles E. Collins, Jr, MS, MBAExecutive Vice President, Managing DirectorEngage Managed Markets

PATIENT ADVOCACY William E. Fassett, BSPharm, MBA, PhDProfessor of Pharmacy Law & EthicsVice Chair, Dept. of PharmacotherapyCollege of Pharmacy, Washington StateUniversity, Spokane, WA

PERSONALIZED MEDICINE Wayne A. Rosenkrans, Jr, PhDChairman and President, Personalized Medicine Coalition, Distinguished Fellow,MIT Center for Biomedical Innovation

PHARMACOECONOMICSJeff Jianfei Guo, BPharm, MS, PhDProfessor of Pharmacoeconomics& Pharmacoepidemiology, College of Pharmacy, University of Cincinnati Medical Center, OH

PHARMACY BENEFIT DESIGN Joel V. Brill, MDChief Medical Officer, Predictive Health, Phoenix, AZ

William J. Cardarelli, PharmDDirector of Pharmacy, Atrius HealthHarvard Vanguard Medical Associates

Leslie S. Fish, PharmDSenior Director of Pharmacy ServicesFallon Community Health Plan, MA

Michael S. Jacobs, RPhVice President National AccountsTruveris, Inc., New York, NY

Matthew Mitchell, PharmD, MBAManager, Pharmacy ServicesSelectHealth, Salt Lake City, UT

Paul Anthony Polansky, BSPharm, MBASenior Field Scientist, Health Outcomesand PharmacoEconomics (HOPE) Endo Pharmaceuticals, Chadds Ford, PA

Scott R. Taylor, RPh, MBAAssociate Director, Industry RelationsGeisinger Health System, Danville, PA

POLICY & PUBLIC HEALTH Joseph R. Antos, PhDWilson H. Taylor Scholar in Health CareRetirement PolicyAmerican Enterprise Institute

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

Walid F. Gellad, MD, MPHAssistant Professor of Medicine, Universityof Pittsburgh, Staff Physician, PittsburghVA Medical Center, Adjunct Scientist,RAND Health

Alex Hathaway, MD, MPH, FACPMPresident & Founder, J.D. BioEdgeHealth quality & biomedical research consultancy

J. Warren Salmon, PhDProfessor of Health Policy & AdministrationSchool of Public HealthUniversity of Illinois at Chicago

RESEARCH & DEVELOPMENT Michael F. Murphy, MD, PhDChief Medical Officer and Scientific Officer Worldwide Clinical TrialsFaculty, Center for Experimental Pharmacology and Therapeutics, Harvard-MIT Division of Health Sciences andTechnology, Cambridge, MA

SPECIALTY PHARMACYAtheer A. Kaddis, PharmDSenior Vice President, ManagedMarkets/Clinical SerivcesDiplomat Specialty Pharmacy Flint, MI

James T. Kenney, Jr, RPh, MBAPharmacy Operations Manager Harvard Pilgrim Health Care Wellesley, MA

APPROVED FO

R

SUBCUTANEO

US AND IV

ADMINISTRAT

ION

VELCADEHCP.COM

If you defi ne value as an overall survival advantage:VELCADE® (bortezomib) DELIVERED A >13-MONTH OVERALL SURVIVAL ADVANTAGE

At 5-year median follow-up, VELCADE (bortezomib)+MP* provided a median overall survival of 56.4 months vs 43.1 months with MP alone (HR=0.695 [95% CI, 0.57-085]; p<0.05)†

At 3-year median follow-up, VELCADE+MP provided an overall survival advantage over MP that was not regained with subsequent therapies

If you defi ne value as defi ned length of therapy: Results achieved using VELCADE twice-weekly followed by weekly dosing for a median of 50 weeks (54 planned)1

If you defi ne value as medication cost: Medication cost is an important factor when considering overall drug spend. The Wholesale Acquisition Cost for VELCADE is $1,471 per 3.5-mg vial as of January 2012

Health plans should consider medication cost, length of therapy, and dosing regimens when determining the value of a prescription drug regimen. This list of considerations is not meant to be all-inclusive; there are multiple other factors to consider when determining value for a given regimen

VELCADE Indication and Important Safety InformationINDICATIONVELCADE is indicated for the treatment of patients with multiple myeloma.

CONTRAINDICATIONSVELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. VELCADE is contraindicated for intrathecal administration.

WARNINGS, PRECAUTIONS AND DRUG INTERACTIONS Peripheral neuropathy, including severe cases, may occur — manage with dose modifi cation or discontinuation. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefi t assessment

Hypotension can occur. Use caution when treating patients receiving antihypertensives, those with a history of syncope, and those who are dehydrated

Closely monitor patients with risk factors for, or existing heart disease

Acute diffuse infi ltrative pulmonary disease has been reported

Nausea, diarrhea, constipation, and vomiting have occurred and may require use of antiemetic and antidiarrheal medications or fl uid replacement

Thrombocytopenia or neutropenia can occur; complete blood counts should be regularly monitored throughout treatment

Tumor Lysis Syndrome, Reversible Posterior Leukoencephalopathy Syndrome, and Acute Hepatic Failure have been reported

Women should avoid becoming pregnant while being treated with VELCADE. Pregnant women should be apprised of the potential harm to the fetus

Closely monitor patients receiving VELCADE in combination with strong CYP3A4 inhibitors. Concomitant use of strong CYP3A4 inducers is not recommended

ADVERSE REACTIONSMost commonly reported adverse reactions (incidence ≥30%) in clinical studies include asthenic conditions, diarrhea, nausea, constipation, peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, psychiatric disorders, anorexia and decreased appetite, neutropenia, neuralgia, leukopenia, and anemia. Other adverse reactions, including serious adverse reactions, have been reported

Please see Brief Summary for VELCADE on the next page of this advertisement.

To contact a reimbursement specialist: Please call 1-866-VELCADE, Option 2 (1-866-835-2233).

*Melphalan+prednisone.† VISTA: a randomized, open-label, international phase 3 trial (N=682) evaluating the effi cacy and safety of VELCADE administered intravenously in combination with MP vs MP in previously untreated multiple myeloma. The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and overall survival. At a pre-specifi ed interim analysis (median follow-up 16.3 months), VELCADE+MP resulted in signifi cantly superior results for TTP (median 20.7 months with VELCADE+MP vs 15.0 months with MP [p=0.000002]), PFS, overall survival, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition. Updated analyses were performed.

Reference: 1. Mateos M-V, Richardson PG, Schlag R, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol. 2010;28(13):2259-2266.

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Brief Summary

INDICATIONS:VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. VELCADE is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy.CONTRAINDICATIONS: VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. VELCADE is contraindicated for intrathecal administration. WARNINGS AND PRECAUTIONS: VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE.Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory. However, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥ Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. In the Phase 3 relapsed multiple myeloma trial comparing VELCADE subcutaneous vs. intravenous the incidence of Grade ≥ 2 peripheral neuropathy events was 24% for subcutaneous and 41% for intravenous. Grade ≥ 3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 16% in the intravenous treatment group. Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy.Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may benefit from a decrease in the dose and/or a less dose-intense schedule. In the single agent phase 3 relapsed multiple myeloma study of VELCADE vs. Dexamethasone following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ≥ Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥ Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 13%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics.Cardiac Disorders: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study of VELCADE vs. dexamethasone, the incidence of any treatment-emergent cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively. The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and 4%, respectively. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.Pulmonary Disorders: There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, a prompt comprehensive diagnostic evaluation should be conducted.Reversible Posterior Leukoencephalopathy Syndrome (RPLS): There have been reports of RPLS in patients receiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing RPLS is not known.Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration.Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study of VELCADE vs. dexamethasone, the incidence of significant bleeding events (≥Grade 3) was similar on both the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%.Tumor Lysis Syndrome: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, the complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.Hepatic Events: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of VELCADE. There is limited re-challenge information in these patients.Hepatic Impairment: Bortezomib is metabolized by liver enzymes. Bortezomib exposure is increased in patients with moderate or severe hepatic impairment; these patients should be treated with VELCADE at reduced starting doses and closely monitored for toxicities.Use in Pregnancy: Pregnancy Category D. Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses.

ADVERSE EVENT DATA: Safety data from phase 2 and 3 studies of single-agent VELCADE (bortezomib) 1.3 mg/m2/dose administered intravenously twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously treated multiple myeloma (N=1008, not including the phase 3, VELCADE plus DOXIL® [doxorubicin HCI liposome injection] study) and previously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma.In the integrated analysis, the most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated); (39%), thrombocytopenia and appetite decreased (including anorexia); (each 36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache, paresthesia and dysesthesia (each 22%), dyspnea (21%), cough and insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo); (each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension (each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia (each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%). Twenty percent (20%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (5%) and neutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies. The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%).In the phase 3 VELCADE + melphalan and prednisone study in previously untreated multiple myeloma, the safety profile of VELCADE administered intravenously in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse events in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%), nausea (48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%), constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%), pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%), asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%), rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%), dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain (14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%), hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension (12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%), arthralgia (11% vs 15%) and pruritus (10% vs 5%).In the phase 3 VELCADE subcutaneous vs. intravenous study in relapsed multiple myeloma, safety data were similar between the two treatment groups. The most commonly reported adverse events in this study were peripheral neuropathy NEC (38% vs 53%), anemia (36% vs 35%), thrombocytopenia (35% vs 36%), neutropenia (29% vs 27%), diarrhea (24% vs 36%), neuralgia (24% vs 23%), leukopenia (20% vs 22%), pyrexia (19% vs 16%), nausea (18% vs 19%), asthenia (16% vs 19%), weight decreased (15% vs 3%), constipation (14% vs 15%), back pain (14% vs 11%), fatigue (12% vs 20%), vomiting (12% vs 16%), insomnia (12% vs 11%), herpes zoster (11% vs 9%), decreased appetite (10% vs 9%), hypertension (10% vs 4%), dyspnea (7% vs 12%), pain in extremities (5% vs 11%), abdominal pain and headache (each 3% vs 11%), abdominal pain upper (2% vs 11%). The incidence of serious adverse events was similar for the subcutaneous treatment group (36%) and the intravenous treatment group (35%). The most commonly reported SAEs were pneumonia (6%) and pyrexia (3%) in the subcutaneous treatment group and pneumonia (7%), diarrhea (4%), peripheral sensory neuropathy (3%) and renal failure (3%) in the intravenous treatment group.DRUG INTERACTIONS: Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients. Therefore, patients should be closely monitored when given bortezomib in combination with strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%. Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur. Efficacy may be reduced when VELCADE is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s Wort (Hypericum perforatum) may decrease bortezomib exposure unpredictably and should be avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant.USE IN SPECIFIC POPULATIONS:Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, 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.Pediatric Use: The safety and effectiveness of VELCADE in children has not been established.Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out.Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, VELCADE should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer’s prescribing information.Patients with Hepatic Impairment: The exposure of bortezomib is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients.Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication.Please see full Prescribing Information for VELCADE at VELCADEHCP.com.

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners.

Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright © 2012, Millennium Pharmaceuticals, Inc.All rights reserved. Printed in USA V-12-0095 6/12

EDITORIAL


For the political junkies among us, the acronymSCOTUS (otherwise known as the Supreme Courtof the United States) has practically become a

household word. By now, oceans of ink have been devot-ed to media coverage of the Affordable Care Act(ACA), the 3 days of unprecedented legal hearings andspeculation about the potential outcome to beannounced sometime in June. My colleagues in healthpolicy circles have been making friendly wagers, not justabout what the ultimate decision will be, but how theactual vote count will fall. Democrats and Republicanshave flooded the airways, and the expert “talking heads”have impressed us with their punditry. By March 29,2012, major national newspapers, such as the Wall StreetJournal and the New York Times had already lined up thefaithful on their respective editorial pages.

The tenor and tone of the exchange between theJustices and the attorneys arguing for and against the leg-islation were eye opening. It seemed as if the justices wereasking the same questions as everyday people, “Do youreally want us to read all 2700 pages?” and, “Are we doinga wrecking project or a salvage project?” Some politicalcommentators framed the arguments in terms of socialclass, maligning the “punditocracy,” and calling the legis-lation itself a “masterpiece of mandarin abstraction.”1

I became more than a casual observer once I was invit-ed to serve as a panelist on a local national public radio(NPR) program devoted to the topic. In a few paragraphs,I would like to quickly reframe some of the issues fromthis past spring, reflect on my own personal experiencein the eye of the storm, and attempt to answer therhetorical question, “Will they or won’t they?”

As best as I can tell, the Supreme Court is going toaddress 4 questions.2 First, the Court will determinewhether the Tax Anti-Injunction Act (AIA), an archaiclaw from the late 1800s, precludes a review of the ACAuntil 2014, when any financial penalties would beassessed on individuals who do not purchase healthinsurance. Some experts contend that this penaltywould, in effect, be a tax and therefore fall under theAIA. The AIA provides that the legality of a tax cannotbe challenged until the tax has actually been assessed.Because no penalty (tax) will be assessed until 2014, thewhole conversation is premature.

The second question that the Court will review

remains the “hot button” issue—whether the federalgovernment can compel citizens to purchase healthinsurance (otherwise known as the “individual man-date”). The government attorneys argued strenuouslythat the federal government has this authority under theConstitution’s Commerce Clause; previously, theSupreme Court has interpreted the section as providingCongress with wide latitude in this arena. The chal-lengers argued that the mandate to purchase a productfrom a private entity is unprecedented and an intrusionon individual liberty.

If the Court rules the mandate unconstitutional, thethird question they must consider is whether the man-date is “severable” from the rest of the law. Opponents ofthe ACA argue that the entire law must be overturnedif the Court invalidates any part of it, and that the man-date is inextricably entangled with the other elements.On the other hand, the government argues that only 2other portions of the law would fall if the mandate werestruck down. These other conditions are the require-ments that ensure coverage for people with preexistingconditions (the “guaranteed issue”), while not chargingthem higher premiums (the “community rate”).

The fourth and final question is regarding the consti-tutionality of the ACA’s Medicaid expansion, andwhether states must comply with it to remain eligible toreceive any federal Medicaid funds.

We all need to take a collective step backward andreexamine the core issues that the bill is attempting toaddress. The easiest way to frame this argument is therecognition that the ACA is really like 2 laws in 1. Oneaspect deals with insurance reform; in my view, the ques-tions to be considered by the Court fall into this category.The other aspect of the law deals with delivery reform.

The healthcare industry has been working diligentlyon healthcare delivery reform for more than 2 years. OurJefferson School of Population Health has been educat-ing leaders to be active participants in the conversationregarding delivery reform. We embrace the now-famousTriple Aim, which was articulated by Donald M.Berwick, MD, several years ago.3 We recognize that wemust improve the health of the population, enhance theexperience of care, and decrease cost by reducing waste.

We support payment reform that accelerates themove from “volume to value.” We certainly support inte-

“SCOTUS”: Will They or Won’t They?David B. Nash, MD, MBA

Editor-in-Chief, American Health & Drug Benefits; Dean, the Dr Raymond C. and Doris N. Grandon Professor, Jefferson School of Population Health

gration via bundled payment and coordination of chron-ic care, because these are the critical underpinnings ofthe population health model. In my columns and in myspeaking engagements around the country, I haveattempted to summarize the entire delivery reform aspectof the bill in 4 simple words: “no outcome, no income.”4

In my view, the 4 questions being considered by theCourt essentially ignore these central issues. They alsoignore the fact that stakeholders within the healthcaresystem have made substantive progress toward these crit-ically important delivery system goals in the past 2 years.

On the third and final day of the hearings, I was priv-ileged to appear on Radio Times with Marty Moss-Coane,a popular radio program produced by WHYY, thePhiladelphia public broadcasting station. I thought I hadprepared well for this important opportunity to help clar-ify what I perceived were some of the missing issues inthe public debate about the ACA.

Of course, I sadly recognize that these complex con-cepts cannot be distilled into a 15-second sound bite—especially on the radio. When the program was open toquestions from listeners, I was truly depressed by thequestions, because they focused on a narrow interpreta-tion of the individual mandate.

A December 2011 tracking poll from the KaiserFamily Foundation found that support for the mandatevaried from 17% to 61%, depending on which messagesor information opponents or supporters of the mandatehear on the issue.5 One thing all of the experts agree on,regardless of where their opinions lie, is that the admin-istration has done a poor job of communicating how thevarious components of the ACA would play out once itis fully implemented.

“Perhaps, surprisingly, the most effective informa-tion on changing people’s minds is the basic reminderthat, ‘under the reform law, most Americans would stillget coverage through their employers and so wouldautomatically satisfy the requirement without having

to buy any new insurance.’ After hearing that message,favorable reviews of the mandate went up 28 percent-age points to 61%.”5

Although the 1 hour flew by quickly, I was happy tohave expert colleagues sitting on either side of me in thestudio. I thought we handled the live phone-in portionof the program with relaxed camaraderie and ease. Laterthat same day, most of my e-mails and text messages werepositive, although a few people took issue with my posi-tion that the discussion should center on delivery reformand not these narrow constitutional issues.

Where does all of this public attention on the health-care system over the past several months leave us? Thatis the question of the hour for our industry. Does thenotion of the Triple Aim mean anything to our citizenry?Is the public so afraid of “government intervention” intheir lives that they lose sight of the fact that the billitself represents a colossal compromise, wherein moststakeholders put future economic rewards aside so that ahistoric bill could be fashioned and approved? Walkingback from the local NPR studio to my office, I askedmyself these same questions and found no ready answers.

Will they or won’t they? There’s no future in predict-ing the future, but I will add my voice to the cacophonyattempting to answer this important health policy ques-tion. I tend to believe that the court will strike down theindividual mandate and uphold its severability. In such acase, the insurance industry will respond with a flurry ofactivity. There is no doubt that premiums will continuetheir inexorable rise.

But there is some good news—those much-neededdelivery system reforms will continue to transform.Cooler heads will prevail, and we will make progress inour unique American journey to improve the health ofthe population and reduce waste in our system.Somehow we must find a way to achieve value for the$8000 per person that we spend annually. Of course, Iam interested to hear your views, and you can reach meat [email protected]. ■

References1. Henninger D. We’re not France yet. Wall Street Journal. May 29, 2012:A17.2. Curfman GD, Abel BS, Landers RM. Supreme Court review of the health carereform law. N Engl J Med. 2012;366:977-979.3. Berwick DM, Nolan TW, Whittington J. The triple aim: care, health and cost.Health Aff (Millwood). 2008;27:759-769.4. Jacoby R, Berman B, Nash DB. No outcome, no income CMS’s “meaningful use”initiative. Health Policy Newsl. 2011;24:1-2. http://jdc.jefferson.edu/hpn/vol24/iss1/12/.Accessed May 31, 2012.5. The Henry J. Kaiser Family Foundation. Kaiser Public Opinion. March 2012.www.kff.org/healthreform/upload/8296.pdf. Accessed May 31, 2012.

EDITORIAL


Cooler heads will prevail, and we will makeprogress in our unique American journey toimprove the health of the population andreduce waste in our system. Somehow wemust find a way to achieve value for the$8000 per person that we spend annually.

CLINICAL


Hypertension, defined as systolic blood pressure(BP) ≥140 mm Hg, diastolic BP ≥90 mm Hg,increases with age, affecting more than 50% of

patients aged ≥60 years, and approximately 66% ofthose aged ≥65 years.1-3 It is well known that by 2030, 1of 5 Americans is expected to be 65 years or older.Hypertension is the number one diagnosis in the ambu-latory setting, and is one of the top diagnoses in the nurs-ing home.4 Data from the Framingham Heart Study sug-gest that patients who are normotensive at age 55 years

have a 90% lifetime risk of developing hypertension.5Between 1988-1994 and 2005-2008, the prevalence

of hypertension increased among patients aged ≥65years.6 The use of antihypertensive medications alsoincreased during that period.6 As life expectancy contin-ues to rise, approaching 75 years for men and 80 years forwomen, the use of antihypertensive medications in theelderly will intensify.6 Approximately 10% of the currentUS total annual drug expenditure is spent on antihyper-tensive medications.7 In 2009, the total direct and indi-rect costs attributable to hypertension in the UnitedStates were estimated to be $73.4 billion.8

Special Considerations in the Elderly PopulationIn the United States, the prevalence of elderly

patients with adequately treated hypertension (definedas BP <140/90 mm Hg) is quite low, estimated to be only30% (range, 23%-38%).9 Elderly patients are more proneto having isolated systolic hypertension (ISH)—systolicBP ≥140 mm Hg; diastolic BP <90 mm Hg—which is

Dr QT Nguyen is an Endocrinologist, Carson TahoePhysicians Clinic-Carson City, Adjunct Associate ProfessorEndocrinology and Internal Medicine, Touro UniversityNevada, College of Osteopathic Medicine; Mr Anderson isSenior Medical Student, University of Nevada School ofMedicine, Reno; Dr Sanders is Senior Medical Resident,Internal Medicine Program, University of Nevada; Dr LDNguyen is Clinical Pharmacy Specialist, VA Sierra NevadaHealth Care System, Reno.

Review ARticle

Managing Hypertension in the Elderly: ACommon Chronic Disease with Increasing AgeQuang t. Nguyen, DO, FAce; Scott R. Anderson, MS iv; lindsay Sanders, DO, MPH; loida D. Nguyen, PharmD, BcPS

Background: Hypertension increases with age, affecting approximately 66% of the elderly pop-

ulation (aged ≥65 years). By the year 2030, 1 of 5 Americans will be aged ≥65 years. A number

of placebo-controlled clinical trials have demonstrated that blood pressure (BP) control reduces

cardiovascular events in elderly patients, even in those aged >80 years. Despite advances in

medical care, hypertension control rates remain low, especially in the elderly population.

Objective: The goal of this article is to review the information that addresses hypertension

in the elderly and current strategies that can facilitate improvement in the management of

this common, chronic, and life-threatening condition, which is often undertreated or inappro-

priately managed.

Discussion: The goals and strategies of treating hypertension in the elderly population are dif-

ferent from, and more challenging than, those in younger patients. Lifestyle modification is effec-

tive in this population, but it is difficult to maintain. Many antihypertensive medications are avail-

able, with thiazide diuretics being the preferred first-line treatment. Beta-blockers and

alpha-blockers are generally not recommended in this population. A majority of older patients

will require 2 or 3 antihypertensive medications to reach BP goal. This article reviews current

data on hypertensive treatment in the elderly and summarizes the strategies and challenges

healthcare providers face when dealing with this population.

Conclusion: Understanding the strategies and challenges that apply to the management of

hypertension in the US elderly population can help providers and payers better address the

growing need for improving the management of this condition in the elderly, because their num-

bers are expected to increase dramatically in the coming decades.

Am Health Drug Benefits.2012;5(3):146-153www.AHDBonline.com

Disclosures are at end of text

Stakeholder Perspective,page 153

Quang T. Nguyen

Managing Hypertension in the Elderly


likely a result of an increase in arterial stiffness from ar -teriosclerosis or impairment of nitric oxide–mediatedvasodilation.10-12

ISH occurs in the majority of elderly patients withhypertension: more than 65% of hypertensive patientsaged ≥60 years and more than 90% of those aged >70years have ISH.1,13 ISH is associated with a 2- to 4-foldincrease in the risk for stroke, myocardial infarction(MI), or cardiovascular (CV) mortality.14,15

Elderly persons are more sensitive to salt intake com-pared with a younger population, leading to higher sys-tolic BP and higher pulse pressure (ie, the differencebetween systolic BP and diastolic BP) when more salt isconsumed by elderly individuals.16

Finally, elderly persons are at increased risk for devel-oping orthostatic hypotension, a potentially dangerousdrop in BP during positional change from supine tostanding position, increasing the risk for syncope, falls,and injuries.

These characteristics must be taken into account andconsidered carefully when choosing an appropriate treat-ment protocol for this patient population.

Treatment ConsiderationsThe goals and strategies for treating hypertension in

the elderly population are different from, and more chal-lenging than, in younger patients. Lifestyle modification iseffective in this population, but it is difficult to maintain.

The Seventh Report of the Joint National Committeeon Prevention, Detection, Evaluation, and Treatmentof High Blood Pressure (JNC 7) recommends treatingall patients, including the elderly population from theage of 65 through 79 years who have uncomplicatedhypertension, to a target BP of <140/90 mm Hg.17 JNC8 is anticipated to be released at the end of 2012, but itis unclear whether the report will have specific recom-mendations regarding hypertension management inthe elderly population.

The American College of Cardiology (ACC) and theAmerican Heart Association (AHA) recently releasedthe first expert consensus statement to help clinicianseffectively manage hypertension in the elderly popula-tion.18 Like JNC 7, the ACC/AHA document recom-mends BP measurement of <140/90 mm Hg for thoseaged 65 to 79 years. For patients aged ≥80 years, mostexperts, including the ACC/AHA statement, recom-mend a less-stringent systolic BP goal of 140 to 145 mmHg, to minimize side effects.18

This ACC/AHA document further recommendsstarting the evaluation of the elderly patient with knownor suspected hypertension with 3 measurements of BP,including in the standing position, to obtain an accu-rate BP value. If BP is elevated, the cause should be iso-

lated. Any organ damage should be assessed. Other CVdisease (CVD) risk factors or comorbid conditionsshould be identified, along with any potential barriersto treatment adherence.18

According to this ACC/AHA statement, lifestylemodifications may be all that is necessary to treatmilder forms of hypertension in elderly patients. Inpatients with resistant hypertension, drug therapy isrecommended and should be started at the lowest dosepossible, with gradual increases depending on response.Diuretics, angiotensin-converting enzyme (ACE)inhibitors, angiotensin receptor blockers (ARBs), andcalcium channel blockers (CCBs) are effective in low-ering BP and reducing CV outcomes in the elderly.Beta-blockers are inferior in benefits compared withthese drug classes, but they may be used in selectedcases in the elderly population.18

Nonpharmacologic TreatmentLifestyle modification is recommended as the first-

line treatment for all patients with hypertension, espe-cially in the elderly population, where polypharmacy,potential drug interactions, and nonadherence to treat-

KEY POINTS➤ Approximately 10% of the US total annual drug

expenditure is spent on antihypertensive medications.➤ It is estimated that only 30% (range, 23%-38%) of

elderly patients with hypertension are adequatelymanaged in the United States, leaving considerableroom for improvement.

➤ JNC 7 recommends treating all patients withuncomplicated hypertension, including those aged65 to 79 years, to a target blood pressure (BP) of<140/90 mm Hg.

➤ For patients aged ≥80 years, most expertsrecommend a systolic BP goal of 140-145 mm Hg,to minimize medication side effects.

➤ A recent ACC/AHA statement suggests thatlifestyle modifications may be all that is needed totreat milder forms of hypertension in elderlypatients; in those with resistant hypertension, drugtreatment is recommended.

➤ First-line drug therapy with diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptorblockers, or calcium channel blockers should bestarted at the lowest dose, and titrated as tolerated.

➤ The unique characteristics responsible for theincreased risk for hypertension in the elderlypopulation must be taken into account andconsidered carefully when choosing a treatmentprotocol.

CLINICAL


ment regimens are serious concerns. Weight control,adoption of the Dietary Approaches to Stop Hyper -tension (DASH), dietary sodium restriction, increasingactivity level, and limiting alcohol intake are effectivetools in the treatment of hypertension (Table).17,19-23

One landmark study that proved that nonpharmaco-logic intervention is effective in treating older patients isthe Trial of Nonpharmacologic Interventions in theElderly (TONE).21 In this trial, 975 men and womenwith hypertension (aged 60-80 years; BP <145/85 mmHg on 1 antihypertensive drug) were recruited. Obeseand normal-weight subjects were separated and random-ly assigned to the following groups: usual care, saltrestriction (≤1800 mg per 24 hours), weight loss (obesepatients, ≥10-lb goal), or salt restriction and weight loss.Withdrawal of the drug being taken for hypertension wasattempted after 3 months of intervention. The primaryoutcome end point was a diagnosis of high BP at 1 ormore follow-up appointments, treatment with antihy-

pertensive drugs, or a CV event. The study yielded posi-tive results, with significant reductions in BP seen in allintervention groups compared with the usual-care group.The primary end point at 30 months occurred signifi-cantly less in the intervention groups compared with theusual-care group, illustrating that “reduced sodiumintake and weight loss constitute a feasible, effective,and safe nonpharmacologic therapy of hypertension inolder persons.”21

The beneficial effects of exercise on hypertension con-trol in the elderly population have been illustrated in anumber of studies24-26 and in a meta-analysis.27 These stud-ies solidify the concept that it is never too late to imple-ment lifestyle changes in the control of hypertension.

One study explored the effect of moderate andintense aerobic exercise on the BP of sedentary patientsaged ≥75 years.28 The subjects were randomized into 1 of3 groups: a control group (no exercise), a moderate-intensity group (3 days per week for a total of 30 exercisesessions of 40-minute duration each) at 65% to 70% ofmaximal heart rate), and a high-intensity group (85%-90% of maximal heart rate).

After only 10 weeks of exercise, significant reductionsin systolic BP (–7.8 mm Hg) and diastolic BP (–9.6 mmHg) were seen in the high-intensity group comparedwith the control group (+2.6 mm Hg). The effects wereseen independent of weight changes. The editorialaccompanying the study agreed that “these data supportthe contention that pharmacologic intervention shouldbe coupled with exercise and other lifestyle modificationeven in our more elderly patients.”29

Pharmacologic TherapyMany placebo-controlled trials, as well as meta-analy-

ses, have demonstrated the benefits of antihypertensivetherapy in the elderly population.17,30-47 There is no agelimit at which antihypertensive drugs should not beused. Initiation of antihypertensive drugs should be start-ed at the lowest dose, with gradual incremental increaseas tolerated. If the first agent fails to lower BP to goal atfull dose, a second and third medication should be addedas tolerated. When BP is >20/10 mm Hg above goal,consideration toward initiating 2 antihypertensives or acombination drug therapy is warranted. The risks andbenefits of treatment should be continuously reevaluat-ed. In the elderly population, especially those aged >80years, a systolic BP of 140 to 145 mm Hg is acceptable inindividual cases.

DiureticsThiazide diuretics are inexpensive, are generally well

tolerated, and are recommended as a first-line therapy inthe treatment of hypertension in the elderly population.17

Table Lifestyle Modifications and Benefitsa

Modification RecommendationApproximate

SBP reductionb

Weight reduction

Maintain normal body weight (BMI, 18.5-24.9 kg/m2)

5-20 mm Hg/10-kg weight loss

Adopt DASH diet

Consume diet rich infruits/vegetables, and low-fat dairy products with a reduced content of saturated and total fat

8-14 mm Hg

Dietary sodiumreduction

Reduce intake to ≤2.4 g sodium or ≤6 g sodium chloride/day

2-8 mm Hg

Engage in physical activity

≥30 minutes aerobic activity per day, most days of the week

4-9 mm Hg

Moderate alcohol intake

≤2 drinks per day for men and ≤1 drink per

day for women

2-4 mm Hg

aFor overall cardiovascular risk reduction, stop smoking. bThe effects of implementing these modifications are dose- andtime-dependent and could be greater for some individuals. BMI indicates body mass index; DASH, Dietary Approaches toStop Hypertension; SBP, systolic blood pressure. Source: The Seventh Report of the Joint National Committeeon Prevention, Detection, Evaluation, and Treatment of HighBlood Pressure. National High Blood Pressure EducationProgram. Bethesda, MD: National Heart, Lung, and BloodInstitute (US); August 2004. Report No. 04-5230.



One landmark study that supports the use of thiazidediuretics in the treatment of ISH in older patients is theSystolic Hypertension in the Elderly Program (SHEP).30In this trial, 4736 older individuals with systolic BP lev-els ≥160 mm Hg and diastolic BP levels <90 mm Hg(mean BP, 170/77 mm Hg) were randomized to treat-ment with the thiazide diuretic chlorthalidone or withplacebo. Significant improvement in BP was accom-plished in the treatment group compared with the groupreceiving placebo (systolic BP, 143 mm Hg vs 155 mmHg, respectively), leading to significant reduction instroke (36%), coronary artery disease (CAD; 27%),chronic heart failure (HF; 55%, 81% in those with pre-vious MI), and all-cause CVD (32%).30

Another landmark trial demonstrating that thiazidediuretics are as effective as any drug for first-line treat-ment of hypertension in the elderly population is theAntihypertensive and Lipid-Lowering Treatment toPrevent Heart Attack Trial (ALLHAT) study.31 Thistrial included 42,418 patients (mean age, 67 years) withhypertension and at least 1 other risk factor for CAD.The patients were randomized to a treatment group witha thiazide-type diuretic (chlorthalidone), a beta-blocker(atenolol), a CCB (amlodipine), an ACE inhibitor(lisinopril), or an alpha-blocker (doxazosin). Other thanthe group receiving doxazosin, which was stopped earlybecause of higher rates of adverse events, final datashowed no differences in the primary outcome of fatal ornonfatal coronary events and no mortality differencebetween the CCB, ACE inhibitor, and diuretic groups.Patients who received the diuretic had a lower incidenceof CV events (secondary outcomes) compared with theother groups. The diuretic treatment group had lowerHF rates compared with the CCB group (relative risk[RR], 1.33; 95% confidence interval [CI], 1.18-1.49) andlower combined CV outcomes (RR, 1.13; 95% CI, 1.06-1.20), and HF (RR, 1.20; 95% CI, 1.09-1.34) comparedwith the ACE inhibitor group.31

Indapamide, a nonthiazide diuretic, was featured inthe Hypertension in the Very Elderly Trial (HYVET).33In this highly anticipated study published in 2008, morethan 3800 elderly patients (patients aged ≥80 years;mean, 83.6 years) with systolic hypertension, diastolichypertension, or ISH were randomly assigned to takeindapamide or placebo. The primary end point was fatalor nonfatal stroke. Significant reduction in mean BP wasachieved in the treatment group (143/78 mm Hg vs158/84 mm Hg). The study was stopped early as a resultof significant reductions in fatal stroke (6.5% in theactive group vs 10.7% in the placebo group) and all-cause mortality (47.2% in the active group, 59.6% in theplacebo group). This is the first trial that provided evi-dence that treatment of hypertension in the very elderly

(aged >80 years) is beneficial and should be pursued.33Other diuretics, such as loop diuretics, mineralocorti-

coid antagonists, or sodium transport channel antago-nists, can also be used in the elderly as adjunct treat-ments when appropriate.18

Calcium Channel BlockersCCBs can be used as first-line hypertension treatment

in the elderly if a diuretic is contraindicated or if thepatient has angina or heart rhythm/conduction prob-lems. In general, CCBs are well tolerated in the elderly.The most common adverse events for the dihydropyri-dine CCBs are symptoms of vasodilation, such as ankleedema, headache, or postural hypotension. Commonadverse events for the nondihydropyridine CCBsinclude constipation, bradycardia, and potential forheart block; as such, this subclass should be avoided inelderly patients with underlying cardiac conductiondefects or with left-ventricular systolic dysfunction.18

Several clinical trials have shown that CCBs are effec-tive and safe in the elderly population.31,34-36 One land-mark study involving this drug class includes SystolicHypertension in Europe (Syst-Eur).34,35 In this study,more than 4600 elderly patients (mean age, 76 years)with ISH were randomized to receive dihydropyridinenitrendipine or placebo. The trial was stopped earlierthan anticipated as a result of a significant reduction instroke (42% reduction; P = .003) and all fatal and nonfa-tal cardiac end points, including sudden death (26%reduction; P = .03) in the treatment group.34 The authorscalculated that treatment of 1000 patients for 5 yearswith this type of regimen may prevent 29 strokes or 53major CV end points. The prevalence of vascular demen-tia was significantly lowered in the group receiving anti-hypertensives compared with those receiving placebo(3.8 vs 7.7 cases per 1000 patient-years, respectively).35

The efficacy and safety of CCBs in combinationwith other medications for the elderly patients wereillustrated in the Avoiding Cardiovascular Eventsthrough Combination Therapy in Patients Living withSystolic Hypertension (ACCOMPLISH) trial.36 Morethan 11,500 elderly patients with hypertension (meanage, 68 years; mean BP, 145/88 mm Hg) were random-ized to receive the ACE inhibitors (benazepril) with aCCB (amlodipine) or a diuretic (hydrochlorothiazide).The primary end point was the composite of death fromCV causes, nonfatal MI, nonfatal stroke, hospitaliza-tion for angina, resuscitation after sudden cardiacarrest, and coronary revascularization. The trial wasterminated early after a mean follow-up of 36 monthswhen significantly fewer primary end points were seenin the group receiving benazepril/amlodipine—552(9.6%) primary-outcome events in the group receiving

CLINICAL


benazepril/amlodipine versus 679 (11.8%) in the groupreceiving benazepril/hydrochlorothiazide.36

ACE InhibitorsACE inhibitors lower BP by inhibiting the conver-

sion of angiotensin I to angiotensin II, thereby prevent-ing vasoconstriction (by angiotensin II) and aldosteroneproduction. ACE inhibitors are considered alternativefirst-line hypertension treatments in the elderly popula-tion if a diuretic is contraindicated.18

ACE inhibitors have been shown to decrease morbid-ity and mortality in patients with MI, with HF (systolicdysfunction), or in those with diabetic renal disease.37-39The main side effects of ACE inhibitors are dry coughand hypotension.18 Hyperkalemia can occur with ACEinhibitor use. Close monitoring and extreme caution arerecommended if they are going to be used in elderlypatients with renal impairment.18

One important clinical trial that illustrated the effec-tiveness and beneficial effects of ACE inhibitors in theelderly population with hypertension is the SecondAustralian National Blood Pressure Study (ANBP2).40This study randomized 6083 patients with hypertension(aged 65-84 years) to receive either enalapril orhydrochlorothiazide. At study end, BP reduction wasfound to be similar in both groups. The ACE inhibitorgroup was found to have fewer CV events/all-causedeath (695 vs 736, respectively) and fewer cerebrovascu-lar events (152 vs 163, respectively) compared with thediuretic group. In addition, males receiving an ACEinhibitor achieved a 17% reduction in all CV events.40

Two landmark trials involving ACE inhibitors andhigh-risk elderly patients with hypertension are theHeart Outcomes Prevention Evaluation (HOPE)41 andPerindopril Protection Against Recurrent Stroke Study(PROGRESS).42 In the HOPE trial, 9297 high-riskpatients (aged ≥55 years) who had evidence of vasculardisease or diabetes plus 1 other CV risk factor and whowere not known to have a low ejection fraction or HFwere randomly assigned to receive oral ramipril (10 mgonce daily) or matching placebo for a mean of 5 years.Significant reductions in CV death (26%), all-causemortality (16%), stroke (32%), and HF (23%) were seenin the ramipril group at the end of the study.41

In the PROGRESS trial, 6105 patients (mean age, 64years) who had suffered a stroke or transient ischemicattack were assigned to perindopril (4 mg daily) with theaddition of the diuretic indapamide at the discretion oftreating physicians or placebo.42 At the end of the study,combination therapy with perindopril plus indapamidereduced BP by 12/5 mm Hg and stroke risk by 43%.Single-drug therapy reduced BP by 5/3 mm Hg and pro-duced no reduction in stroke risk.42

Angiotensin Receptor BlockersARBs work by blocking the effects of angiotensin II

on vascular smooth muscle, thus causing vasodilation.ARBs also decrease the production of aldosterone, there-by lowering sodium reabsorption and fluid retention.ARBs are considered the alternative first-line treatmentfor hypertension in the elderly population when a diuret-ic is contraindicated. In elderly hypertensive patientswith diabetes or HF, ARBs are considered first-line treat-ment and an alternative to ACE inhibitors.

Some landmark trials involving ARBs in the treat-ment of hypertension in elderly patients are the LosartanIntervention for End point Reduction in Hypertension(LIFE),43 the Study on Cognition and Prognosis in theElderly (SCOPE),44 and the Acute Candesartan CilexetilTherapy in Stroke Survivors (ACCESS) study.45

The LIFE trial randomized 9193 patients aged 55 to80 years with hypertension and left-ventricular hyper -trophy on electrocardiogram to losartan or atenolol.43Although reductions in BP were similar in both groups,CV death, stroke, and MI were reduced by >13% inthose participants receiving losartan compared withatenolol (508 vs 588, respectively). In addition, signifi-cant reduction in fatal or nonfatal stroke was seen in thegroup receiving losartan (25%; 232 vs 309 actual events,respectively). In the subgroup with diabetes (n = 1195),there was a greater reduction in CV and all-cause mor-tality for losartan versus atenolol.43

The SCOPE trial involved 4964 patients aged 70 to89 years, with systolic BP 160 mm Hg to 179 mm Hgand/or diastolic BP 90 mm Hg to 99 mm Hg and aMini-Mental State Examination test score ≥24.44Patients were assigned randomly to receive the ARBcandesartan or placebo, with open-label active antihy-pertensive therapy added as needed. Mean follow-upwas 3.7 years. Reduction in BP for the group receivingcandesartan was 21.7/10.8 mm Hg. Significant reduc-tion in nonfatal stroke was seen (27.8%; 95% CI, 1.3-47.2; P = .04) with a trend for reduction in fatal stroke(23.6%; 95% CI, –0.7-42.1; P = .056).44

The ACCESS trial was designed to assess the safety ofmodest BP reduction by candesartan cilexetil in the earlytreatment of stroke.45 The study was stopped early as aresult of significant reductions in deaths, CV events, orcerebrovascular events in the candesartan group comparedwith placebo (odds ratio, 0.475; 95% CI, 0.252-0.895).45

Direct Renin InhibitorsRenin inhibitors bind the active site of renin, such

that it cannot act to cleave angiotensinogen toangiotensin I, preventing the conversion of angiotensinI to angiotensin II. This prevents the vasoconstriction ofarterial smooth muscle that angiotensin II is responsible



for. In addition, angiotensin II would not be available tostimulate the production of aldosterone and decreasefluid retention.48

Renin inhibitors are as effective as ACE inhibitors orARBs for the treatment of hypertension, and they arewell tolerated in the elderly population.49

There are few clinical trials involving aliskiren andelderly patients. The Aliskiren for Geriatric Lowering ofSystolic Hypertension (AGELESS) trial comparedaliskiren with ramipril for treatment of essential systolichypertension in elderly patients.46 A total of 901 elderlypatients (aged ≥65 years) with systolic BP ≥140 mm Hgwere randomized to receive aliskiren or ramipril. Theprimary end point was noninferiority of aliskiren versusramipril monotherapy for change from baseline in meansitting systolic BP at week 12. At week 36, fewer patientsreceiving aliskiren-based therapy required add-on treat-ment with hydrochlorothiazide or amlodipine (P = .01and P = .048, respectively). The authors concluded that“in elderly patients with systolic hypertension, aliskirenproved to be more effective and better overall antihyper-tensive therapy compared to ramipril.”46

The Aliskiren Observation of Heart Failure Treat -ment (ALOFT) trial studied the effects of adding thedirect renin inhibitor aliskiren to an ACE inhibitor inelderly patients (mean age, 68 years) with HF.47 Theauthors found that the “addition of aliskiren to an ACEinhibitor (or angiotensin receptor blocker) and beta-blocker had favorable neurohumoral effects in heart fail-ure and appeared to be well tolerated.”47

Beta-BlockersBeta-blockers are not the optimal first-line treatment

for elderly patients with hypertension.18 They are associat-ed with more adverse events, and their evidence of bene-fits is weaker compared with other drug classes (ie, diuret-ics, ACE inhibitors, ARBs, CCBs).18,30,43 A recentmeta-analysis comparing beta-blockers and diureticsshowed that diuretics are more effective as monotherapyand are superior to beta-blockers in all clinical outcomes.50

Beta-blockers have been shown to provide less pro-tection from stroke in the elderly patient with hyperten-sion according to the International Verapamil SR-Trandolapril Study (INVEST).51 This randomized,blinded, prospective trial was aimed to understand thedifferences in outcomes of newer antihypertensive med-ications compared with the traditional treatment withbeta-blockers and diuretics. The study recruited 22,576elderly patients with hypertension who were randomizedto receive either verapamil or atenolol, and followedoutcomes for at least 2 years.

The results of the study showed similar control in BPbetween the 2 treatment groups. However, there was a

higher incidence of new-onset diabetes, stroke, and mor-tality in the atenolol group. Of interest, beta-blockersshowed more protection from MIs but were also associ-ated with a higher incidence of persistent depressivemood, which is a rising problem among the elderly pop-ulation. Although beta-blockers may lower the rate ofstroke in patients with hypertension compared withplacebo, they have been shown to be inadequate com-pared with newer antihypertensive medications in theaging population.51

Beta-blockers can be added in combination therapyand have a proven role in the treatment of elderlypatients with hypertension complicated by CAD, HF,or arrhythmias.52

Other DrugsAlpha-adrenergic blocking agents are used primarily

for urinary symptoms related to benign prostate hypertro-phy and should not be considered a first-line hyperten-sive drug in the elderly.18,31 They can induce orthostatichypotension and increase the risk of falls and injuries.Minoxidil and hydralazine can cause fluid retention,reflex tachycardia, and atrial arrhythmia, and they shouldnot be used as first-line therapy or monotherapy in thetreatment of hypertension in the elderly. Centrally actingagents such as clonidine can cause sedation, bradycardia,and rebound hypertension if stopped abruptly, and theyshould not be used as monotherapy in the elderly or inthose patients who are noncompliant. Nitrates have norole in the long-term treatment of hypertension in theelderly because of tolerance. They can be used as anantianginal agent as needed.18

ConclusionsJNC 7 recommends a treatment BP target of <140/90

mm Hg for all patients with hypertension, including theelderly population. Clinical trials that included patientsaged >65 years have shown that patients who receivetreatment for their elevated BP have fewer strokes, fewerheart attacks, and less congestive HF compared withthose with untreated hypertension. In patients aged 40 to89 years, each 20-mm Hg increase in systolic BP or 10-mm Hg increase in diastolic BP is associated with a 2-foldincrease in mortality from ischemic heart disease and amore than 2-fold increase in mortality from stroke.53

There is great benefit in the successful treatment ofhypertension in the elderly population. Encouraginglifestyle changes is the first-line treatment. Medicationsshould be started as appropriate. Diuretics, ACE in -hibitors, ARBs, and CCBs have all been proved as first-line treatment agents, and should be started with thelowest dose and titrated as tolerated. Vigilance is neededto avoid treatment-related adverse events. For very eld-

CLINICAL


erly patients (aged >80 years), the risks and benefits oftight control need to be frequently reevaluated. ■

Author Disclosure StatementDr QT Nguyen, Mr Anderson, Dr Sanders, and Dr LD

Nguyen reported no conflicts of interest.

References1. Burt VL, Whelton P, Roccella EJ, et al. Prevalence of hypertension in the US adultpopulation. Results from the Third National Health and Nutrition ExaminationSurvey, 1988-1991. Hypertension. 1995;25:305-313.2.Ostchega Y, Dillon CF, Hughes JP, et al. Trends in hypertension prevalence, aware-ness, treatment, and control in older U.S. adults: data from the National Health andNutrition Examination Survey 1988 to 2004. J Am Geriatr Soc. 2007;55:1056-1065.3. Vasan RS, Larson MG, Leip EP, et al. Assessment of frequency of progression tohypertension in non-hypertensive participants in the Framingham Heart Study: acohort study. Lancet. 2001;358:1682-1686.4. Centers for Disease Control and Prevention. FastStats: hypertension. www.cdc.gov/nchs/hyprtens.htm. Accessed April 18, 2012.5. Vasan RS, Beiser A, Seshadri S, et al. Residual lifetime risk for developing hyper-tension in middle-aged women and men: the Framingham Heart Study. JAMA.2002;287:1003-1010.6.Centers for Disease Control and Prevention. Health, United States, 2010: In Brief.Hyattsville, MD: National Center for Health Statistics; 2011:33-53. www.cdc.gov/nchs/data/hus/hus10.pdf. Accessed May 21, 2012.7. Spurgeon D. NIH promotes use of lower cost drugs for hypertension. BMJ.2004;328:539.8. Lloyd-Jones D, Adams R, Carnethon M, et al. Heart disease and stroke statistics—2009 update: a report from the American Heart Association Statistics Committeeand Stroke Statistics Subcommittee. Circulation. 2009;119:e21-181.9. Lloyd-Jones DM, Evans JC, Levy D. Hypertension in adults across the age spec-trum: current outcomes and control in the community. JAMA. 2005;294:466-472.10. Franklin SS, Jacobs MJ, Wong ND, et al. Predominance of isolated systolichypertension among middle-aged and elderly US hypertensives: analysis based onNational Health and Nutrition Examination Survey (NHANES) III. Hypertension.2001;37:869-874.11. Kannel WB. Blood pressure as a cardiovascular risk factor: prevention and treat-ment. JAMA. 1996;275:1571-1576.12.O’Rourke MF, Nichols WW. Aortic diameter, aortic stiffness, and wave reflectionincrease with age and isolated systolic hypertension. Hypertension. 2005;45:652-658.13. Franklin SS, Gustin W 4th, Wong ND, et al. Hemodynamic patterns of age-related changes in blood pressure. The Framingham Heart Study. Circulation. 1997;96:308-315.14. Izzo JL Jr, Levy D, Black HR. Clinical Advisory Statement. Importance of systolicblood pressure in older Americans. Hypertension. 2000;35:1021-1024.15. Young JH, Klag MJ, Muntner P, et al. Blood pressure and decline in kidney func-tion: findings from the Systolic Hypertension in the Elderly Program (SHEP). J AmSoc Nephrol. 2002;13:2776-2782.16. Weinberger MH, Miller JZ, Luft FC, et al. Definitions and characteristics ofsodium sensitivity and blood pressure resistance. Hypertension. 1986;8(suppl II):II127-II134.17. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the JointNational Committee on Prevention, Detection, Evaluation, and Treatment of HighBlood Pressure: the JNC 7 report. JAMA. 2003;289:2560-2572.18. Aronow WA, Fleg JL, Pepine CJ, et al. ACCF/AHA 2011 expert consensusdocument on hypertension in the elderly: a report of the American College ofCardiology Foundation Task Force on Clinical Expert Consensus Documents.Circulation. 2011;123:2434-2506.19. He J, Whelton PK, Appel LJ, et al. Long-term effects of weight loss and dietarysodium reduction on incidence of hypertension. Hypertension. 2000;35:544-549.20. Sacks FM, Svetkey LP, Vollmer WM, et al. Effects on blood pressure of reduceddietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet.DASH-Sodium Collaborative Research Group. N Engl J Med. 2001;344:3-10.21. Whelton PK, Appel LJ, Espeland MA, et al. Sodium reduction and weight lossin the treatment of hypertension in older persons: a randomized controlled trial ofnonpharmacologic interventions in the elderly (TONE). TONE CollaborativeResearch Group. JAMA. 1998;279:839-846.22. Kelley GA, Kelley KS. Progressive resistance exercise and resting blood pressure:a meta-analysis of randomized controlled trials. Hypertension. 2000;35:838-843.23. Xin X, He J, Frontini MG, et al. Effects of alcohol reduction on blood pressure:a meta-analysis of randomized control trials. Hypertension. 2001;38:1112-1117.24. Hagberg JM, Park JJ, Brown MD. The role of exercise training in the treatmentof hypertension: an update. Sports Med. 2000;30:193-206.25. Hamdorf PA, Penhall RK. Walking with its training effects on the fitness andactivity patterns of 79-91 year old females. Aust N Z J Med. 1999;29:22-28.26. Brandão Rondon MU, Alves MJ, Braga AM, et al. Postexercise blood pressure

reduction in elderly hypertensive patients. J Am Coll Cardiol. 2002;39:676-682.27. Kelley GA, Sharpe Kelley K. Aerobic exercise and resting blood pressure in olderadults: a meta-analysis review of randomized controlled trials. J Gerontol A Biol MedSci. 2001;56:M298-M303.28. Huang G, Thompson CJ, Osness WH. Influence of a 10-week controlled exerciseprogram on resting blood pressure in sedentary older adults. J Appl Res. 2006;6:188-195.29. Toth PP. Short-term aerobic exercise in the elderly promotes blood pressurereduction. J Appl Res. 2006;6:186-187.30. Prevention of stroke by antihypertensive drug treatment in older persons withisolated systolic hypertension. Final results of the Systolic Hypertension in theElderly Program (SHEP). SHEP Cooperative Research Group. JAMA. 1991;265:3255-3264.31. ALLHAT Officers and Coordinators for the ALLHAT Collaborative ResearchGroup. The Antihypertensive and Lipid-Lowering Treatment to Prevent HeartAttack Trial. Major outcomes in high-risk hypertensive patients randomized toangiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: theAntihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial(ALLHAT). JAMA. 2002;288:2981-2997.32. Staessen JA, Gasowski J, Wang JG, et al. Risks of untreated and treated isolatedsystolic hypertension in the elderly: meta-analysis of outcome trials. Lancet. 2000;355:865-872.33. Beckett NS, Peters R, Fletcher AE, et al. Treatment of hypertension in patients80 years of age or older. N Engl J Med. 2008;358:1887-1898.34. Staessen JA, Fagard R, Thijs L, et al. Randomised double-blind comparison ofplacebo and active treatment for older patients with isolated systolic hypertension.The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Lancet. 1997;350:757-764.35. Forette F, Seux ML, Staessen JA, et al. Prevention of dementia in randomiseddouble-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial.Lancet. 1998;352:1347-1351.36. Jamerson K, Weber MA, Bakris GL, et al. Benazepril plus amlodipine orhydrochlorothiazide for hypertension in high-risk patients. N Engl J Med. 2008;359:2417-2428.37. Effect of enalapril on survival in patients with reduced left ventricular ejectionfractions and congestive heart failure. The SOLVD Investigators. N Engl J Med.1991;325:293-302.38. Effects of enalapril on mortality in severe congestive heart failure. Results of theCooperative North Scandinavian Enalapril Survival Study (CONSENSUS). TheCONSENSUS Trial Study Group. N Engl J Med. 1987;316:1429-1435.39. Effects of ramipril on cardiovascular and microvascular outcomes in people withdiabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. HeartOutcome Prevention Evaluation Study Investigators. Lancet. 2000;355:253-259.40. Wing LMH, Reid CM, Ryan P, et al. A comparison of outcomes with angio -tensin-converting-enzyme inhibitors and diuretics for hypertension in the elderly. NEngl J Med. 2003;348:583-592.41. Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensin-converting-enzymeinhibitor, ramipril, on cardiovascular events in high risk patients. the Heart OutcomesPrevention Evaluation Study Investigators. N Engl J Med. 2000;342:145-153.42. PROGRESS Collaborative Group. Randomized trial of a perindopril-based bloodpressure–lowering regimen among 6105 individuals with previous stroke or transientischemic attack. Lancet. 2001;358:1033-1041.43. Lindholm LH, Ibsen H, Dahlöf B, et al. Cardiovascular morbidity and mortalityin patients with diabetes in the Losartan Intervention For Endpoint reduction inhypertension study (LIFE): a randomized trial against atenolol. Lancet. 2002;359:1004-1010.44. Lithell H, Hansson L, Skoog I, et al. The Study on Cognition and Prognosis inthe Elderly (SCOPE): principal results of a randomized double-blind interventiontrial. J Hypertens. 2003;21:875-886.45. Schrader J, Lüders S, Kulschewski A, et al. The ACCESS Study: evaluation ofAcute Candesartan Cilexetil Therapy in Stroke Survivors. Stroke. 2003;34:1699-1703.46.Duprez DA, Munger MA, Botha J, et al. Aliskiren for geriatric lowering of systolichypertension: a randomized controlled trial. J Hum Hypertens. 2010;24:600-608.47. McMurray JJ, Pitt B, Latini R, et al. Effects of the oral direct renin inhibitoraliskiren in patients with symptomatic heart failure. Circ Heart Fail. 2008;1:17-24.48.Volpe M, Pontremoli R, Borghi C. Direct renin inhibition: from pharmacologicalinnovation to novel therapeutic opportunities. High Blood Press Cardiovasc Prev.2011;18:93-105.49. Verdecchia P, Calvo C, Möckel V, et al. Safety and efficacy of the oral directrenin inhibitor aliskiren in elderly patients with hypertension. Blood Press. 2007;16:381-391.50.Messerli FH, Grossman E, Goldbourt U. Are beta-blockers efficacious as first-linetherapy for hypertension in the elderly? A systemic review. JAMA.1998;279:1903-1907.51. Cooper-DeHoff RM, Handberg EM, Mancia G, et al. INVEST revisited: reviewof findings from the International Verapamil SR-Trandolapril Study. Expert RevCardiovasc Ther. 2009;7:1329-1340.52. Fleg JL, Aronow WS, Frishman WH. Cardiovascular drug therapy in the elderly:benefits and challenges. Nat Rev Cardiol. 2011;8:13-28.53. Lewington S, Clarke R, Qizilbash N, et al. Age-specific relevance of usual bloodpressure to vascular mortality: a meta-analysis of individual data for one millionadults in 61 prospective studies. Lancet. 2002;360:1903-1913.



Improving Hypertension Management in the Elderly a Core Clinical Goal

PATIENTS: According to the National Healthand Nutrition Examination Survey 2007-2008, ap -proximately 20% of patients with hypertension aged>60 years are unaware that they have the condition.1The symptoms of hypertension are generally silent, andpatients often do not understand the importance ofblood pressure (BP) control to reduce the risk of stroke,coronary artery disease, and chronic kidney disease.Patients need to be educated about the disease stateand the importance of medication compliance. In addi-tion, patients need to understand the impact they canpersonally have in reaching their BP goals throughlifestyle modifications such as those described in thearticle by Nguyen and colleagues. Patients should alsobe encouraged to record home BP readings, which canhelp them understand how certain behaviors affect BPand to give their providers an idea of BP trends outsideof office visits.

PAYERS: Payers have several reasons for improvinghypertension control in their patient populations.Antihypertensive therapy can reduce the risk of con-gestive heart failure by approximately 40%, stroke by30%, coronary heart disease by 15%, and all-causemortality by 10%.2 The cost-savings for preventingthese long-term complications far outweigh the price ofantihypertensive therapy. Furthermore, with the widevariety of generic antihypertensive medications nowavailable, payers have greater flexibility to reduce thecost of hypertension management. Utilization manage-ment strategies, such as step therapy through a genericmedication and quantity limits to promote dose opti-mization, can encourage cost-effective options.

An additional reason to improve BP control is theNational Committee for Quality Assurance HealthcareEffectiveness Data and Information Set (HEDIS),which evaluates health plans with regard to certainoutcomes to facilitate comparison of health plans. The

HEDIS measure for hypertension is the percentage ofpatients (aged 18-85 years) with a diagnosis of hyper-tension whose most recent BP was adequately con-trolled (<140/90 mm Hg).3 Hypertension managementis also included in the HEDIS measure that focuses oncomprehensive diabetes care.

Payers need to be proactive to ensure that patientshave adequate BP control to perform well in theseHEDIS measures. Methods that payers can use to assistwith BP control include education for providers and forpatients, low-priced cost-sharing, and direct incentivesif certain BP goals are met.

In addition to HEDIS measures, hypertension hasalso been chosen as one of the 9 core chronic condi-tions to qualify patients for Medicare Part D Medica -tion Therapy Management (MTM).4 Pharmacists andother qualified providers involved in MTM programswill be able to help providers optimize antihypertensivetherapy and will be in a position to counsel patientsabout their medication therapy. Cooperation betweenpatients, providers, and payers is imperative to improveoutcomes in elderly patients with hypertension.

Katrina Moore, PharmDClinical Pharmacy Coordinator

SelectHealth, Salt Lake City, UT

1. Egan BM, Zhao Y, Axon RN. US trends in prevalence, awareness, treatment,and control of hypertension, 1988-2008. JAMA. 2010;303:2043-2050.2. Psaty BM, Lumley T, Furberg CD, et al. Health outcomes associated with variousantihypertensive therapies used as first-line agents: a network meta-analysis.JAMA. 2003;289:2534-2544.3. National Committee for Quality Assurance. The State of Health Care Quality:Reform, The Quality Agenda and Resource Use. 2010. www.ncqa.org/portals/0/state%20of%20health%20care/2010/sohc%202010%20-%20full2.pdf. AccessedJune 13, 2012. 4. Centers for Medicare & Medicaid Services. Prescription drug coverage-generalinformation. Memorandum: CY 2013 Medication Therapy Management ProgramGuidance and Submission Instructions. April 10, 2012. www.cms.gov/Medicare/Prescription-Drug-Coverage/PrescriptionDrugCovGenIn/Downloads/Memo-Contract-Year-2013-Medication-Therapy-Management-MTM-Program-Submission-v041012.pdf. Accessed June 13, 2012.

STAKEHOLDER PERSPECTIVE

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Ms Fitch is a Principal and Healthcare Management Consultant, Mr Broulette is an Actuarial Analyst, Mr Pyenson is a Principaland Consulting Actuary, Mr Iwasaki is a Consulting Actuary, all at Milliman, Inc, New York, NY; Dr Kwong is Senior Director,Health Economics and Outcomes Research, Daiichi Sankyo, Inc, Parsippany, NJ. Part of the study findings was presented at theAcademy of Managed Care Pharmacy 24th Annual Meeting and Exposition, April 20, 2012, San Francisco, CA.

Original research

Utilization of Anticoagulation Therapyin Medicare Patients with NonvalvularAtrial FibrillationKate Fitch, rn, Med; Jonah Broulette; Bruce Pyenson, Fsa, Maaa; Kosuke iwasaki, FiaJ, Maaa;Winghan Jacqueline Kwong, PharmD, PhD

Background: Clinical guidelines recommend oral anticoagulation for stroke prevention in

patients with atrial fibrillation (AF) at moderate or high risk for stroke but not at high risk for

bleeding; however, studies consistently report suboptimal use of such therapy. This study used

Medicare Part D claims data to assess the use of warfarin in the Medicare population.

Objectives: To compare real-world warfarin utilization with current treatment guideline recom-

mendations, and to assess the effect of warfarin exposure level on patient outcomes in

Medicare beneficiaries with nonvalvular AF (NVAF).

Methods: Patients who were recently diagnosed with NVAF were identified using a random

5% sample of Research Identifiable Files of Medicare beneficiaries in 2006 or 2007. Individuals

with moderate-to-high stroke risk per CHADS2 but not at high bleeding risk per ATRIA

(Anticoagulation and Risk Factors in Atrial Fibrillation) bleeding risk score were evaluated for

warfarin use, as identified by the presence of ≥1 warfarin prescription claims within 12 months

after the index diagnosis. Warfarin exposure level was assessed by the proportion of days cov-

ered during the 12-month follow-up period. The effect of warfarin exposure on ischemic stroke

and major bleeding event rates during the 12-month follow-up period were assessed using

multivariate logistic regression.

Results: Data from 14,149 newly diagnosed patients with NVAF (mean age, 79 years; 58.7%

female) were analyzed, and of these, 7524 (53.2%) patients were identified as having moder-

ate-to-high stroke risk and not being at high bleeding risk. Of these patients, 3110 (41.3%) did

not receive warfarin within 12 months of the index diagnosis. The risk for ischemic stroke was

significantly lower in those with warfarin exposure versus no warfarin exposure (adjusted odds

ratio [OR], 0.51; confidence interval [CI], 0.43-0.61; P <.001) and in patients with warfarin pro-

portion of days covered ≥80% versus those with proportion of days covered <80% (adjusted

OR, 0.59; 95% CI, 0.48-0.72; P<.001). Warfarin exposure was associated with a significantly

higher major bleeding rate (adjusted OR, 1.19; 95% CI, 1.04-1.36; P = .013), with this signifi-

cant difference being driven by patients aged >65 years.

Conclusions: Based on a risk-stratification scheme composed of previously published tools,

such as CHADS2 and the ATRIA bleeding risk index, a significant proportion of Medicare ben-

eficiaries with AF are not receiving guideline-recommended anticoagulation therapy, which

leads to an excess rate of ischemic stroke in this patient population. These findings highlight

quality-of-care issues for patients with AF and the need to improve compliance with anticoag-

ulation guidelines in the Medicare population.




Atrial fibrillation (AF) is a significant health andcost concern for the Medicare population (age≥65 years), because of its association with an

increased risk for stroke and all-cause mortality.1 The risk

for stroke in patients with AF is almost 5-fold higherthan in patients without AF.2 One of every 6 strokes inthe United States is associated with AF,3 and strokes inpatients with AF are more severe and disabling than in

patients without AF.4 The prevalence of AF in theMedicare population increased from 3.2% in 1992 to6.0% in 2002.5 Recent estimates indicate the prevalencerate is rising.6 The prevalence of AF increases with age,currently affecting approximately 3.8% of persons aged≥60 years and 9.0% of persons aged ≥80 years.7 It isexpected that by 2050 the prevalence of AF will doublefrom current estimates, when 88% (4.9 million) of thosewith AF will be aged ≥65 years and 53% (2.9 million)will be aged ≥80 years.7

Oral anticoagulation therapy is the cornerstone ofstroke prevention for patients with AF. Warfarin reducesthe risk for ischemic stroke by 67% compared withplacebo and by 38% compared with aspirin.8 Recentclinical trials of newer oral anticoagulation agents reporta similar or a greater rate of stroke risk reduction withthese agents than with warfarin in patients with AF.9-11Antithrombotic treatment guidelines from theAmerican College of Cardiology/American HeartAssociation recommend oral anticoagulation therapy forpatients with AF and moderate-to-high stroke risk,assuming that patients are not at high bleeding risk.12,13

Several evaluation schemes are available to estimatea stroke risk, including CHADS2

14 and CHA2DS2-VASc.15 Similarly, several bleeding risk schemes areavailable to assess the risk of bleeding, includingHEMORR2HAGES,16 HAS-BLED,17 and, more recent-ly, the ATRIA (Anticoagulation and Risk Factors inAtrial Fibrillation) bleeding risk scheme.18

Despite well-established guideline recommendations,however, oral anticoagulation therapy is underutilized.19-24Underutilization has been linked to healthcare system,physician, and patient factors.25 A major factor cited forunderutilization involves physician concern with hemor-rhage associated with oral anticoagulation.26 For patientswho receive warfarin, optimizing anticoagulation andmaintaining anticoagulation within the recommendedinternational normalized ratio (INR) therapeutic rangecan also be a challenge. A large, nationwide study of elec-tronic medical records reported that patients spent only48% of study days within the recommended INR range.23Another study showed that approximately 33% ofpatients were within the INR therapeutic range less than20% of the time, and only 19% of patients were withinthe therapeutic range all or almost all of the time.27

Physician surveys suggest that healthcare system bar-riers to optimizing anticoagulation include delays inlaboratory reports for INR levels, the general incon-venience of INR monitoring, and the lack of consult-ant services for anticoagulation management.28Without careful monitoring of INR levels, suprathera-peutic INR levels can and do lead to major bleedingevents. Bleedings associated with oral anticoagulation

therapy are reported as a significant portion of emer-gency department visits for drug-related adverse eventsamong older adults.29

The objective of this study was to compare actual war-farin utilization with current treatment guideline recom-mendations, and to assess the effect of warfarin exposurelevel on ischemic stroke and bleeding rates in Medicarebeneficiaries (ie, age ≥65 years) with AF. This analysisused the 5% Sample Medicare Research Identifiable File(RIF) dataset with Medicare Part A and Part B claimsdata linked to Part D prescription drug claims, unlikeprevious analyses that were based on 5% SampleMedicare Limited Dataset (LDS), which uses INR mon-itoring and prothrombin time claims as a proxy for war-farin use.30 This current approach provides a more preciseestimate of warfarin use in the Medicare population.

MethodsStudy Population and Characteristics

Study participants were patients in the Medicare 5%Sample RIF who were designated as having AF by theCenters for Medicare & Medicaid Services (CMS)Chronic Condition Data Warehouse (CCW) in theyears 2006 or 2007. For each patient with AF, theMedicare RIF data included all Medicare Part A and

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KEY POINTS➤ Patients with atrial fibrillation (AF) are at a

significant, 5-fold increased risk for stroke and all-cause mortality compared with those without AF.

➤ Oral anticoagulation therapy is recommended bynational guidelines as the cornerstone for strokeprevention in patients with AF.

➤ Warfarin significantly reduces the risk for ischemicstroke; newer anticoagulant agents have showneven greater reduction of stroke risk in patientswho are not at risk for bleeding.

➤ Although AF risk increases with age, this presentstudy shows that anticoagulation therapy isunderutilized in Medicare beneficiaries who havenonvalvular AF (NVAF), resulting in an increasein ischemic strokes.

➤ These findings suggest the need to follow guideline-based anticoagulation recommendations in patientswith NVAF to prevent strokes and the associatedexcess in healthcare costs, reduced quality of life,and even death.

➤ These findings also raise the need to investigateprovider compliance with clinical guidelinesregarding oral anticoagulation therapy for strokeprevention in older patients (aged >65 years) with NVAF.

Part B claims incurred between 2005 and 2008, monthlyeligibility data for each patient with AF from 2005 to2008, and all Medicare Part D claims incurred from 2006to 2008. Unlike LDS data, the actual date of service foreach claim was provided in the RIF data.

Patients included in this analysis were required tohave ≥2 medical claims (inpatient, emergency depart-ment, observation unit, physician evaluation and man-agement [E/M] office visit) coded with an InternationalClassification of Diseases, Ninth Revision (ICD-9) diag-nosis code of 427.31 between January 1, 2006, andDecember 31, 2007. At least 2 of the claims wererequired to occur at least 30 days apart, with 1 of theclaims incurred in an outpatient setting. To ensure thateligible beneficiaries were patients with newly diagnosedAF, patients with ≥1 claim associated with AF in the 12-month period before the index AF diagnosis (first claimassociated with the ICD-9 code 427.31 between January1, 2006, and December 31, 2007) were excluded fromthe analysis.

The sample was further limited to patients with non-valvular AF (NVAF), by excluding AF patients withclaims identified by ICD-9 codes for mitral and/or aorticvalvular disease, repair or replacement, transient preoper-ative AF, or hyperthyroidism in the 12 months before andafter the index AF diagnosis date (Appendix 1, page 166).

Eligible patients were further required to have contin-uous enrollment in Medicare Part A and Part B benefitsfor 12 months before the index AF diagnosis date and forthe lesser of 12 months after the AF index diagnosis dateor the date of mortality, and Part D enrollment for thelesser of 12 months after the AF index date or the dateof mortality. Patients who had an ischemic stroke within7 days before or after the AF index diagnosis date wereexcluded from the analysis.

CHADS2 stroke risk14 and ATRIA bleeding risk18

scores were calculated using claim data 12 months beforethe index AF diagnosis for each eligible patient. TheCHADS2 and ATRIA risk factors (Table 1) of conges-tive heart failure, hypertension, diabetes, anemia, severerenal disease, prior bleeding, and history of stroke ortransient ischemic attack were identified by ≥1 inpa-tient, emergency department, hospital observation unit,or physician E/M office visit claims associated with spe-cific ICD-9 diagnosis codes (Appendix 2, page 166).

Newly diagnosed patients with NVAF and moderateor high CHADS2 stroke risk (CHADS2 score ≥2) andlow-to-moderate ATRIA bleeding risk (score ≤4) wereidentified.

Outcome MeasuresWarfarin Use

Warfarin use was determined by the presence of ≥1

warfarin prescription claim within 12 months after theindex AF diagnosis. Patients who had a warfarin pre-scription claim within 12 months after the index AFdiagnosis but not until after an ischemic stroke claim,and those who had no warfarin prescription claims duringthe 12-month period after the index AF diagnosis, wereconsidered in this analysis to have not received warfarin.

Warfarin claims were identified using a comprehen-sive National Drug Code list, which was obtained fromthe Medi-Span Master Drug Database from WoltersKluwer Health in May 2011. The algorithm by Go andcolleagues31 was adopted to determine the duration ofwarfarin therapy. The duration of warfarin therapy wascalculated based on the number of days of supply associ-ated with each prescription claim; continuous warfarinuse was assumed for periods of ≤60 days between any 2consecutive warfarin prescriptions.

For gaps lasting longer than 60 days, continuous war-farin use was assumed if there were intervening out -patient INR measurements at least every 42 days.Otherwise, the patient was considered not to be takingwarfarin from day 31 after the end date of the first pre-scription until the start date of the next prescription.Warfarin exposure level was assessed by the proportionof days covered, by dividing the total duration of war-farin therapy during the 12-month follow-up period bythe length of follow-up.

Stroke and Major Hemorrhage EventsThe rate of ischemic strokes and major hemorrhage

were identified based on claims data in the 12 months

Utilization of Anticoagulation Therapy


Table 1 CHADS2 Stroke Risk and ATRIA Bleeding Risk Variablesand Scoring Schemes

CHADS2 scoring ATRIA scoring

Variable Points Variable Points

Prior stroke or TIA 2 Anemia 3

Age ≥75 years atindex diagnosis year

1 Age ≥75 years atindex diagnosis year

2

Hypertension 1 Severe renal disease 3

Diabetes 1 Prior bleeding 1

Heart failure 1 Hypertension 1

CHADS2 scoring: 0-1 point, low risk; 2 points, moderate risk; ≥3 points, high risk. ATRIA scoring: 0-3 points, low risk; 4 points, moderate risk; 5-10 points, high risk. ATRIA indicates Anticoagulation and Risk Factors in AtrialFibrillation; TIA, transient ischemic attack.

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Medicare beneficiaries identified as patients with AF in 2006-2007

N = 189,835

AF patients with <2 medical claims associated with ICD-9 code of 427.31 during

1/1/06-12/31/07N = 24,715

AF patients with claims associated with ICD-9 codesfor mitral and/or aortic valvular disease, repair, orreplacement; transient AF; or hyperthyroidism

N = 10,501

Patients with ≥1 claims associated with AF in the 12 months before the index AF diagnosis

N = 99,682

Patients not eligible for Parts A and B for 12 mobefore the index AF and Parts A, B, and D for 12 mo

after the index AF or date of deathN = 40,382

Patients who had a stroke on or within 7 days before or after AF index date

N = 406

AF patients with ≥2 medical claims associated with an ICD-9 diagnosis code of 427.31 during

1/1/06-12/31/07N = 165,120

Patients with newly diagnosed AFN = 65,438

Patients with NVAFN = 54,937

Patients eligible for Parts A and B for 12 mo beforethe index AF and eligible for Parts A, B, and D for thelesser of 12 mo after the index AF or date of death

N = 14,555

Patients who did not have a stroke on or within 7 days before or after the AF index date

N = 14,149

AF indicates atrial fibrillation; ICD-9, International Classification of Diseases, Ninth Revision; NVAF, nonvalvular atrial fibrillation.

Figure 1 Sample Selection Criteria

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after the index AF diagnosis. Ischemic strokes weredefined as an inpatient or emergency department claimassociated with a primary ICD-9 diagnosis of 433.xx,434.xx, or 436.xx. A major hemorrhage was defined asan inpatient admission with an ICD-9 diagnosis code foreither an extracranial hemorrhage in the primary diag-nosis position or an ICD-9 code for intracranial hemor-rhage in any position of the claim (Appendix 3, page 166).

Statistical AnalysisThe proportion of patients receiving warfarin within

12 months after the index AF diagnosis was evaluatedand compared with guideline recommendations byCHADS2 stroke risk and ATRIA bleeding risk levels.Specifically, this was the cohort of patients with moder-ate-to-high stroke risk who were not at high risk forbleeding and filled at least 1 warfarin prescription duringthe 12 months after the index AF diagnosis.

To assess the effect of warfarin exposure level on therates of ischemic stroke and major bleeding events forthose receiving and not receiving warfarin within 12months of the index AF diagnosis, incidence rates forischemic stroke and major bleeding events were sepa-rately analyzed, using multivariate logistic regression bycontrolling for differences in baseline characteristics.Ischemic stroke rates were also compared in patientswith any exposure to warfarin (proportion of days cov-ered >0%), in those with warfarin proportion of dayscovered exposure ≥80%, and in patients who did notreceive warfarin during the 12-month follow-up period.

Covariates included in the ischemic stroke modelwere age, dual-eligibility (Medicare and Medicaid eligi-bility) status, and CHADS2 score. Major bleeding eventrates were compared for patients who had any exposureto warfarin versus those who did not receive warfarinduring the 12-month follow-up period. Covariatesincluded in the major bleeding event model were age,dual-eligibility status (Medicare and Medicaid eligibili-ty), and ATRIA score.

ResultsA total of 189,835 Medicare beneficiaries with AF

were identified by CMS CCW as having AF in 2006 andin 2007. Limiting the sample to AF patients with ≥2medical claims associated with an ICD-9 diagnosis codeof 427.31 from January 1, 2006, to December 31, 2007,reduced the initial cohort to 165,120 beneficiaries withAF. Limiting this sample to patients with newly diag-nosed AF reduced the sample size to 65,438, and furtherlimiting the sample to patients with NVAF reduced thesample size to 54,937.

Requiring Medicare Parts A and B eligibility for the12 months before the AF index and requiring Medicare

Parts A, B, and D eligibility for the lesser of 12 monthsafter the AF index date or date of death reduced thesample size to 14,555 patients with newly diagnosedNVAF. Removing patients with a stroke on or within 7days before or after the AF index date reduced the sam-ple size to a final total of 14,149 patients with newlydiagnosed NVAF (Figure 1).

Baseline characteristics for patients who receivedwarfarin were generally similar to those who did notreceive warfarin within 12 months after the indexNVAF diagnosis, with a few noteworthy exceptions.There was a higher proportion of patients who had dualeligibility for Medicare and Medicaid (12.6% vs 7.6%,respectively), as well as a higher proportion of patientsaged ≥85 years (37.1% vs 21.1%, respectively) amongthose who did not receive warfarin.

The mean CHADS2 score was significantly lower inpatients receiving warfarin, and patients not receivingwarfarin had a higher mean ATRIA bleeding risk score(3.7 vs 3.2, respectively; Table 2, page 162).

Of the 14,149 patients with newly diagnosed NVAF,75.8% had moderate or high stroke risk (CHADS2 score≥2), and 24.5% had high bleeding risk (ATRIA score≥5). The proportion of patients with high bleeding riskincreased from 8% of those with low stroke risk to 43%in the group with high stroke risk (Figure 2, page 163).

Warfarin UseOverall, 6981 (49.3%) patients received warfarin

within 12 months of the index AF diagnosis. Figure 3(page 163) presents the number and proportion ofpatients who received warfarin within 12 months of theindex AF date at each stroke and bleeding risk level.Warfarin use was lower in the group with a high bleedingrisk than in the groups with low/moderate bleeding riskacross all stroke risk levels.

However, warfarin use did not seem to differ acrossstroke risk levels. Of the 14,149 patients with NVAFincluded in the study, 10,725 patients (75.8%) had mod-erate (CHADS2, 2 or 3) or high (CHADS2 ≥4) strokerisk; of these, 7524 patients did not have high bleedingrisk (ATRIA ≥5) and would meet the recommendationsfor oral anticoagulation therapy. Those recommendedfor oral anticoagulation therapy (moderate-to-highstroke risk and low-to-moderate bleeding risk) com-prised 53.2% (7524/14,149) of the study sample of

Among patients recommended for oralanticoagulation therapy, 41.3% did notreceive warfarin within 12 months of theindex NVAF diagnosis.

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Table 2 Baseline Characteristics for Patients with NVAF, by Patient Population

Study population of patients with NVAF

Patients not receiving warfarinwithin 12 moa

Patients receiving warfarin

within 12 mo

Patients, N 14,149 6248 7901

Dual-eligible patients, % 9.8 12.6 7.6b

Age, yr

Mean (SD) 79.3 (8.3) 80.9 (8.6) 78.1 (7.9)b

Median (min-max) 80 (38-106) 82 (38-106) 78 (38-104)

Age, %

<65 yr 2.6 2.2 2.9b

65-74 yr 25.7 21.4 29.0b

75-84 yr 43.6 39.3 47.0b

≥85 yr 28.1 37.1 21.1b

Sex, %

Male 41.3 41.5 41.1

Female 58.7 58.5 58.9

CHADS2 score

Mean (SD) 2.31 (1.18) 2.35 (1.17) 2.27 (1.18)b

Median (min-max) 2 (0-6) 2 (0-6) 2 (0-6)

Risk conditions, %

Prior stroke or TIA (2 pt) 10.8 10.6 11.0

Hypertension (1 pt) 79.1 79.2 79.0

Diabetes (1 pt) 26.6 25.4 27.5b

Heart failure (1 pt) 31.5 32.7 30.6b

Age ≥75 yr (1 pt) 71.7 76.4 68.1b

ATRIA score

Mean (SD) 3.43 (2.23) 3.75 (2.32) 3.17 (2.13)b

Median (min-max) 3 (0-10) 3 (0-10) 3 (0-10)

Risk conditions, %

Anemia (3 pt) 22.0 26.6 18.5b

Severe renal disease (3 pt) 13.4 15.6 11.6b

Prior bleeding (1 pt) 14.0 16.6 12.0b

Hypertension (1 pt) 79.1 79.2 79.0

Age ≥75 yr (2 pt) 71.7 76.4 68.1b

aIncludes patients who received warfarin within 12 months, but only after having had a stroke. bP <.05 versus patients not receiving warfarin within 12 months.ATRIA indicates Anticoagulation and Risk Factors in Atrial Fibrillation; NVAF, nonvalvular atrial fibrillation; SD, standard deviation; TIA, transient ischemic attack.

patients with newly diagnosed NVAF. Among patientsrecommended for oral anticoagulation therapy, 41.3%(3110/7524) did not receive warfarin within 12 monthsof the index NVAF diagnosis (Table 3).

Stroke and Bleeding EventsThe unadjusted rate of ischemic stroke during the 12-

month period after the index NVAF diagnosis was 2.6%for those receiving warfarin within 12 months of theindex NVAF versus 5.5% for those not receiving war-farin within 12 months of the index NVAF. After adjust-ing for age, dual-eligibility status, and CHADS2 score,the risk for ischemic stroke was 49% lower (odds ratio[OR], 0.51; 95% confidence interval [CI], 0.43-0.61;P <.001) for patients receiving warfarin compared withthose not receiving warfarin within 12 months.

Among patients who received warfarin within 12months after the index AF date, 66.74% had warfarinexposure proportion of days covered ≥80% during thefollow-up period. After adjusting for age, dual-eligibilitystatus, and CHADS2 score using regression, the risk ofischemic stroke for patients with warfarin exposure pro-



Figure 2 Distribution of ATRIA Bleeding Risk Score by CHADS2Stroke Risk Level (N = 14,149)

Moderate stroke risk(2-3)

Low stroke risk(0-1)

High stroke risk(4-6)

Patients, %

High bleeding risk (5-10)Moderate bleeding risk (4)Low bleeding risk (0-3)

ATRIA indicates Anticoagulation and Risk Factors in AtrialFibrillation.

100

90

80

70

60

50

40

30

20

10

0

270184

2970

2301

773

5559

900

157

1035

Figure 3 Actual Warfarin Use, by CHADS2 and ATRIA Risk Level (N = 14,149)

Patients, %

Receiving warfarin within 12 monthsNot receiving warfarin within 12 monthsa

100

90

80

70

60

50

40

30

20

10

0

aPatients who received warfarin within 12 months but only after having had a stroke are not considered to be receiving warfarinwithin 12 months.ATRIA indicates Anticoagulation and Risk Factors in Atrial Fibrillation.

Low bleeding risk(21% of study

sample)

Low stroke risk

Moderatebleeding risk(1% of study

sample)

Highbleeding risk(2% of study

sample)


sample)


sample)


sample)


sample)


sample)


sample)

Moderate stroke risk High stroke risk

1779 110 111 3301 414 1051 601 98 436

1191 74 159 2258 359 1250 434 59 464

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portion of days covered ≥80% was significantly lower(unadjusted stroke rate of 2.9% vs 4.8%; adjusted OR,0.586; 95% CI, 0.48-0.72; P <.001) compared with thosewho had proportion of days covered <80% (includingpatients who did not receive any warfarin) during the12-month postindex AF date. However, among warfarinusers, no significant difference was seen in ischemicstroke risk between patients with warfarin exposure pro-portion of days covered ≥80% (unadjusted stroke rate,2.9%) and patients with warfarin exposure proportionof days covered <80% (unadjusted stroke rate, 1.7%;adjusted OR, 0.95; 95% CI, 0.71-1.27).

The unadjusted major bleeding event rate during the12-month period after the index AF diagnosis was 6.8%for those receiving warfarin within 12 months of indexNVAF versus 6.5% for those not receiving warfarinwithin 12 months of the index NVAF. After adjustingfor age, dual-eligibility status, and ATRIA score usinglogistic regression, the major bleeding rate for patientswho received warfarin was statistically higher (adjustedOR, 1.19; 95% CI, 1.04-1.36; P = .013) than patientswho did not receive warfarin within 12 months of theindex NVAF. Subgroup analysis found that warfarinexposure was significantly associated with increasedbleeding risk in patients aged ≥65 years (OR, 1.17; 95%CI, 1.02-1.35; P = .024) but not for patients aged <65years (OR, 1.32; 95% CI, 0.45-3.91; P = .613).

DiscussionOur results confirm previous studies regarding the

underuse of warfarin for patients with NVAF, and thelower rate of stroke for those receiving warfarin. UsingINR monitoring claims as a proxy for warfarin use,Mercaldi and colleagues found that 58.5% of patientswith NVAF were receiving warfarin, and the incidenceof ischemic stroke was 27% lower in patients taking war-farin than in those not taking warfarin.30 Using a similarmethodology, Lakshminarayan and colleagues reported a26% lower risk of ischemic stroke in patients withNVAF taking warfarin.5

We found that 41.3% of patients at moderate-to-highstroke risk and not at high risk of bleeding were notreceiving warfarin within 12 months of the index diag-nosis, which amounts to 22% of the total patients withAF study sample. For those taking warfarin within 12months of the index diagnosis, the relative risk ofischemic stroke was 49% lower than for those not takingwarfarin within 12 months. The level of ischemic strokereduction observed in our study fell within similar rangesreported in previous clinical trials,9 where the relativerisk reductions of stroke for adjusted-dose warfarin versusaspirin and placebo were 38% and 67%, respectively.Similar to previous clinical trials, we found that absoluteincreases in major hemorrhage were less than theabsolute reductions in stroke.

These findings highlight quality-of-care issues forpatients with AF and the need to improve compliancewith anticoagulation guidelines in the Medicare popula-tion, which would be associated with fewer stroke-relat-ed deaths and lower stroke-related healthcare costs forMedicare. Several studies have emphasized the overesti-mation of bleeding risk and underestimation of strokerisk as reasons for underprescribing anticoagulants inpatients with AF,28,32,33 and our study results corroboratethese reports.

We further found that warfarin use was sensitive tobleeding risk, but it did not vary across stroke risk levels.Although the CHADS2 score has been available andvalidated for stroke risk stratification for the past decade,and was cited by national treatment guidelines as a toolto determine when oral anticoagulation is warranted, itremains unclear to what extent it has been routinelyused in clinical practice to guide decisions on anticoag-ulation therapy.34 It has been suggested that theCHADS2 score may not be sensitive in stratifyingpatients clearly into low-, intermediate-, and high-riskgroups in clinical practice.34

The more recently developed stroke stratificationscheme, CHA2DS2-VASc,15 which was endorsed byEuropean guidelines,35 may provide more specificity onanticoagulation decision, especially in patients with

Table 3 Percent of Patients with NVAF Not Receiving Warfarinwithin 12 Months, by CHADS2 and ATRIA Scores

Stroke risk

Patient population, % (study sample, %)

Low bleedingrisk

Moderatebleeding risk

High bleedingrisk

Low 40.1 (21.0) 40.2 (1.3) 58.9 (1.9)

Moderate 40.6 (39.3) 46.4 (5.5) 54.3 (16.3)

High 41.9 (7.3) 37.6 (1.1) 51.6 (6.4)

NOTE: Patients who received warfarin within 12 months butonly after having a stroke are not considered to be receivingwarfarin within 12 months. ATRIA indicates Anticoagulation and Risk Factors in AtrialFibrillation; NVAF, nonvalvular atrial fibrillation.

These findings highlight quality-of-careissues for patients with AF and the need toimprove compliance with anticoagulationguidelines in the Medicare population.

moderate stroke risk based on CHADS2. However, theperformance of this new scheme in predicting strokes inclinical practice remains to be confirmed.36 These resultssuggest the need for action by health insurers and policy-makers to develop programs to aid clinicians to over-come the clinical decision challenges in prescribing oralanticoagulation therapy for the population with NVAF.

The strength of this study is the use of Medicare PartD data to evaluate warfarin use among patients withNVAF who are recommended for oral anticoagulationtherapy and, in particular, the identification of patientswith newly diagnosed NVAF and their use of warfarinafter the index diagnosis. Past studies have used a proxyof INR testing to establish warfarin use, and dates ofservice have been unavailable to precisely identify anindex diagnosis date and stroke incidence date after thediagnosis of NVAF.

Studies that do not have precise start dates of warfarinand stroke incidence dates may inadvertently assignindividuals to the group receiving warfarin when in factthey were prescribed warfarin after their stroke occurred.This will understate the outcomes differences betweenthe groups taking and not taking warfarin. We have triedto control for this by identifying patients who are newlydiagnosed with NVAF and excluding strokes that occur7 days before or after the index diagnosis, and by exclud-ing from the cohort receiving warfarin within 12months, those receiving warfarin within 12 months butonly after a stroke.

Novel oral anticoagulants, including dabigatran andrivaroxaban, have recently been approved for stroke pre-vention in US patients with AF. Clinical studies haveshown that these new agents have either similar or bet-ter efficacy in preventing stroke while having a lowerrisk for intracranial bleeding than warfarin. Future stud-ies are needed to determine whether these newer agentswould reduce underutilization of anticoagulation thera-py for stroke prevention in patients with AF. Additionalstudies to assess compliance of warfarin and novel oralanticoagulants and their implications on patient out-comes are also warranted.

LimitationsThe present study has several limitations. First, it

shares the limitations associated with all administrativeclaims studies, and it depends on accurate and completecoding practices by providers. Because of data availability,we were limited to a 12-month period preceding the indexAF diagnosis to determine whether a patient was newlydiagnosed with AF. This methodology cannot rule out theexclusion of all existing patients with AF, because it is pos-sible that a patient with AF may not get coded with AFduring a 12-month preindex period, especially if other

conditions become more prominent in the patient’s care. An insufficient preindex period may also underesti-

mate the prevalence of the risk factors for the CHADS2stroke and ATRIA bleeding risk schemes, leading tolower than actual stroke and bleeding risk levels. In addi-tion, clinical information not available in claims dataand inaccurate coding practice may introduce bias whendetermining stroke and bleeding risk levels in this study.

Because we required Medicare patients to have 12months of eligibility before the index diagnosis, we inad-vertently excluded 65-year-old Medicare beneficiarieswho are new to Medicare through aging. Therefore, ourpatient selection methodology may have resulted in aslightly older population, which can impact risk factorprevalence. Warfarin use and level of warfarin exposurewere identified by filled warfarin prescription claims,which may not accurately represent patient adherenceto warfarin therapy.

In this study, we used the ATRIA bleeding riskscheme as a tool to stratify patients into different bleed-ing risk levels. Different bleeding risk assessmentschemes have been developed for the past decade.Current treatment guidelines for anticoagulation do notspecify a standard instrument that should be used forbleeding risk assessment. We arbitrarily chose to use theATRIA bleeding risk scheme because it was developedand validated based on administrative claims data ofpatients receiving warfarin. The ATRIA bleeding riskscheme has been shown to identify a higher proportionof patients at high bleeding risk and higher major bleed-ing rates than other bleeding risk schemes.18 Therefore,our estimate that 53.2% of patients with NVAF are eli-gible for oral anticoagulation therapy (ie, at moderate-to-high stroke risk and not at high bleeding risk) is aconservative estimate, because using other bleeding riskschemes may lead to a higher proportion of patients withNVAF being eligible for oral anticoagulation therapy.Further studies are needed to confirm our study findings.

ConclusionAF is a prevalent disease in the Medicare population,

with patients with AF having a 5-fold higher risk of



Studies that do not have precise start datesof warfarin and stroke incidence dates mayinadvertently assign individuals to thegroup receiving warfarin when in fact they were prescribed warfarin after theirstroke occurred.

stroke than those without AF. Strokes in the AF popula-tion are more severe and disabling than in patients with-out AF. Oral anticoagulation significantly reduces therisk of stroke for patients with AF, yet there is continuedunderuse of anticoagulation therapy for this population.Notwithstanding its limitation, this study corroboratesresults from the previous literature and highlights theneed for quality improvement initiatives to reduceunderuse of oral anticoagulation in patients with clini-cally indicated AF to reduce stroke-related mortality andhealthcare resource use.

Funding SourceThe study and the preparation of this manuscript were

funded by Daiichi Sankyo, Inc.

Author Disclosure StatementMs Fitch, Mr Broulette, Mr Pyenson, and Mr Iwasaki

have reported no conflicts of interest. Dr Kwong is anemployee of Daiichi Sankyo, Inc.

References1. Stewart S, Hart CL, Hole DJ, McMurray JJ. A population-based study of the long-term risks associated with atrial fibrillation: 20-year follow-up of the Renfrew/Paisleystudy. Am J Med. 2002;113:359-364.2.Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factorfor stroke: the Framingham Study. Stroke. 1991;22:983-988.3. Hart RG, Halperin JL. Atrial fibrillation and thromboembolism: a decade ofprogress in stroke prevention. Ann Intern Med. 1999;131:688-695.4. Lin HJ, Wolf PA, Kelly-Hayes M, et al. Stroke severity in atrial fibrillation. TheFramingham Study. Stroke. 1996;27:1760-1764.

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Appendix 2 Diagnosis Codes Used to Identify CHADS2 StrokeRisk and ATRIA Bleeding Risk Factors

Risk factor ICD-9 codes

Prior stroke/TIA 433.xx, 434.xx, 435.0, 435.1, 435.2, 435.3,435.8, 435.9

Hypertension 401.xx-405.x

Diabetes 250.xx

Heart failure 398.91, 402.01, 402.11, 425.1, 425.4, 425.7,428.xx

Anemia 285.1, 282.41, 282.42, 282.5, 282.60-282.64,282.68, 282.69, 280.1, 280.8, 280.9, 281.0,281.1, 281.2, 281.3, 281.4, 281.8, 281.9, 284.0,284.01, 284.09, 284.1, 284.8, 284.81, 284.89,284.9, 280, 283.0, 283.1, 283.11, 283.19, 283.2,283.9, 282.0, 282.1, 282.2, 282.3, 282.4, 282.49,282.7, 282.8, 282.9, 284.2, 285.0, 285.21,285.22, 285.29, 285.8, 285.9

Severe renal disease

584, 584.5, 584.6, 584.7, 584.8, 584.9, 585,585.3, 585.4, 585.5, 585.6, 585.9, 586, 792.5,V420, V451, V4511, V4512, V560, V561,V562, V5631, V5632, V568

Bleeding 423.0, 430.**, 431.**, 432.**, 852.0*, 852.2*,852.4*, 853.0*, 455.2, 455.5, 455.8, 456.0,456.20, 459.0, 530.7, 530.82, 531.00, 531.01,531.20, 531.21, 531.40, 531.41, 531.60, 531.61,533.01, 533.20, 533.21, 533.40, 533.41, 533.60,533.61, 534.00, 534.01, 534.20, 534.21, 534.40,534.41, 534.60, 534.61, 535.11, 535.21, 535.31,535.41, 535.51, 535.61, 537.83, 562.02, 562.03,562.12, 562.13, 568.81, 569.3, 569.85, 578, 578.0,578.1, 578.9, 593.81, 599.7, 719.10, 719.11,719.12, 719.13, 719.14, 719.15, 719.16, 719.17,719.18, 719.19, 784.7, 784.8, 786.3

ATRIA indicates Anticoagulation and Risk Factors in AtrialFibrillation; ICD-9, International Classification of Diseases, NinthRevision; TIA, transient ischemic attack.

Appendix 3 Diagnosis Codes Used to Identify MajorHemorrhage

ICD-9 codes

Major hemorrhage

423.0, 430.**, 431.**, 432.**, 852.0*,852.2*, 852.4*, 853.0*, 455.2, 455.5,455.8, 456.0, 456.20, 459.0, 530.7, 530.82,531.00, 531.01, 531.20, 531.21, 531.40,531.41, 531.60, 531.61, 533.01, 533.20,533.21, 533.40, 533.41, 533.60, 533.61,534.00, 534.01, 534.20, 534.21, 534.40,534.41, 534.60, 534.61, 535.11, 535.21,535.31, 535.41, 535.51, 535.61, 537.83,562.02, 562.03, 562.12, 562.13, 568.81,569.3, 569.85, 578, 578.0, 578.1, 578.9,593.81, 599.7, 719.10, 719.11, 719.12,719.13, 719.14, 719.15, 719.16, 719.17,719.18, 719.19, 784.7, 784.8, 786.31 inpatient claim with ICD-9 code430.**, 431.**, 432.**, 852.0*, 852.2*,852.4*, 853.0* in any position of theclaim and the remaining ICD-9 codesin the primary position of the claim

ICD-9 indicates International Classification of Diseases,Ninth Revision.

Appendix 1 ICD-9/CPT Codes for Exclusion Criteria

ICD-9/CPT codes

Type of condition/event

1 inpatient, emergency department, observa-tion stay, or physician E/M claim with ICD-9code in any position of the claim

Valvular AF exclusions

35.00-35.04, 35.10-35.14, 35.2-35.28, 35.3-35.35, 35.39, 35.4-35.42, 35.5-35.54, 35.6-35.63,35.7-35.73, 36.1-36.17, 36.19, 37.1-37.12, 37.3-37.33, 37.4

Valvular AF exclusions

394.0, 394.2, 396.0, 396.1, 396.8, V42.2, V43.3,242

AF indicates atrial fibrillation; CPT, Current ProceduralTerminology; E/M, evaluation and management; ICD-9,International Classification of Diseases, Ninth Revision.CPT copyright 2012 American Medical Association. All rightsreserved. CPT is a registered trademark of the AmericanMedical Association.



5. Lakshminarayan K, Solid CA, Collins AJ, et al. Atrial fibrillation and stroke inthe general medicare population: a 10-year perspective (1992 to 2002). Stroke.2006;37:1969-1974.6. Naccarelli GV, Varker H, Lin J, Schulman KL. Increasing prevalence of atrial fib-rillation and flutter in the United States. Am J Cardiol. 2009;104:1534-1539.7.Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation inadults: national implications for rhythm management and stroke prevention: theAnticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study. JAMA.2001;285:2370-2375.8. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to pre-vent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med.2007;146:857-867.9. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvularatrial fibrillation. N Engl J Med. 2011;365:883-891.10. Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fib-rillation. N Engl J Med. 2011;364:806-817.11.Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patientswith atrial fibrillation. N Engl J Med. 2009;361:1139-1151.12. Fuster V, Rydén LE, Cannom DS, et al. ACC/AHA/ESC 2006 Guidelines for theManagement of Patients with Atrial Fibrillation: a report of the American Collegeof Cardiology/American Heart Association Task Force on Practice Guidelines andthe European Society of Cardiology Committee for Practice Guidelines (WritingCommittee to Revise the 2001 Guidelines for the Management of Patients WithAtrial Fibrillation): developed in collaboration with the European Heart RhythmAssociation and the Heart Rhythm Society. Circulation. 2006;114:e257-e354.13. Wann LS, Curtis AB, Ellenbogen KA, et al. 2011 ACCF/AHA/HRS focusedupdate on the management of patients with atrial fibrillation (update on dabigatran):a report of the American College of Cardiology Foundation/American HeartAssociation Task Force on practice guidelines. Circulation. 2011;123:1144-1150.14. Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classificationschemes for predicting stroke: results from the National Registry of Atrial Fibrillation.JAMA. 2001;285:2864-2870.15. Lip GY, Nieuwlaat R, Pisters R, et al. Refining clinical risk stratification for pre-dicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-basedapproach: the Euro Heart Survey on atrial fibrillation. Chest. 2010;137:263-272.16. Gage BF, Yan Y, Milligan PE, et al. Clinical classification schemes for predictinghemorrhage: results from the National Registry of Atrial Fibrillation (NRAF). AmHeart J. 2006;151:713-719.17. Pisters R, Lane DA, Nieuwlaat R, et al. A novel user-friendly score (HAS-BLED)to assess 1-year risk of major bleeding in patients with atrial fibrillation: the EuroHeart Survey. Chest. 2010;138:1093-1100.18. Fang MC, Go AS, Chang Y, et al. A new risk scheme to predict warfarin-associ-ated hemorrhage: the ATRIA (Anticoagulation and Risk Factors in AtrialFibrillation) Study. J Am Coll Cardiol. 2011;58:395-401.19. Fang MC, Stafford RS, Ruskin JN, Singer DE. National trends in antiarrhythmicand antithrombotic medication use in atrial fibrillation. Arch Intern Med. 2004;164:55-60.

20.Waldo AL, Becker RC, Tapson VF, et al. Hospitalized patients with atrial fibril-lation and a high risk of stroke are not being provided with adequate anticoagulation.J Am Coll Cardiol. 2005;46:1729-1736.21. Samsa GP, Matchar DB, Goldstein LB, et al. Quality of anticoagulation manage-ment among patients with atrial fibrillation: results of a review of medical recordsfrom 2 communities. Arch Intern Med. 2000;160:967-973.22. Glazer N, Dublin S, Smith NL, et al. Newly detected atrial fibrillation and com-pliance with antithrombotic guidelines. Arch Intern Med. 2007;167:246-252.23. Boulanger L, Kim J, Friedman M, et al. Patterns of use of antithrombotic therapyand quality of anticoagulation among patients with non-valvular atrial fibrillation inclinical practice. Int J Clin Pract. 2006;60:258-264.24.Harley CR, Riedel AA, Hauch O, et al. Anticoagulation therapy in patients withchronic atrial fibrillation: a retrospective claims data analysis. Curr Med Res Opin.2005;21:215-222.25. Kneeland PP, Fang MC. Current issues in patient adherence and persistence:focus on anticoagulants for the treatment and prevention of thromboembolism.Patient Prefer Adherence. 2010;4:51-60.26. Gross CP, Vogel EW, Dhond AJ, et al. Factors influencing physicians’ reporteduse of anticoagulation therapy in nonvalvular atrial fibrillation: a cross-sectional sur-vey. Clin Ther. 2003;25:1750-1764.27.Walker AM, Bennett D. Epidemiology and outcomes in patients with atrial fib-rillation in the United States. Heart Rhythm. 2008;5:1365-1372.28. Bungard TJ, Ghali WA, Teo KK, et al. Why do patients with atrial fibrillationnot receive warfarin? Arch Intern Med. 2000;160:41-46.29. Budnitz DS, Shehab N, Kegler SR, Richards CL. Medication use leading to emer-gency department visits for adverse drug events in older adults. Ann Intern Med.2007;147:755-765.30. Mercaldi CJ, Ciarametaro M, Hahn B, et al. Cost efficiency of anticoagulationwith warfarin to prevent stroke in medicare beneficiaries with nonvalvular atrial fib-rillation. Stroke. 2011;42:112-118.31. Go AS, Hylek EM, Chang Y, et al. Anticoagulation therapy for stroke preven-tion in atrial fibrillation: how well do randomized trials translate into clinical prac-tice? JAMA. 2003;290:2685-2692.32. Bungard TJ, Ghali WA, McAlister FA, et al. The relative importance of barriersto the prescription of warfarin for nonvalvular atrial fibrillation. Can J Cardiol. 2003;19:280-284.33. Beyth RJ, Antani MR, Covinsky KE, et al. Why isn’t warfarin prescribed topatients with nonrheumatic atrial fibrillation? J Gen Intern Med. 1996;11:721-728.34. Klein D, Levine M. Are family physicians using the CHADS2 score? Is it usefulfor assessing risk of stroke in patients with atrial fibrillation? Can Fam Physician.2011;57:e305-e309.35.Camm AJ, Kirchhof P, Lip GY, et al, for the European Heart Rhythm Association,European Association for Cardio-Thoracic Surgery. Guidelines for the management ofatrial fibrillation: the Task Force for the Management of Atrial Fibrillation of theEuropean Society of Cardiology (ESC). Eur Heart J. 2010;31:2369-2429.36. Singer DE, Fang MC, Go AS. CHA2DS2-VASc risk scheme not ready for clinicaluse. Chest. 2010;138:1020; author reply 1020-1021.

Warfarin Utilization in Medicare Patients with Nonvalvular AtrialFibrillation: Sentinel Data from an Administrative Claims DatabasePROVIDERS/PATIENTS: Warfarin is the pri-

mary therapy for reducing the risk of thromboembolicevents in patients with atrial fibrillation (AF).Treatment guidelines recommend oral anticoagula-tion in patients with AF who are at moderate-to-highrisk for stroke but with no high bleeding risk.1 Under -utilization of warfarin in clinical practice in patientswith AF appears to stem from intrinsic limitations

that include food and drug interactions, the need forregular blood monitoring, and dose adjustments tomaintain anticoagulation levels within the recom-mended international normalized ratio (INR).2 Neweranticoagulant agents, such as apixaban, dabigatran,and rivaroxaban, are also effective in reducing the riskfor stroke in patients with AF, while having a lower riskof intracranial bleeding compared with warfarin.3,4


(Continued)

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However, compliance with guidance also may bedictated by nonpharmacologic variables within thesystem, the physician, and the patient. The need tounderstand the underlying causes of deviation fromguidelines in the use of anticoagulation therapy inclinical practice has implications that transcend ther-apeutic class.RESEARCHERS: Warfarin underutilization in the

Medicare population with nonvalvular AF (NVAF) isconfirmed in this new research by Fitch and colleagues:41% of patients with NVAF with moderate-high strokeand low bleeding risk did not receive warfarin within12 months of the index NVAF diagnosis, which isapproximately 22% of the total AF data set. In contrastwith previous studies, where warfarin use was inferredusing INR ratios and prothrombin time as proxies,5 theapproach in the current study uses Medicare Parts Aand B claims data linked to Part D claims informationto provide a precise estimate of warfarin use, includingdate of service for each claim.

The methodology in this study illustrates a “state-of-the-art” approach to the use of administrative claimsdata for estimating utilization in a naturalistic setting,yielding estimates for risk reductions for stroke versusincreases in major hemorrhage, which neverthelesswere congruent with randomized trials. Selection crite-ria and the impact on sample size at each decisionpoint are described, eligibility criteria that are associat-ed with stroke and major hemorrhage events parallelthe care taken in the characterization of warfarin usage,and statistical analyses adjust for prognostically impor-tant confounders. The discussion of research method-ology is a model of an objective exposé of strengths andlimitations of this method.PAYERS/POLICYMAKERS: This study corrobo-

rates previous findings that have demonstrated the clin-ical value of anticoagulation therapy for prevention of

stroke in patients with AF with appropriate risk stratifi-cation. Although no information on the cost burden ofAF with or without antithrombotic prophylaxis is pro-vided, previous research has estimated the healthcarecost burden in patients with AF in a privately insuredpopulation6 and the US population,7 with significantcost-savings for Medicare patients with NVAF takingwarfarin based on multivariate modeling.5

Clinical decision barriers that limit warfarin utiliza-tion provide a catalyst for quality control interven-tions, because available algorithms for risk stratifica-tion, such as CHADS2, may poorly stratify patients orincompletely penetrate the practice environment. Inaddition, evaluating the interaction of pharmacothera-py and system attributes with physician and patientperception of benefit versus risk for oral anticoagula-tion in NVAF is needed to provide a 3-dimensionalcharacterization of the significant gap in critical pro-phylactic care.

Michael F. Murphy, MD, PhDChief Medical Officer and Scientific Officer

Worldwide Clinical Trials

1. European Heart Rhythm Association; European Association for Cardio-Thoracic Surgery, Camm AJ, et al. Guidelines for the management of atrial fibril-lation: the Task Force for the Management of Atrial Fibrillation of the EuropeanSociety of Cardiology (ESC). Eur Heart J. 2010;31:2369-2429.2. Bungard TJ, Ghali WA, Teo KK, et al. Why do patients with atrial fibrillationnot receive warfarin? Arch Intern Med. 2000;160:41-46.3. Mega JL. A new era for anticoagulation in atrial fibrillation. N Engl J Med. 2011;365:1052-1054.4. Miller CS, Grandi SM, Shimony A, et al. Meta-analysis of efficacy and safety ofnew oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus warfarin inpatients with atrial fibrillation. Am J Cardiol. 2012 Apr 24. [Epub ahead of print].5. Mercaldi CJ, Ciarametaro M, Hahn B, et al. Cost efficiency of anticoagulationwith warfarin to prevent stroke in Medicare beneficiaries with nonvalvular atrialfibrillation. Stroke. 2011;42:112-118.6. Wu EQ, Birnbaum HG, Mareva M, et al. Economic burden and comorbiditiesof atrial fibrillation in a privately insured population. Curr Med Res Opin. 2005;21:1693-1699.7. Bajpai A, Savelieva I, Camm AJ. Epidemiology and economic burden of atrialfibrillation. US Cardiovascular Dis. 2007;4:14-17.

STAKEHOLDER PERSPECTIVE (Continued)

In the March/April issue of the journal, the articletitled, “Benefits of novel oral anticoagulant agents forthromboprophylaxis after total hip or knee arthroplasty”(2012;3[4]:115-122) contained 2 errors.

On page 117, the following statement is incorrect:“For example, a patient aged >75 years who weighs >50kg and has compromised renal function is at anincreased risk for a major bleeding event.” The correctsentence should have read: “For example, a patient aged >75

years who weighs <50 kg and has compromised renal func-tion is at increased risk for having a major bleeding event.”

On page 119, the following statement is incorrect:“Dabigatran requires a dose adjustment if creatinineclearance is <50 mL/min.” The correct statement shouldhave read: “Dabigatran requires a dose adjustment if creati-nine clearance is <30 mL/min.”

This article has been corrected online atwww.AHDBonline.com.

Correction

Help manage

MANY THREATS: Rheumatoid Arthritis. Psoriatic Arthritis. Ankylosing Spondylitis.

Please see Brief Summary of full Prescribing Information on last pages of this advertisement.

Indications1

Moderate to severe rheumatoid arthritis: HUMIRA is indicated, alone or in combination with methotrexate or other non-biologic DMARDs, for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active rheumatoid arthritis.

Psoriatic arthritis: HUMIRA is indicated, alone or in combination with non-biologic DMARDs, for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in adult patients with active psoriatic arthritis.

Ankylosing spondylitis: HUMIRA is indicated for reducing signs and symptoms in adult patients with active ankylosing spondylitis.

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40 mg every other week. Some patients with RA not receiving methotrexate may benefit from increasing the frequency to 40 mg every week.

Reference: 1. HUMIRA Injection [package insert]. North Chicago, IL: Abbott Laboratories.

Safety Considerations1

Serious Infections: Patients treated with HUMIRA are at increased risk for developing serious infections that may lead to hospitalization or death. These infections include active tuberculosis (TB), reactivation of latent TB, invasive fungal infections, and bacterial, viral, and other infections due to opportunistic pathogens. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.

Malignancies: Lymphoma, including a rare type of T-cell lymphoma, and other malignancies, some fatal, have been reported in patients treated with TNF blockers, including HUMIRA.

Other Serious Adverse Reactions: Patients treated with HUMIRA also may be at risk for other serious adverse reactions, including anaphylaxis, hepatitis B virus reactivation, demyelinating disease, cytopenias, pancytopenia, heart failure, and a lupus-like syndrome.

Please see Important Safety Information, including BOXED WARNING on Serious Infections and Malignancy, on the following page.

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©2012 Abbott Laboratories Abbott Park, IL 60064 64C-7 58606 201January 2 Printed in U.S.A.

Reference: 1. HUMIRA Injection [package insert]. North Chicago, IL: Abbott Laboratories.

IMPORTANT SAFETY INFORMATION1

SERIOUS INFECTIONSPatients treated with HUMIRA are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. HUMIRA should be discontinued if a patient develops a serious infection or sepsis. Reported infections include:

HYPERSENSITIVITY

Please see Brief Summary of full Prescribing Information on the following pages of this advertisement.

WARNINGS: SER IOUS INFECTIONS AND MALIGNANCY SERIOUS INFECTIONS Patients treated with HUMIRA are at increased risk for developing serious infections that may lead to hospitalization or death [see Warnings and Precautions]. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. HUMIRA should be discontinued if a patient develops a serious infection or sepsis. Reported infections include:• Active tuberculosis (TB), including reactivation of latent TB.

Patients with TB have frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent TB before HUMIRA use and during therapy. Treatment for latent TB should be initiated prior to HUMIRA use.

• Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized, disease. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Empiric anti-fungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness.

• Bacterial, viral and other infections due to opportunistic pathogens, including Legionella and Listeria.

The risks and benefi ts of treatment with HUMIRA should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with HUMIRA, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy. [See Warnings and Precautions and Adverse Reactions] MALIGNANCY Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, of which HUMIRA is a member. [See Warnings and Precautions] Post-marketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers including HUMIRA. These cases have had a very aggressive disease course and have been fatal. The majority of reported TNF blocker cases has occurred in patients with Crohn’s disease or ulcerative colitis and the majority were in adolescent and young adult males. Almost all these patients had received treatment with azathioprine or 6-mercaptopurine concomitantly with a TNF blocker at or prior to diagnosis. It is uncertain whether the occurrence of HSTCL is related to use of a TNF blocker or a TNF blocker in combination with these other immunosuppressants.

I NDICATIONS AND USAGER heumatoid ArthritisHU MIRA is indicated for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active rheumatoid arthritis. HUMIRA can be used alone or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs).Juve nile Idiopathic ArthritisHUMIR A is indicated for reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in pediatric patients 4 years of age and older. HUMIRA can be used alone or in combination with methotrexate.Psori atic ArthritisHUMIR A is indicated for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in adult patients with active psoriatic arthritis. HUMIRA can be used alone or in combination with non-biologic DMARDs.Ankyl osing SpondylitisHUMIR A is indicated for reducing signs and symptoms in adult patients with active ankylosing spondylitis.Crohn ’s DiseaseHUMIR A is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in adult patients with moderately to severely active Crohn’s disease who have had an inadequate response to conventional therapy. HUMIRA is indicated for reducing signs and symptoms and inducing clinical remission in these patients if they have also lost response to or are intolerant to infl iximab.Plaque PsoriasisHUMIRA is indicated for the treatment of adult patients with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy, and when other systemic therapies are medically less appropriate. HUMIRA should only be administered to patients who will be closely monitored and have regular follow-up visits with a physician [see Boxed Warnings and Warnings and Precautions].CONTRAINDICATIONSNone.WAR NINGS AND PRECAUTIONS(see also Boxed WARNINGS)Serious I nfectionsPatients treated with HUMIRA are at increased risk for developing serious infections involving various organ systems and sites that may lead to hospitalization or death. Opportunistic infections due to bacterial, mycobacterial, invasive fungal, viral, parasitic, or other opportunistic pathogens including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, legionellosis, listeriosis, pneumocystosis and tuberculosis have been reported with TNF blockers. Patients have frequently presented with disseminated rather than localized disease.The conco mitant use of a TNF blocker and abatacept or anakinra was associated with a higher risk of serious infections in patients with rheumatoid arthritis (RA); therefore, the concomitant use of HUMIRA and these biologic products is not recommended in the treatment of patients with RA [see Warnings and Precautions and Drug Interactions].Treatment with HUMIRA should not be initiated in patients with an active infection, including localized infections. Patients greater than 65 years of age, patients with co-morbid conditions and/or patients taking concomitant immunosuppressants (such as corticosteroids or methotrexate), may be

at greater risk of infection. The risks and benefi ts of treatment should be considered prior to initiating therapy in patients:• with chronic or recurrent infection;• who have been exposed to tuberculosis;• with a history of an opportunistic infection;• who have resided or traveled in areas of endemic tuberculosis or endemic

mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis; or• with underlying conditions that may predispose them to infection.Tuberculo sisCases of reactivation of tuberculosis or new tuberculosis infections have been observed in patients receiving HUMIRA, including patients who have previously received treatment for latent or active tuberculosis. Patients should be evaluated for tuberculosis risk factors and tested for latent infection prior to initiating HUMIRA and periodically during therapy.Treatment of latent tuberculosis infection prior to therapy with TNF blocking agents has been shown to reduce the risk of tuberculosis reactivation during therapy.Anti-tuberculosis therapy should also be considered prior to initiation of HUMIRA in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confi rmed, and for patients with a negative test for latent tuberculosis but having risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision whether initiating anti-tuberculosis therapy is appropriate for an individual patient.Tuberculosis should be strongly considered in patients who develop a new infection during HUMIRA treatment, especially in patients who have previously or recently traveled to countries with a high prevalence of tuberculosis, or who have had close contact with a person with active tuberculosis.Monitorin gPatients should be closely monitored for the development of signs and symptoms of infection during and after treatment with HUMIRA, including the development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy. Tests for latent tuberculosis infection may also be falsely negative while on therapy with HUMIRA.HUMIRA should be discontinued if a patient develops a serious infection or sepsis. A patient who develops a new infection during treatment with HUMIRA should be closely monitored, undergo a prompt and complete diagnostic workup appropriate for an immunocompromised patient, and appropriate antimicrobial therapy should be initiated.Invasive Fungal InfectionsFor patients who reside or travel in regions where mycoses are endemic, invasive fungal infection should be suspected if they develop a serious systemic illness. Appropriate empiric antifungal therapy should be considered while a diagnostic workup is being performed. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. When feasible, the decision to administer empiric antifungal therapy in these patients should be made in consultation with a physician with expertise in the diagnosis and treatment of invasive fungal infections and should take into account both the risk for severe fungal infection and the risks of antifungal therapy.Malignanc iesThe risks and benefi ts of TNF-blocker treatment including HUMIRA should be considered prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing a TNF blocker in patients who develop a malignancy.Malignancies in AdultsIn the controlled portions of clinical trials of some TNF-blockers, including HUMIRA, more cases of malignancies have been observed among TNF-blocker-treated adult patients compared to control-treated adult patients. During the controlled portions of 32 global HUMIRA clinical trials in adult patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), Crohn’s disease (CD), and plaque psoriasis (Ps), malignancies, other than non-melanoma (basal cell and squamous cell) skin cancer, were observed at a rate (95% confi dence interval) of 0.6 (0.38, 0.93) per 100 patient-years among 6694 HUMIRA-treated patients versus a rate of 0.5 (0.28, 1.05) per 100 patient-years among 3749 control-treated patients (median duration of treatment of 4 months for HUMIRA-treated patients and 4 months for control-treated patients). In 45 global controlled and uncontrolled clinical trials of HUMIRA in adult patients with RA, PsA, AS, CD and Ps, the most frequently observed malignancies, other than lymphoma and NMSC, were breast, colon, prostate, lung, and melanoma. The malignancies in HUMIRA-treated patients in the controlled and uncontrolled portions of the studies were similar in type and number to what would be expected in the general U.S. population according to the SEER database (adjusted for age, gender, and race).In controlled trials of other TNF blockers in adult patients at higher risk for malignancies (i.e., patients with COPD with a signifi cant smoking history and cyclophosphamide-treated patients with Wegener’s granulomatosis), a greater portion of malignancies occurred in the TNF blocker group compared to the control group.Non-Melanoma Skin CancerDuring the controlled portions of 32 global HUMIRA clinical trials in adult patients with RA, PsA, AS, CD, and Ps, the rate (95% confi dence interval) of NMSC was 0.7 (0.50, 1.11) per 100 patient-years among HUMIRA-treated patients and 0.2 (0.06, 0.56) per 100 patient-years among control-treated patients. All patients, and in particular patients with a medical history of prior prolonged immunosuppressant therapy or psoriasis patients with a history of PUVA treatment should be examined for the presence of NMSC prior to and during treatment with HUMIRA.Lymphoma and LeukemiaIn the controlled portions of clinical trials of all the TNF-blockers in adults, more cases of lymphoma have been observed among TNF blocker-treated patients compared to control-treated patients. In the controlled portions of 32 global HUMIRA clinical trials in adult patients with RA, PsA, AS, CD, and Ps, 3 lymphomas occurred among 6694 HUMIRA-treated patients versus 1 among 3749 control-treated patients. In 45 global controlled and uncontrolled clinical trials of HUMIRA in adult patients with RA, PsA, AS, CD and Ps with a median duration of approximately 0.6 years, including 22,026 patients and over 32,000 patient-years of HUMIRA, the observed rate of lymphomas was approximately 0.11 per 100 patient-years. This is approximately 3-fold higher than expected in the general U.S. population according to the SEER database (adjusted for age, gender, and race). Rates of lymphoma in clinical trials of HUMIRA cannot be compared to rates of lymphoma in clinical trials of other TNF blockers and may not predict the rates observed in a broader patient population. Patients with RA and other chronic infl ammatory diseases, particularly those with highly active disease and/or chronic exposure to immunosuppressant therapies, may be at a higher risk (up to several fold) than the general population for the development

of lymphoma, even in the absence of TNF blockers. Post-marketing cases of acute and chronic leukemia have been reported in association with TNF-blocker use in RA and other indications. Even in the absence of TNF-blocker therapy, patients with RA may be at a higher risk (approximately 2-fold) than the general population for the development of leukemia.Malignanc ies in Pediatric Patients and Young AdultsMalignanc ies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNF-blockers (initiation of therapy 18 years of age), of which HUMIRA is a member. Approximately half the cases were lymphomas, including Hodgkin’s and non-Hodgkin’s lymphoma. The other cases represented a variety of different malignancies and included rare malignancies usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months of therapy (range 1 to 84 months). Most of the patients were receiving concomitant immunosuppressants. These cases were reported post-marketing and are derived from a variety of sources including registries and spontaneous postmarketing reports.Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers including HUMIRA. These cases have had a very aggressive disease course and have been fatal. The majority of reported TNF blocker cases has occurred in patients with Crohn’s disease or ulcerative colitis and the majority were in adolescent and young adult males. Almost all of these patients had received treatment with the immunosuppressants azathioprine or 6-mercaptopurine concomitantly with a TNF blocker at or prior to diagnosis. It is uncertain whether the occurrence of HSTCL is related to use of a TNF blocker or a TNF blocker in combination with these other immunosuppressants.Hypersensit ivity ReactionsIn postmark eting experience, anaphylaxis and angioneurotic edema have been reported rarely following HUMIRA administration. If an anaphylactic or other serious allergic reaction occurs, administration of HUMIRA should be discontinued immediately and appropriate therapy instituted. In clinical trials of HUMIRA in adults, allergic reactions overall (e.g., allergic rash, anaphylactoid reaction, fi xed drug reaction, non-specifi ed drug reaction, urticaria) have been observed in approximately 1% of patients.Hepatitis B Virus ReactivationUse of TNF blockers, including HUMIRA, may increase the risk of reactivation of hepatitis B virus (HBV) in patients who are chronic carriers of this virus. In some instances, HBV reactivation occurring in conjunction with TNF blocker therapy has been fatal. The majority of these reports have occurred in patients concomitantly receiving other medications that suppress the immune system, which may also contribute to HBV reactivation. Patients at risk for HBV infection should be evaluated for prior evidence of HBV infection before initiating TNF blocker therapy. Prescribers should exercise caution in prescribing TNF blockers for patients identifi ed as carriers of HBV. Adequate data are not available on the safety or effi cacy of treating patients who are carriers of HBV with anti-viral therapy in conjunction with TNF blocker therapy to prevent HBV reactivation. In patients who develop HBV reactivation, HUMIRA should be stopped and effective anti-viral therapy with appropriate supportive treatment should be initiated. The safety of resuming TNF blocker therapy after HBV reactivation is controlled is not known.Neurologic ReactionsUse of TNF blocking agents, including HUMIRA, has been associated with rare cases of new onset or exacerbation of clinical symptoms and/or radiographic evidence of central nervous system demyelinating disease, including multiple sclerosis (MS) and optic neuritis, and peripheral demyelinating disease, including Guillain-Barré syndrome. Prescribers should exercise caution in considering the use of HUMIRA in patients with preexisting or recent-onset central or peripheral nervous system demyelinating disorders.Hematological ReactionsRare reports of pancytopenia including aplastic anemia have been reported with TNF blocking agents. Adverse reactions of the hematologic system, including medically signifi cant cytopenia (e.g., thrombocytopenia, leukopenia) have been infrequently reported with HUMIRA. The causal relationship of these reports to HUMIRA remains unclear. All patients should be advised to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection (e.g., persistent fever, bruising, bleeding, pallor) while on HUMIRA. Discontinuation of HUMIRA therapy should be considered in patients with confi rmed signifi cant hematologic abnormalities.Use with Anak inraConcurrent use of anakinra (an interleukin-1 antagonist) and another TNF-blocker, was associated with a greater proportion of serious infections and neutropenia and no added benefi t compared with the TNF-blocker alone in patients with RA. Therefore, the combination of HUMIRA and anakinra is not recommended [see Drug Interactions].Heart Failure Cases of wors ening congestive heart failure (CHF) and new onset CHF have been reported with TNF blockers. Cases of worsening CHF have also been observed with HUMIRA. Physicians should exercise caution when using HUMIRA in patients who have heart failure and monitor them carefully. AutoimmunityTreatment wit h HUMIRA may result in the formation of autoantibodies and, rarely, in the development of a lupus-like syndrome. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with HUMIRA, treatment should be discontinued [see Adverse Reactions].Immunizations In a placebo- controlled clinical trial of patients with rheumatoid arthritis, no difference was detected in anti-pneumococcal antibody response between HUMIRA and placebo treatment groups when the pneumococcal polysaccharide vaccine and infl uenza vaccine were administered concurrently with HUMIRA. Patients on HUMIRA may receive concurrent vaccinations, except for live vaccines. No data are available on the secondary transmission of infection by live vaccines in patients receiving HUMIRA.It is recomme nded that juvenile idiopathic arthritis patients, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating HUMIRA therapy. Patients on HUMIRA may receive concurrent vaccinations, except for live vaccines. Use with Abat aceptIn controlled trials, the concurrent administration of TNF-blockers and abatacept was associated with a greater proportion of serious infections than the use of a TNF-blocker alone; the combination therapy, compared to the use of a TNF-blocker alone, has not demonstrated improved clinical benefi t in the treatment of RA. Therefore, the combination of abatacept with TNF-blockers including HUMIRA is not recommended [see Drug Interactions].

HUMIRA® (adalimumab) PROFESSIONAL BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

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ADVERSE REACT IONSClinical Stud ies ExperienceThe most seri ous adverse reactions were:• Serious Infec tions [see Warnings and Precautions]• Malignancies [see Warnings and Precautions]The most comm on adverse reaction with HUMIRA was injection site reactions. In placebo-controlled trials, 20% of patients treated with HUMIRA developed injection site reactions (erythema and/or itching, hemorrhage, pain or swelling), compared to 14% of patients receiving placebo. Most injection site reactions were described as mild and generally did not necessitate drug discontinuation.The proportio n of patients who discontinued treatment due to adverse reactions during the double-blind, placebo-controlled portion of Studies RA-I, RA-II, RA-III and RA-IV was 7% for patients taking HUMIRA and 4% for placebo-treated patients. The most common adverse reactions leading to discontinuation of HUMIRA were clinical fl are reaction (0.7%), rash (0.3%) and pneumonia (0.3%).InfectionsIn the contro lled portions of the 32 global HUMIRA clinical trials in adult patients with RA, PsA, AS, CD and Ps, the rate of serious infections was 4.7 per 100 patient-years in 6694 HUMIRA-treated patients versus a rate of 2.7 per 100 patient-years in 3749 control-treated patients. Serious infections observed included pneumonia, septic arthritis, prosthetic and post-surgical infections, erysipelas, cellulitis, diverticulitis, and pyelonephritis [see Warnings and Precautions].Tuberculosis and Opportunistic InfectionsIn 45 global controlled and uncontrolled clinical trials in RA, PsA, AS, CD and Ps that included 22,026 HUMIRA-treated patients, the rate of reported active tuberculosis was 0.22 per 100 patient-years and the rate of positive PPD conversion was 0.07 per 100 patient-years. In a subgroup of 8940 U.S. and Canadian HUMIRA-treated patients, the rate of reported active TB was 0.07 per 100 patient-years and the rate of positive PPD conversion was 0.06 per 100 patient-years. These trials included reports of miliary, lymphatic, peritoneal, and pulmonary TB. Most of the TB cases occurred within the fi rst eight months after initiation of therapy and may refl ect recrudescence of latent disease. In these global clinical trials, cases of serious opportunistic infections have been reported at an overall rate of 0.07 per 100 patient-years. Some cases of serious opportunistic infections and TB have been fatal [see Warnings and Precaut ions].Autoantibodie sIn the rheumatoid arthritis controlled trials, 12% of patients treated with HUMIRA and 7 % of placebo-treated patients that had negative baseline ANA titers developed positive titers at week 24. Two patients out of 3046 treated with HUMIRA developed clinical signs suggestive of new-onset lupus-like syndrome. The patients improved following discontinuation of therapy. No patients developed lupus nephritis or central nervous system symptoms. The impact of long-term treatment with HUMIRA on the development of autoimmune diseases is unknown.Liver Enzyme ElevationsThere have been reports of severe hepatic reactions including a cute liver failure in pat ients receiving TNF-blockers. In controlled Phase 3 trials of HUMIRA (40 mg SC every other week) in patients with RA, PsA, and AS with control period duration ranging from 4 to 104 weeks, ALT elevations 3 x ULN occurred in 3.5% of HUMIRA-treated patients and 1.5% of control-treated patients. Since many of these patients in these trials were also taking medications that cause liver enzyme elevations (e.g., NSAIDS, MTX), the relationship between HUMIRA and the liver enzyme elevations is not clear. In controlled Phase 3 trials of HUMIRA (initial doses of 160 mg and 80 mg, or 80 mg and 40 mg on Days 1 and 15, respectively, followed by 40 mg every other week) in patients with Crohn’s disease with control period duration ranging from 4 to 52 weeks, ALT elevations

3 x ULN occurred in 0.9% of HUMIRA-treated patients and 0.9% of control-treated patients. In controlled Phase 3 trials of HUMIRA (initial dose of 80 mg then 40 mg every other week) in patients with plaque psoriasis with control period duration ranging from 12 to 24 weeks, ALT elevations 3 x ULN occurred in 1.8% of HUMIRA-treated patients and 1.8% of control-treated patients.ImmunogenicityPatients in Studies RA-I, RA-II, and RA-III were tested at multiple time points for antibodies to adalimumab during the 6- to 12-month period. Approximately 5% (58 of 1062) of adult rheumatoid arthritis patients receiving HUMIRA developed low-titer antibodies to adalimumab at least once during treatment, which were neutralizing in vitro. Patients treated with concomitant methotrexate had a lower rate of antibody development than patients on HUMIRA monotherapy (1% versus 12%). No apparent correlation of antibody development to adverse reactions was observed. With monotherapy, patients receiving every other week dosing may develop antibodies more frequently than those receiving weekly dosing. In patients receiving the recommended dosage of 40 mg every other week as monotherapy, the ACR 20 response was lower among antibody-positive patients than among antibody-negative patients. The long-term immunogenicity of HUMIRA is unknown. In patients with juvenile idiopathic arthritis, adalimumab antibodies were identifi ed in 16% of HUMIRA-treated patients. In patients receiving concomitant methotrexate, the incidence was 6% compared to 26% with HUMIRA monotherapy.In patients with ankylosing spondylitis, the rate of development of antibodies to adalimumab in HUMIRA-treated patients was comparable to patients with rheumatoid arthritis. In patients with psoriatic arthritis, the rate of antibody development in patients receiving HUMIRA monotherapy was comparable to patients with rheumatoid arthritis; however, in patients receiving concomitant methotrexate the rate was 7% compared to 1% in rheumatoid arthritis. In patients with Crohn’s disease, the rate of antibody development was 3%. In patients with plaque psoriasis, the rate of antibody development with HUMIRA monotherapy was 8%. However, due to the limitation of the assay conditions, antibodies to adalimumab could be detected only when serum adalimumab levels were < 2 ug/ml. Among the patients whose serum adalimumab levels were < 2 ug/ml (approximately 40% of total patients studied), the immunogenicity rate was 20.7%. In plaque psoriasis patients who were on HUMIRA monotherapy and subsequently withdrawn from the treatment, the rate of antibodies to adalimumab after retreatment was similar to the rate observed prior to withdrawal.Other Adverse ReactionsThe data described below refl ect exposure to HUMIRA in 2468 patients, i ncluding 2073 exposed fo r 6 months, 1497 exposed for greater than one year and 1380 in adequate and well-controlled studies (Studies RA-I, RA-II, RA-III, and RA-IV). HUMIRA was studied primarily in placebo-controlled trials and in long-term follow up studies for up to 36 months duration. The population had a mean age of 54 years, 77% were female, 91% were Caucasian and had moderately to severely active rheumatoid arthritis. Most patients received 40 mg HUMIRA every other week. Table 1 summarizes reactions reported at a rate of at least 5% in patients treated with HUMIRA 40 mg every other week compared to placebo and with an incidence higher than placebo. In Study RA-III, the types and frequencies of adverse reactions in the second year open-label extension were similar to those observed in the one-year double-blind portion.

Table 1. Adverse Reactions Reported by 5% of Patients Treated with HUMIRA During Placebo-Controlled Period of

Rheumatoid Arthritis StudiesHUMIRA

40 mg subcutaneousEvery Other Week

Placebo

(N=705) (N=690)Adverse Reaction (Preferred Term)Respiratory Upper respiratory infection 17% 13% Sinusitis 11% 9% Flu syndrome 7% 6%Gastrointestinal Nausea 9% 8% Abdominal pain 7% 4%Laboratory Tests* Laboratory test abnormal 8% 7% Hypercholesterolemia 6% 4% Hyperlipidemia 7% 5% Hematuria 5% 4% Alkaline phosphatase increased 5% 3%Other Headache 12% 8% Rash 12% 6% Accidental injury 10% 8% Injection site reaction ** 8% 1% Back pain 6% 4% Urinary tract infection 8% 5% Hypertension 5% 3%* Laboratory test abnormalities were reported as adverse reactions in European trials** Does not include injection site erythema, itching, hemorrhage, pain or swelling

Juvenile Idiopathic Arthritis Clinical StudiesIn general, the adverse reactions in the HUMIRA-treated pediatric patients in the juvenile idiopathi c arthritis (JIA) trial were similar in frequency and type to those seen in adult patients [see Warnings and Precautions, Adverse Reactions]. Important fi ndings and differences from adults are discussed in the following paragraphs.HUMIRA was studied in 171 pediatric patients, 4 to 17 years of age, with polyarticular JIA. Severe a dverse reactions reported in the study included neutropenia, streptococcal pharyngitis, increased aminotransferases, herpes zoster, myositis, metrorrhagia, appendicitis. Serious infections were observed in 4% of patients within approximately 2 years of initiation of treatment with HUMIRA and included cases of herpes simplex, pneumonia, urinary tract infection, pharyngitis, and herpes zoster.A total of 45% of children experienced an infection while receiving HUMIRA with or without concomita nt MTX in the fi rst 16 weeks of treatment. The types of infections reported in HUMIRA-treated patients were generally similar to those commonly seen in JIA patients who are not treated with TNF blockers. Upon initiation of treatment, the most common adverse reactions occurring in the pediatric population treated with HUMIRA were injection site pain and injection site reaction (19% and 16%, respectively). A less commonly reported adverse event in children receiving HUMIRA was granuloma annulare which did not lead to discontinuation of HUMIRA treatment.In the fi rst 48 weeks of treatment, non-serious hypersensitivity reactions were seen in approximatel y 6% of children and included primarily localized allergic hypersensitivity reactions and allergic rash.Isolated mild to moderate elevations of liver aminotransferases (ALT more common than AST) were obse rved in children with JIA exposed to HUMIRA alone; liver enzyme test elevations were more frequent among those treated with the combination of HUMIRA and MTX than those treated with HUMIRA alone. In general, these elevations did not lead to discontinuation of HUMIRA treatment.In the JIA trial, 10% of patients treated with HUMIRA who had negative baseline anti-dsDNA antibodie s developed positive titers after 48 weeks of treatment. No patient developed clinical signs of autoimmunity during the clinical trial.Approximately 15% of children treated with HUMIRA developed mild-to-moderate elevations of creatine phosphokinase (CPK). Elevations exceeding 5 times the upper limit of normal were observed in several patients. CPK levels decreased or returned to normal in all patients. Most patients were able to continue HUMIRA without interruption.Psoriatic Arthritis and Ankylosing Spondylitis Clinical StudiesHUMIRA has been studied in 395 patie nts with psoriatic arthritis (PsA) in two placebo-controlled tri als and in an open label study and in 393 patients with ankylosing spondylitis (AS) in two placebo-controlled studies. The safety profi le for patients with PsA and AS treated with HUMIRA 40 mg every other week was similar to the safety profi le seen in patients with RA, HUMIRA Studies RA-I through IV.Crohn’s Disease Clinical StudiesHUMIRA has been studied in 1478 patients with Crohn’s disease in fo ur placebo-controlled and two ope n-label extension studies. The safety profi le for patients with Crohn’s disease treated with HUMIRA was similar to the safety profi le seen in patients with RA.Plaque Psoriasis Clinical StudiesHUMIRA has been studied in 1696 patients with plaque psoriasis in placebo-controlled and open-label extension studies. The safety profi le for patients with plaque psoriasis treated with HUMIRA was similar to the safety profi le seen in patients with RA with the following exceptions. In the placebo-controlled portions of the clinical trials in plaque psoriasis patients, HUMIRA-treated patients had a higher incidence of arthralgia when compared to controls (3% vs. 1%).Postmarketing ExperienceAdverse reactions have been reported during post-approval use of HUMIRA. B ecause these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to HUMIRA exposure.Gastrointestinal disorders: Diverticulitis, large bowel perforations including perforations associat ed with diverticulitis and appendiceal perforations associated with appendicitis, pancreatitisRespiratory disorders: Interstitial lung disease, including pulmonary fi brosisSkin reactions: Stev ens Johnson Syndrome, cutaneous vasculitis, erythema multiforme, new or worsenin g psoriasis (all sub-types including pustular and palmoplantar)Vascular disorders: Systemic vasculitis

DRUG INTERACTIONSMethotrexateAlthough methotrexate (MTX) reduces the apparent adalimumab clearan ce, the data do not suggest the n eed for dose adjustment of either HUMIRA or MTX. Biologic ProductsIn clinical studies in patients with RA, an increased risk of serious infections has been seen with the combination of TNF blockers with anakinra or abatacept, with no added benefi t; therefore, use of HUMIRA with abatacept or anakinra is not recommended in patients with RA [see Warnings and Precautions]. A higher rate of serious infections has also been observed in patients with RA treated with rituximab who received subsequent treatment with a TNF blocker. There is insuffi cient information to provide recommendations regarding the concomitant use of HUMIRA and other biologic products for the treatment of RA, PsA, AS, Crohn’s Disease, and plaque psoriasis.Live VaccinesLive vaccines should not be given concurrently with HUMIRA [see Warnings and Precauti ons].USE IN SP ECIFIC POPULATIONSPregnancyPregnancy Category B - There are no adequate and well-contro lled studies in pregnant wome n. Because animal reproduction and developmental studies are not always predictive of human response, HUMIRA should be used during pregnancy only if clearly needed.Pregnancy Registry: To monitor outcomes of pregnant women exposed to HUMIRA, a pregnancy registry ha s been established. Physicians are encouraged to register patients by calling 1-877-311-8972.Nursing MothersIt is not known whether adalimumab is excreted in human milk or absorbed systemical ly after ingestio n. Because many drugs and immunoglobulins are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from HUMIRA, 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.Pediatric UseSafety and effi cacy of HUMIRA in pediatric patients for uses other than juvenile idio pathic arthriti s (JIA) have not been established.Juvenile Idiopathic Arthritis In the JIA trial, HUMIRA was shown to reduce signs and symptoms of act ive polyarticular JIA in patie nts 4 to 17 years of age. HUMIRA has not been studied in children less than 4 years of age, and there are limited data on HUMIRA treatment in children with weight <15 kg.The safety of HUMIRA in pediatric patients in the JIA trial was generally similar to that observed i n adults with certain exceptions [see Adverse Reactions].Post-marketing cases of malignancies, some fatal, have been reported among children, adolescents, an d young adults who received treatment with TNF-blockers including HUMIRA [see Warnings and Precautions].Geriatric UseA total of 519 rheumatoid arthritis patients 65 years of age and older, including 107 patients 75 ye ars of age and older, received HUMIRA in clinical studies RA-I through IV. No overall difference in effectiveness was observed between these subjects and younger subjects. The frequency of serious infection and malignancy among HUMIRA treated subjects over 65 years of age was higher than for those under 65 years of age. Because there is a higher incidence of infections and malignancies in the elderly population in general, caution should be used when treating the elderly.OVERDOSAGEDoses up to 10 mg/kg have been administered to patients in clinical trials without evide nce of dose- limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately.NONCLINICAL TOXICOLOGYCarcinogenesis, Mutagenesis, Impairment of FertilityLong-term animal studies of HUMIRA have not be en conducted to evaluate the carcinogenic potential or its effect on fertility. No clastogenic or mutagenic effects of HUMIRA were observed in the in vivo mouse micronucleus test or the Salmonella-Escherichia coli (Ames) assay, respectively.PATIENT COUNSELING INFORMATIONPatients or their caregivers should be provided the HUMIRA “Medication Guide” and provided an opport unity to read it and ask questions prior to initiation of therapy. The healthcare provider should ask the patient questions to determine any risk factors for treatment. Patients developing signs and symptoms of infection should seek medical evaluation immediately.Patient CounselingPatients should be advised of the potential benefi ts and risks of HUMIRA. Physic ians should instruct their patients to read the Medication Guide before starting HUMIRA therapy and to reread each time the prescription is renewed.• Infections Inform patients that HUMIRA may lower the ability of their immune system to

fi ght infecti ons. Instruct patients of the importance of contacting their doctor if they develop any symptoms of infection, including tuberculosis, invasive fungal infections, and reactivation of hepatitis B virus infections.

• Malignancies Patients should be counseled about the risk of malignancies while receiving

HUMIRA.• Allergic Reactions Patients should be advised to seek immediate medical attention if they

experience any symptoms of severe allergic reactions. Advise latex-sensitive patients that the needle cap of the prefi lled syringe contains latex.

• Other Medical Conditions Advise patients to report any signs of new or worsening medical conditions

such as congestive heart failure, neurological disease, autoimmune disorders, or cytopenias. Advise patients to report any symptoms suggestive of a cytopenia such as bruising, bleeding, or persistent fever.

Revised: December, 2011Ref: 03-A569-R27Abbott LaboratoriesNorth Chicago, IL 60064, U.S.A.

Master # 64C-75820264C-758606

1:38 PM

AMCP HIGHLIGHTS


Electronic Service Alerts Providers of Low-Cost Drugs, Shows SignificantCost-SavingsIdentifying low-cost medication alternatives can be

time-consuming and is often therefore not followed byclinicians. A group of pharmacists led by Nicole Allie,PharmD, CGP, at Atrius Health, Watertown, MA, insti-tuted the Chart Flag Service, a program designed to alertprescribing providers, in real time, on appropriate, low-cost medication alternatives.This service involves a monthly list of patients with

upcoming appointments who are prescribed nonpreferredmedications. If the pharmacist determines an alternatepreferred medication is appropriate for the patient, the cli-nician is notified by e-mail the day before an appointmentand via notations in the clinician’s electronic schedule.To evaluate the effectiveness of the Chart Flag

Service at Atrius Health—an alliance of 5 multispecialtygroups serving approximately 700,000 patients at 24eastern Massachusetts sites—a survey was sent to 178 cli-nicians and 12 clinical pharmacists.

Overall, a 2-week analysis showed significant cost-sav-ings, with an average cost-saving of $78.33 per lower-costmedication recommendation. The total annual savings forthe group of patients included in this analysis was estimat-ed at $51,014. A conservative estimate of the total sav-ings for the program for 1 year is approximately $850,000.Of the 25% of clinicians who responded to the survey,

80% found that a recommended medication switchcould be completed in ≤5 minutes. Clinicians followed31.1% of the medication-switching recommendations,and the program was considered useful by 84% of theresponding clinicians.Alternate medications were considered appropriate for

30.6% of the 849 patient appointments. The service wasconsidered useful or very useful by 83% of clinical phar-macist respondents. [Allie N, Lubelczyk E, Robin S. Successwith electronic chart flags to alert clinicians about medicationcost-savings opportunities at the time of patient visits.] ■

Consumer-Directed Health Plans’ Impact on Medication Adherence inChronic ConditionsEnrollment in consumer-directed health plans

(CDHPs) has evolved as a strategy to control healthcarecosts and improve member satisfaction. According to theMercer National Survey of Employer-Sponsored HealthPlans, in 2010, 10% of employers offered their employeesCDHPs; in 2011, that grew to 13%; and by June 8, 2012,10% of employers offered CDHPs to their employees.Including a preventive therapy option—which

excludes drugs for chronic conditions from the member’sdeductible and typically offers a lower cost-sharing tomembers—may contribute to better value by increasingmember access to medications for chronic diseases,according to Shalini Thuppal Prakash, BPharm, MS, ofCVS Caremark, Northbrook, IL. Mr Prakash comparedadherence outcomes among CDHPs that offered a pre-ventive therapy option, those that did not, and tradition-al health plans. Previous studies have shown that med-ication adherence can result in cost-savings to members,in addition to improving outcomes.Using an integrated database of administrative pharma-

cy claims, Mr Prakash analyzed quarterly data (spanningthe year 2010) from 47 clients with more than 1.2 millionmembers in voluntary CDHPs and 1.8 million members in

traditional health plans. Approximately 305,000 CDHPmembers had a preventive therapy option.Adherence to medications for chronic diseases was

significantly greater in CDHPs that offered a preventivetherapy option than CDHPs without such an option—65% versus 60%, respectively, for antidiabetes drugs;69% versus 63%, respectively, for antihypertensive med-ications; and 67% versus 61%, respectively, for choles-terol-lowering drugs. However, the differences were notsignificant compared with traditional plans.In addition, fewer members stopped taking their anti-

hypertensive agents in CDHPs with a preventive therapyoption compared with plans with no preventive therapyoption (26% vs 30%, respectively) or cholesterol-loweringdrugs (26% vs 29%, respectively); the one exception wasfor antidiabetes medications (33% vs 24%, respectively).Finally, cost-sharing for prescription drugs was signifi-

cantly greater in CDHPs than in the traditional plans—34% versus 19%, respectively, for CDHP with a preven-tive therapy option (and 39% for CDHPs with nopreventive therapy option). [Prakash TS. Consumerdirected health plans (CDH plans): impact on member adher-ence to chronic condition medications.] ■

Continued

The following summaries of posters presented at the 2012 Annual Meeting of the Academy ofManaged Care Pharmacy (AMCP), April 18-20, 2012, in San Francisco, represent areas of

direct relevance to payers, employers, providers, and other healthcare stakeholders.

AMCP HIGHLIGHTS


High-Deductible Health Plans: Mixed Results in Clinical Outcomes,Associated CostsThe use of high-deductible health plans (HDHPs) is a

growing strategy by employers to control costs, whoclaim that they encourage member responsibility andreduce unnecessary care utilization. Opponents ofHDHPs suggest that this may result in some membersgoing without necessary care. Katrina Moore, PharmD,and colleagues at SelectHealth, Murray, UT, conducteda retrospective database analysis to compare medical andpharmacy costs, as well as clinical outcomes, betweenmembers in traditional health plans (N = 21,480) or inan HDHP (N = 971). They also compared outcomes forthose choosing an HDHP compared with membersoffered only an HDHP option by their employer.There were no significant differences in median

changes in glycated hemoglobin values or in low-densitylipoprotein levels among the different plan options.However, there was a small, but significant, difference in

the median number of asthma exacerbations amongmembers enrolled in an HDHP compared with those ina traditional plan, with fewer exacerbations seen in thelatter (P = .011). These results were not affected bywhether a member had the ability to choose an HDHP,although more data are needed. In addition, members switching to an HDHP had

higher out-of-pocket pharmacy costs, but lower medicalcosts, in the year after switching from a traditional plan.Furthermore, the health plan had significantly lowermedical and pharmacy costs associated with membersswitching to an HDHP during that year. The investigators noted that these results suggest

that more studies are needed to evaluate the trueimpact of HDHP on healthcare costs and utilizations.[Moore K, Dunn J, Mitchell M, et al. Clinical outcomes inhigh-deductible health plans.] ■

Pharmacists’ Knowledge Gap about Oncology Genetic Testing, Benefit DesignKnowledge of pharmacogenomics—a collection of

genomic factors contributing to individual variability inresponse to drug therapy—enhances the ability to diag-nose, prevent, and treat disease. Although understand-ing the correct application of pharmacogenomics maybe essential to providing cost-effective care, barriersinclude the absence of provider knowledge and inappro-priate reimbursement strategies. Angela Luong, PharmD,and colleagues at OPTUMInsight conducted a survey ofpharmacists regarding their knowledge of genetic testingand utilization strategies.A total of 19 pharmacists at 4 different managed care

organizations responded to the survey, revealing a basiclack of knowledge of pharmacogenomics (or personalizedmedicine). The majority of respondents (84%) agreed orstrongly agreed that pharmacogenomics will have animpact on healthcare expenditures and that pharmacistsshould have a good knowledge base of pharmacogenomics-related drug therapies and tests; however, the majority(84%) did not routinely have much education in this area.Overall, 95% of participants scored <60% on a pharma-cogenomics knowledge test.In addition, knowledge of pharmacogenomics does

not necessarily have a direct impact on patient care or

benefit design. Only 47% (n = 9) of respondents saidtheir plan requires prior authorization (PA) for the use ofthe US Food and Drug Administration–approved com-panion diagnostic test for vemurafenib compared with58% (n = 11) of respondents whose plans require a PAfor the companion test for crizotinib. By contrast, only16% (n = 3) of respondents said their plans require test-ing for HER2 mutation before prescribing trastuzumabcompared with 58% (n = 11) of respondents whose plansdo not require testing and 26% (n = 5) who did notknow whether their plans require such testing.Furthermore, the majority of respondents did not

know whether their plans had reimbursement policiesrelated to pharmacogenomics. Overall, this surveyreveals gaps in pharmacists’ knowledge of pharmacoge-nomics utility and its related benefit design strategies. Asa result of the growing impact of personalized medicineand tests for pharmacogenomics, understanding anddesigning appropriate benefit policies are essential; thegroup at OPTUMInsight plans on continuing thisresearch with a larger pharmacist population. [Luong A,Lal L, King K, et al. Assessment for clinical utility of current-ly available oncology genetic tests and assessment of pharma-cogenomics knowledge of pharmacists.] ■

Online First: Comparing Cost-Effectiveness of First-Line Therapies for AdvancedNSCLC (www.AHDBonline.com)

Karen’s doctor said taking Levemir ® (insulin detemir [rDNA origin] injection)

once-daily may get her the control she needs & more

Low rates of hypoglycemia

In 1 study, approximately 45% of patients in each treatmentarm achieved A1C <7% with no hypoglycemic events

within the last 4 weeks of observation.1

A single major hypoglycemic event was reported in the 70-90 mg/dL group; no major hypoglycemic events in the 80-110 mg/dL group

Minor hypoglycemia rates were 5.09 (70-90 mg/dL) and 3.16 (80-110 mg/dL) per patient-year*

From a 20-week, randomized, controlled, multicenter, open-label, parallel-group, treat-to-target trial using a self-titration algorithm in insulin-naïve patients with type 2 diabetes, A1C ≥7% and ≤9% on OAD therapy randomized to Levemir® and OAD (1:1) to 2 different fasting plasma glucose (FPG) titration targets (70-90 mg/dL [n=121] or 80-110 mg/dL [n=122]). At study end, in the 80-110 mg/dL group, 55% of patients achieved goal (A1C <7%) with A1C decrease of 0.9%. The mean A1C was 7%.1

24/7 GLUCOSE CONTROL

For your patients with type 2 diabetes who need more than A1C control, choose Levemir ® (insulin detemir [rDNA origin] injection)

Covered on more than 90% of managed care plans2 †

hypoglycemia usually reflects the time action profile of the administered insulin formulations. Glucose monitoring is essential for all patients receiving insulin therapy. Any changes to an insulin regimen should be made cautiously and only under medical supervision.Needles and Levemir® FlexPen® must not be shared.Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including Levemir®. Adverse reactions associated with Levemir® include hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, rash and pruritus. Careful glucose monitoring and dose adjustments of insulin, including Levemir®, may be necessary in patients with renal or hepatic impairment.Levemir® has not been studied in children with type 2 diabetes, and in children with type 1 diabetes under the age of six.

Please see brief summary of Prescribing Information on adjacent page.Needles are sold separately and may require a prescription in some states.

Indications and UsageLevemir® (insulin detemir [rDNA origin] injection) is indicated to improve glycemic control in adults and children with diabetes mellitus.

Important Limitations of Use: Levemir® is not recommended for the treatment of diabetic ketoacidosis. Intravenous rapid-acting orshort-acting insulin is the preferred treatment forthis condition.

Important Safety InformationLevemir® is contraindicated in patients hypersensitive to insulin detemir or one of its excipients. Do not dilute or mix Levemir® with any other insulin solution, or use in insulin infusion pumps. Do not administer Levemir® intravenously or intramuscularly because severe hypoglycemia can occur.Hypoglycemia is the most common adverse reaction of insulin therapy, including Levemir®. The timing of

On your iPhone®

Scan the QR code to download the NovoDose™ app to knowhow to optimally dose Levemir®

* Minor=SMPG <56 mg/dL and not requiring third-party assistance.† Intended as a guide. Lower acquisition costs alone do not necessarily refl ect a

cost advantage in the outcome of the condition treated because othervariables affect relative costs. Formulary status issubject to change.

iPhone® is a registered trademark of Apple, Inc.FlexPen® and Levemir® are registered trademarks and NovoDose™ is a trademark of Novo Nordisk A/S.© 2012 Novo Nordisk Printed in the U.S.A. 0911-00005042-1 April 2012

References: 1. Blonde L, Merilainen M, Karwe V, Raskin P; TITRATE™ Study Group. Patient-directed titration for achieving glycaemic goals using a once-daily basal insulin analogue: an assessment of two different fasting plasma glucose targets - the TITRATE™ study. Diabetes Obes Metab. 2009;11(6):623-631. 2. Data on fi le. Novo Nordisk Inc, Princeton, NJ.

MORE

LEVEMIR® (insulin detemir [rDNA origin] injection)Rx ONLYBRIEF SUMMARY. Please consult package insert for full prescribing infor-mation.INDICATIONS AND USAGE: LEVEMIR® is indicated to improve glycemic control in adults and children with diabetes mellitus. Important Limitations of Use: LEVEMIR® is not recommended for the treatment of diabetic ketoacidosis. Intravenous rapid-acting or short-acting insulin is the preferred treatment for this condition.CONTRAINDICATIONS: LEVEMIR® is contraindicated in patients with hypersensi-tivity to LEVEMIR® or any of its excipients. Reactions have included anaphylaxis.WARNINGS AND PRECAUTIONS: Dosage adjustment and monitoring: Glucose monitoring is essential for all patients receiving insulin therapy. Changes to an insulin regimen should be made cautiously and only under medical supervision. Changes in insulin strength, manufacturer, type, or method of administration may result in the need for a change in the insulin dose or an adjustment of concomitant anti-diabetic treatment. As with all insulin preparations, the time course of action for LEVEMIR® may vary in different individuals or at different times in the same indi-vidual and is dependent on many conditions, including the local blood supply, local temperature, and physical activity. Administration: LEVEMIR® should only be administered subcutaneously. Do not administer LEVEMIR® intravenously or intra-muscularly. The intended duration of activity of LEVEMIR® is dependent on injection into subcutaneous tissue. Intravenous or intramuscular administration of the usual subcutaneous dose could result in severe hypoglycemia. Do not use LEVEMIR® in insulin infusion pumps. Do not dilute or mix LEVEMIR® with any other insulin or solution. If LEVEMIR® is diluted or mixed, the pharmacokinetic or pharmacodynamic profile (e.g., onset of action, time to peak effect) of LEVEMIR® and the mixed insulin may be altered in an unpredictable manner. Hypoglycemia: Hypoglycemia is the most common adverse reaction of insulin therapy, including LEVEMIR®. The risk of hypoglycemia increases with intensive glycemic control. Patients must be educated to recognize and manage hypoglycemia. Severe hypoglycemia can lead to unconscious-ness or convulsions and may result in temporary or permanent impairment of brain function or death. Severe hypoglycemia requiring the assistance of another person or parenteral glucose infusion, or glucagon administration has been observed in clinical trials with insulin, including trials with LEVEMIR®. The timing of hypoglycemia usually reflects the time-action profile of the administered insulin formulations. Other factors such as changes in food intake (e.g., amount of food or timing of meals), exercise, and concomitant medications may also alter the risk of hypoglycemia. The prolonged effect of subcutaneous LEVEMIR® may delay recovery from hypoglycemia. As with all insulins, use caution in patients with hypoglycemia unawareness and in patients who may be predisposed to hypoglycemia (e.g., the pediatric population and patients who fast or have erratic food intake). The patient’s ability to concentrate and react may be impaired as a result of hypoglycemia. This may present a risk in situations where these abilities are especially important, such as driving or operating other machinery. Early warning symptoms of hypoglycemia may be different or less pronounced under certain conditions, such as longstanding diabetes, diabetic neuropathy, use of medications such as beta-blockers, or intensified glycemic control. These situations may result in severe hypoglycemia (and, possibly, loss of consciousness) prior to the patient’s awareness of hypoglycemia. Hypersensitivity and allergic reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including LEVEMIR®. Renal Impairment: No difference was observed in the pharmacokinetics of insulin detemir between non-diabetic individuals with renal impairment and healthy volunteers. However, some studies with human insulin have shown increased circulating insulin concentrations in patients with renal impairment. Careful glucose monitoring and dose adjustments of insulin, including LEVEMIR®, may be necessary in patients with renal impairment. Hepatic Impairment: Non-diabetic individuals with severe hepatic impairment had lower systemic exposures to insulin detemir compared to healthy volunteers. However, some studies with human insulin have shown increased circulating insulin concentrations in patients with liver impairment. Careful glucose monitoring and dose adjustments of insulin, including LEVEMIR®, may be necessary in patients with hepatic impairment. Drug interac-tions: Some medications may alter insulin requirements and subsequently increase the risk for hypoglycemia or hyperglycemia.ADVERSE REACTIONS: The following adverse reactions are discussed elsewhere: Hypoglycemia; Hypersensitivity and allergic reactions. Clinical trial experience: Because clinical trials are conducted under widely varying designs, the adverse reaction rates reported in one clinical trial may not be easily compared to those rates reported in another clinical trial, and may not reflect the rates actually observed in clinical practice. The frequencies of adverse reactions (excluding hypoglycemia) reported during LEVEMIR® clinical trials in patients with type 1 diabetes mellitus and

type 2 diabetes mellitus are listed in Tables 1-4 below. See Tables 5 and 6 for the hypoglycemia findings.Table 1: Adverse reactions (excluding hypoglycemia) in two pooled clinical trials of 16 weeks and 24 weeks duration in adults with type 1 diabetes (adverse reactions with incidence ≥ 5%)

LEVEMIR®, % (n = 767)

NPH, % (n = 388)

Upper respiratory tract infection 26.1 21.4Headache 22.6 22.7Pharyngitis 9.5 8.0Influenza-like illness 7.8 7.0Abdominal Pain 6.0 2.6

Table 2: Adverse reactions (excluding hypoglycemia) in a 26-week trial comparing insulin aspart + LEVEMIR® to insulin aspart + insulin glargine in adults with type 1 diabetes (adverse reactions with incidence ≥ 5%)

LEVEMIR®, % (n = 161)

Glargine, % (n = 159)

Upper respiratory tract infection 26.7 32.1Headache 14.3 19.5Back pain 8.1 6.3Influenza-like illness 6.2 8.2Gastroenteritis 5.6 4.4Bronchitis 5.0 1.9

Table 3: Adverse reactions (excluding hypoglycemia) in two pooled clinical trials of 22 weeks and 24 weeks duration in adults with type 2 diabetes (adverse reactions with incidence ≥ 5%)

LEVEMIR®, % (n = 432)

NPH, % (n = 437)

Upper respiratory tract infection 12.5 11.2Headache 6.5 5.3

Table 4: Adverse reactions (excluding hypoglycemia) in a 26-week clinical trial of children and adolescents with type 1 diabetes (adverse reactions with incidence ≥ 5%)

LEVEMIR®, % (n = 232)

NPH, % (n = 115)

Upper respiratory tract infection 35.8 42.6Headache 31.0 32.2Pharyngitis 17.2 20.9Gastroenteritis 16.8 11.3Influenza-like illness 13.8 20.9Abdominal pain 13.4 13.0Pyrexia 10.3 6.1Cough 8.2 4.3Viral infection 7.3 7.8Nausea 6.5 7.0Rhinitis 6.5 3.5Vomiting 6.5 10.4

Hypoglycemia: Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including LEVEMIR®. Tables 5 and 6 summarize the incidence of severe and non-severe hypoglycemia in the LEVEMIR® clinical trials. Severe hypogly-cemia was defined as an event with symptoms consistent with hypoglycemia requiring assistance of another person and associated with either a blood glucose below 50 mg/dL or prompt recovery after oral carbohydrate, intravenous glucose or glucagon admin-istration. Non-severe hypoglycemia was defined as an asymptomatic or symptomatic plasma glucose < 56 mg/dL (<50 mg/dL in Study A and C) that was self-treated by the patient. The rates of hypoglycemia in the LEVEMIR® clinical trials (see Section 14 for a description of the study designs) were comparable between LEVEMIR®-treated patients and non-LEVEMIR®-treated patients (see Tables 5 and 6).

Insulin Initiation and Intensification of Glucose Control: Intensification or rapid improvement in glucose control has been associated with a transitory, reversible ophthalmologic refraction disorder, worsening of diabetic retinopathy, and acute painful peripheral neuropathy. However, long-term glycemic control decreases the risk of diabetic retinopathy and neuropathy. Lipodystrophy: Long-term use of insulin, including LEVEMIR®, can cause lipodystrophy at the site of repeated insulin injections. Lipodystrophy includes lipohypertrophy (thickening of adipose tissue) and lipoatrophy (thinning of adipose tissue), and may affect insulin adsorption. Rotate insulin injection sites within the same region to reduce the risk of lipodystrophy. Weight Gain: Weight gain can occur with insulin therapy, including LEVEMIR®, and has been attributed to the anabolic effects of insulin and the decrease in glucosuria. Peripheral Edema: Insulin, including LEVEMIR®, may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy. Allergic Reactions: Local Allergy: As with any insulin therapy, patients taking LEVEMIR ® may experience injection site reactions, including localized erythema, pain, pruritis, urticaria, edema, and inflammation. In clinical studies in adults, three patients treated with LEVEMIR® reported injection site pain (0.25%) compared to one patient treated with NPH insulin (0.12%). The reports of pain at the injection site did not result in discontinuation of therapy. Rotation of the injection site within a given area from one injection to the next may help to reduce or prevent these reactions. In some instances, these reactions may be related to factors other than insulin, such as irritants in a skin cleansing agent or poor injection technique. Most minor reactions to insulin usually resolve in a few days to a few weeks. Systemic Allergy: Severe, life-threatening, gener-alized allergy, including anaphylaxis, generalized skin reactions, angioedema, bron-chospasm, hypotension, and shock may occur with any insulin, including LEVEMIR®, and may be life-threatening. Antibody Production: All insulin products can elicit the formation of insulin antibodies. These insulin antibodies may increase or decrease the efficacy of insulin and may require adjustment of the insulin dose. In phase 3 clinical trials of LEVEMIR®, antibody development has been observed with no apparent impact on glycemic control. Postmarketing experience: The following adverse reactions have been identified during post approval use of LEVEMIR®. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Medication errors have been reported during post-approval use of LEVEMIR® in which other insulins, particularly rapid-acting or short-acting insulins, have been accidentally administered instead of LEVEMIR®. To avoid medication errors between LEVEMIR® and other insulins, patients should be instructed always to verify the insulin label before each injection.

For information about LEVEMIR® contact: Novo Nordisk Inc., 100 College Road West Princeton, NJ 08540 1-800-727-6500 www.novonordisk-us.comManufactured by: Novo Nordisk A/S DK-2880 Bagsvaerd, DenmarkRevised: 1/2012Novo Nordisk®, Levemir®, NovoLog®, FlexPen®, and NovoFine® are registered trademarks of Novo Nordisk A/S.LEVEMIR® is covered by US Patent Nos. 5,750,497, 5,866,538, 6,011,007, 6,869,930 and other patents pending.FlexPen® is covered by US Patent Nos. 6,582,404, 6,004,297, 6,235,400 and other patents pending.© 2005-2012 Novo Nordisk 0212-00007333-1 2/2012

More detailed information is available upon request.

Table 5: Hypoglycemia in Patients with Type 1 DiabetesStudy A

Type 1 Diabetes Adults

16 weeks In combination with insulin aspart

Study B Type 1 Diabetes

Adults 26 weeks

In combination with insulin aspart

Study C Type 1 Diabetes

Adults 24 weeks

In combination with regular insulin

Study D Type 1 Diabetes

Pediatrics 26 weeks

In combination with insulin aspartTwice-Daily LEVEMIR® Twice-Daily NPH Twice-Daily

LEVEMIR®Once-Daily

GlargineOnce-Daily LEVEMIR® Once-Daily NPH Once- or Twice

Daily LEVEMIR®Once- or Twice

Daily NPHSevere hypo-glycemia

Percent of patients with at least 1 event (n/total N)

8.7 (24/276)

10.6 (14/132)

5.0 (8/161)

10.1 (16/159)

7.5 (37/491)

10.2 (26/256)

15.9 (37/232)

20.0 (23/115)

Event/patient/year 0.52 0.43 0.13 0.31 0.35 0.32 0.91 0.99Non-severe hypoglycemia

Percent of patients (n/total N)

88.0 (243/276)

89.4 (118/132)

82.0 (132/161)

77.4 (123/159)

88.4 (434/491)

87.9 (225/256)

93.1 (216/232)

95.7 (110/115)

Event/patient/year 26.4 37.5 20.2 21.8 31.1 33.4 31.6 37.0

Table 6: Hypoglycemia in Patients with Type 2 DiabetesStudy E

Type 2 Diabetes Adults

24 weeks In combination with oral agents

Study F Type 2 Diabetes

Adults 22 weeks

In combination with insulin aspartTwice-Daily LEVEMIR® Twice-Daily NPH Once- or Twice Daily LEVEMIR® Once- or Twice Daily NPH

Severe hypo-glycemia

Percent of patients with at least 1 event (n/total N)

0.4 (1/237)

2.5 (6/238)

1.5 (3/195)

4.0 (8/199)

Event/patient/year 0.01 0.08 0.04 0.13Non-severe hypoglycemia

Percent of patients (n/total N)

40.5 (96/237)

64.3 (153/238)

32.3 (63/195)

32.2 (64/199)

Event/patient/year 3.5 6.9 1.6 2.0


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Miss Jing Guo is a PhD student at James L. Winkle College of Pharmacy, University of Cincinnati Academic Health Center; Dr Kelton is Professor, College of Business, University of Cincinnati; and Dr Jeff J. Guo is Professor, James L. Winkle College ofPharmacy, University of Cincinnati Academic Health Center, OH. A version of this work was presented at the 17th AnnualMeeting of the International Society for Pharmacoeconomics and Outcomes Research in Washington, DC, June 4-6, 2012.

Original research

Recent Developments, Utilization, andSpending Trends for Pompe DiseaseTherapiesJing guo, BPharm; christina M.l. Kelton, PhD; Jeff J. guo, PhD

Background: Pompe disease is a rare condition, with an incidence rate estimated to bebetween 1 in 40,000 and 1 in 300,000 live births worldwide. For an infant who contracts thedisease, which is an inherited metabolic myopathy caused by deficiency of the acid alpha-glucosidase (GAA) enzyme in lysosomal cells, the survival rate to age 1 year is estimated tobe 25.7%. Before 2006, no therapies were available for this disease.

Objectives: The goals of this study were to review recent developments in therapies forPompe disease, including the US Food and Drug Administration (FDA) approval of 2 biologicdrugs, and to describe the associated drug utilization and spending trends in the US Medicaidprogram for patients with this disease.

Methods: We reviewed 2 recently approved therapies for Pompe disease and compared theirindications, as well as their efficacy and safety profiles. A retrospective analysis was performedusing the national Medicaid pharmacy claims database. Quarterly prescriptions and reimburse-ment amounts were calculated for each drug from 2006 quarter 2 through 2011 quarter 2.Average per-prescription spending was calculated by dividing the drug reimbursement by thenumber of prescriptions written for that drug.

Results: Myozyme (alglucosidase alfa, recombinant human GAA) and Lumizyme (alglucosi-dase alfa), the first 2 enzyme replacement therapies available for Pompe disease, wereapproved as orphan drugs by the FDA in 2006 and in 2010, respectively. Myozyme is indicatedfor infantile-onset Pompe disease; Lumizyme is indicated for patients aged ≥8 years. Althoughboth drugs have been shown to improve patient survival rates, they both also have a boxedwarning, because of the possibility of life-threatening allergic reactions. Moreover, Lumizymehas a restricted distribution system to ensure it is used by the correct patient population. In2010, Medicaid spending for Myozyme was $3.6 million. In the first 2 quarters of 2011,Medicaid spending for Lumizyme was $1.8 million. Prescriptions for Myozyme increased from1 in 2006 quarter 2 to 127 in 2011 quarter 2, whereas prescriptions for Lumizyme increasedfrom 6 in 2010 quarter 3 to 60 in 2011 quarter 2. During the same period, expenditures rosefrom $9450 to $930,459 for Myozyme and from $119,691 to $1.16 million for Lumizyme. Theaverage price per prescription was approximately $10,000 for Myozyme and approximately$20,000 for Lumizyme over the study period.

Conclusion: As can be expected after the FDA’s approval of Myozyme and Lumizyme,Medicaid beneficiaries have experienced rising utilization of the 2 therapies. Spending byMedicaid has increased proportionately, implying a steady per-prescription average price forboth drugs where if both numerator and denominator increase at the same rate, the ratio(price) should remain the same. New promising therapies for Pompe disease are currentlybeing studied.




Jing Guo

Recent Developments in Pompe Disease


Pompe disease is a rare condition, with a global inci-dence rate estimated to be between 1 in 40,000(0.0025%) and 1 in 300,000 (0.0003%) live

births.1 According to a study published in 1998, theannual incidence of Pompe disease in New York Citywas estimated to be approximately 1 in 40,000 births,and approximately 90 babies are assumed born withPompe disease in the United States annually.2 A similarincidence rate was found in the Dutch population (1 in40,000 births), a relatively lower rate was found amongthe Chinese (1 in 50,000 births; 0.0020%), and a higherrate was seen among African Americans (1 in 31,000births; 0.0032%).2-4

In 1998, the total number of patients with Pompe dis-ease was estimated to be between 1900 and 3000 in theUnited States.2 By 2004, the estimated number ofpatients with Pompe disease was between 5000 and10,000 worldwide.5

Pompe disease is named after Johannes CassianusPompe, the physician who was first to identify it as aglycogen storage disease in 1932. Pompe disease is alsoreferred to as glycogen storage disease (GSD) type II(GSD II) or acid maltase deficiency.6 For an infant whocontracts the disease, the survival rate to age 12 monthsis estimated to be 25.7%.7

As an autosomal recessive disease, Pompe disease iscaused by an acid alpha-glucosidase (GAA) gene disor-der that leads to the GAA deficiency in this disease.GAA is the only enzyme that is active in the acidicmilieu of the lysosomes for degradation of glycogen.8Because the glycogen cannot be broken down effectivelyinto a simpler sugar (glucose), which is the main sourceof body energy, the accumulation of the glycogen inorgans and tissues causes myopathy, with progressivemuscle weakness. The heart, liver, respiratory system,and nervous system are all affected.

The goals of this study were to review recent develop-ments in Pompe disease therapies and describe drug uti-lization and spending trends associated with this diseasein the US Medicaid program.

The 2 Forms of Pompe DiseaseDepending on whether symptoms occur within the

first 6 months after birth or, alternatively, later in life,Pompe disease is classified as infantile-onset or late-onset illness, respectively.3 The late-onset form of thedisease progresses more slowly than the infantile-onsetand can present in patients as old as age 60 years.

Common signs and symptoms of infantile-onset dis-ease include cardiomegaly, hypotonia (ie, muscle weak-ness), hepatomegaly, cardiomyopathy, respiratory dis-tress, enlarged tongue (ie, macroglossia), feedingdifficulties, and failure to thrive.7 Heart failure and respi-

ratory weakness are the most common causes of deathamong infants with Pompe disease.3

The primary clinical manifestations of late-onset dis-ease include progressive proximal muscle weakness(especially in the body and legs), exercise intolerance,exertional dyspnea, sleep apnea, and joint contractures.For those who contract the disease in childhood oradolescence, additional symptoms include scoliosis,hepatomegaly, macroglossia, and cardiac hypertrophy.9The main cause of death for patients with late-onsetPompe disease is respiratory failure.9

Current TreatmentsBefore 2006, there was no effective treatment for

Pompe disease, despite several decades of studyingpotential treatments in clinical trials. Unsuccessful trialsinvolved altering the synthesis of glycogen, bone-mar-row transplantation, and administration of unphospho-rylated enzyme isolated from Aspergillus niger or fromhuman placenta.10

MyozymeOn April 28, 2006, under priority review, the US

Food and Drug Administration (FDA) approved aBiologic License Application for the orphan drugMyozyme (alglucosidase alfa, recombinant human[rh]GAA) for patients with Pompe disease.11 Myozymereceived marketing authorization in the EuropeanUnion slightly earlier, in March 2006.12 Myozyme is anenzyme replacement therapy (ERT) drug, which usesrecombinant DNA technology to produce the enzymefrom Chinese hamster ovary cells.12 Clinical studies have

KEY POINTS➤ Pompe disease is a rare inherited metabolic

myopathy caused by deficiency of the acid alpha-glucosidase enzyme in lysosomal cells, which causesprogressive muscle weakness.

➤ With a global incidence rate estimated to bebetween 1 in 40,000 and 1 in 300,000 live births,infants who contract the disease have anapproximate 25.7% survival rate to age 1 year.

➤ Before 2006, no effective treatments were availablefor Pompe disease.

➤ Like most biologics, Myozyme and Lumizyme, the 2recently approved enzyme replacement therapies forPompe disease, are costly; the cost of Lumizyme isapproximately double that of Myozyme.

➤ Because these new drugs can have serious life-threatening adverse events, their use should becarefully monitored by Medicaid and by other payers.

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shown that Myozyme can improve ventilator-free sur-vival in patients with infantile-onset Pompe disease.13This therapy has several adverse reactions, includingpneumonia, respiratory failure and distress, infections,and fever. Myozyme may also be involved in life-threat-ening allergic reactions, heart or lung failure, andimmune-mediated reactions.13 A boxed warning isincluded in the Myozyme label to caution about possiblelife-threatening allergic reactions.11

LumizymeOn May 25, 2010, the FDA approved Lumizyme

(alglucosidase alfa), the first treatment for late-onsetPompe disease, which is indicated for patients aged ≥8years (younger children may experience more rapid dis-ease progression while receiving Lumizyme).1 Also usingthe ERT principle, Lumizyme is believed to work byreplacing the deficient GAA enzyme, thereby allowing

the breakdown of glycogen in the heart and skeletalmuscle cells. However, although both Myozyme andLumizyme have the same generic ingredient and work byenzyme replacement, the FDA considers the 2 treat-ments as different drugs, with distinct manufacturingprocesses, as well as some biologic differences.

Lumizyme cannot be used in patients who have car-diac hypertrophy (enlarged heart), because it may causelife-threatening allergic reactions, heart or lung failure,and immune-mediated reactions—the same serious sideeffects as those associated with Myozyme. Moreover,according to postmarketing experience with Lumizymetherapy, the drug may be involved in cardiorespiratoryarrest, respiratory failure, hemothorax, pneumothorax,cardiac failure, sepsis, aortic dissection, cerebrovascularaccident, and skin necrosis.14

Lumizyme is available only through a restricted distri-bution system called the Lumizyme Alglucosidase Alfa

Table Comparing Myozyme and Lumizyme for Pompe Disease

VariableMyozyme

(alglucosidase alfa, rhGAA)Lumizyme

(alglucosidase alfa)

Source of biologics Derived from CHO cells Derived from CHO cells

Mechanism Enzyme replacement therapy Enzyme replacement therapy

Manufacturing process 160-L bioreactor 4000-L bioreactor

Dosage 20 mg/kg body weight, administered every 2 weeks

20 mg/kg body weight, administered every 2 weeks

Formulation 50 mg/vial 50 mg/vial

Route of administration Intravenous infusion Intravenous infusion

Indications Only for infantile-onset Pompe disease Only for patients aged ≥8 years

Efficacy profile Improve ventilator-free survival(based on 39 patients with infantile-onset Pompe disease, aged 1 month-3.5 years)

Reduce the accumulated glycogen in heart and skeletal muscle cells (based on 90 patients aged 10-70 years with late-onset Pompe disease)

Safety profile Serious AEs include life-threateningallergic reactions, heart and lung failure, and immune-mediated reactions; boxed warning

Serious AEs include life-threatening allergicreactions, anaphylaxis, and immune-mediatedreactions; boxed warning; only availablethrough a restricted distribution system forpatients aged ≥8 years; the LumizymeAlglucosidase Alfa Control and Education program is approved by the FDA

FDA approval date April 28, 2006 May 25, 2010

Manufacturer Genzyme Genzyme

AEs indicates adverse events; CHO, Chinese hamster ovary; FDA, US Food and Drug Administration; rhGAA, recombinant human acid alpha-glucosidase.



Control and Education (ACE) program,1 one of theFDA’s approved risk evaluation and mitigation strategyprograms. The primary goal of the ACE program is toensure that known risks of anaphylaxis and severe aller-gic reactions associated with Lumizyme are communicat-ed to patients, caregivers, and prescribers.

ERT has been tried for some lysosomal storage dis-eases, such as Gaucher disease, Fabry disease, andmucopolysaccharidoses (MPS I, MPS II, MPS VI).15With these first-approved ERTs for Pompe disease (GSDII) comes the hope that ERT may also prove effective forother GSDs as well. The current primary treatment forother GSDs involves control of hypoglycemia.16

The Table summarizes the basic characteristics ofMyozyme and Lumizyme therapies.

MethodsA retrospective analysis was conducted for the peri-

od between the second quarter of 2006 (first approvalof Myozyme) and the second quarter of 2011 (the mostcurrent data available). The primary data source is thepublicly available National Summary Files for theMedicaid State Drug Utilization Data, which are main-tained by the Centers for Medicare & MedicaidServices (CMS). The database covers Medicaid benefi-ciaries in 49 states (all states except Arizona) and theDistrict of Columbia, and it is restricted to outpatientpharmaceuticals.17 The National Summary Files werecompiled by aggregating state databases. Because thedata are collected as part of the Medicaid RebateProgram, they include fee for service but not managedMedicaid pharmacy claims.

Each data record included the National Drug Code(NDC), drug name, year and quarter of Medicaid expen-diture, number of pharmacy claims, number of units, andtotal pharmacy reimbursement amount, including costsof the drug and its administration. We searched the data-base for Myozyme and for Lumizyme.

For each drug, quarterly prescription counts and reim-bursement amounts were calculated by summing dataacross individual NDCs for the 2 drugs. Quarterly per-claim pharmacy reimbursement, as a proxy for drugprice, was computed for the 2 drugs. Reimbursements areinclusive of the costs for the drug ingredients and admin-istration, but they do not include manufacturer rebates.All of the data analyses were conducted using the SASsoftware package for Windows (Version 9.1.3; SASInstitute, Inc; Cary, NC).

ResultsPrescriptions for Myozyme increased from 1 in 2006

quarter 2 to 127 in 2011 quarter 2, whereas prescriptionsfor Lumizyme increased from 6 in 2010 quarter 3 to 60 in

2011 quarter 2. During the same period, expendituresrose from $9450 to $930,459 for Myozyme and from$119,691 to $1.16 million for Lumizyme. The averageprice per prescription was approximately $10,000 forMyozyme and approximately $20,000 for Lumizyme overthe study period.Figure 1 depicts the quarterly trends of utilization for

Myozyme and Lumizyme, and Figure 2 describes thequarterly trends of reimbursement (or Medicaid spend-ing) for Myozyme and Lumizyme. As seen in Figure 3,average reimbursement per prescription (or spending perprescription) as a proxy for drug price remained high andstable over time.

DiscussionBecause Myozyme and Lumizyme are the first 2 ther-

apies to be approved by the FDA for Pompe disease, theincrease in their utilization is not surprising. Moreover,because of the higher proportion of infants and childrenamong Medicaid beneficiaries than among the popula-tion as a whole, some incidence of Pompe disease is cer-tainly expected. The price per prescription for Lumizymewas essentially double the price for Myozyme. This dif-ference is likely a result of the higher dosages required forolder/larger patients with late-onset Pompe disease com-pared with small infants with Pompe disease (see Table).The price for both medications is high and is expected toremain so. The 2 therapies were approved as orphandrugs, which are usually priced higher than drugs with alarge target market.

Given patent protection, coupled with the complexi-ty of production procedures for biologic therapies, it isunlikely that another company will compete anytimesoon with Genzyme, the manufacturer of both drugs.The high cost of the medication, and the potential foroff-label use and serious adverse events related to heartor lung failure, argue for careful monitoring of thesemedications by Medicaid, as well as by other payers.

Potential Future TreatmentsIn the United States, currently 18 clinical trials are

studying Pompe disease and its treatment and arerecruiting patients.18 Among them is a study about the

The high cost of the medication, and thepotential for off-label use and seriousadverse events related to heart or lungfailure, argue for careful monitoring ofthese medications by Medicaid, as well asby other payers.

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2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 22006 2006 2006 2007 2007 2007 2007 2008 2008 2008 2008 2009 2009 2009 2009 2010 2010 2010 2010 2011 2011

Figure 1 Quarterly Utilization of Myozyme and Lumizyme in Medicaid, from 2006 Quarter 2 to 2011 Quarter 2Nu

mber o

f prescrip

tions

MyozymeLumizyme

160

140

120

100

80

60

40

20

0

2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 22006 2006 2006 2007 2007 2007 2007 2008 2008 2008 2008 2009 2009 2009 2009 2010 2010 2010 2010 2011 2011

Figure 2 Quarterly Reimbursement (or Spending) on Myozyme and Lumizyme in Medicaid, from 2006 Quarter 2 to 2011 Quarter 2

Amount of s

pending, current $

MyozymeLumizyme

1,600,000

1,400,000

1,200,000

1,000,000

800,000

600,000

400,000

200,000

0

Period

Period



safety, tolerability, pharmacokinetics, pharmacodynam-ics, and efficacy of BMN-701 (GILT-tagged rhGAA) inpatients with late-onset Pompe disease. BMN-701,which is manufactured by BioMarin, is an rhGAA. Itcan increase the number of mannose-6-phosphates thatprovide better delivery of GAA to the lysosome, whereit causes Pompe disease, thereby improving efficacy, withless enzyme.19 Because the enzyme for Pompe diseaseneeds life-long infusions, a limitation of ERT is the highcost of the recombinant enzyme and the extremely highdoses of the drug.8 BMN-701 may solve this problem byrequiring lower enzyme doses, at a lower cost, which is abig improvement over ERT.

Gene therapy is another possibility for the treatmentof Pompe disease. The idea is to create a permanentGAA source through the use of adenoviral (Ad), adeno-associated (AAV), or hybrid Ad-AAV vectors to intro-duce a correct sequence coding gene for the deficientenzyme into cells. The first clinical trial for recombinantAAV-mediated gene-based therapy for Pompe diseaseachieved some success.20

Nutrition and exercise therapy may help patientswith late-onset Pompe disease to increase muscle pro-tein synthesis and muscle fibers.21According to Schoserand colleagues, nutrition and exercise therapy includesa combination of a high-protein, low-carbohydrate diet

and daily conditioning aerobic exercise.8 Among allknown treatments for Pompe disease, it is the onlytherapy that can slow the progressive deterioration inmuscle function.22

LimitationsThis study has a number of limitations. First, patient-

specific information was not available in the nationalMedicaid pharmacy file provided by CMS. Therefore, itwas not possible to determine the cost per patient and/orindication for medication use.

In addition, adherence to medication therapy couldnot be assessed. As with all database studies, misclassifi-cation bias may be present if the CMS data containreporting errors. All data are prerebate; hence, to somedegree (that we cannot measure), they overstate theactual acquisition cost to the US Medicaid program.

Moreover, the results of this study are specific to theMedicaid population, which is heavily comprised of low-

2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 22006 2006 2006 2007 2007 2007 2007 2008 2008 2008 2008 2009 2009 2009 2009 2010 2010 2010 2010 2011 2011

Figure 3 Average Reimbursement (or Spending) per Prescription for Myozyme and Lumizyme in Medicaid, from 2006 Quarter 2 to 2011 Quarter 2

Spending

per perscrip

tion, current $

MyozymeLumizyme

22,000

20,000

18,000

16,000

14,000

12,000

10,000

8000

6000

4000

2000

0

Period

Nutrition and exercise therapy may helppatients with late-onset Pompe disease toincrease muscle protein synthesis andmuscle fibers.

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income women and children. Hence, they do not neces-sarily represent utilization and expenditure trends inother populations.

Finally, comparing the pricing data among states, as wellas exploring data regarding utilization trends in the com-mercial population, are beyond the scope of this article.

ConclusionMedicaid spent $3.6 million in 2010 on Myozyme

and $1.8 million in 2011 on Lumizyme, the only 2 FDA-approved therapies (both ERTs) for the treatment ofPompe disease. ERT has been a major breakthrough inthe treatment of patients with Pompe disease. It canchange the course of the disease and can prolong apatient’s survival, although there are still many chal-lenges. Other promising treatments for Pompe diseasethat are currently under study may expand the treatmentoptions in the near future. ■

Author Disclosure StatementThe authors have no conflict of interest concerning this

research. They did not receive any consulting fees, grants,honoraria, patents, royalties, stocks, or other financial ormaterial gain that may involve the subject matter of the arti-cle. Dr Jeff J. Guo and Dr Kelton have received researchgrants from Novartis, Johnson & Johnson, and Eli Lilly.Miss Jing Guo has nothing to disclose.

References1. FDA approves new treatment for late-onset Pompe disease [news release]. SilverSpring, MD: US Food and Drug Administration; May 25, 2010. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2010/ucm213282.htm. Accessed

May 9, 2012.2.Martiniuk F, Chen A, Mack A, et al. Carrier frequency for glycogen storage diseasetype II in New York and estimates of affected individuals born with the disease. AmJ Med Genet. 1998;79:69-72.3. Di Rocco M, Buzzi D, Tarò M. Glycogen storage disease type II: clinical overview.Acta Myologica. 2007;26:42-44.4. Ausems MG, ten Berg K, Kroos MA, et al. Glycogen storage disease type II: birthprevalence agrees with predicted genotype frequency. Community Genet. 1999;2:91-96.5.Werber Y. Lysosomal storage diseases market. Nat Rev Drug Discov. 2004;3:9-10.6. Kishnani PS, Steiner RD, Bali D, et al. Pompe disease diagnosis and managementguideline. Genet Med. 2006;8:267-288.7. Kishnani PS, Hwu WL, Mandel H, et al. A retrospective, multinational, multicen-ter study on the natural history of infantile-onset Pompe disease. J Pediatr. 2006;148:671-676.8. Schoser B, Hill V, Raben N. Therapeutic approaches in Glycogen Storage Diseasetype II (GSDII)/Pompe disease. Neurotherapeutics. 2008;5:569-578.9.Winkel LP, Hagemans ML, van Doorn PA, et al. The natural course of non-classicPompe’s disease; a review of 225 published cases. J Neurol. 2005;252:875-884.10. Kishnani PS, Howell RR. Pompe disease in infants and children. J Pediatr. 2004;144(5 suppl):S35-S43.11. FDA approves first treatment for Pompe disease [news release]. Silver Spring,MD: US Food and Drug Administration; April 28, 2006. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2006/ucm108645.htm. Accessed May 9, 2012.12. Erasmus MC Pompe Center. Treatment. www.erasmusmc.nl/klinische_genetica/research/pompe_center/behandeling/?lang=en. Accessed May 9, 2012.13.Myozyme [prescribing information]. Cambridge, MA: Genzyme Corporation; 2006.14. Lumizyme [prescribing information]. Cambridge, MA: Genzyme Corporation; 2010.15.Neufeld EF. Enzyme replacement therapy—a brief history. In: Mehta A, Beck M,Sunder-Plassmann G, eds. Fabry Disease: Perspectives from 5 Years of FOS. Oxford,England: Oxford PharmaGenesis; 2006.16.Hendriksz CJ, Gissen P. Glycogen storage disease. Paediatr Child Health. 2011;21:84-89.17. Centers for Medicare & Medicaid Services. State Drug Utilization Data. www.cms.hhs.gov/MedicaidDrugRebateProgram/SDUD/list.asp#TopOfPage. Accessed Decem -ber 9, 2011.18. ClinicalTrials.gov. Pompe trials. www.clinicaltrials.gov/ct2/results?term=pompe.Accessed May 23, 2012.19. BioMarin Company. BMN-701: IFG2-GAA for Pompe. www.bmrn.com/patients-physicians/pompe-disease.php. Accessed May 9, 2012.20. Byrne BJ, Falk DJ, Pacak CA, et al. Pompe disease gene therapy. Hum Mol Genet.2011;20(R1):R61-R68.21. Slonim AE, Bulone L, Minikes J, et al. Benign course of glycogen storage diseasetype IIb in two brothers: nature or nurture? Muscle Nerve. 2006;33:571-574.22. Slonim AE, Bulone L, Goldberg T, et al. Modification of the natural history ofadult-onset acid maltase deficiency by nutrition and exercise therapy. Muscle Nerve.2007;35:70-77.

Beyond “Patient Amusement”: New Treatments and Genetic DiseaseVoltaire once remarked that “the role of the doctor

is to amuse the patient whilst nature takes its course.”Until recently, this comment would seem especiallyappropriate for how physicians addressed the needs ofpatients with certain rare genetic diseases. In mostinstances, these diseases—which result from the com-bination of recessive genes and are more commonthan those resulting from spontaneous mutations—had no effective therapies or interventions.Individuals with genetic diseases, whether from inbornerrors of metabolism, sickle-cell anemia, or other con-ditions, suffered greatly.

More recently, the role of the physician has evolved

from “amusing the patient” to being able to offer somealleviation to the patient’s suffering. This “holistic heal-ing,” as Egnew calls it, involves transcending suffering.1This transcendence involves shifting the patient’s rela-tionship to the illness. Although some of this shiftinvolves helping the patient accept his or her fate, therest involves providing treatment when it is available.

The provision of said treatment, in this case forPompe disease, is aptly discussed in the article by Guoand colleagues in this issue of American Health & DrugBenefits. The authors provide a review of Pompe diseaseand of current treatment options for this rare condition.Most important, this article shows that because


(Continued)



Myozyme and Lumizyme define the only treatmentoptions for Pompe disease, one can infer several things.PROVIDERS: Providers want to treat their patients

holistically and effectively. The availability of newoptions to mitigate the patient’s suffering helps physi-cians do what they were meant to do—to help a “fellowcreature in pain.”2 Physicians should be expected to usetherapies at their disposal to treat specific conditions.PAYERS: Payers should expect that costly biologic

therapies will be used not only for Pompe disease butfor other genetic conditions for which treatmentoptions are limited. Some may even argue that healthinsurance, in its purest form, requires that health plansprovide coverage for biologics, such as those used totreat Pompe disease. “Real insurance” pays for treat-ments that are unavoidable, prohibitively expensive,and appropriate for rare illnesses.3 If the evidenceshows that the treatment meets the need, payers have

shown themselves amenable to stepping up and pro-viding coverage.

Ultimately, why are these inferences important?They become important because providers and payerswant to do right by their patients/members, and, indoing so, they develop processes of assessing value fortreatments that result in improved health and/ordecreased suffering. Doing so becomes paramount andis beyond mere amusement.

Albert Tzeel, MD, MHSA, FACPENational Medical Director, HumanaOne & KMG

Clinical Leadership & Policy Development

1. Egnew TR. Suffering, meaning and healing: challenges of contemporary medi-cine. Ann Fam Med. 2009;7:170-175.2. Fordham University. Oath of Maimonides. www.fordham.edu/halsall/source/rambam-oath.asp. Accessed June 10, 2012.3. Kling A. Insulation versus insurance. Cato Unbound. January 8, 2007.www.cato-unbound.org/2007/01/08/arnold-kling/insulation-vs-insurance/.Accessed June 10, 2012.

STAKEHOLDER PERSPECTIVE (Continued)

CALL FOR PAPERSValue-Based Care in Cardiometabolic Health

American Health & Drug Benefits will be publishing a Theme Issue on Cardiometabolic Healththis year. Readers are invited to submit articles on topics relevant to the clinical, business, and policyaspects of cardiometabolic health. Original research studies, white papers, evidence-based comprehensivereviews, and case studies are of particular interest.

Readers are invited to submit original, outcomes-based research, white papers, evidence-based critical reviews, and case studies on topics such as:

Submission deadline for this issue is July 5, 2012. All articles will undergo the Journal’s standard peer-review process.Articles should follow the Manuscript Instructions for Authors (www.AHDBonline.com)

Submit articles to [email protected], or call 732-992-1889

• Benefit designs and cardiometabolic outcomes• Best practices in insulin control, lipid

management, or blood pressure control• Comparative effectiveness analyses of best

therapies for cardiovascular health• Cost-effectiveness comparisons • New and emerging therapies• Health plan initiatives in cardiometabolic

health and wellness

• Hot topics in diabetes, obesity, or CVD• Lifestyle strategies and cardiometabolic health• Lipid management• Medication adherence and diabetes

progression• New biomarkers for assessing

cardiometabolic risk • Prevention strategies for cardiometabolic risk

reduction

Constipation 5.3 0.9 1.7Dyspepsia 5.2 0.9 2.6

Add-on to Metformin + GlimepirideVictoza® 1.8 + Metformin +

Glimepiride N = 230

Placebo + Metformin + Glimepiride

N = 114

Glargine + Metformin + Glimepiride

N = 232Adverse Event Term (%) (%) (%)Nausea 13.9 3.5 1.3Diarrhea 10.0 5.3 1.3Headache 9.6 7.9 5.6Dyspepsia 6.5 0.9 1.7Vomiting 6.5 3.5 0.4

Add-on to Metformin + RosiglitazoneAll Victoza® + Metformin +

Rosiglitazone N = 355Placebo + Metformin

+ Rosiglitazone N = 175Adverse Event Term (%) (%)Nausea 34.6 8.6Diarrhea 14.1 6.3Vomiting 12.4 2.9Decreased Appetite 9.3 1.1Anorexia 9.0 0.0Headache 8.2 4.6Constipation 5.1 1.1Fatigue 5.1 1.7

Table 3: Treatment-Emergent Adverse Events in 26 Week Open-Label Trial versus Exenatide (Adverse events with frequency ≥5% and occurring more frequently with Victoza® compared to exenatide are listed)

Victoza® 1.8 mg once daily + metformin and/or

sulfonylurea N = 235

Exenatide 10 mcg twice daily + metformin and/or

sulfonylurea N = 232Preferred Term (%) (%)Diarrhea 12.3 12.1Dyspepsia 8.9 4.7Constipation 5.1 2.6

Gastrointestinal adverse events: In the five clinical trials of 26 weeks duration or longer, gastrointestinal adverse events were reported in 41% of Victoza®-treated patients and were dose-related. Gastroin-testinal adverse events occurred in 17% of comparator-treated patients. Events that occurred more commonly among Victoza®-treated patients included nausea, vomiting, diarrhea, dyspepsia and con-stipation. In a 26-week study of Victoza® versus exenatide, both in combination with metformin and/or sulfonylurea overall gastrointestinal adverse event incidence rates, including nausea, were similar in patients treated with Victoza® and exenatide. In five clinical trials of 26 weeks duration or longer, the percentage of patients who reported nausea declined over time. Approximately 13% of Victoza®-treated patients and 2% of comparator-treated patients reported nausea during the first 2 weeks of treatment. In a 26 week study of Victoza® versus exenatide, both in combination with metformin and/or sulfonylurea, the proportion of patients with nausea also declined over time. Immunogenicity: Con-sistent with the potentially immunogenic properties of protein and peptide pharmaceuticals, patients treated with Victoza® may develop anti-liraglutide antibodies. Approximately 50-70% of Victoza®-treated patients in the five clinical trials of 26 weeks duration or longer were tested for the presence of anti-liraglutide antibodies at the end of treatment. Low titers (concentrations not requiring dilu-tion of serum) of anti-liraglutide antibodies were detected in 8.6% of these Victoza®-treated patients. Sampling was not performed uniformly across all patients in the clinical trials, and this may have resulted in an underestimate of the actual percentage of patients who developed antibodies. Cross-reacting anti-liraglutide antibodies to native glucagon-like peptide-1 (GLP-1) occurred in 6.9% of the Victoza®-treated patients in the 52-week monotherapy trial and in 4.8% of the Victoza®-treated patients in the 26-week add-on combination therapy trials. These cross-reacting antibodies were not tested for neutralizing effect against native GLP-1, and thus the potential for clinically significant neutralization of native GLP-1 was not assessed. Antibodies that had a neutralizing effect on liraglutide in an in vitro assay occurred in 2.3% of the Victoza®-treated patients in the 52-week monotherapy trial and in 1.0% of the Victoza®-treated patients in the 26-week add-on combination therapy trials. Among Victoza®-treated patients who developed anti-liraglutide antibodies, the most common category of adverse events was that of infections, which occurred among 40% of these patients compared to 36%, 34% and 35% of antibody-negative Victoza®-treated, placebo-treated and active-control-treated patients, respectively. The specific infections which occurred with greater frequency among Victoza®-treated antibody-positive patients were primarily nonserious upper respiratory tract infections, which occurred among 11% of Victoza®-treated antibody-positive patients; and among 7%, 7% and 5% of antibody-negative Victoza®-treated, placebo-treated and active-control-treated patients, respectively. Among Victoza®-treated antibody-negative patients, the most common category of adverse events was that of gastrointestinal events, which occurred in 43%, 18% and 19% of antibody-negative Victoza®-treated, placebo-treated and active-control-treated patients, respectively. Antibody formation was not associ-ated with reduced efficacy of Victoza® when comparing mean HbA1c of all antibody-positive and all antibody-negative patients. However, the 3 patients with the highest titers of anti-liraglutide antibodies had no reduction in HbA1c with Victoza® treatment. In clinical trials of Victoza®, events from a compos-ite of adverse events potentially related to immunogenicity (e.g. urticaria, angioedema) occurred among 0.8% of Victoza®-treated patients and among 0.4% of comparator-treated patients. Urticaria accounted for approximately one-half of the events in this composite for Victoza®-treated patients. Patients who developed anti-liraglutide antibodies were not more likely to develop events from the immunogenic-ity events composite than were patients who did not develop anti-liraglutide antibodies. Injection site reactions: Injection site reactions (e.g., injection site rash, erythema) were reported in approximately 2% of Victoza®-treated patients in the five clinical trials of at least 26 weeks duration. Less than 0.2% of Victoza®-treated patients discontinued due to injection site reactions. Papillary thyroid carcinoma: In clinical trials of Victoza®, there were 6 reported cases of papillary thyroid carcinoma in patients treated with Victoza® and 1 case in a comparator-treated patient (1.9 vs. 0.6 cases per 1000 patient-years). Most of these papillary thyroid carcinomas were <1 cm in greatest diameter and were diagnosed in surgical pathology specimens after thyroidectomy prompted by findings on protocol-specified screen-ing with serum calcitonin or thyroid ultrasound. Hypoglycemia: In the clinical trials of at least 26 weeks

duration, hypoglycemia requiring the assistance of another person for treatment occurred in 7 Victoza®-treated patients (2.6 cases per 1000 patient-years) and in two comparator-treated patients. Six of these 7 patients treated with Victoza® were also taking a sulfonylurea. One other patient was taking Victoza® in combination with metformin but had another likely explanation for the hypoglycemia (this event occurred during hospitalization and after insulin infusion) (Table 4). Two additional cases of hypo-glycemia requiring the assistance of another person for treatment have subsequently been reported in patients who were not taking a concomitant sulfonylurea. Both patients were receiving Victoza®, one as monotherapy and the other in combination with metformin. Both patients had another likely explanation for the hypoglycemia (one received insulin during a frequently-sampled intravenous glucose tolerance test, and the other had intracranial hemorrhage and uncertain food intake).Table 4: Incidence (%) and Rate (episodes/patient year) of Hypoglycemia in the 52-Week Monotherapy Trial and in the 26-Week Combination Therapy Trials

Victoza® Treatment

Active Comparator

Placebo Comparator

Monotherapy Victoza® (N = 497)

Glimepiride (N = 248)

None

Patient not able to self−treat 0 0 —Patient able to self−treat 9.7 (0.24) 25.0 (1.66) —Not classified 1.2 (0.03) 2.4 (0.04) —Add-on to Metformin

Victoza® + Metformin (N = 724)

Glimepiride + Metformin (N = 242)

Placebo + Metformin (N = 121)

Patient not able to self−treat 0.1 (0.001) 0 0Patient able to self−treat 3.6 (0.05) 22.3 (0.87) 2.5 (0.06)Add-on to Glimepiride Victoza® +

Glimepiride (N = 695)

Rosiglitazone + Glimepiride

(N = 231)

Placebo + Glimepiride

(N = 114)Patient not able to self−treat 0.1 (0.003) 0 0Patient able to self−treat 7.5 (0.38) 4.3 (0.12) 2.6 (0.17)Not classified 0.9 (0.05) 0.9 (0.02) 0Add-on to Metformin + Rosiglitazone

Victoza® + Metformin +

Rosiglitazone (N = 355)

None

Placebo + Metformin +

Rosiglitazone (N = 175)

Patient not able to self−treat 0 — 0Patient able to self−treat 7.9 (0.49) — 4.6 (0.15)Not classified 0.6 (0.01) — 1.1 (0.03)Add-on to Metformin + Glimepiride

Victoza® + Metformin + Glimepiride

(N = 230)

Insulin glargine + Metformin + Glimepiride

(N = 232)

Placebo + Metformin + Glimepiride

(N = 114)Patient not able to self−treat 2.2 (0.06) 0 0Patient able to self−treat 27.4 (1.16) 28.9 (1.29) 16.7 (0.95)Not classified 0 1.7 (0.04) 0

In a pooled analysis of clinical trials, the incidence rate (per 1,000 patient-years) for malignant neo-plasms (based on investigator-reported events, medical history, pathology reports, and surgical reports from both blinded and open-label study periods) was 10.9 for Victoza®, 6.3 for placebo, and 7.2 for active comparator. After excluding papillary thyroid carcinoma events [see Adverse Reactions], no par-ticular cancer cell type predominated. Seven malignant neoplasm events were reported beyond 1 year of exposure to study medication, six events among Victoza®-treated patients (4 colon, 1 prostate and 1 nasopharyngeal), no events with placebo and one event with active comparator (colon). Causality has not been established. Laboratory Tests: In the five clinical trials of at least 26 weeks duration, mildly elevated serum bilirubin concentrations (elevations to no more than twice the upper limit of the refer-ence range) occurred in 4.0% of Victoza®-treated patients, 2.1% of placebo-treated patients and 3.5% of active-comparator-treated patients. This finding was not accompanied by abnormalities in other liver tests. The significance of this isolated finding is unknown. Post-Marketing Experience: The fol-lowing additional adverse reactions have been reported during post-approval use of Victoza®. Because these events are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal: nausea, vomiting and diarrhea sometimes resulting in dehydration [see Warnings and Precautions]. Renal and Urinary Disorders: increased serum creatinine, acute renal failure or worsening of chronic renal failure, which may sometimes require hemodialysis [see Warnings and Precautions].OVERDOSAGE: In a clinical trial, one patient with type 2 diabetes experienced a single overdose of Victoza® 17.4 mg subcutaneous (10 times the maximum recommended dose). Effects of the overdose included severe nausea and vomiting requiring hospitalization. No hypoglycemia was reported. The patient recovered without complications. In the event of overdosage, appropriate supportive treatment should be initiated according to the patient’s clinical signs and symptoms.More detailed information is available upon request. For information about Victoza® contact: Novo Nordisk Inc., 100 College Road West, Princeton, New Jersey 08540, 1−877-484-2869Date of Issue: May 18, 2011 Version: 3Manufactured by: Novo Nordisk A/S, DK-2880 Bagsvaerd, DenmarkVictoza® is a registered trademark of Novo Nordisk A/S. Victoza® is covered by US Patent Nos. 6,268,343; 6,458,924; and 7,235,627 and other patents pending. Victoza® Pen is covered by US Patent Nos. 6,004,297; 6,235,004; 6,582,404 and other patents pending.© 2011 Novo Nordisk 140586-R3 6/2011

© 2012 Novo Nordisk 1111-00006045-1 January 2012Victoza® is a registered trademark and VictozaCare™ is a trademark of Novo Nordisk A/S.

Help adult patients with type 2 diabetes gain greater access

Get to know Victoza®

on a deeper level.Powerful reductions in A1C from -0.8% to -1.5%*

To see how Victoza® works for your patients, visit VictozaPro.com/GLP1.

Indications and usageVictoza® is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Because of the uncertain relevance of the rodent thyroid C-cell tumor fi ndings to humans, prescribe Victoza® only to patients for whom the potential benefi ts are considered to outweigh the potential risk. Victoza® is not recommended as fi rst-line therapy for patients who have inadequate glycemic control on diet and exercise.

In clinical trials of Victoza®, there were more cases of pancreatitis with Victoza® than with comparators. Victoza® has not been studied suffi ciently in patients with a history of pancreatitis to determine whether these patients are at increased risk for pancreatitis while using Victoza®. Use with caution in patients with a history of pancreatitis.

Victoza® is not a substitute for insulin. Victoza® should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings.

The concurrent use of Victoza® and insulin has not been studied.

Important safety informationLiraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether Victoza® causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as human relevance could not be ruled out by clinical or nonclinical studies. Victoza® is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Based on the fi ndings in rodents, monitoring with serum calcitonin or thyroid ultrasound was performed during clinical trials, but this may have increased the number of unnecessary thyroid surgeries. It is unknown whether monitoring with serum

calcitonin or thyroid ultrasound will mitigate human risk of thyroid C-cell tumors. Patients should be counseled regarding the risk and symptoms of thyroid tumors.

If pancreatitis is suspected, Victoza® should be discontinued. Victoza® should not be re-initiated if pancreatitis is confi rmed.

When Victoza® is used with an insulin secretagogue (e.g. a sulfonylurea) serious hypoglycemia can occur. Consider lowering the dose of the insulin secretagogue to reduce the risk of hypoglycemia.

Renal impairment has been reported postmarketing, usually in association with nausea, vomiting, diarrhea, or dehydration, which may sometimes require hemodialysis. Use caution when initiating or escalating doses of Victoza® in patients with renal impairment.

There have been no studies establishing conclusive evidence of macrovascular risk reduction with Victoza® or any other antidiabetic drug.

The most common adverse reactions, reported in ≥5% of patients treated with Victoza® and more commonly than in patients treated with placebo, are headache, nausea, diarrhea, and anti-liraglutide antibody formation. Immunogenicity-related events, including urticaria, were more common among Victoza®-treated patients (0.8%) than among comparator-treated patients (0.4%) in clinical trials.

Victoza® has not been studied in type 2 diabetes patients below 18 years of age and is not recommended for use in pediatric patients.

Victoza® should be used with caution in patients with hepatic impairment.

Please see brief summary of Prescribing Information on adjacent page.

* Victoza® 1.2 mg and 1.8 mg when used alone or in combination with OADs. † Crossix ScoreBoard™ Report, September 2011. Adherence measured by number of actual Victoza® prescriptions fi lled for existing Victoza® patients enrolled in VictozaCare™ versus a match-pair control group not enrolled in VictozaCare™ through fi rst 8 months of enrollment.

Low rate ofhypoglycemia

May reduce weight— Victoza® is not indicated

for the management of obesity, and weight change was a secondary end point in clinical trials

Flexible dosing any time of day, independent of meals

VictozaCare™ helps patients stay on track with ongoing support— Patients enrolled in

VictozaCare™ were more adherent to Victoza® than those not enrolled†

May/June 2012, Vol 5, No 3

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