November/December 2009, Vol 2, No 7

Wellness and the Governing Dynamics of Healthcare ReformRobert E. Henry

How the US Government Rations Healthcare Scott Gottlieb, MD

Doctors on Healthcare Reform Betsy McCaughey

Health Plan Retention and Pharmacy Costs of Newly Diagnosed Patientswith Chronic Kidney Disease in a Managed Care PopulationMaureen Kubacki, PharmD, MBA; Chureen Carter, PharmD, MS; Alan D.L. Herrera, PharmD; Jim Wang, PhD; Janice M. Lopez, PharmD; Catherine T. Piech, MBA

Stakeholder Perspective by Jeff Januska, PharmD

Quality Improvement Initiatives: The Missed Opportunity for Health PlansSara Fernandez-Lopez, PhD; Barbara Lennert, RN, BSN, MAOM

Stakeholder Perspective Jeffrey A. Bourret, MS, RPh, FASHP

Economic Evaluation of Quality-of-Life Improvement with Second-GenerationAntihistamines and Montelukast in Patients with Allergic RhinitisKim R. Saverno, RPh; Brian Seal, PhD; Michael J. Goodman, PhD; Kellie Meyer, PharmD

Stakeholder Perspective by Paul Anthony Polansky, BSPharm, MBA

◆ Industry TrendsManagement Tools for Molecular Diagnostic Testing

◆ Generic Drug TrendsIncreases in Drug Utilization and Patent Expirations: A Recipe for Growth ofGenerics’ Market Share, despite Stalling on Biosimilars

REGULATORY

BUSINESS

EDITORIAL

CLINICAL

COMMENTARIES

DEPARTMENTS

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©2009 Engage Healthcare Communications, LLCwww.AHDBonline.com

NOVEMBER/DECEMBER 2009 VOLUME 2, NUMBER 7

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN™

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

Covers:Cover 12/11/09 4:25 PM Page C1

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Significantly Lower Erythropoiesis-Stimulating Agent (ESA) Cost With PROCRIT®1

Significantly Lower Mean ESA Cost per Hospitalization5

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(units PROCRIT®:mcg darbepoetin alfa) (units PROCRIT®:mcg darbepoetin alfa)

255:1 211:1 * Based on Analysource pricing, July 22, 2009. † The weekly dose equivalent for this ratio is 40,000 U:114 mcg.

<350:1infers lower cost for PROCRIT®,

based on July 2009 WAC* †

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CONTROL THE COST. MEASURE THE SAVINGS.

For Anemic Cancer Patients on Myelosuppressive Chemotherapy…

Signifi cantly Better Drug Cost Control With PROCRIT®

OUTPATIENT SETTING

INPATIENT SETTING

Calculation of breakeven ratio:

• PROCRIT® = $14.44/1000 Units • Darbepoetin alfa = $5.06/mcg • How many Units of PROCRIT® for $5.06? (1000 Units x $5.06)/(14.44) = 350 Units

References: 1. Vekeman F, McKenzie RS, Bookhart BK, et al. Drug utilisation and cost considerations of erythropoiesis stimulating agents in oncology patients receiving chemotherapy: observations from a large managed-care database. J Med Econ. 2009;12(1):1-8. 2. Burton T, Larholt K, Apgar E, et al. Hematologic outcomes of FDA-approved fi xed initial erythropoiesis-stimulating agent (ESA) doses in cancer patients with chemotherapy-induced anemia (CIA): real world data from an observational study. Poster presented at: the 4th Annual Chicago Supportive Oncology Conference; October 15-18, 2008; Chicago, IL. 3. Harley C, Muser E, Rey GG, McKenzie RS, Piech CT, Borah B. Comparison of utilization patterns, resource use and treatment costs among cancer patients treated with epoetin alfa or darbepoetin alfa. Poster presented at: the 41st American Society of Health-System Pharmacy (ASHP) Midyear Clinical Meeting and Exhibition; December 3-7, 2006; Orange County, CA. 4. McLaughlin T, Mody SH, McKenzie RS. Real-world dosing of erythropoietic agents in a nationwide sample of patients with cancer receiving chemotherapy: results from a large retrospective, observational study. Poster presented at: the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) 11th Annual International Meeting; May 20-24, 2006; Philadelphia, PA. 5. Vekeman F, Bailey RA, Lafeuille M-H, McKenzie RS, Herrera A, Lefebvre P. Comparison of Epoetin alfa and darbepoetin alfa dosing patterns and costs in cancer inpatients receiving chemotherapy. Poster presented at: International Society for Pharmacoeconomics and Outcomes Research (ISPOR) 14th Annual International Meeting; May 16-20, 2009; Orlando, FL.

HCEI for formulary committees or similar entities as per FDAMA section 114.

Please see Indication and Important Safety Information, including Boxed WARNINGS, on adjacent page.

Retrospective cohort study of PharMetrics Patient-Centric database from >85 US healthcare plans during January 2006 to January 2008.1

• Patients received ≥2 doses of either PROCRIT® (n=4111) or darbepoetin alfa (n=6817)

• Based on 2008 wholesale acquisition cost (WAC): PROCRIT®, $13.13/1000 Units; darbepoetin alfa, $4.722/mcg

• Mean cumulative dose: PROCRIT®, 329,129 Units; darbepoetin alfa, 1289 mcg

These fi ndings are consistent with previous studies2-4 and provide an additional basis of comparison of ESA treatments for healthcare professionals, hospital systems, and policy decision makers.1

• This information is not intended to make comparative effi cacy, safety, or dosing comparisons between these agents

Retrospective analysis of records from the Premier Perspective Comparative Hospital database of >500 hospitals nationwide during January 2006 to March 2008.5

• Patients received ≥1 dose of either PROCRIT® (n=8854) or darbepoetin alfa (n=2709)

• Based on 2008 WAC: PROCRIT®, $13.77/1000 Units; darbepoetin alfa, $4.818/mcg

• This information is not intended to make comparative effi cacy, safety, or dosing comparisons between these agents


PROCRIT® Indication PROCRIT® is indicated for the treatment of anemia due to the effect of concomitantly administered chemotherapy based on studies that have shown a reduction in the need for RBC transfusions in patients with metastatic, non-myeloid malignancies receiving chemotherapy for a minimum of 2 months. Studies to determine whether PROCRIT®

increases mortality or decreases progression-free/recurrence-free survival are ongoing. • PROCRIT® is not indicated for use in patients receiving hormonal

agents, therapeutic biologic products, or radiotherapy unless receivingconcomitant myelosuppressive chemotherapy.

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

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

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

Important Safety Information

WARNINGS: INCREASED MORTALITY, SERIOUS CARDIOVASCULAR and THROMBOEMBOLIC EVENTS, and INCREASED RISK OF TUMOR PROGRESSION OR RECURRENCERenal failure: Patients experienced greater risks for death and serious cardiovascular events when administered erythropoiesis-stimulating agents (ESAs) to target higher versuslower hemoglobin levels (13.5 vs. 11.3 g/dL; 14 vs. 10 g/dL) in two clinical studies. Individualize dosing to achieve and maintain hemoglobin levels within the range of 10 to 12 g/dL. Cancer: • ESAs shortened overall survival and/or increased the risk of

tumor progression or recurrence in some clinical studies in patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers (see WARNINGS: Table 1).

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

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

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

• Discontinue following the completion of a chemotherapy course.Perisurgery: PROCRIT® (Epoetin alfa) increased the rate of deep venous thromboses in patients not receiving prophylactic anticoagulation. Consider deep venous thrombosis prophylaxis.

Contraindications• PROCRIT® is contraindicated in patients with uncontrolled hypertension

or with known hypersensitivity to albumin (human) or mammalian cell-derived products.

Additional Important Safety Information• Patients with chronic renal failure experienced greater risks for death

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

• PROCRIT® therapy should not be initiated at hemoglobin levels 10 g/dL.

• The dose of PROCRIT® should be titrated for each patient to achieve and maintain the lowest hemoglobin level suffi cient to avoid the need for blood transfusion.

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

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

• Cases of pure red cell aplasia (PRCA) and of severe anemia, with or without other cytopenias, associated with neutralizing antibodies to erythropoietin have been reported in patients treated with PROCRIT®; predominantly in patients with chronic renal failure receiving PROCRIT® by subcutaneous administration. PRCA has also been reported in patients receiving ESAs while undergoing treatment for hepatitis C with interferon and ribavirin. If any patient develops a sudden loss of response to PROCRIT®, accompanied by severe anemia and low reticulocyte count, and anti-erythropoietin antibody-associated anemia is suspected, withhold PROCRIT® and other erythropoietic proteins. Contact ORTHO BIOTECH (1-888-2ASKOBI or 1-888-227-5624) to perform assays for binding and neutralizing antibodies. If erythropoietin antibody-mediated anemia is confirmed, PROCRIT® should be permanently discontinued and patients should not be switched to other erythropoietic proteins.

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

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

• Prior to and regularly during PROCRIT® therapy monitor iron status; transferrin saturation should be 20% and ferritin should be

100 ng/mL. During therapy absolute or functional iron deficiency may develop and all patients will eventually require supplemental iron to adequately support erythropoiesis stimulated by PROCRIT®.

• Treatment of patients with grossly elevated serum erythropoietin levels (e.g., >200 mUnits/mL) is not recommended.

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

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

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

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

Manufactured by: Amgen Inc., Thousand Oaks, California 91320-1799 Distributed by: Centocor Ortho Biotech Products, L.P., Horsham, Pennsylvania 19044-3607 © Centocor Ortho Biotech Products, L.P. 2009 10/09 08PCO9019 445782

• Darbepoetin alfa = $5.06/mcg • How many Units of PROCRIT®

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BRIEF SUMMARY OF PROCRIT® PRESCRIBING INFORMATION FOR THE TREATMENT OF ANEMIA INCANCER PATIENTS ON CHEMOTHERAPY

PROCRIT®

(Epoetin alfa)FOR INJECTION

FOR FULL PRESCRIBING INFORMATION FOR ALL INDICATIONS, REFER TO THE PHYSICIANS’ DESK REFERENCE®

INDICATIONS AND USAGEPROCRIT® is indicated for the treatment of anemia due to the effect of concomitantly administeredchemotherapy based on studies that have shown a reduction in the need for RBC transfusions in patients withmetastatic, non-myeloid malignancies receiving chemotherapy for a minimum of 2 months. Studies to determinewhether PROCRIT® increases mortality or decreases progression-free/recurrence-free survival are ongoing.• PROCRIT® is not indicated for use in patients receiving hormonal agents, therapeutic biologic products, or

radiotherapy unless receiving concomitant myelosuppressive chemotherapy.• PROCRIT® is not indicated for patients receiving myelosuppressive therapy when the anticipated outcome

is cure due to the absence of studies that adequately characterize the impact of PROCRIT® on progression-free and overall survival (see WARNINGS: Increased Mortality and/or Increased Risk of Tumor Progressionor Recurrence).

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

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

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

WARNINGSPediatricsRisk in Premature InfantsThe multidose preserved formulation contains benzyl alcohol. Benzyl alcohol has been reported to beassociated with an increased incidence of neurological and other complications in premature infants which aresometimes fatal.

AdultsIncreased Mortality, Serious Cardiovascular and Thromboembolic EventsPatients with chronic renal failure experienced greater risks for death and serious cardiovascular events whenadministered erythropoiesis-stimulating agents (ESAs) to target higher versus lower hemoglobin levels (13.5vs. 11.3 g/dL; 14 vs. 10 g/dL) in two clinical studies. Patients with chronic renal failure and an insufficienthemoglobin response to ESA therapy may be at even greater risk for cardiovascular events and mortality thanother patients. PROCRIT® and other ESAs increased the risks for death and serious cardiovascular events incontrolled clinical trials of patients with cancer. These events included myocardial infarction, stroke, congestiveheart failure, and hemodialysis vascular access thrombosis. A rate of hemoglobin rise of > 1 g/dL over 2 weeksmay contribute to these risks.In a randomized prospective trial, 1432 anemic chronic renal failure patients who were not undergoing dialysiswere assigned to Epoetin alfa (rHuEPO) treatment targeting a maintenance hemoglobin concentration of 13.5 g/dL or 11.3 g/dL. A major cardiovascular event (death, myocardial infarction, stroke, or hospitalization forcongestive heart failure) occurred among 125 (18%) of the 715 patients in the higher hemoglobin groupcompared to 97 (14%) among the 717 patients in the lower hemoglobin group (HR 1.3, 95% CI: 1.0, 1.7, p = 0.03).Increased risk for serious cardiovascular events was also reported from a randomized, prospective trial of 1265hemodialysis patients with clinically evident cardiac disease (ischemic heart disease or congestive heartfailure). In this trial, patients were assigned to PROCRIT® treatment targeted to a maintenance hematocrit ofeither 42 ± 3% or 30 ± 3%. Increased mortality was observed in 634 patients randomized to a targethematocrit of 42% [221 deaths (35% mortality)] compared to 631 patients targeted to remain at a hematocritof 30% [185 deaths (29% mortality)]. The reason for the increased mortality observed in this study is unknown,however, the incidence of non-fatal myocardial infarctions (3.1% vs. 2.3%), vascular access thromboses (39%vs. 29%), and all other thrombotic events (22% vs. 18%) were also higher in the group randomized to achievea hematocrit of 42%. An increased incidence of thrombotic events has also been observed in patients withcancer treated with erythropoietic agents. In a randomized controlled study (referred to as Cancer Study 1 - the ‘BEST’ study) with another ESA in 939women with metastatic breast cancer receiving chemotherapy, patients received either weekly Epoetin alfa orplacebo for up to a year. This study was designed to show that survival was superior when an ESA wasadministered to prevent anemia (maintain hemoglobin levels between 12 and 14 g/dL or hematocrit between36% and 42%). The study was terminated prematurely when interim results demonstrated that a highermortality at 4 months (8.7% vs. 3.4%) and a higher rate of fatal thrombotic events (1.1% vs. 0.2%) in the first4 months of the study were observed among patients treated with Epoetin alfa. Based on Kaplan-Meierestimates, at the time of study termination, the 12-month survival was lower in the Epoetin alfa group than inthe placebo group (70% vs. 76%; HR 1.37, 95% CI: 1.07, 1.75; p = 0.012).A systematic review of 57 randomized controlled trials (including Cancer Studies 1 and 5 - the ‘BEST’ and‘ENHANCE’ studies) evaluating 9353 patients with cancer compared ESAs plus red blood cell transfusion withred blood cell transfusion alone for prophylaxis or treatment of anemia in cancer patients with or withoutconcurrent antineoplastic therapy. An increased relative risk of thromboembolic events (RR 1.67, 95% CI: 1.35,2.06; 35 trials and 6769 patients) was observed in ESA-treated patients. An overall survival hazard ratio of 1.08(95% CI: 0.99, 1.18; 42 trials and 8167 patients) was observed in ESA-treated patients.An increased incidence of deep vein thrombosis (DVT) in patients receiving Epoetin alfa undergoing surgicalorthopedic procedures has been observed (see ADVERSE REACTIONS, Surgery Patients: Thrombotic/VascularEvents in full Prescribing Information). In a randomized controlled study (referred to as the ‘SPINE’ study), 681adult patients, not receiving prophylactic anticoagulation and undergoing spinal surgery, received either 4 doses of 600 U/kg Epoetin alfa (7, 14, and 21 days before surgery, and the day of surgery) and standard ofcare (SOC) treatment, or SOC treatment alone. Preliminary analysis showed a higher incidence of DVT,

determined by either Color Flow Duplex Imaging or by clinical symptoms, in the Epoetin alfa group [16 patients(4.7%)] compared to the SOC group [7 patients (2.1%)]. In addition, 12 patients in the Epoetin alfa group and 7 patients in the SOC group had other thrombotic vascular events. Deep venous thrombosis prophylaxis shouldbe strongly considered when ESAs are used for the reduction of allogeneic RBC transfusions in surgical patients(see BOXED WARNINGS and DOSAGE AND ADMINISTRATION in full Prescribing Information).Increased mortality was also observed in a randomized placebo-controlled study of PROCRIT® in adult patientswho were undergoing coronary artery bypass surgery (7 deaths in 126 patients randomized to PROCRIT®

versus no deaths among 56 patients receiving placebo). Four of these deaths occurred during the period ofstudy drug administration and all four deaths were associated with thrombotic events. ESAs are not approvedfor reduction of allogeneic red blood cell transfusions in patients scheduled for cardiac surgery.

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

Table 1: Randomized, Controlled Trials with Decreased Survival and/or Decreased Locoregional ControlAdverse

Achieved Outcome for Hemoglobin Hemoglobin Primary ESA-containing

Study / Tumor / (n) Target (Median Q1,Q3) Endpoint ArmChemotherapyCancer Study 1Metastatic breast 12-14 g/dL 12.9 g/dL 12-month overall Decreased 12-monthcancer (n=939) 12.2, 13.3 g/dL survival survivalCancer Study 2Lymphoid 13-15 g/dL (M) 11.0 g/dL Proportion of Decreased overallmalignancy (n=344) 13-14 g/dL (F) 9.8, 12.1 g/dL patients achieving survival

a hemoglobinresponse

Cancer Study 3Early breast 12.5-13 g/dL 13.1 g/dL Relapse-free and Decreased 3 yr. cancer (n=733) 12.5, 13.7 g/dL overall survival relapse-free and

overall survivalCancer Study 4Cervical Cancer 12-14 g/dL 12.7 g/dL Progression-free Decreased 3 yr. (n=114) 12.1, 13.3 g/dL and overall survival progression-free

and locoregional and overall survivalcontrol and locoregional

controlRadiotherapy AloneCancer Study 5Head and neck 15 g/dL (M) Not available Locoregional Decreased 5-yearcancer (n=351) 14 g/dL (F) progression-free locoregional

survival progression-free survival

Decreased overallsurvival

Cancer Study 6Head and neck 14-15.5 g/dL Not available Locoregional Decreasedcancer (n=522) disease control locoregional

disease controlNo Chemotherapy or RadiotherapyCancer Study 7Non-small cell 12-14 g/dL Not available Quality of life Decreased overalllung cancer (n=70) survivalCancer Study 8Non-myeloid 12-13 g/dL 10.6 g/dL RBC transfusions Decreased overallmalignancy (n=989) 9.4, 11.8 g/dL survival

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

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

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

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

Decreased progression-free survival and overall survival:Cancer Study 3 (the ‘PREPARE’ study) was a randomized controlled study in which darbepoetin alfa wasadministered to prevent anemia conducted in 733 women receiving neo-adjuvant breast cancer treatment.After a median follow-up of approximately 3 years, the survival rate (86% vs. 90%, HR 1.42, 95% CI: 0.93, 2.18)and relapse-free survival rate (72% vs. 78%, HR 1.33, 95% CI: 0.99, 1.79) were lower in the darbepoetin alfa-treated arm compared to the control arm.

Cancer Study 4 (protocol GOG 191) was a randomized controlled study that enrolled 114 of a planned 460cervical cancer patients receiving chemotherapy and radiotherapy. Patients were randomized to receiveEpoetin alfa to maintain hemoglobin between 12 and 14 g/dL or to transfusion support as needed. The studywas terminated prematurely due to an increase in thromboembolic events in Epoetin alfa-treated patientscompared to control (19% vs. 9%). Both local recurrence (21% vs. 20%) and distant recurrence (12% vs. 7%)were more frequent in Epoetin alfa-treated patients compared to control. Progression-free survival at 3 yearswas lower in the Epoetin alfa-treated group compared to control (59% vs. 62%, HR 1.06, 95% CI: 0.58, 1.91).Overall survival at 3 years was lower in the Epoetin alfa-treated group compared to control (61% vs. 71%, HR1.28, 95% CI: 0.68, 2.42).

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

WARNINGS: INCREASED MORTALITY, SERIOUS CARDIOVASCULAR and THROMBOEMBOLIC EVENTS,and INCREASED RISK OF TUMOR PROGRESSION OR RECURRENCERenal failure: Patients experienced greater risks for death and serious cardiovascular events whenadministered erythropoiesis-stimulating agents (ESAs) to target higher versus lower hemoglobinlevels (13.5 vs. 11.3 g/dL; 14 vs. 10 g/dL) in two clinical studies. Individualize dosing to achieve andmaintain hemoglobin levels within the range of 10 to 12 g/dL. Cancer:• ESAs shortened overall survival and/or increased the risk of tumor progression or recurrence in

some clinical studies in patients with breast, non-small cell lung, head and neck, lymphoid, andcervical cancers (see WARNINGS: Table 1).

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

• Use ESAs only for treatment of anemia due to concomitant myelosuppressive chemotherapy. • ESAs are not indicated for patients receiving myelosuppressive therapy when the anticipated

outcome is cure.• Discontinue following the completion of a chemotherapy course. Perisurgery: PROCRIT® increased the rate of deep venous thromboses in patients not receiving prophylactic anticoagulation. Consider deep venous thrombosis prophylaxis.(See WARNINGS: Increased Mortality, Serious Cardiovascular and Thromboembolic Events,WARNINGS: Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence, INDICATIONS AND USAGE, and DOSAGE AND ADMINISTRATION in full Prescribing Information.)


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

Pure Red Cell AplasiaCases of pure red cell aplasia (PRCA) and of severe anemia, with or without other cytopenias, associated withneutralizing antibodies to erythropoietin have been reported in patients treated with PROCRIT®. This has beenreported predominantly in patients with CRF receiving ESAs by subcutaneous administration. PRCA has alsobeen reported in patients receiving ESAs while undergoing treatment for hepatitis C with interferon andribavirin. Any patient who develops a sudden loss of response to PROCRIT®, accompanied by severe anemiaand low reticulocyte count, should be evaluated for the etiology of loss of effect, including the presence ofneutralizing antibodies to erythropoietin (see PRECAUTIONS: Lack or Loss of Response). If anti-erythropoietinantibody-associated anemia is suspected, withhold PROCRIT® and other ESAs. Contact ORTHO BIOTECH at 1 888 2ASK OBI (1-888-227-5624) to perform assays for binding and neutralizing antibodies. PROCRIT® shouldbe permanently discontinued in patients with antibody-mediated anemia. Patients should not be switched toother ESAs as antibodies may cross-react (see ADVERSE REACTIONS: Immunogenicity).Albumin (Human)PROCRIT® contains albumin, a derivative of human blood. Based on effective donor screening and productmanufacturing processes, it carries an extremely remote risk for transmission of viral diseases. A theoreticalrisk for transmission of Creutzfeldt-Jakob disease (CJD) also is considered extremely remote. No cases oftransmission of viral diseases or CJD have ever been identified for albumin.

PRECAUTIONSThe parenteral administration of any biologic product should be attended by appropriate precautions in caseallergic or other untoward reactions occur (see CONTRAINDICATIONS). In clinical trials, while transient rasheswere occasionally observed concurrently with PROCRIT® therapy, no serious allergic or anaphylactic reactionswere reported (see ADVERSE REACTIONS in full Prescribing Information for more information regarding allergicreactions).The safety and efficacy of PROCRIT® therapy have not been established in patients with a known history of aseizure disorder or underlying hematologic disease (eg, sickle cell anemia, myelodysplastic syndromes, orhypercoagulable disorders).In some female patients, menses have resumed following PROCRIT® therapy; the possibility of pregnancy shouldbe discussed and the need for contraception evaluated.Hematology: Exacerbation of porphyria has been observed rarely in patients with CRF treated with PROCRIT®.However, PROCRIT® has not caused increased urinary excretion of porphyrin metabolites in normal volunteers,even in the presence of a rapid erythropoietic response. Nevertheless, PROCRIT® should be used with cautionin patients with known porphyria.In preclinical studies in dogs and rats, but not in monkeys, PROCRIT® therapy was associated with subclinicalbone marrow fibrosis. Bone marrow fibrosis is a known complication of CRF in humans and may be related tosecondary hyperparathyroidism or unknown factors. The incidence of bone marrow fibrosis was not increasedin a study of adult patients on dialysis who were treated with PROCRIT® for 12 to 19 months, compared to theincidence of bone marrow fibrosis in a matched group of patients who had not been treated with PROCRIT®.Cancer patients should have hemoglobin measured once a week until hemoglobin has been stabilized, andmeasured periodically thereafter. Lack or Loss of Response: If the patient fails to respond or to maintain a response to doses within therecommended dosing range, the following etiologies should be considered and evaluated: 1. Iron deficiency:Virtually all patients will eventually require supplemental iron therapy (see IRON EVALUATION); 2. Underlyinginfectious, inflammatory, or malignant processes; 3. Occult blood loss; 4. Underlying hematologic diseases (ie, thalassemia, refractory anemia, or other myelodysplastic disorders); 5. Vitamin deficiencies: Folic acid orvitamin B12; 6. Hemolysis; 7. Aluminum intoxication; 8. Osteitis fibrosa cystica; 9. Pure Red Cell Aplasia (PRCA)or anti-erythropoietin antibody-associated anemia: In the absence of another etiology, the patient should beevaluated for evidence of PRCA and sera should be tested for the presence of antibodies to erythropoietin (seeWARNINGS: Pure Red Cell Aplasia).Iron Evaluation: During PROCRIT® therapy, absolute or functional iron deficiency may develop. Functional irondeficiency, with normal ferritin levels but low transferrin saturation, is presumably due to the inability tomobilize iron stores rapidly enough to support increased erythropoiesis. Transferrin saturation should be atleast 20% and ferritin should be at least 100 ng/mL.Prior to and during PROCRIT® therapy, the patient’s iron status, including transferrin saturation (serum irondivided by iron binding capacity) and serum ferritin, should be evaluated. Virtually all patients will eventuallyrequire supplemental iron to increase or maintain transferrin saturation to levels which will adequately supporterythropoiesis stimulated by PROCRIT®. Drug Interaction: No evidence of interaction of PROCRIT® with other drugs was observed in the course ofclinical trials.Carcinogenesis, Mutagenesis, and Impairment of Fertility: Carcinogenic potential of PROCRIT® has notbeen evaluated. PROCRIT® does not induce bacterial gene mutation (Ames Test), chromosomal aberrations inmammalian cells, micronuclei in mice, or gene mutation at the HGPRT locus. In female rats treated IV withPROCRIT®, there was a trend for slightly increased fetal wastage at doses of 100 and 500 Units/kg.Pregnancy Category C: PROCRIT® has been shown to have adverse effects in rats when given in doses 5 times the human dose. There are no adequate and well-controlled studies in pregnant women. PROCRIT®

should be used during pregnancy only if potential benefit justifies the potential risk to the fetus.In studies in female rats, there were decreases in body weight gain, delays in appearance of abdominal hair,delayed eyelid opening, delayed ossification, and decreases in the number of caudal vertebrae in the F1 fetusesof the 500 Units/kg group. In female rats treated IV, there was a trend for slightly increased fetal wastage atdoses of 100 and 500 Units/kg. PROCRIT® has not shown any adverse effect at doses as high as 500 Units/kgin pregnant rabbits (from day 6 to 18 of gestation).Nursing Mothers: Postnatal observations of the live offspring (F1 generation) of female rats treated withPROCRIT® during gestation and lactation revealed no effect of PROCRIT® at doses of up to 500 Units/kg. Therewere, however, decreases in body weight gain, delays in appearance of abdominal hair, eyelid opening, anddecreases in the number of caudal vertebrae in the F1 fetuses of the 500 Units/kg group. There were noPROCRIT®-related effects on the F2 generation fetuses.It is not known whether PROCRIT® is excreted in human milk. Because many drugs are excreted in human milk,caution should be exercised when PROCRIT® is administered to a nursing woman.Pediatric Use: See WARNINGS: PediatricsPediatric Cancer Patients on Chemotherapy: The safety and effectiveness of PROCRIT® were evaluated in arandomized, double-blind, placebo-controlled, multicenter study (see CLINICAL EXPERIENCE, Weekly (QW)Dosing, Pediatric Patients in full Prescribing Information).Geriatric Use: Insufficient numbers of patients age 65 or older were enrolled in clinical studies of PROCRIT®

for the treatment of anemia associated with pre-dialysis chronic renal failure, cancer chemotherapy, andZidovudine-treatment of HIV infection to determine whether they respond differently from younger subjects.

Information for PatientsPatients should be informed of the increased risks of mortality, serious cardiovascular events, thromboembolicevents, and increased risk of tumor progression or recurrence (see WARNINGS). In those situations in which thephysician determines that a patient or their caregiver can safely and effectively administer PROCRIT® at home,instruction as to the proper dosage and administration should be provided. Patients should be instructed to readthe PROCRIT® Medication Guide and Patient Instructions for Use and should be informed that the MedicationGuide is not a disclosure of all possible side effects. Patients should be informed of the possible side effects ofPROCRIT® and of the signs and symptoms of allergic drug reaction and advised of appropriate actions. If homeuse is prescribed for a patient, the patient should be thoroughly instructed in the importance of proper disposaland cautioned against the reuse of needles, syringes, or drug product. A puncture-resistant container should be

available for the disposal of used syringes and needles, and guidance provided on disposal of the full container. Hypertension: Hypertension, associated with a significant increase in hemoglobin, has been noted rarely inpatients treated with PROCRIT®. Nevertheless, blood pressure in patients treated with PROCRIT® should bemonitored carefully, particularly in patients with an underlying history of hypertension or cardiovasculardisease.Seizures: In double-blind, placebo-controlled trials, 3.2% (n = 2/63) of patients treated with PROCRIT® TIWand 2.9% (n = 2/68) of placebo-treated patients had seizures. Seizures in 1.6% (n = 1/63) of patients treatedwith PROCRIT® TIW occurred in the context of a significant increase in blood pressure and hematocrit frombaseline values. However, both patients treated with PROCRIT® also had underlying CNS pathology which mayhave been related to seizure activity.In a placebo-controlled, double-blind trial utilizing weekly dosing with PROCRIT®, 1.2% (n = 2/168) of safety-evaluable patients treated with PROCRIT® and 1% (n = 1/165) of placebo-treated patients had seizures.Seizures in the patients treated with weekly PROCRIT® occurred in the context of a significant increase inhemoglobin from baseline values however significant increases in blood pressure were not seen. Thesepatients may have had other CNS pathology.Thrombotic Events: In double-blind, placebo-controlled trials, 3.2% (n = 2/63) of patients treated withPROCRIT® TIW and 11.8% (n = 8/68) of placebo-treated patients had thrombotic events (eg, pulmonaryembolism, cerebrovascular accident), (see WARNINGS: Increased Mortality, Serious Cardiovascular andThromboembolic Events).In a placebo-controlled, double-blind trial utilizing weekly dosing with PROCRIT®, 6.0% (n = 10/168) of safety-evaluable patients treated with PROCRIT® and 3.6% (n = 6/165) (p = 0.444) of placebo-treated patients hadclinically significant thrombotic events (deep vein thrombosis requiring anticoagulant therapy, embolic eventincluding pulmonary embolism, myocardial infarction, cerebral ischemia, left ventricular failure and thromboticmicroangiopathy). A definitive relationship between the rate of hemoglobin increase and the occurrence ofclinically significant thrombotic events could not be evaluated due to the limited schedule of hemoglobinmeasurements in this study. The safety and efficacy of PROCRIT® were evaluated in a randomized, double-blind, placebo-controlled,multicenter study that enrolled 222 anemic patients ages 5 to 18 receiving treatment for a variety of childhoodmalignancies. Due to the study design (small sample size and the heterogeneity of the underlying malignanciesand of anti-neoplastic treatments employed), a determination of the effect of PROCRIT® on the incidence ofthrombotic events could not be performed. In the PROCRIT® arm, the overall incidence of thrombotic events was10.8% and the incidence of serious or life-threatening events was 7.2%.

ADVERSE REACTIONSImmunogenicityAs with all therapeutic proteins, there is the potential for immunogenicity. Neutralizing antibodies toerythropoietin, in association with PRCA or severe anemia (with or without other cytopenias), have been reportedin patients receiving PROCRIT® (see WARNINGS: Pure Red Cell Aplasia) during post-marketing experience.There has been no systematic assessment of immune responses, i.e., the incidence of either binding orneutralizing antibodies to PROCRIT®, in controlled clinical trials.Where reported, the incidence of antibody formation is highly dependent on the sensitivity and specificity of theassay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assaymay be influenced by several factors including assay methodology, sample handling, timing of samplecollection, concomitant medications, and underlying disease. For these reasons, comparison of the incidenceof antibodies across products within this class (erythropoietic proteins) may be misleading.

Adverse Experiences Reported in Clinical TrialsIn double-blind, placebo-controlled studies of up to 3 months duration involving 131 cancer patients, adverseevents with an incidence > 10% in either patients treated with PROCRIT® or placebo-treated patients were asindicated below:

Percent of Patients Reporting Event

Patients Treated Placebo-treatedWith PROCRIT® Patients

Event (n = 63) (n = 68)Pyrexia 29% 19%Diarrhea 21%* 7%Nausea 17%* 32%Vomiting 17% 15%Edema 17%* 1%Asthenia 13% 16%Fatigue 13% 15%Shortness of Breath 13% 9%Parasthesia 11% 6%Upper Respiratory Infection 11% 4%Dizziness 5% 12%Trunk Pain 3%* 16%

* Statistically significant

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

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

OVERDOSAGEThe expected manifestations of PROCRIT® overdosage include signs and symptoms associated with anexcessive and/or rapid increase in hemoglobin concentration, including any of the cardiovascular eventsdescribed in WARNINGS and listed in ADVERSE REACTIONS in full Prescribing Information. Patients receiving anoverdosage of PROCRIT® should be monitored closely for cardiovascular events and hematologicabnormalities. Polycythemia should be managed acutely with phlebotomy, as clinically indicated. Followingresolution of the effects due to PROCRIT® overdosage, reintroduction of PROCRIT® therapy should beaccompanied by close monitoring for evidence of rapid increases in hemoglobin concentration (>1 gm/dL per14 days). In patients with an excessive hematopoietic response, reduce the PROCRIT® dose in accordance withthe recommendations described in DOSAGE AND ADMINISTRATION in full Prescribing Information.

PROCRIT® (Epoetin alfa) FOR INJECTION

Manufactured by:Amgen Inc.One Amgen Center DriveThousand Oaks, CA 91320-1799

Distributed by:Ortho Biotech Products, L.P.Raritan, New Jersey 08869-0670

Revised 04/2009© OBPLP 200010112803BC

3-4 1 3:54 PM


266 AMERICAN HEALTH & DRUG BENEFITS November/December 2009 VOL. 2 NO. 7

EDITORIAL BOARD

CLINICAL EDITOR Thomas G. McCarter, MD, FACPChief Clinical OfficerExecutive Health Resources, PA

GOVERNMENT EDITORKevin B. “Kip” Piper, MA, FACHEPresident, Health Results GroupSr. Counselor, Fleishman-Hillard Washington, DC

ACTUARY David WilliamsMilliman Health ConsultantWindsor, CT

CANCER RESEARCHAl B. Benson, III, MD, FACPProfessor of MedicineAssociate Director for ClinicalInvestigationsRobert H. Lurie Comprehensive CancerCenter, Northwestern UniversityChair, Board of Directors, NCCN

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

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

EMPLOYERSAlberto M. Colombi, MD, MPHCorporate Medical DirectorPPG Industries, Pittsburgh, PA

Wayne M. Lednar, MD, PhDGlobal Chief Medical OfficerDirector, Integrated Health ServicesDuPont, Wilmington, DE

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

F. Randy Vogenberg, RPh, PhDChief Strategy OfficerEmployer-based Pharmaceutical StrategiesSenior Scholar, Department of Health Policy, Thomas Jefferson University

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

Nirav R. Shah, MD, MPHAssistant Professor of MedicineNYU School of Medicine, NYCSenior Investigator, Geisinger HealthSystem, Danville, PA

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

HEALTH OUTCOMES RESEARCH Gordon M. Cummins, MSDirector, IntegriChain

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

MANAGED CARE & GOVERNMENT AFFAIRSSharad Mansukani, MDChief Strategic Officer, Nations HealthSenior Advisor, Texas Pacific Group, FL

MANAGED MARKETS Jeffrey A. Bourret, MS, RPh, FASHPSenior Director, Customer Marketing & Innovation, US Specialty CustomersPfizer Specialty Business UnitCollegeville, PA

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

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, PhDAssociate Professor 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 PharmacyAtrius HealthHarvard Vanguard Medical Associates

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

Paul Anthony Polansky, BSPharm, MBAExecutive VP and Chief Pharmacy OfficerSanovia Corp., Philadelphia, 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

Alex Hathaway, MD, MPH, FACPMSenior Medical Policy AdvisorGovernment ProgramsGlaxoSmithKline, Philadelphia, PA

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

REIMBURSEMENT POLICYGrant D. Lawless, BSPharm, MD, FACPExecutive Director for Payor RelationsCorporate AccountAmgen, Thousand Oaks, CA

Michael Schaffer, PharmD, MBADirector, Pharmacy ProgramsSanovia Co., Philadelphia, PA

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, PharmDVice President, Managed MarketsDiplomat Specialty PharmacySwartz Creek, MI

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

TOC_EditBoard:Cover 12/11/09 5:16 PM Page 266

JOIN AHDB PEER REVIEW

Articles fall into 3 main areas related to healthcare:Regulatory, Business, and Clinical. These main categoriesare represented from the different vantage points of allstakeholders in healthcare and are divided into manysubcategories, including (but not limited to):

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American Health & Drug Benefits is foundedon the concept that health and drug benefitshave undergone a transformation: the econo -metric value of a drug is of equal importanceto clinical outcomes as it is to serving as thebasis for securing coverage in formulariesand benefit designs. Benefit designs aregreatly affected by clinical, business, andpolicy conditions.

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Mission Statement

EDITORIAL

274 Wellness and the Governing Dynamics of Healthcare ReformRobert E. Henry

COMMENTARY

277 How the US Government Rations Healthcare Scott Gottlieb, MD

279 Doctors on Healthcare Reform Betsy McCaughey

BUSINESS

283 Health Plan Retention and Pharmacy Costs of Newly Diagnosed Patients withChronic Kidney Disease in a Managed Care PopulationMaureen Kubacki, PharmD, MBA; Chureen Carter, PharmD, MS; Alan D.L. Herrera,PharmD; Jim Wang, PhD; Janice M. Lopez, PharmD; Catherine T. Piech, MBA

290 Stakeholder Perspective by Jeff Januska, PharmD

REGULATORY

297 Quality Improvement Initiatives: The Missed Opportunity for Health PlansSara Fernandez-Lopez, PhD; Barbara Lennert, RN, BSN, MAOM

304 Stakeholder Perspective by Jeffrey A. Bourret, MS, RPh, FASHP

TABLE OF CONTENTS

Continued on page 270

(11/09) DI69732

1 1 5:06:19 PM


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269September/October 2009 www.AHDBonline.comVOL. 2 NO. 6

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American Health & Drug Benefits, ISSN 1942-2962 (print); ISSN 1942-2970 (online), ispublished 6 times a year by Engage HealthcareCommunications, LLC, 241 Forsgate Drive,Suite 205A, Monroe Township, NJ 08831.Copyright © 2009 by Engage Healthcare Communications, LLC. All rights reserved.American Health & Drug Benefits and The Peer-Reviewed Forum for Evidence in BenefitDesign are trademarks of Engage HealthcareCommunications, LLC. No part of this publication may be reproduced or transmittedin any form or by any means now or hereafterknown, electronic or mechanical, includingphotocopy, recording, or any informationalstorage and retrieval system, without writtenpermission from the Publisher. Printed in theUnited States of America.

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The ideas and opinions expressed in AmericanHealth & Drug Benefits do not necessarily reflect those of the Editorial Board, the Editors,or the Publisher. Publication of an advertise-ment or other product mentioned in American Health & Drug Benefits should not beconstrued as an endorsement of the product orthe manufacturer’s claims. Readers are encour-aged to contact the manufacturers about anyfeatures or limitations of products mentioned.Neither the Editors nor the Publisher assumeany responsibility for any injury and/or damageto persons or property arising out of or related to any use of the material mentionedin this publication.

POSTMASTER: CORRESPONDENCE REGARDING SUBSCRIPTIONS ORCHANGE OF ADDRESS should be directedto CIRCULATION DIRECTOR, AmericanHealth & Drug Benefits, 241 Forsgate Drive,Suite 205A, Monroe Township, NJ 08831.Fax: 732-992-1881. YEARLY SUBSCRIPTIONRATES: One year: $99.00 USD; Two years:$149.00 USD; Three years: $199.00 USD.

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CLINICAL

309 Economic Evaluation of Quality-of-Life Improvement with Second-GenerationAntihistamines and Montelukast in Patients with Allergic RhinitisKim R. Saverno, RPh; Brian Seal, PhD; Michael J. Goodman, PhD; Kellie Meyer, PharmD

316 Stakeholder Perspective by Paul Anthony Polansky, BSPharm, MBA

DEPARTMENTS

291 INDUSTRY TRENDSManagement Tools for Molecular Diagnostic Testing: Financial and ClinicalImplicationsDouglas Moeller, MD

293 GENERIC DRUG TRENDSIncreases in Drug Utilization and Patent Expirations: A Recipe for Growth ofGenerics’ Market Share, despite Stalling on Biosimilars Dalia Buffery, MA, ABD

318 ExECUTIvE SUMMARIES

CAPTION CONTEST

280

TABLE OF CONTENTS (Continued)


KAPIDEX is the fi rst and only PPI with a Dual Delayed Release™ (DDR) formulation, which provides a second release of drug

1200

1000

800

600

400

200

00 6 12 18 24

Time (h)

Mean plasma concentration (in healthy subjects; day 5; ng/mL)1

KAPIDEX 60 mgKAPIDEX 30 mgKAKKAKAKAKAKAKKKKKKAKAKAKAKAKAKAKAKAAAAAAKAKKAKAKAKAKKKAKAKAAKKKAKAKAKAKKAKAKAKAKAKAKKAKAKKKAKKAKAKKAKA

• KAPIDEX 30 mg provided full 24-hour heartburn relief in a majority of symptomatic non-erosive gastroesophageal reflux disease patients at week 41

• KAPIDEX 60 mg provided consistently high erosive esophagitis healing rates at week 81

• KAPIDEX offers a safety and tolerability profile similar to lansoprazole1

• KAPIDEX can be taken without regard to food1

KAPIDEX should be swallowed whole. Alternatively, capsules can be opened, sprinkled on 1 tablespoon of applesauce, and swallowed immediately. While KAPIDEX can be taken without regard to food, some patients may benefit from administering the dose prior to a meal if post-meal symptoms do not resolve under post-fed conditions.

Conclusions of comparative effi cacy cannot be drawn from this information.

IndicationsKAPIDEX is indicated for healing all grades of erosive esophagitis (EE) for up to 8 weeks, maintaining healing of EE for up to 6 months, and treating heartburn associated with symptomatic non-erosive gastroesophageal reflux disease (GERD) for 4 weeks.Important Safety Information KAPIDEX is contraindicated in patients with known hypersensitivity to any component of the formulation. Hypersensitivity and anaphylaxis have been reported with KAPIDEX use. Symptomatic response with KAPIDEX does not preclude the presence of gastric malignancy. Most commonly reported treatment-emergent adverse reactions (≥2%): diarrhea (4.8%), abdominal pain (4.0%), nausea (2.9%), upper respiratory tract infection (1.9%), vomiting (1.6%), and flatulence (1.6%). Do not co-administer atazanavir with KAPIDEX because atazanavir systemic concentrations may be substantially decreased. KAPIDEX may interfere with absorption of drugs for which gastric pH is important for bioavailability (e.g., ampicillin esters, digoxin, iron salts, ketoconazole). Patients taking concomitant warfarin may require monitoring for increases in international normalized ratio (INR) and prothrombin time. Increases in INR and prothrombin time may lead to abnormal bleeding, which can lead to serious consequences.Please see adjacent brief summary of prescribing information for KAPIDEX.

KAPIDEX WORKS ASECOND SHIFT TO HELP SHUT DOWN ACID PUMPS


BRIEF SUMMARY OF FULL PRESCRIBING INFORMATIONKAPIDEX™ (dexlansoprazole) delayed release capsules

INDICATIONS AND USAGEKAPIDEX is indicated for:

CONTRAINDICATIONS

[see Adverse Reactions]

WARNINGS AND PRECAUTIONSGastric Malignancy

ADVERSE REACTIONSClinical Trials Experience

Table 2: Incidence of Treatment-Emergent Adverse Reactions in Controlled Studies

Adverse Reaction

Placebo

(N=896)%

KAPIDEX 30 mg

(N=455)%

KAPIDEX 60 mg

(N=2218)%

KAPIDEX Total

(N=2621)%

Lansoprazole30 mg

(N=1363)%

Tract Infection

Blood and Lymphatic System Disorders: Cardiac Disorders:

Ear and Labyrinth Disorders: Endocrine Disorders: Eye Disorders:

Gastrointestinal Disorders:

General Disorders and Administration Site Conditions:

Hepatobiliary Disorders:Immune System Disorders:

Infections and Infestations:

Injury, Poisoning and Procedural Complications:Laboratory Investigations:

Metabolism and Nutrition Disorders: Musculoskeletal and Connective Tissue Disorders:

Nervous System Disorders:

Psychiatric Disorders: Renal and Urinary Disorders: Reproductive System and Breast Disorders:

; Respiratory, Thoracic and Mediastinal Disorders:

Skin and Subcutaneous Tissue Disorders: Vascular Disorders:

DRUG INTERACTIONSDrugs with pH-Dependent Absorption Pharmacokinetics

Warfarin

USE IN SPECIFIC POPULATIONS

PregnancyTeratogenic Effects


Nursing Mothers

[see Carcinogenesis, Mutagenesis, Impairment of Fertility]

Pediatric Use

Geriatric Use

]

Renal Impairment

.

Hepatic Impairment

.

OVERDOSAGE

CLINICAL PHARMACOLOGY

Pharmacodynamics

[see Nonclinical Toxicology ]

c

c

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

[see Clinical Pharmacology].

PATIENT COUNSELING INFORMATION

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

Information for Patients

Takeda Pharmaceuticals America, Inc.

Reference: 1. KAPIDEX (dexlansoprazole) package insert, Takeda Pharmaceuticals America, Inc.

KAPIDEX™ and Dual Delayed Release™ are trademarks of Takeda Pharmaceuticals North America, Inc., and are used under license by Takeda Pharmaceuticals America, Inc.

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


FROM THE EDITOR

274 I AMERICAN HEALTH & DRUG BENEFITS I November/December 2009 VOL. 2 I NO. 7

On October 29, 2009, a leadership summit onhealthcare reform was in progress in Washing ton,DC. No, not Congress; the participants were not

Democrats and Republicans locked in a death grip toimpose, or block, government-mandated healthcarereform. This was a conference of leading healthcareauthorities representing clinical, business, and policy sec-tors in healthcare, organizing the elements of a strategy toreform healthcare into a new paradigm that improveshealth, reduces costs, and encourages innovation—thatendangered species of the healthcare ecosystem.

The occasion was the 2nd Annual Summit onStakeholder Integration of American Health & DrugBenefits (AHDB), and the theme was the changeoverto wellness-based system for chronic diseases, focusingon prevention, intervention, and innovation. Thesummit was marked by the nonpartisan environmentand exchange of ideas and data and the compellingnature of the information. The summit experts wereusing the highest principles of medicine, science, eco-nomics, business, and policy to craft an organizing prin-ciple for healthcare. Not evidence-based medicine orbenefit design, not comparative effectiveness research,not personalized medicine. These are only tools to beused in the grander, simpler vision for how health, notjust healthcare, must proceed.

What makes wellness-based healthcare so importantat this time of national angst is that it answers theessential governing dynamics of value-based health—cost, quality, and access. Moreover, wellness is intrinsi-cally apolitical, providing an opportunity for consensusin healthcare policy, because wellness does not exist ina vacuum within policy but extends to the other 2 sec-tors—clinical and business.

But wellness is not a silver bullet; it sets out on itsjourney incompletely informed—nothing new tohealthcare. The various stakeholder groups have beendevising new systems that enable the prevention ofchronic diseases, a more efficient management, andnew technologies for treatment. These have been hap-pening spontaneously, the inevitable result of progressin the many parties comprising the great “healthcareecosystem.” They need only be arranged coherently.

Armed with vital new information on the nature ofdisease, insurance, policy, and people’s peculiar resist-ance to self-preservation (as manifested in poor adher-ence to treatment regimens and strong adherence to asedentary lifestyle and juicy hamburgers), healthcare

professionals are in a position to organize these findingsinto a coherent, actionable program to improve healthand reduce waste spending. This program, called “well-ness,” will entail the reinvention of every stakehold-er—payers, purchasers, providers, patients, manufac-turers, researchers, and policymakers. Change is noteasy, but incessant incremental, patchwork changes tothe existing healthcare system is getting intolerable.This is not a “system”; at last year’s AHDB summit, acomparison was made to Voltaire’s great remark aboutthe Holy Roman Empire being “neither holy, norRoman, nor an empire.” A paradigm shift was neededto the political organization of the Holy RomanEmpire, if it were to offer political relevance.

Our own shambles of a healthcare “system” is suffi-cient cause to inspire change, but to what? Out of thefrying pan into the fire? The American healthcareprocess is saving countless lives and must not be aban-doned wholesale. And the insistence on controllingone’s individual destiny, sometimes derisively referredto as “American exceptionalism,” has something to it.

The proceedings of the wellness summit will be pub-lished in a special supplement to AHDB in early 2010.We hope it will offer the various stakeholders action-able steps to bring together the great forces and groupscharged with administering, monitoring, and protect-ing the process of patient care. Meanwhile, we mightresist the urge to authorize the government to reignsupreme in health, not its strong suit or its tradition.The danger to health is evident in a quote from thestatesman Thomas More, “If the world is round, willthe King’s command flatten it?”

Government mandate is not a good way of manag-ing health. In contrast, wellness-based healthcare pro-vides a rational organizing principle for medicine, busi-ness, and government to collaborate in a structure thatpreserves a system informed by innovation, sound med-ical and business practices, and good sense on the partof the populace. Let us not lose heart that such sanityis attainable. It is no longer a dream; it is coming intobeing and needs time, focus, and stakeholder collabo-ration to become a system, which we have been work-ing without for all these years. ■

Robert E. HenryEditor-in-Chief

Wellness and the Governing Dynamics ofHealthcare Reform

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2.5 mg, 5 mg, 10 mg and 20 mg

Brief Summary: For complete details please see full Prescribing Information for BYSTOLIC.

INDICATIONS AND USAGEBYSTOLIC is indicated for the treatment of hypertension. BYSTOLIC may be usedalone or in combination with other antihypertensive agents.

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

WARNINGSAbrupt Cessation of Therapy Patients with coronary artery disease treated with BYSTOLIC should be advisedagainst abrupt discontinuation of therapy. Severe exacerbation of angina and theoccurrence of myocardial infarction and ventricular arrhythmias have been reportedin patients with coronary artery disease following the abrupt discontinuation of therapy with β-blockers. Myocardial infarction and ventricular arrhythmias may occurwith or without preceding exacerbation of the angina pectoris. Even patients withoutovert coronary artery disease should be cautioned against interruption or abrupt discontinuation of therapy. As with other β-blockers, when discontinuation ofBYSTOLIC is planned, patients should be carefully observed and advised to minimizephysical activity. BYSTOLIC should be tapered over 1 to 2 weeks when possible. If the angina worsens or acute coronary insufficiency develops, it is recommended that BYSTOLIC be promptly reinstituted, at least temporarily.Cardiac FailureSympathetic stimulation is a vital component supporting circulatory function in thesetting of congestive heart failure, and β-blockade may result in further depressionof myocardial contractility and precipitate more severe failure. In patients who havecompensated congestive heart failure, BYSTOLIC should be administered cautiously.If heart failure worsens, discontinuation of BYSTOLIC should be considered.Angina and Acute Myocardial InfarctionBYSTOLIC was not studied in patients with angina pectoris or who had a recent MI.Bronchospastic DiseasesIn general, patients with bronchospastic diseases should not receive β-blockers. Anesthesia and Major SurgeryIf BYSTOLIC is to be continued perioperatively, patients should be closely monitored when anesthetic agents which depress myocardial function, such asether, cyclopropane, and trichloroethylene, are used. If β-blocking therapy is withdrawn prior to major surgery, the impaired ability of the heart to respond toreflex adrenergic stimuli may augment the risks of general anesthesia and surgicalprocedures.The β-blocking effects of BYSTOLIC can be reversed by β-agonists, e.g., dobuta-mine or isoproterenol. However, such patients may be subject to protracted severehypotension. Additionally, difficulty in restarting and maintaining the heartbeat hasbeen reported with β-blockers.Diabetes and Hypoglycemiaβ-blockers may mask some of the manifestations of hypoglycemia, particularlytachycardia. Nonselective β-blockers may potentiate insulin-induced hypoglycemiaand delay recovery of serum glucose levels. It is not known whether nebivolol hasthese effects. Patients subject to spontaneous hypoglycemia, or diabetic patientsreceiving insulin or oral hypoglycemic agents, should be advised about these possibilities and nebivolol should be used with caution.Thyrotoxicosisβ-blockers may mask clinical signs of hyperthyroidism, such as tachycardia.Abrupt withdrawal of β-blockers may be followed by an exacerbation of the symptoms of hyperthyroidism or may precipitate a thyroid storm.Peripheral Vascular Diseaseβ-blockers can precipitate or aggravate symptoms of arterial insufficiency in patientswith peripheral vascular disease. Caution should be exercised in these patients.Non-dihydropyridine Calcium Channel BlockersBecause of significant negative inotropic and chronotropic effects in patients treatedwith β-blockers and calcium channel blockers of the verapamil and diltiazem type,caution should be used in patients treated concomitantly with these agents and ECGand blood pressure should be monitored.

PRECAUTIONSUse with CYP2D6 InhibitorsNebivolol exposure increases with inhibition of CYP2D6 (see Drug Interactions).The dose of BYSTOLIC may need to be reduced.Impaired Renal FunctionBYSTOLIC should be used with caution in patients with severe renal impairmentbecause of decreased renal clearance. BYSTOLIC has not been studied in patientsreceiving dialysis.Impaired Hepatic FunctionBYSTOLIC should be used with caution in patients with moderate hepatic impairment because of decreased metabolism. Since BYSTOLIC has not been studied in patients with severe hepatic impairment, BYSTOLIC is contraindicated in this population (see CLINICAL PHARMACOLOGY, Special Populations andDOSAGE AND ADMINISTRATION).Risk of Anaphylactic Reactions While taking β-blockers, patients with a history of severe anaphylactic reactions toa variety of allergens may be more reactive to repeated challenge either accidental,diagnostic, or therapeutic. Such patients may be unresponsive to the usual dosesof epinephrine used to treat allergic reactions.In patients with known or suspected pheochromocytoma, an α-blocker should beinitiated prior to the use of any β-blocker.Information for PatientsPatients should be advised to take BYSTOLIC regularly and continuously, as directed. BYSTOLIC can be taken with or without food. If a dose is missed, thepatient should take the next scheduled dose only (without doubling it). Patientsshould not interrupt or discontinue BYSTOLIC without consulting the physician.Patients should know how they react to this medicine before they operate auto-mobiles, use machinery, or engage in other tasks requiring alertness.Patients should be advised to consult a physician if any difficulty in breathingoccurs, or if they develop signs or symptoms of worsening congestive heart failuresuch as weight gain or increasing shortness of breath, or excessive bradycardia.

Patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulinor oral hypoglycemic agents, should be cautioned that β-blockers may mask someof the manifestations of hypoglycemia, particularly tachycardia. Nebivolol should beused with caution in these patients.Drug InteractionsBYSTOLIC should be used with care when myocardial depressants or inhibitors of AV conduction, such as certain calcium antagonists (particularly of the phenyl-alkylamine [verapamil] and benzothiazepine [diltiazem] classes), or antiarrhythmicagents, such as disopyramide, are used concurrently. Both digitalis glycosides andβ-blockers slow atrioventricular conduction and decrease heart rate. Concomitantuse can increase the risk of bradycardia.BYSTOLIC should not be combined with other β-blockers. Patients receiving catecholamine-depleting drugs, such as reserpine or guanethidine, should beclosely monitored, because the added β-blocking action of BYSTOLIC may produceexcessive reduction of sympathetic activity. In patients who are receivingBYSTOLIC and clonidine, BYSTOLIC should be discontinued for several days beforethe gradual tapering of clonidine.CYP2D6 Inhibitors: Use caution when BYSTOLIC is co-administered with CYP2D6inhibitors (quinidine, propafenone, fluoxetine, paroxetine, etc.) (see CLINICALPHARMACOLOGY, Drug Interactions).Carcinogenesis, Mutagenesis, Impairment of FertilityIn a two-year study of nebivolol in mice, a statistically significant increase in the incidence of testicular Leydig cell hyperplasia and adenomas was observed at40 mg/kg/day (5 times the maximally recommended human dose of 40 mg on amg/m2 basis). Similar findings were not reported in mice administered doses equalto approximately 0.3 or 1.2 times the maximum recommended human dose. Noevidence of a tumorigenic effect was observed in a 24-month study in Wistar rats receiving doses of nebivolol 2.5, 10 and 40 mg/kg/day (equivalent to 0.6, 2.4,and 10 times the maximally recommended human dose). Co-administration ofdihydrotestosterone reduced blood LH levels and prevented the Leydig cell hyper-plasia, consistent with an indirect LH-mediated effect of nebivolol in mice and notthought to be clinically relevant in man. A randomized, double-blind, placebo- and active-controlled, parallel-group study in healthy male volunteers was conducted to determine the effects of nebivolol on adrenal function, luteinizing hormone, and testosterone levels. This studydemonstrated that 6 weeks of daily dosing with 10 mg of nebivolol had no significant effect on ACTH-stimulated mean serum cortisol AUC0-120 min, serum LH,or serum total testosterone. Effects on spermatogenesis were seen in male rats and mice at ≥40 mg/kg/day (10 and 5 times the MRHD, respectively). For rats the effects on spermatogenesiswere not reversed and may have worsened during a four-week recovery period. Theeffects of nebivolol on sperm in mice, however, were partially reversible.Mutagenesis: Nebivolol was not genotoxic when tested in a battery of assays(Ames, in vitro mouse lymphoma TK+/-, in vitro human peripheral lymphocyte chromosome aberration, in vivo Drosophila melanogaster sex-linked recessivelethal, and in vivo mouse bone marrow micronucleus tests).Pregnancy: Teratogenic Effects. Pregnancy Category C:Decreased pup body weights occurred at 1.25 and 2.5 mg/kg in rats, when exposedduring the perinatal period (late gestation, parturition and lactation). At 5 mg/kg andhigher doses (1.2 times the MRHD), prolonged gestation, dystocia and reducedmaternal care were produced with corresponding increases in late fetal deaths andstillbirths and decreased birth weight, live litter size and pup survival. Insufficientnumbers of pups survived at 5 mg/kg to evaluate the offspring for reproductive performance. In studies in which pregnant rats were given nebivolol during organogenesis,reduced fetal body weights were observed at maternally toxic doses of 20 and 40 mg/kg/day (5 and 10 times the MRHD), and small reversible delays in sternaland thoracic ossification associated with the reduced fetal body weights and a smallincrease in resorption occurred at 40 mg/kg/day (10 times the MRHD). No adverseeffects on embryo-fetal viability, sex, weight or morphology were observed in studies in which nebivolol was given to pregnant rabbits at doses as high as 20 mg/kg/day (10 times the MRHD).Labor and DeliveryNebivolol caused prolonged gestation and dystocia at doses ≥5 mg/kg in rats (1.2 times the MRHD). These effects were associated with increased fetal deathsand stillborn pups, and decreased birth weight, live litter size and pup survival rate, events that occurred only when nebivolol was given during the perinatal period (late gestation, parturition and lactation).No studies of nebivolol were conducted in pregnant women. BYSTOLIC should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.Nursing MothersStudies in rats have shown that nebivolol or its metabolites cross the placental barrier and are excreted in breast milk. It is not known whether this drug is excretedin human milk.Because of the potential for β-blockers to produce serious adverse reactions innursing infants, especially bradycardia, BYSTOLIC is not recommended duringnursing.Geriatric UseOf the 2800 patients in the U.S.-sponsored placebo-controlled clinical hypertensionstudies, 478 patients were 65 years of age or older. No overall differences in efficacyor in the incidence of adverse events were observed between older and youngerpatients. Pediatric UseSafety and effectiveness in pediatric patients have not been established. Pediatricstudies in ages newborn to 18 years old have not been conducted because ofincomplete characterization of developmental toxicity and possible adverse effectson long-term fertility (see Carcinogenesis, Mutagenesis, and Impairment ofFertility).

ADVERSE REACTIONSThe data described below reflect worldwide clinical trial exposure to BYSTOLIC in6545 patients, including 5038 patients treated for hypertension and the remaining1507 subjects treated for other cardiovascular diseases. Doses ranged from 0.5 mgto 40 mg. Patients received BYSTOLIC for up to 24 months, with over 1900 patientstreated for at least 6 months, and approximately 1300 patients for more than one year. In placebo-controlled clinical trials comparing BYSTOLIC with placebo,discontinuation of therapy due to adverse events was reported in 2.8% of patientstreated with nebivolol and 2.2% of patients given placebo. The most commonadverse events that led to discontinuation of BYSTOLIC were headache (0.4%),nausea (0.2%) and bradycardia (0.2%).Adverse Reactions in Controlled TrialsTable 1 lists treatment-emergent signs and symptoms that were reported in three 12-week, placebo-controlled monotherapy trials involving 1597 hypertensive patientstreated with either 5 mg, 10 mg or 20-40 mg of BYSTOLIC and 205 patients givenplacebo and for which the rate of occurrence was at least 1% of patients treated withnebivolol and greater than the rate for those treated with placebo in at least one dosegroup.

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

Placebo Nebivolol Nebivolol Nebivolol 5 mg 10 mg 20-40 mg

(n = 205) (n = 459) (n = 461) (n = 677)(%) (%) (%) (%)

Headache 6 9 6 7Fatigue 1 2 2 5Dizziness 2 2 3 4Diarrhea 2 2 2 3Nausea 0 1 3 2Insomnia 0 1 1 1Chest pain 0 0 1 1Bradycardia 0 0 0 1Dyspnea 0 0 1 1Rash 0 0 1 1Peripheral edema 0 1 1 1

Other Adverse Events Observed During Worldwide Clinical TrialsListed below are other reported adverse events with an incidence of at least 1% in the more than 5300 patients treated with BYSTOLIC in controlled or open-labeltrials, whether or not attributed to treatment, except for those already appearing in Table 1, terms too general to be informative, minor symptoms, or events unlikely to be attributable to drug because they are common in the population.These adverse events were in most cases observed at a similar frequency in placebo-treated patients in the controlled studies.Body as a Whole: asthenia.Gastrointestinal System Disorders: abdominal pain Metabolic and Nutritional Disorders: hypercholesterolemia and hyperuricemia Nervous System Disorders: paraesthesiaLaboratoryIn controlled monotherapy trials, BYSTOLIC was associated with an increase inBUN, uric acid, triglycerides and a decrease in HDL cholesterol and platelet count. Events Identified from Spontaneous Reports of BYSTOLIC Received WorldwideThe following adverse events have been identified from spontaneous reports ofBYSTOLIC received worldwide and have not been listed elsewhere. These adverseevents have been chosen for inclusion due to a combination of seriousness, frequency of reporting or potential causal connection to BYSTOLIC. Events commonin the population have generally been omitted. Because these events were reportedvoluntarily from a population of uncertain size, it is not possible to estimate their frequency or establish a causal relationship to BYSTOLIC exposure: abnormal hepatic function (including increased AST, ALT and bilirubin), acute pulmonaryedema, acute renal failure, atrioventricular block (both second- and third-degree),bronchospasm, erectile dysfunction, hypersensitivity (including urticaria, allergicvasculitis and rare reports of angioedema), myocardial infarction, pruritus, psoriasis, Raynaud’s phenomenon, peripheral ischemia/claudication, somnolence,syncope, thrombocytopenia, various rashes and skin disorders, vertigo, and vomiting.

OVERDOSAGEIn clinical trials and worldwide postmarketing experience there were reports ofBYSTOLIC overdose. The most common signs and symptoms associated withBYSTOLIC overdosage are bradycardia and hypotension. Other important adverse events reported with BYSTOLIC overdose include cardiac failure, dizziness,hypoglycemia, fatigue and vomiting. Other adverse events associated with β-blocker overdose include bronchospasm and heart block.The largest known ingestion of BYSTOLIC worldwide involved a patient who ingested up to 500 mg of BYSTOLIC along with several 100 mg tablets of acetylsalicylic acid in a suicide attempt. The patient experienced hyperhidrosis, pallor, depressed level of consciousness, hypokinesia, hypotension, sinus bradycardia, hypoglycemia, hypokalemia, respiratory failure and vomiting. Thepatient recovered.Due to extensive drug binding to plasma proteins, hemodialysis is not expected toenhance nebivolol clearance.If overdose occurs, BYSTOLIC should be stopped and general supportive and specific symptomatic treatment should be provided. Based on expected pharma-cologic actions and recommendations for other β-blockers, the following generalmeasures should be considered when clinically warranted:Bradycardia: Administer IV atropine. If the response is inadequate, isoproterenol or another agent with positive chronotropic properties may be given cautiously.Under some circumstances, transthoracic or transvenous pacemaker placementmay be necessary.Hypotension: Administer IV fluids and vasopressors. Intravenous glucagon may beuseful.Heart Block (second or third degree): Patients should be carefully monitored and treated with isoproterenol infusion. Under some circumstances, transthoracicor transvenous pacemaker placement may be necessary.Congestive Heart Failure: Initiate therapy with digitalis glycoside and diuretics. In certain cases, consideration should be given to the use of inotropic and vasodilating agents.Bronchospasm: Administer bronchodilator therapy such as a short-acting inhaledβ2-agonist and/or aminophylline.Hypoglycemia: Administer IV glucose. Repeated doses of IV glucose or possiblyglucagon may be required.In the event of intoxication where there are symptoms of shock, treatment must becontinued for a sufficiently long period consistent with the 12-19 hour effectivehalf-life of BYSTOLIC. Supportive measures should continue until clinical stabilityis achieved.Call the National Poison Control Center (800-222-1222) for the most current information on β-blocker overdose treatment.

Forest Pharmaceuticals, Inc.Subsidiary of Forest Laboratories, Inc.

St. Louis, MO 63045, USALicensed from Mylan Laboratories, Inc.

Under license from JanssenPharmaceutica N.V., Beerse, Belgium

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

Rx Only

Henry:Cover 12/11/09 5:21 PM Page 275

Important Safety InformationPatients being treated with BYSTOLIC should be advised against abrupt discontinuation of therapy. Severe exacerbation of angina and the occurrence of myocardial infarction and ventricular arrhythmias have been reported following the abrupt cessation of therapy with beta blockers. When discontinuation is planned, the dosage should be reduced gradually over a 1- to 2-week period and the patient carefully monitored.BYSTOLIC is contraindicated in severe bradycardia, heart block greater than first degree, cardiogenic shock, decompensated cardiac failure, sick sinus syndrome (unless a permanent pacemaker is in place), severe hepatic impairment (Child-Pugh >B), and in patients who are hypersensitive to any component of this product.BYSTOLIC should be used with caution in patients with peripheral vascular disease, thyrotoxicosis, in patients treated concomitantly with beta blockers and calcium channel blockers of the verapamil and diltiazem type (ECG and blood pressure should be monitored), severe renal impairment, and any degree of hepatic impairment or in patients undergoing major surgery. In patients who have compensated congestive heart failure, BYSTOLIC should be administered cautiously. If heart failure worsens, discontinuation of BYSTOLIC should be considered. Caution should also be used in diabetic patients as beta blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia.Use caution when BYSTOLIC is co-administered with CYP2D6 inhibitors (quinidine, propafenone, fluoxetine, paroxetine, etc). When BYSTOLIC is administered with fluoxetine, significant increases in d-nebivolol may be observed (ie, an 8-fold increase in AUC). In general, patients with bronchospastic disease should not receive beta blockers. BYSTOLIC should not be combined with other beta blockers.The most common adverse events with BYSTOLIC versus placebo (approximately ≥1% and greater than placebo) were headache, fatigue, dizziness, diarrhea, nausea, insomnia, chest pain, bradycardia, dyspnea, rash, and peripheral edema.

Please see brief summary of Prescribing Information on adjacent page.References: 1. BYSTOLIC [package insert]. St. Louis, Mo: Forest Pharmaceuticals, Inc.; 2008. 2. Data on file. Forest Laboratories, Inc. 3. Saunders E, Smith WB, DeSalvo KB, Sullivan WA. The efficacy and tolerability of nebivolol in hypertensive African American patients. J Clin Hypertens. 2007;9:866-875. ©2009 Forest Laboratories, Inc 44-1014950 01/09

For the treatment of hypertension

BYSTOLIC.Significant blood pressure reductions with a low incidence of side effects.1-3

www.BYSTOLIC.com

Gottlieb_Cover 10/14/09 6:29 PM Page 214

COMMENTARY

277VOL. 2 I NO. 7 www.AHDBonline.com I

President Barack Obama deflects criticism that hishealthcare plan will bring on governmentrationing of medical care by arguing that insur-

ance companies ration care. Everyone knows privatepayers limit access to some health care. But govern-ment does it in far more Byzantine and arbitrary ways.Consider the $450-billion Medicare program. It pro-vides a model for—indeed its bureaucracy could wellend up running—the “public option” health plan thatPresident Obama wants to offer all Americans underthe age of 65. In recent years, Medicare’s staff has beenaggressively restricting coverage for costly treatments.Looking for ways to control pending on medical prod-ucts—and preserve the illusory “trust fund” that paysMedicare claims—is what shapes the culture of theorganization and motivates the agency’s staff.

This often means limiting access to the costliesttechnologies. To do this Medicare relies on itsrationing and pricing systems. National coverage deci-sions are assessments issued by Medicare’s medical staffthat define who is eligible for new but often expensivetreatments. Medicare then assigns medical productsand procedures with “codes” that determine which reg-ulated category they fall into. Finally, price “schedules”are developed by Medicare’s staff each year to assigneach unique code with its own updated payment rate.

The process for getting a favorable code on a newproduct is a source of intense lobbying. It can make orbreak a technology. For a remote agency like Medicare,far removed from clinical practice, it’s easier to try andmanage the use of a high-cost but specialty treatmentthan a much lower-cost but very widely used product.Yet cheaper, more commonly used products can still bemispriced and account for more total cost to theagency. For example, low-tech orthotic devices andother “durable medical equipment” are a known sourceof wasteful spending. These medical products oftenevade Medicare’s attention in favor of less used butmore expensive items such as a biologic cancer drug.

Take the agency’s tortured decisions concerning the

use of implantable defibrillators that jump-startstopped hearts during cardiac arrest. Medicare sharplyrestricted their use in the 1990s. Mounting researchproved that the $30,000 devices could be saving manymore lives. So in 2003 Medicare adopted a novel theo-ry to expand coverage to some, but not everyone, whoneeded one. The agency said only patients with certainmeasures on their electrocardiograms (called “wideQRS”) seemed to benefit.

It was an easily measurable but ultimately impreciseway to allocate the devices. After another major studyfirmly refuted the QRS theory, Medicare expandedcoverage again in 2005, potentially saving 2500 addi-tional lives, according to a press release issued withthat decision.

That experience was not unique. From 1999 to2007, Medicare denied access in a third of the treat-ments it evaluated through its coverage process, takingan average of eight months to complete its reviews.When coverage was granted, in 85% of cases the treat-ments were restricted, usually to patients with moreadvanced illnesses.

Medicare is lately increasing its use of the nationalcoverage process and is becoming more tightfisted.Since 2008, according to my review of Medicare data,it conditioned access in 29% of its reviews and deniednew or expanded coverage in fully 53% of cases.

Medicare’s methods can also be arbitrary. Take thetravails of the pharmaceutical company Sepracor andits drug Xopenex, an innovative respiratory medicinethat competes with the chemically distinct and muchcheaper generic albuterol. Both are inhaled aerosolsused to treat asthma and chronic obstructive pul-monary disease. Xopenex has the same benefits asalbuterol, but some people believe it has fewer cardiacside effects. Medicare did not agree.

The agency tried to make a “national coverage deci-sion” on Xopenex but could not come up with a clini-cal justification to limit the drug’s use. So Medicaremanipulated its payment process, saying it would payXopenex a price equivalent to the “least costly alterna-tive” form of generic albuterol, 10 cents for a treatmentcompared with about $2.50 for Xopenex. ThenMedicare was sued by a patient, and a federal courtrecently ruled that the agency exceeded its authority.

Dr Gottlieb is a resident fellow at the American EnterpriseInstitute and a former senior official at the Centers forMedicare and Medicaid Services. He is partner to a firm thatinvests in healthcare companies, and he advises health plans.

How the US Government Rations HealthcareScott Gottlieb, MD

Continued

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COMMENTARY


Medicare finally succeeded in reigning in the use ofXopenex with its coding system. By issuing Xopenexthe same classification as generic albuterol, it was ableto pay both products the same “blended” price—anaverage of the cost of each individual drug. That low-ered the price on Xopenex, but ironically increased

what Medicare paid for the generics. It is not a stretchto say that Medicare spent hundreds of cumulativeman-hours focusing on Xopenex, while other prioritieslanguished. The question is why? There were not safe-ty concerns. Xopenex may have been used in lieu of acheaper alternative, but at peak Medicare sales of about$300 million it represented far less than one one-thou-sandth of the agency’s budget. Simply put, a few staffersinside Medicare were consumed with the drug and itshigher price—revealing a process that is capricious andoften disconnected from science.

Worse still is how impenetrable these programs havebecome. Drug and device companies spend millions ofdollars trying to influence Medicare decisions. Thehundreds of consultants they hire to advise them typi-cally command $20,000-a-month retainers.

Formal patient and provider appeals to Medicaretook an average of 21 months, according to a reportissued in 2003 by the Government AccountabilityOffice (using 2001 data), with delays in “administrativeprocessing” due to “inefficiencies and incompatibility”of data systems eating up 70% of the time spent pro-cessing appeals.

There is nothing inherently wrong with a programlike Medicare seeking value for taxpayers. But it shouldnot make up the rules as it goes. When private plansration care, patients can appeal directly to an insurer’smedical staff. Only a small fraction of Medicare’sdenied claims—about 5%—are ever formally appealedbecause its process is so impenetrable. People can alsoswitch insurers, and in many cases patients chose a pol-icy because it matched their preferences in the firstplace. These options don’t exist in a governmenthealth program. ■

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Only a small fraction of Medicare’s deniedclaims—about 5%—are ever formally appealedbecause its process is so impenetrable.

Gottlieb:Cover 12/11/09 5:40 PM Page 278

COMMENTARY


Doctors from across the country were invited tothe White House on October 5, but thePresident did most of the talking. Medical pro-

fessionals are being ignored or vilified more often thanconsulted in the current healthcare reform debate. Tobroaden the discussion, the Committee to ReduceInfection Deaths invited 16 highly regarded physiciansto convene at the Grand Hyatt in New York City onOctober 19 to reflect on the current legislative propos-als. Here’s what they had to say on four key issues.

Government-Imposed Treatment GuidelinesDr Jeffrey Borer, Cardiologist, named to Castle

Connolly’s America’s Top Doctors: “What’s the impactof guidelines on the doctor–patient relationship?Guidelines step in between the doctor and the patient.If it’s necessary to respond to guidelines rather than whatyou see, feel and hear when you’re evaluating a person,then perhaps you’re going to do something that isn’treally the right thing. There really isn’t an averagepatient. Every person that you see with a medical prob-lem has some unusual or unique characteristic and thisoften has to be considered in dealing with the problem.”

Dr David Fields, Obstetrician and Gynecologist,Lenox Hill Hospital, New York: “They tend to forbidbetter-than-average medical care; guidelines are alwaysaverage medical care...they tend to cramp the physi-cian who can do better than average.”

Dr Borer: “One of the more common problems thatpeople have as they get older is a disease called aorticstenosis….[W]e can relieve that aortic stenosis with anoperation with really very acceptable safety, low mortal-ity rates….If that 85 year old cannot walk down the streetbecause he or she is too breathless to do so…or feels light-headed or could faint and break a hip…then there isreally a very good justification for offering the therapy.”

Dr Richard Amerling, Nephrologist, Beth IsraelMedical Center, New York: “The example that yougive of valve surgery in an 85 year old is just not goingto happen under [White House Healthcare Adviser]Ezekiel Emanuel. He’s going to just say that that’s anonstarter. That person has outlived their useful years,no matter how long they could live beyond that.”

Dr Borer: “What we’re hearing from the President’smedical advisers is that what we have is good enough andwe really shouldn’t be wanting or expecting any more.”

Dr Seymour Cohen, Oncologist, named to America’sTop Doctors: “When we went to medical school, peopleused to die at age 66, 67, and 68. Medicare paid for twoor three years. Social Security paid for two or three years.We’re the bad guys. We’re responsible for keeping peoplealive to 85. So we’re now going to try to change health-care because people are living too long. It just doesn’tmake very good sense to me.”

Shifting Resources from Specialty to Primary CareDr Cohen: “Let’s talk about specialization for a

moment….We don’t go to our general attorney whenwe have a patent problem, but they’re telling us to dothis now in medicine. We have different types of engi-neers, even journalists. There’s a financial writer,there’s a sportswriter….Now in healthcare we’re tellingeverybody, ‘You just go to the guy who’s your generaldoc. He’s going to know everything and maybe we’llfind a specialist for you if the panel decides maybeyou’re sick enough to need a specialist.’ It really doesn’tmake sense at all.”

Dr Jeffrey Moses, Interventional Cardiologist, namedto America’s Top Doctors: “If you have heart failure orheart attack or coronaries in general in the hospital youneed to be treated by a cardiologist. Study after studyshows that…when you have an illness and you want tohave an accurate diagnosis and the most up-to-date andaccurate treatment, you want a specialist.”

Patient PrivacyDr Samuel Guillory, Ophthalmologist, Refractive and

Orbital Surgery, named to Castle Connolly’s New York’sTop Doctors: “We’re being asked by the executive

Ms McCaughey is chairman of the Committee to ReduceInfection Deaths and a former Lt Governor of New YorkState. For a complete transcript of the physicians’ meetings,visit www.defendyourhealthcare.us. Reprinted with permission.Originally printed in Opinion Journal. The Wall StreetJournal. November 6, 2009.

Doctors on Healthcare ReformBetsy McCaughey

Government is in the process of duplicating everything that managed caredid for the last 15 years that was reviled by everybody.—Dr David Fields

McCaughey:Cover 12/11/09 5:01 PM Page 279

COMMENTARY


branch…to break the code with patients and deliver alltheir records into electronic medical records.”

Cost-Cutting MethodsDr Fields: “Government is in the process of dupli-

cating everything that managed care did for the last 15years that was reviled by everybody and which wefought very hard to overcome. The courts finally said,‘You can’t have withholds. You can’t pay people todeny care. You can’t have gag rules.’ The government isin the process of doing all that. Massachusetts is aboutto establish capitation [a fixed payment remitted at reg-ular intervals to a medical provider] as the rule of thestate. Capitation was the worst thing that ever hap-pened to medical care.”

Dr Joel Kassimir, Dermatologist, Mt. Sinai Hospital,New York: “We’re now being told by physicians advis-ing the president that we take the Hippocratic Oathtoo seriously.”

Dr Tracy Pfeifer, Plastic Surgeon, President, NewYork Regional Society of Plastic Surgeons: “Whenphysicians graduate from medical school we take anoath, the Hippocratic Oath, to do no harm to ourpatients. It’s a very important philosophy to us and weuphold it and hold it very dear to our hearts. Plato,another philosopher, used to say things like, ‘Thosewith a poor physical constitution should be allowed todie. The weak and the ill-constituted shall perish.’

These government programs that are being proposedI think are very scary in the sense that physicians couldbe induced to violate the Hippocratic Oath. There’s alimit to how much of a financial penalty each individ-ual practitioner is going to be able to bear….If thepatient is sitting in the examination room with us andthey’re wondering, ‘Is the doctor not ordering a test forme because he’s going to get penalized if he does it?’This is a major, major problem for patients and physi-cians alike.” ■

1 1 6:37:36 PM

CAPTION CONTEST

Winners receive $50.

Winners’ names will beposted online.

Submit your caption at www.AHDBonline.com.


Copyright © 2009, Boehringer Ingelheim Pharmaceuticals, Inc. All rights reserved. Printed in U.S.A. (10/09) MC68413

For additional information, please ask your local sales representative.

MICARDIS 80 mgNow for Cardiovascular (CV) Risk Reduction1

MICARDIS® (telmisartan) tablets are indicatedfor reduction of the risk of myocardial infarction,stroke, or death from CV causes in patients55 years of age or older at high risk of developingmajor CV events who are unable to takeACE inhibitors.1

WARNING: AVOID USE IN PREGNANCYWhen used in pregnancy, drugs that act directly on therenin-angiotensin system can cause injury and evendeath to the developing fetus. When pregnancy is detected,MICARDIS® (telmisartan) tablets should be discontinued assoon as possible (See Warnings and Precautions ).

Because studies with telmisartan did not exclude that itmay not preserve a meaningful fraction of the effect ofthe ACE inhibitor to which it was compared, considerusing the ACE inhibitor first.

Volume depletion and/or salt depletion should be corrected in patientsbefore initiation of therapy or symptomatic hypotension may occur.

In patients with renal artery stenosis or severe renal impairment,care should be exercised with dosing of MICARDIS. In patientswith severe heart failure, decline in renal function and, rarely,acute renal failure and/or death has been associated withinhibiting the renin-angiotensin system.

Use of MICARDIS with an ACE inhibitor is not recommended.

Please see Brief Summary of Prescribing Information, includingfull indication, on adjacent page.

Reference: 1. Micardis PI. Ridgefield, CT: Boehringer IngelheimPharmaceuticals, Inc.; 2009.

IMPORTANT SAFETY INFORMATION

6:37:36 PM


BBRRIIEEFF SSUUMMMMAARRYY OOFF PPRREESSCCRRIIBBIINNGG IINNFFOORRMMAATTIIOONN

IINNDDIICCAATTIIOONNSS AANNDD UUSSAAGGEEHypertension: MICARDIS is indicated for the treatment of hypertension. It may be used alone or incombination with other antihypertensive agents. Cardiovascular Risk Reduction: MICARDIS isindicated for reduction of the risk of myocardial infarction, stroke, or death from cardiovascular causes inpatients 55 years of age or older at high risk of developing major cardiovascular events who are unableto take ACE inhibitors. High risk for cardiovascular events can be evidenced by a history of coronary arterydisease, peripheral arterial disease, stroke, transient ischemic attack, or high-risk diabetes (insulin-dependent or non-insulin dependent) with evidence of end-organ damage. MICARDIS can be used inaddition to other needed treatment (such as antihypertensive, antiplatelet or lipid-lowering therapy).Studies of telmisartan in this setting do not exclude that it may not preserve a meaningful fraction of theeffect of the ACE inhibitor to which it was compared. Consider using the ACE inhibitor first, and, if it isstopped for cough only, consider re-trying the ACE inhibitor after the cough resolves. Use of telmisartanwith an ACE inhibitor is not recommended.

CONTRAINDICATIONSNone.

WARNINGS AND PRECAUTIONSFetal/Neonatal Morbidity and Mortality: Drugs that act directly on the renin-angiotensin system cancause fetal and neonatal morbidity and death when administered to pregnant women. Several dozencases have been reported in the world literature in patients who were taking angiotensin convertingenzyme inhibitors. When pregnancy is detected, discontinue MICARDIS tablets as soon as possible [seeBoxed Warning]. The use of drugs that act directly on the renin-angiotensin system during the secondand third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypoten-sion, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnioshas also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in thissetting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lungdevelopment. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also beenreported, although it is not clear whether these occurrences were due to exposure to the drug. Theseadverse effects do not appear to have resulted from intrauterine drug exposure that has been limited tothe first trimester. Inform mothers whose embryos and fetuses are exposed to an angiotensin II receptorantagonist only during the first trimester that most reports of fetal toxicity have been associated withsecond and third trimester exposure. Nonetheless, when patients become pregnant or are consideringpregnancy, have the patient discontinue the use of MICARDIS tablets as soon as possible. Rarely (probablyless often than once in every thousand pregnancies), no alternative to an angiotensin II receptor antago-nist will be found. In these rare cases, the mothers should be apprised of the potential hazards to theirfetuses, and serial ultrasound examinations should be performed to assess the intra-amniotic environ-ment. If oligohydramnios is observed, MICARDIS should be discontinued unless they are considered life-saving for the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling(BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should beaware, however, that oligohydramnios may not appear until after the fetus has sustained irreversibleinjury. Infants with histories of in utero exposure to an angiotensin II receptor antagonist should be closelyobserved for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directedtoward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be requiredas a means of reversing hypotension and/or substituting for disordered renal function. Hypotension: Inpatients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients (e.g.,those being treated with high doses of diuretics), symptomatic hypotension may occur after initiation oftherapy with MICARDIS. Either correct this condition prior to administration of MICARDIS, or starttreatment under close medical supervision with a reduced dose. If hypotension does occur, the patientshould be placed in the supine position and, if necessary, given an intravenous infusion of normal saline.A transient hypotensive response is not a contraindication to further treatment, which usually can becontinued without difficulty once the blood pressure has stabilized. Hyperkalemia: Hyperkalemia mayoccur in patients on ARBs, particularly in patients with advanced renal impairment, heart failure, on renalreplacement therapy, or on potassium supplements, potassium-sparing diuretics, potassium-containingsalt substitutes or other drugs that increase potassium levels. Consider periodic determinations of serumelectrolytes to detect possible electrolyte imbalances, particularly in patients at risk. Impaired HepaticFunction: As the majority of telmisartan is eliminated by biliary excretion, patients with biliary obstruc-tive disorders or hepatic insufficiency can be expected to have reduced clearance. Initiate telmisartan atlow doses and titrate slowly in these patients. Impaired Renal Function: As a consequence of inhibit-ing the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in suscepti-ble individuals. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure or renal dysfunction), treatmentwith angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor antagonists has beenassociated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death.Similar results have been reported with MICARDIS. In studies of ACE inhibitors in patients with unilateralor bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen were observed.There has been no long term use of MICARDIS in patients with unilateral or bilateral renal artery stenosisbut anticipate an effect similar to that seen with ACE inhibitors. Dual Blockade of the Renin-Angiotensin-Aldosterone System: As a consequence of inhibiting the renin-angiotensin-aldosteronesystem, changes in renal function (including acute renal failure) have been reported. Dual blockade of therenin-angiotensin-aldosterone system (e.g., by adding an ACE-inhibitor to an angiotensin II receptorantagonist) should include close monitoring of renal function. The ONTARGET trial enrolled 25,620patients ≥55 years old with atherosclerotic disease or diabetes with end-organ damage, randomizingthem to telmisartan only, ramipril only, or the combination, and followed them for a median of 56 months.Patients receiving the combination of MICARDIS and ramipril did not obtain any additional benefitcompared to monotherapy, but experienced an increased incidence of renal dysfunction (e.g., acute renalfailure) compared with groups receiving telmisartan alone or ramipril alone. Concomitant use of MICARDISand ramipril is not recommended.

ADVERSE REACTIONSThe following adverse reaction is described elsewhere in labeling: Renal dysfunction upon use withramipril. Clinical Trials Experience: Because clinical studies are conducted under widely varyingconditions, adverse reactions rates observed in the clinical studies of a drug cannot be directly comparedto rates in the clinical studies of another drug and may not reflect the rates observed in practice.Hypertension: MICARDIS has been evaluated for safety in more than 3700 patients, including 1900treated for over six months and more than 1300 for over one year. Adverse experiences have generallybeen mild and transient in nature and have infrequently required discontinuation of therapy. In placebo-controlled trials involving 1041 patients treated with various doses of MICARDIS (20-160 mg) monother-apy for up to 12 weeks, the overall incidence of adverse events was similar to that in patients treated withplacebo. Adverse events occurring at an incidence of ≥1% in patients treated with MICARDIS and at agreater rate than in patients treated with placebo, irrespective of their causal association, are presentedin Table 1.

Table 1 Adverse Events Occurring at an Incidence of ≥ 1% in Patients Treated with MICARDIS and at a Greater Rate Than in Patients Treated with placebo

In addition to the adverse events in the table, the following events occurred at a rate of ≥1% but were atleast as frequent in the placebo group: influenza-like symptoms, dyspepsia, myalgia, urinary tractinfection, abdominal pain, headache, dizziness, pain, fatigue, coughing, hypertension, chest pain, nausea,and peripheral edema. Discontinuation of therapy because of adverse events was required in 2.8% of1455 patients treated with MICARDIS tablets and 6.1% of 380 placebo patients in placebo-controlledclinical trials. The incidence of adverse events was not dose-related and did not correlate with gender,age, or race of patients. The incidence of cough occurring with telmisartan in 6 placebo-controlled trialswas identical to that noted for placebo-treated patients (1.6%). In addition to those listed above, adverseevents that occurred in more than 0.3% of 3500 patients treated with MICARDIS monotherapy incontrolled or open trials are listed below. It cannot be determined whether these events were causallyrelated to MICARDIS tablets: Autonomic Nervous System: impotence, increased sweating, flushing; Bodyas a Whole: allergy, fever, leg pain, malaise; Cardiovascular: palpitation, dependent edema, anginapectoris, tachycardia, leg edema, abnormal ECG; CNS: insomnia, somnolence, migraine, vertigo, paresthe-sia, involuntary muscle contractions, hypoaesthesia; Gastrointestinal: flatulence, constipation, gastritis,vomiting, dry mouth, hemorrhoids, gastroenteritis, enteritis, gastroesophageal reflux, toothache, non-specific gastrointestinal disorders; Metabolic: gout, hypercholesterolemia, diabetes mellitus;Musculoskeletal: arthritis, arthralgia, leg cramps; Psychiatric: anxiety, depression, nervousness;Resistance Mechanism: infection, fungal infection, abscess, otitis media; Respiratory: asthma, bronchi-tis, rhinitis, dyspnea, epistaxis; Skin: dermatitis, rash, eczema, pruritus; Urinary: micturition frequency,cystitis; Vascular: cerebrovascular disorder; and Special Senses: abnormal vision, conjunctivitis, tinnitus,earache. During initial clinical studies, a single case of angioedema was reported (among a total of 3781patients treated). Clinical Laboratory Findings: In placebo-controlled clinical trials, clinically relevantchanges in standard laboratory test parameters were rarely associated with administration of MICARDIStablets. Hemoglobin: A greater than 2 g/dL decrease in hemoglobin was observed in 0.8% telmisartanpatients compared with 0.3% placebo patients. No patients discontinued therapy due to anemia.Creatinine: A 0.5 mg/dL rise or greater in creatinine was observed in 0.4% telmisartan patients comparedwith 0.3% placebo patients. One telmisartan-treated patient discontinued therapy due to increases increatinine and blood urea nitrogen. Liver Enzymes: Occasional elevations of liver chemistries occurred inpatients treated with telmisartan; all marked elevations occurred at a higher frequency with placebo. Notelmisartan-treated patients discontinued therapy due to abnormal hepatic function. Cardiovascular RiskReduction: Because common adverse reactions were well characterized in studies of telmisartan inhypertension, only adverse events leading to discontinuation and serious adverse events were recordedin subsequent studies of telmisartan for cardiovascular risk reduction. In TRANSCEND (N=5926, 4 yearsand 8 months of follow-up), discontinuations for adverse events were 8.4% on telmisartan and 7.6% onplacebo. The only serious adverse events at least 1% more common on telmisartan than placebo wereintermittent claudication (7% vs 6%) and skin ulcer (3% vs 2%). In clinical studies with patients at highrisk of developing major cardiovascular events, cases of sepsis, including some with fatal outcomes, havebeen reported. Postmarketing Experience: The following adverse reactions have been identified duringpost-approval use of MICARDIS. Because these reactions are reported voluntarily from a population ofuncertain size, it is not always possible to estimate reliably their frequency or establish a causal relation-ship to drug exposure. Decisions to include these reactions in labeling are typically based on one or moreof the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causalconnection to MICARDIS. The most frequently spontaneously reported events include: headache,dizziness, asthenia, coughing, nausea, fatigue, weakness, edema, face edema, lower limb edema,angioneurotic edema, urticaria, hypersensitivity, sweating increased, erythema, chest pain, atrial fibrilla-tion, congestive heart failure, myocardial infarction, blood pressure increased, hypertension aggravated,hypotension (including postural hypotension), hyperkalemia, syncope, dyspepsia, diarrhea, pain, urinarytract infection, erectile dysfunction, back pain, abdominal pain, muscle cramps (including leg cramps),myalgia, bradycardia, eosinophilia, thrombocytopenia, uric acid increased, abnormal hepatic function/liverdisorder, renal impairment including acute renal failure, anemia, increased CPK, anaphylactic reaction,and tendon pain (including tendonitis, tenosynovitis). Rare cases of rhabdomyolysis have been reported inpatients receiving angiotensin II receptor blockers, including MICARDIS.

UUSSEE IINN SSPPEECCIIFFIICC PPOOPPUULLAATTIIOONNSSPregnancy: Teratogenic Effects, Pregnancy Categories C (first trimester) and D (second and thirdtrimesters). See Warnings and Precautions. Nursing Mothers: It is not known whether telmisartan isexcreted in human milk, but telmisartan was shown to be present in the milk of lactating rats. Becauseof the potential for adverse effects on the nursing infant, decide whether to discontinue nursing or discon-tinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: Safety andeffectiveness in pediatric patients have not been established. Geriatric Use: Of the total number ofpatients receiving MICARDIS in hypertension clinical studies, 551 (19%) were 65 to 74 years of age and130 (4%) were 75 years or older. No overall differences in effectiveness and safety were observed in thesepatients compared to younger patients and other reported clinical experience has not identified differ-ences in responses between the elderly and younger patients, but greater sensitivity of some olderindividuals cannot be ruled out. Of the total number of patients receiving MICARDIS in the cardiovascularrisk reduction study (ONTARGET), the percentage of patients ≥65 to <75 years of age was 42%; 15% ofpatients were ≥75 years old. No overall differences in effectiveness and safety were observed in thesepatients compared to younger patients and other reported clinical experience has not identified differ-ences in responses between the elderly and younger patients, but greater sensitivity of some olderindividuals cannot be ruled out. Hepatic Insufficiency: Monitor carefully and uptitrate slowly in patientswith biliary obstructive disorders or hepatic insufficiency.

OOVVEERRDDOOSSAAGGEELimited data are available with regard to overdosage in humans. The most likely manifestation ofoverdosage with MICARDIS tablets would be hypotension, dizziness and tachycardia; bradycardia couldoccur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, supportivetreatment should be instituted. Telmisartan is not removed by hemodialysis.

Rx only

© Copyright 2009, Boehringer Ingelheim International GmbHALL RIGHTS RESERVED

Rev: October 2009 MC-BS (10-09) MC67788

WWAARRNNIINNGG:: AAVVOOIIDD UUSSEE IINN PPRREEGGNNAANNCCYYWhen used in pregnancy, drugs that act directly on the renin-angiotensin system can causeinjury and even death to the developing fetus. When pregnancy is detected, MICARDIS tabletsshould be discontinued as soon as possible. See Warnings and Precautions.

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Upper respiratory tract infection 7 6

Back pain 3 1

Sinusitis 3 2

Diarrhea 3 2

Pharyngitis 1 0

6:37:37 PM


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Chronic kidney disease (CKD) affects approxi-mately 26 million people in the United States.1

Diabetes and hypertension cause up to two thirdsof all new CKD cases.1,2 According to Medicare policy,health plans are financially responsible for the care ofCKD patients for up to 33 months after they havereached the final stage of end-stage renal disease(ESRD).3 Data from the Institute for Health andProductivity Management 2001 database show thattreatment costs nearly double from one stage of CKD tothe next.4 The stages of CKD are defined based on theglomerular filtration rate (GFR) as determined by theNational Kidney Foundation Kidney Disease OutcomesQuality Initiative guidelines.5

Insurance claims for patients with CKD average $5000to $12,000 per patient per year (PPPY) as a patient pro-ceeds from stage 1 (GFR ≥90 mL/min/1.73 m2) to stage2 (GFR 60-89 mL/min/1.73 m2), $15,000 to $28,000PPPY from stage 3 (GFR 30-59 mL/min/1.73 m2) tostage 4 (GFR 15-29 mL/min/1.73 m2), and exceed$70,000 PPPY once the patient reaches stage 5 (GFR<15 mL/min/1.73 m2).4 Progressive CKD presents aburden to employers as suggested by researchers whoexamined ESRD-related nonmedical costs for employ-ers.6 It was estimated that employers may incur lifeinsurance costs of $55,055 per ESRD-related death,disability insurance costs of $31,617 per ESRD disabil-ity, and worker replacement costs of $27,869 perESRD-related lost worker.6

From a managed care perspective, it has been sug-gested that controlling and stabilizing the main comor-bidities of CKD—diabetes and hypertension—mayslow the progression of CKD, which would result in areduction of healthcare costs.7 Factors that may be asso-ciated with optimal quality of care for patients with

Background: Chronic kidney disease is prevalent in the United States, and diabetes and hypertensioncause up to two thirds of all new cases. Many health plans believe that these patients do not retain theirhealth plans for a long duration, therefore plans do not focus on prevention for this disease. Objective: To determine health plan retention rates and direct healthcare costs of adults with newlydiagnosed chronic kidney disease with diabetes or hypertension. Methods: A total of 31,917 patients with chronic kidney disease were included in this study betweenJanuary 1995 and December 2006, using a managed care database. Patients were divided into 3 sub-groups for cost comparison—patients with chronic kidney disease only (n = 8836), those with chronickidney disease with diabetes (n = 11,252), and patients with chronic kidney disease with hypertension

(n = 20,836). Follow-up of patients from index period of initial kidney disease diagnosis was 5 years. Average enrollment dura-tion was 38 months; 60% of all patients remained enrolled at 3 years postdiagnosis.Results: On average, patients with chronic kidney disease and diabetes and those with chronic kidney disease and hyper-tension remained enrolled slightly longer than chronic kidney disease–only patients (39 months, 40 months, and 36 months,respectively). The largest number of claims was for inpatient medical, followed by pharmacy and laboratory. Mean annualdirect healthcare costs were higher for patients with chronic kidney disease and diabetes ($20,165) and those with chronickidney disease and hypertension ($17,612) compared with patients with chronic kidney disease only ($9390).Conclusion: The study findings indicate that most patients who are newly diagnosed with chronic kidney disease retain theirhealth plan affiliation for a considerable period, including those with diabetes or hypertension. Increased direct healthcarecosts were associated with the presence of comorbidities in patients with chronic kidney disease. [AHDB. 2009;2(7):283-290.]

Dr Kubacki is Senior Manager, Dr Carter is AssociateDirector, Dr Herrera is Senior Manager, Dr Wang is AssociateDirector, Biostatistics, Dr Lopez is Regional AssociateDirector, and Ms Piech is Vice President, all at HealthEconomics and Outcomes Research, Centocor Ortho BiotechServices, LLC, Horsham, PA.

Health Plan Retention and Pharmacy Costs ofNewly Diagnosed Patients with ChronicKidney Disease in a Managed Care PopulationMaureen Kubacki, PharmD, MBA; Chureen Carter, PharmD, MS; Alan D.L. Herrera, PharmD; Jim Wang, PhD; Janice M. Lopez, PharmD; Catherine T. Piech, MBA

Maureen Kubacki

Kubacki:Cover 12/11/09 4:57 PM Page 283

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CKD during the 12-month predialysis phase have beenidentified, including predialysis erythropoietin therapy,nephrology referrals, and phosphate binder/vitamin Dadministration. As many as 48.7% of patients did nothave any interventions associated with optimal care,suggesting a need for proactive management of CKD inthe managed care setting to reduce utilization, whileimproving patient outcomes.8 Similarly, a retrospective

claims analysis of 27 health plans in 19 states evaluat-ed resource utilization in 3 defined time periods9:• Predialysis: months 2 to 6 before initial dialysis• Peridialysis: 30 days before and 30 days after dialysis• Postdialysis: months 2 and 3 after initial dialysis.

Per patient per month charges were highest in theperidialysis period ($35,292 vs $4265 for predialysisand $15,399 for postdialysis), and treatments withnutritional supplements and medications such asangiotensin-converting enzyme inhibitors and erythro-poietin were suboptimal.9 A directive has been issuedfor managed care plans to manage CKD through earlyintervention to improve outcomes and reduce costs.10-12

Although data are available that establish the costimpact of CKD, as well as identify gaps in the treat-ment of CKD patients at all stages, data to characterizeretention among newly diagnosed CKD patients inmanaged care plans are limited.

Information regarding retention of CKD patientswill enable managed care plans to understand thepotential impact of treating predialysis CKD as achronic illness on the plan and the impact on its mem-bers. Such data may encourage plans to implementearly-intervention strategies and potentially minimizecostly expenditures in later stages.

The purpose of this study was to examine the healthplan retention rates and pharmacy costs among newlydiagnosed CKD patients, including those with diabetesor hypertension, from a managed care perspective. Themain focus was to look at the length of time patientswith CKD, CKD and diabetes, and CKD and hyper-tension remain within a health plan after the initialCKD diagnosis, and compare the direct costs of CKDalone and the costs of CKD plus these closely relatedcomorbidities.

Methods Data Source

De-identified medical and pharmacy claims from thePharMetrics patient-centric database13 between Jan -uary 1995 and December 2006 were used to conductthis analysis. The PharMetrics database was selectedbecause it is largely representative of the commerciallyinsured population in the United States. This longitu-dinal database captures de-identified medical and phar-macy claims from 85 health plans that are submittingcomplete patient-level data for more than 45 millionmanaged care lives. The average member enrollmentacross the entire database is 2 years. Data elements usedin this analysis include health plan product type,health plan payer type, enrollment records, patientdemographics, diagnoses, Episode Treatment Groups(ETG) codes, and prescription records.

Study DesignWe utilized a retrospective cohort consisting of 3

subgroups of newly diagnosed patients with CKD: (1)CKD only, (2) CKD and diabetes, and (3) CKD andhypertension. All patients were at least 18 years old asof the date of their initial CKD diagnosis, had initiatedhealth plan enrollment between January 1, 1995, andSeptember 2001, and had at least 1 CKD claim, usingInternational Classification of Diseases, Ninth Revision,Clinical Modification (ICD-9-CM) diagnosis codes:

KEY POINTS Approximately 26 million Americans have chronic

kidney disease. About two thirds of all new cases are caused by

diabetes and hypertension, suggesting that earlyintervention can reduce or delay the progression tothis devastating and costly disease.

This study’s findings indicate that most patients whoare newly diagnosed with chronic kidney diseaseretain their health plan for a considerable period.

In this study of 31,917 patients with chronic kidneydisease, the mean annual total medical costs were$22,444 for patients with kidney disease plusdiabetes, $19,667 for those with kidney disease plushypertension, and $10,170 for patients with kidneydisease only.

Information regarding retention of CKDpatients will enable managed care plans tounderstand the potential impact of treatingpredialysis CKD as a chronic illness on the planand the impact on its members. Such data mayencourage plans to implement early-interven-tion strategies and potentially minimize costlyexpenditures in later stages.


Health Plan Retention/Pharmacy Costs of Patients with CKD


585.XX, 592.XX, 593.9, including a 180-day preindexperiod with no evidence of CKD (Figure 1).

Patients were excluded if they had missing memberdata or enrollment data of less than 6 months. Patientsidentified after 2001 were not included, because theobjective was to have a 5-year follow-up period for theidentified diagnosis. Each patient was followed for 5years from index diagnosis, and the length of enrollmentwas captured at the patient level.

Subgroups were identified by segmenting thepatients with CKD according to evidence of the select-ed comorbidities—diabetes and hypertension. Diabetesand hypertension were identified by the presence of cor-responding ETG codes. The ETG coding method is anillness classification system that identifies and classifiesan entire episode of care for a patient, taking intoaccount all medical care delivered in the inpatient andoutpatient setting collectively for that episode.14 TheETG system considers patient age, comorbidities, pro-cedures, clinical complications, and pharmaceuticalclaims in a synergistic manner to group patients by totalclinical activity.

ETG coding was selected for this study over ICD-9-CM codes, because ETG codes more accurately andcompletely represent the patient episodic healthcareprofile. ETG codes allow researchers to capture under-diagnosed cases that would otherwise be missed by ICD-9-CM codes. ETG codes are already formatted and read-ily retrievable from the PharMetrics patient-centricdatabase.13 Patients with no evidence of diabetes orhypertension were categorized as the CKD-only group.CKD patients with ETG codes 278 to 281 and 908-4were categorized as the CKD and diabetes group. CKDpatients with ETG codes 27 to 30 were categorized as theCKD and hypertension group.

Outcomes MeasuresThe overall duration of health plan enrollment was

reported in days and months, as a continuous variable,for each subgroup based on patient level enrollment

records. Enrollment status for each patient was ana-lyzed and aggregated at annual intervals, and reportedas a yearly categorical variable for each subgroup.

This study looked at direct healthcare costs andpharmacy costs, which together comprise total medicalcosts. Annualized direct healthcare costs were calculat-

Table 1 Baseline Characteristics

CharacteristicCKD only(n = 8836)

CKD + diabetes(n = 11,252)

CKD + hypertension(n = 20,836)

Age (mean ± SD), y 45.6 (±16.2) 58.3 (±16.6) 59.2 (±17.2)

Male, N (%) 4169 (47.2) 6049 (53.8) 10,963 (52.6)

Diagnosing physician specialty, N (%)Cardiology 297 (3.4) 1251 (11.1) 2194 (10.5)

Nephrology 507 (5.7) 1620 (14.4) 3158 (15.2)

Endocrinology 43 (0.5) 185 (1.6) 221 (1.1)

Internal medicine 1549 (17.5) 2608 (23.2) 4766 (22.9)

General/familypractice

1646 (18.6) 1983 (17.6) 3194 (15.3)

Othera 4794 (54.3) 3605 (32.0) 7303 (35.0)

Geographic region, N (%)East 1651 (18.7) 2242 (19.9) 4498 (21.6)

Midwest 5641 (63.8) 6585 (58.5) 11,528 (55.3)

South 1265 (14.3) 2070 (18.4) 4112 (19.7)

West 279 (3.2) 355 (3.2) 698 (3.3)

Plan type, N (%)HMO 5307 (60.1) 8930 (79.4) 15,671 (75.2)

Indemnity 76 (0.9) 30 (0.3) 71 (0.3)

PPO 1305 (14.8) 840 (7.5) 2047 (9.8)

Point of service 1733 (19.6) 1072 (9.5) 2251 (10.8)

Missing/unknown 415 (4.7) 380 (3.4) 796 (3.8)aIncludes not specified (41%), urology (17.6%), and emergency departmentphysicians (5.5%).CKD indicates chronic kidney disease; HMO, health maintenance organization;PPO, preferred provider organization.

Diagnosis period for CKDDiagnosis and index date 5-Year follow-up period

6-Month baseline periodNo prior CKD diagnosis

January 1, 1995-June 30, 1995 July 1, 1995-September 30, 2001

Preindex period

Figure 1 Study Timeframe

CKD indicates chronic kidney disease.


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ed based on health plan payments for inpatient, emer-gency department visits, home health visits, office vis-its, laboratory testing, and other outpatient claims.Costs were divided into total inpatient, total outpa-tient, and total medical costs for each subgroup. Theannualized cost of total pharmaceutical treatment wascalculated based on health plan payments for all pre-scription medications. Costs were summarized for eachsubgroup and presented in US dollars.

Statistical AnalysisDescriptive statistics were provided for both contin-

uous and categorical variables by subgroup and overall.All statistical analyses were performed using SASrelease 9.1.3 (SAS Institute, Cary, NC).

Results Study Population

A total of 31,917 eligible patients were identified andcomprised the newly diagnosed CKD cohort. The studypopulation consisted of 8836 CKD-only patients, 11,252patients with CKD and diabetes, and 20,836 patientswith CKD and hypertension. The CKD and diabetesand CKD and hypertension subgroups were not mutual-ly exclusive, and had overlapping patients. Among23,081 patients identified with comorbidities, 9007(39%) patients had both diabetes and hypertension.

Table 1 (page 285) lists the study population base-line characteristics for the subgroups. The average agefor all eligible patients with CKD was 55 years; of thesepatients, 51.2% were men. Patients with CKD and dia-betes (average, 58.3 years) and those with CKD andhypertension (average, 59.2 years) were older than the

CKD-only (average, 45.6 years) patients. The propor-tion of men was higher in the CKD and diabetes(53.8%) and CKD and hypertension (52.6%) sub-groups compared with the CKD-only subset (47.2%).

Slight differences were seen in the initial diagnosisof CKD by physician specialty. There was a trendtoward a greater proportion of patients with CKD anddiabetes and patients with CKD and hypertensiondiagnosed with CKD by a nephrologist compared withthe CKD-only subgroup. A large number of patients ineach subgroup were initially diagnosed with CKD by aphysician who is not specialized in cardiology, nephrol-ogy, endocrinology, or internal medicine/general fami-ly practice. The top identifiable specialties included inthe “other” category were urology and emergencydepartment physicians; however, the majority of physi-cian coding was not specified.

Geographic distribution reflected representationfrom all 4 regions of the United States, with mostpatients residing in the Midwest. The majority of thepatients in each subgroup belonged to a health mainte-nance organization.

Figure 2 outlines the distribution of patients by payertype. A greater proportion of CKD-only patients (63%)was enrolled in a commercial plan compared with thosewith CKD and diabetes (46%) or with CKD and hyper-tension (44%). Conversely, a greater proportion ofpatients with CKD and diabetes (40%) and CKD andhypertension (40%) had coverage through a MedicareRisk plan compared with CKD-only patients (13%).

Duration of EnrollmentThe average duration of enrollment was slightly

aPercentages may not equal 100% because of rounding.CKD indicates chronic kidney disease.

Commercial Medicaid Medicare RiskSelf-insuredUnknown

CKD onlyCKD + hypertension CKD + diabetes

40%

12%2%

2%

44%

1%

3%

2%

3%

Figure 2 Patient Distribution, by Payer Typea

40%

46%

10%19%

13%63%




longer for the CKD and diabetes (1163 days; 39months) and the CKD and hypertension (1190 days;40 months) subgroups compared with the CKD-only(1079 days; 36 months) subgroup. Overall, newly-diag-nosed CKD patients remained enrolled in their healthplan at 3 years postdiagnosis. Table 2 summarizes theenrollment status at yearly intervals for the subgroupsand the overall group.

When grouping the patients into subgroups of CKDonly, CKD and hypertension, or CKD and diabetes, welooked at their entire diagnostic phase and follow-upperiod. For example, for patients to be classified as CKDonly, they could not have hypertension or diabetes mel-litus anytime on or after their first diagnosis of CKD upto 5 years of follow-up period.

CostsAnnual direct healthcare costs are outlined in Table

3 and Figure 3. The mean annual direct healthcarecosts were substantially greater for patients with CKDand diabetes ($20,165) and those with CKD andhypertension ($17,612) compared with patients withCKD only ($9390).

Pharmacy. The mean annual pharmacy costs (Table 3,Figure 4) were substantially higher for the patients withCKD and diabetes ($2409) and CKD and hypertension($2185) compared with the CKD-only ($904) patients.

Medical. The mean annual total medical costs (Table3) were substantially greater for patients with CKD anddiabetes ($22,444) or CKD and hypertension ($19,667)compared with patients with CKD only ($10,170).

Table 3 Healthcare Utilization and Expenditures

Utilization and expendituresCKD only (n = 8836)

CKD + diabetes (n = 11,252)

CKD + hypertension(n = 20,836)

Overall (n = 31,917)

Annualized resource utilization claims,mean (SD)Inpatient 27 (74.4) 43 (66.9) 37 (62.0) 36 (64.8)

Pharmacy 15 (21.4) 46 (40.4) 41 (38.7) 33 (36.2)

Emergency department 5 (13.5) 6 (11.6) 5 (11.3) 5 (11.7)

Home health 6 (17.0) 9 (18.9) 7 (17.2) 7 (18.0)

Office visits 10 (13.4) 18 (23.4) 17 (22.0) 15 (19.8)

Laboratory 13 (22.9) 26 (35.0) 23 (34.9) 20 (31.8)

Other outpatient 16 (24.8) 27 (40.2) 25 (36.8) 22 (34.9)

Annualized total direct healthcare costsMean (SD)

$9390($44,415.70)

$20,165 ($37,685.30)

$17,612 ($34,446.50)

$15,106($37,825.60)

Annualized total medical costsMean (SD)

$10,170($44,824.70)

$422,444 ($39,591.70)

$19,667 ($36,287.90)

$16,748($39,178.80)

Annualized total pharmacy costs Mean (SD)

$904 ($2748.10)

$2409 ($58,990)

$2185 ($5585)

$1793 ($4916)


Table 2 Annual Enrollment Persistence Status

DurationCKD only (n = 8836) N (%)

CKD + diabetes (n = 11,252) N (%)

CKD + hypertension (n = 20,836) N (%)

Overall (n = 31,917) N (%)

1 yr 641 (7.3) 592 (5.3) 1053 (5.1) 1885 (5.9)

2 yrs 2897 (32.8) 2972 (26.4) 5514 (26.5) 9209 (28.9)

3 yrs 5658 (64.0) 6372 (56.6) 12,000 (57.6) 19,094 (59.8)

4 yrs 7061 (79.9) 8873 (78.9) 15,792 (75.8) 24,840 (77.8)

5 yrs 7677 (86.9) 9535 (84.7) 17,113 (82.1) 26,886 (84.2)CKD indicates chronic kidney disease.


BUSINESS


DiscussionThe study used ETG codes to classify the patients

into 3 groups; those with CKD and hypertension andthose with CKD and diabetes mellitus were given thisdesignation at the beginning of the study and werethen compared with the CKD-only group regardingenrollment duration and cost. This project was under-taken to identify the proportion of patients with newlydiagnosed CKD that remain in the same health planover time. An assumption was made that the longer apatient remains within a health plan, the better theopportunity to implement and assess the impact ofearly intervention strategies for disease managementand overall quality of health.

Smith and colleagues documented that per-patientcosts increased as the stages of CKD progressed.15 Ourresults of increased pharmacy costs for CKD patientswith disease-related comorbidities agree with Smith andcolleagues’ findings, which demonstrated that costs for

CKD patients were much higher in those with disease-related comorbidities compared with those with CKDalone. Delay of disease progression to the next stagecould, therefore, also have financial benefits to healthplans. Implementation of an aggressive disease-specificapproach by a health plan could impact patient out-comes by a possible delay of disease progression as well.

In this study, we evaluated 3 groups of newly diag-nosed CKD patients stratified based on the document-ed coexistence of hypertension or diabetes. Patientswith CKD and comorbidities tended to stay with theirsame health plan for approximately 3 months longerthan patients with CKD only. To ensure that CKDpatients were accurately identified, a frequency distri-bution was run, evaluating the number of patients ineach subgroup (ie, CKD only, CKD and diabetes, andCKD and hypertension) with 1 claim for CKD versusthose with more than 1 claim. The subgroups were sim-ilar in that approximately 70% of patients in each sub-group had at least 2 claims for CKD, providing addi-tional validity to the diagnosis of CKD.

Approximately 66% of CKD-only patients wereenrolled in commercial plans, whereas a larger propor-tion of the patients with CKD and diabetes and CKDand hypertension were enrolled in Medicare Riskplans. The average retention time may be influenced ordirected by the Medicare timeline law that dictateswhen Medicare coverage begins for a CKD dialysispatient. As the law extends this timeframe from the

Figure 4 Mean Yearly Pharmacy Costs

3000

2500

2000

1500

1000

500

0

25,000

20,000

15,000

10,000

5000

0 CKD CKD CKD only+ diabetes + hypertensionCKD only CKD + diabetes CKD

+ hypertensionMea

n ph

armac

y co

sts, $

Cost, $

aP <.001.CKD indicates chronic kidney disease.

Total medical costsDirect healthcare costs

$2409

$2185

$904a

Figure 3 Direct Healthcare and Total Medical Costs


Early intervention in these populations isparamount to preventing or delaying diseaseprogression and, in parallel, to potential costreduction for the health plan, employers, andpatients/members.

Kubacki:Cover 12/11/09 4:57 PM 8



current 33 months to the proposed 42 months, reten-tion time in health plans will most likely expand, fur-ther necessitating the need to intervene as early as pos-sible in these at-risk employee populations.16

Early intervention in these populations is para-mount to preventing or delaying disease progressionand, in parallel, to potential cost reduction for thehealth plan, employers, and patients/members. Ourfindings, which have not been documented extensive-ly in previous studies, support the notion that newlydiagnosed patients with CKD and those with disease-related comorbidities retain their healthcare plans forconsiderable periods.

LimitationsThis study design has several limitations. Our goal

was to highlight the amount of time patients who areactually diagnosed with CKD remain in plans, whichprovide a strong incentive to treat it appropriatelyrather than assume that patients would not be in theplan long enough to reap the benefits of treatment. Weacknowledge that the number of patients diagnosedwith CKD in the real world is well below what wouldbe found if proper screening was conducted. We alsoacknowledge that CKD was likely more prevalent thanit appears in these data we evaluated, although patientswith CKD who are not diagnosed may move betweenplans at similar rates as those without CKD.

In addition, there were potential overlaps betweenthe CKD and diabetes and CKD and hypertension sub-groups. Factors for patient disenrollment were notavailable due to the retrospective nature of the study.Only newly diagnosed CKD patients were included inthe study; therefore, retention periods for existing CKDpatients and a healthy non-CKD cohort were not eval-uated. A diagnosis of CKD was captured during theidentification period only (July 1, 1995-September 30,2001), so patients with a new CKD diagnosis duringthe 5-year follow-up period were not evaluated.

The study design also did not account for patientswhose diagnosis of CKD might have been ruled out byfurther investigation. The retention rates reported maynot be representative of all CKD patients, because theymay be different for patients who had a previouslyestablished CKD diagnosis (not newly diagnosed).

Also, retention rates and costs were not evaluatedwithin and between subgroups for differing stages ofCKD and hypertension or severity of diabetes (eg,requiring oral or injectable medications). Direct com-parison between groups in similar plan types was alsonot evaluated.

This study does not account for access to healthcaredifferences and its impact on costs among differentplans. Finally, the use of ETG codes in this analysis lim-ited the ability to compare it with other studies usingtraditional diagnosis and procedure costs.

ConclusionThe majority of newly diagnosed CKD patients

retain their health plan affiliation for a considerableperiod, including those with diabetes or hypertension.Presence of these comorbidities resulted in increasedtotal direct healthcare costs. Results of this study fur-ther support the need for early intervention in CKD.Managed care plans may benefit from earlier manage-ment strategies for CKD, because these patients couldcontribute to increased healthcare utilization and costover the long-term. ■

AcknowledgmentThis study was funded by Centocor Ortho Biotech Services, LLC.

Disclosure Statement All the authors are employed by Centocor Ortho Biotech Services, LLC.

References1. National Kidney Foundation. The facts about chronic kidney disease (CKD).www.kidney.org/kidneydisease/ckd/index.cfm#facts. Accessed June 28, 2008.2. The American Society of Nephrology. Facts and Statistics. www.asn-online.org/facts_and_statistics/faq.aspx. Accessed June 28, 2008.3. Centers for Medicare & Medicaid Services. Medicare Coverage of Kidney Dialysisand Kidney Transplant Services. May 2008. www.medicare.gov/Publications/Pubs/pdf/10128.pdf. Accessed June 28, 2008.4. Sullivan S. Employer challenges with the chronic kidney disease population. JManag Care Pharm. 2007;13(9 suppl D):S19-S21.5. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kid-ney disease: evaluation, classification and stratification. Am J Kidney Dis. 2002;39(2suppl 1):S1-S266.6. Kamal-Bahl SJ, Pantely S, Pyenson B, Alexander CM. Employer-paid nonmedicalcosts for patients with diabetes and end-stage renal disease. Prev Chronic Disease.2006;3:A83. Epub 2006 Jun 15.7. Rasu RS, Crawford T, Manley HJ, Balkrishnan R. Treatment of hypertension anddiabetes mellitus in patients with chronic kidney disease: a review. Expert OpinPharmacother. 2007;8:2543-2551.8. London R, Solis A, Goldberg GA, et al. Examination of resource use and clinicalinterventions associated with chronic kidney disease in a managed care population.J Manag Care Pharm. 2003;9:248-255.9. Robbins JD, Kim JJ, Zdon G, et al. Resource use and patient care associated withchronic kidney disease in a managed care setting. J Manag Care Pharm. 2003;9:238-247.10. Chronic kidney disease: stating the managed care case for early treatment.Discussion and consensus of presentations of economic analyses, managed care

Managed care plans may benefit from earlier management strategies for CKD,because these patients could contribute toincreased healthcare utilization and cost over the long-term.


BUSINESS


PAYERS: Payers have members and beneficiarieswith certain high-cost and high-utilization diagnoseson their radar screen for a variety of reasons, andchronic kidney disease (CKD) is one such diagnosis.As the authors of this article have nicely quantified,CKD diagnosis—alone or with comorbidities—isassociated with increased costs (ie, medical and phar-macy) and greater utilization of services (ie, outpatientphysician and specialty visits, dialysis, and inpatienthospitalization).

The natural progression of disease managementand financial obligations often flows initially from acommercial or a Medicaid responsibility to eventual-ly becoming a permanent Medicare responsibility.The alignment of incentives within this payer con-tinuum encourages the initial responsible payer tohave early identification means for this diagnosis,through the use of a coding system such as the ICD-9-CM (International Classification of Diseases, NinthRevision, Clinical Modification) or through other diag-nostic identifiers on the medical benefit or the drugsurrogates on the pharmacy benefit.

Once members are identified, health plans are fur-ther incentivized to track and facilitate the progressionof the timeline along the plan care continuum, untilthe next handoff or transition point to a subsequentpayer. Simultaneously, during this timeframe, it is inthe specific plan’s or payer’s best interest to activelycase-manage these members to slow their disease pro-gression and to minimize utilization of avoidable serv-ices, such as preventable hospitalizations.

Proposed regulatory changes that would expandthe tenure of a member’s time on a pre-Medicare cov-erage further encourages a payer’s active case-man-agement of these members during the plan’s time offinancial responsibility.

PATIENTS: Receiving a diagnosis of CKD elicitsa variety of responses in a person, such as fear, anxi-ety, or planning for the future. It also becomes a deci-sion point on how to best manage, live with, andaddress the forthcoming progression.

If the rate of progression can be influenced andmanaged medically, this becomes a time of opportu-nity for member engagement. Members with current-ly stable employment and insurance will often con-sider the risks associated with a job and a coveragechange in light of their now having a preexistingdiagnosis and its implications for a potential carrier.

Often, the thought of the potential risks in such achange make people opt to remain in their currentemployment and under their current medical cover-age, and they begin to reach out to their existing car-rier to understand the resources available to them.

Such a member-directed decision is probably oneof the main contributors to health plan retentionduring the progression down the healthcare payercontinuum for newly diagnosed patients with CKD.

Jeff Januska, PharmDDirector of Pharmacy

CenCal Health Goleta, California

STAKEHOLDER PERSPECTIVEAlignment of Incentives along the Healthcare Payer Continuum for Patients with Kidney Disease

organization case studies, and opportunities for intervention in a managed care set-ting. May 3-5, 2001, Chicago, Illinois. Am J Manag Care. 2002;8(4 suppl):S112-S120.11. Weiner DE. Causes and consequences of chronic kidney disease: implications formanaged health care. J Manag Care Pharm. 2007;13(3 suppl):S1-S9.12. Wright A. Preparing MCOs to manage chronic kidney disease. Manag Care.2003;Spec No:13-6; discussion 17-20.13. IMS Health. PharMetrics patient-centric database. Watertown, MA; 2008.14. Ingenix. Symmetry episode treatment groups: measuring health care with mean-

ingful episodes of care. 2007. www.ingenix.com/content/attachments/SymmetryETG_WhitePaper.pdf. Accessed June 27, 2008.15. Smith DH, Gullion CM, Nichols G, et al. Cost of medical care for chronic kid-ney disease and comorbidity among enrollees in a large HMO population. J Am SocNephrol. 2004;15:1300-1306.16. Geisel J. House panel approves renal care cost-shift. Business Insurance. July 30,2007. www.businessinsurance.com/article/20070730/NEWS/200010770. AccessedOctober 16, 2008.


INDUSTRY TRENDS


INDUSTRY TRENDS

Now that gene tests, markers for tumor receptors,assays for rapid and precise diagnosis of infec-tious agents, and a variety of other molecular

probes have created an entirely new world of personal-ized medicine, it is time to add new information man-agement tools to capture and manage this knowledge.

With more than 1500 documented tests availablefor gene testing alone, new strategies are needed fornaming and classifying these tests, learning when to usethem, and who should pay for all these tests. Even peo-ple in the genetic-testing business are struggling tokeep up with these advances, especially when one con-siders that much of the technology driving this explo-sion is quite new itself. After the completion of theHuman Genome Project in 2003, many researchersturned their attention to the implications of gene test-ing and the clinical applications of molecular diagnos-tics once the genes themselves were identified.

An immediate problem is keeping track of these newstudies with a naming system that uniquely identifieseach test. The coding system of the American MedicalAssociation/Current Procedural Terminology and theCenters for Medicare & Medicaid Services/HealthCare Financing Administration Common ProceduralCoding System (HCPCS) that has been used to orderand bill these tests has not kept pace; the current codespredominantly identify the methodology of laboratoryprocess required and are not unique to each analyte ormarker. These are sometimes called “stacking codes,”because 5 to 10 codes may be required to describe a par-ticular analysis. Other coding systems, such as

SNOMED (Systematized Nomenclature of Medicine)and LOINC (Logical Observation Identifiers Namesand Codes), are used effectively in electronic healthrecord systems but have more characters than can beused by payer claims systems.

New Online Testing RegistryMcKesson Health Solutions has proposed a solution

to this challenge that would use a coding approachmodeled after the S codes in the HCPCS system, wherea panel of industry experts in molecular diagnosticstesting would provide the oversight principles neededto automatically assign a 5-character alphanumericcode to each new test, starting with a Z and using 34letters and numbers. Their proposal would add thenewly registered test to an online master catalog or anonline open registry that anyone can view.

A McKesson web-based application, AdvancedDiagnostics Management, incorporates just such a testcatalog into the heart of its logic. This test registryserves as the master catalog within the application (andwould link directly to a universal catalog if a differentnational standard should emerge); this would allow aphysician (or physician’s office staff) to look up a test,learn about the test and indications for it, and place anorder for the test from a clinical laboratory.

Evidence-based criteria have been developed formore than 300 molecular tests using clinical guidelinedevelopment principles originally developed forInterQual clinical care management criteria. In con-junction with order entry and test-reporting capabili-ties, this software application permits online testauthorization, using established health plan coveragepolicies to verify the appropriateness of the test inaccordance with specific diagnostic informationentered by a physician’s office.

Medical and Financial Implications The implications of this approach are significant for

personalized medicine. Credible information would beavailable to providers during the order entry process,ensuring that the appropriate test is being selected for

Management Tools for Molecular DiagnosticTesting: Financial and Clinical Implications Douglas Moeller, MDMedical Director, Advanced Diagnostics Management, McKesson Health Solutions

With more than 1500 documented tests available for gene testing alone, newstrategies are needed for naming andclassifying these tests, learning when touse them, and who should pay for allthese tests.

IndustryTrends:Cover 12/11/09 5:42 PM Page 291

INDUSTRY TRENDS


INDUSTRY TRENDS

the proper reason. Furthermore, this approach willensure that health plan coverage for the test is con-firmed; if it is not a covered test, then the patient couldmake an informed decision at that point whether toproceed with the recommended test. Once laboratoriesprovide pricing information for self-pay tests, full trans-parency about financial accountability for paying forthese tests will avoid unpleasant surprises later.

The implications for managing the healthcareprocess are critical; this approach permits useful infor-mation about specific tests to be made available to theprovider before or as the test is being ordered. Selectionof the appropriate test to evaluate a genetic coagulationdefect or to quantify the disorder in a drug metabolismpathway (eg, warfarin metabolism) is now a real-timepossibility. By making all this information available tothe physician, the laboratory, and the patient beforethe test is ordered, all parties are made fully aware oftheir options—clinically and financially—before com-mitting to the test itself. Because the system is online,changes could be made dynamically in a way that pro-

motes continuous quality improvement.There are barriers, of course. All key stakeholders

need to have confidence that all information con-veyed through this system is objective and offers state-

of-the-art solutions. The feedback loops that supportcontinuous quality improvement must also be fullytransparent. And, finally, health plans and clinicallaboratories must achieve a new level of clarity aboutwhat criteria are applied to medical coverage foremerging technology, and what criteria are useful insetting prices for new studies. ■

By making all this information availableto the physician, the laboratory, and the patient before the test is ordered, all parties are made fully aware of their options.

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GENERIC DRUG TRENDS


As 2009 is coming to a close, the future of gener-ics appears brighter than ever, with manybrand-name medications pending patent expi-

ration by 2011, accounting for about $34 billion intotal sales in 2008.1 The drug patent expiration outlook

overshadows the recent Senate vote to extend thepatent exclusivity period for biologics to 12 years, asrequested by the biotechnology industry, thereby sig-nificantly delaying the introduction of potentialbiosimilars to the market. A biosimilars pathway nowseems likely to become a reality by 2010 or 2011.

Nevertheless, with drug costs doubling in the decadebetween 1996 and 2006, as was recently shown in a newreport from the Agency for Healthcare Research andQuality (AHRQ),2 and the continuing trend of growingutilization of generics in the United States, the growthin first-time generics will likely continue to rise (even ifat a lower rate than before), further increasing the com-petition with brand-name products and possibly con-tributing to their price inflation, especially after 2011.1

According to the AHRQ report, “Prescription med-ications accounted for a notably higher share of totalexpenses for adults ages 18-44 in 2006 than in 1996(17.6 percent versus 10.2 percent),”2 and “The averageexpense for a prescription medication purchase wasnotably higher [for that age group] in 2006 than in 1996($161 versus $79).”2

Similarly, Medco projects an increase in health plandrug utilization between 2009 and 2011 (from 0%-1% to1%-2%, respectively) and in drug price (from 3%-4% to4%-5%, respectively) per member per year,1 all pointingto the continuing trend of greater generics utilization inthe coming years.

A select list of brand-name drugs expected to losetheir patent by 2011, as well as their US retail sales in2008, is listed in the Table. Many of these drugs will like-ly appear as generics by 2011. If by then a biosimilarpathway becomes available, as is widely anticipated inthe industry, the total utilization rate of generics/biosim-ilars and their share of the total market are likely toincrease even further. ■

References1. Medco Health. Medco 2009 Drug Trend Report. 2009.http://filecache.drivetheweb.com/mr4enh_medco/177/2009+DRUG+TREND+REPORT.pdf. Accessed December 9, 2009.2. MEPS. AHRQ. Trends in Health Care Expenditures for Adults Ages 18-44: 2006 versus 1996. Statistical Brief #254. August 2009 (availableDecember 9 only). www.meps.ahrq.gov/mepsweb/data_files/publications/st254/stat254.pdf. Accessed December 10, 2009.

Increases in Drug Utilization and Patent Expirations:A Recipe for Growth of Generics’ Market Share, despiteStalling on BiosimilarsDalia Buffery, MA, ABD

Table Drug Patent Expiration, 2009-2011

Potential patentexpirationa Brand (generic)

2008 US sales,$ million

2009 Adderall XR (amphetamine salts) 1585Ambien CR (zolpidem controlled-release) 986CellCept (mycophenolate mofetil)b 777Clarinex (desloratadine) 251Prevacid (lansoprazole) 2948c

Pulmicort Respules (budesonide) 876Topamax (topiramate) 2356Valtrex (valacyclovir) 2020

2010 Aldara (imiquimod topical cream) 375Arimidex (anastrozole) 617Astelin (azelastine nasal spray) 273Cozaar (losartan) 731Differin (adapalene topical)b 282Effexor XR (venlafaxine extended-release) 2791Flomax (tamsulosin)b 1318Hyzaar (losartan/hydrochlorothiazide) 548Mirapex (pramipexole) 344

2011 Aricept (donepezil) 1224Actos (pioglitazone)b 2569Caduet (amlodipine/atorvastatin) 418Levaquin (levofloxacin) 1719Lipitor (atorvastatin) 6392Patanol (olopatadine ophthalmic solution)b 256

Temodar (temozolomide) 224Xalatan (latanoprost ophthalmic solution) 494Zyprexa (olanzapine) 1853

aThese dates can change for many reasons, including patent protections/litigationor exclusivities.

bPatent expiration assumes a pediatric extension.cSales figure apply to the capsule formulation only. Source: Medco 2009 Drug Trend Report. 2009, page 53.

Generics:Cover 12/11/09 5:44 PM Page 294

Q. Which Global Generic Company’s TransdermalPatches Were Most Dispensed in the U.S.Last Year?

A. Mylan Pharmaceuticals.*With one of the most advanced transdermal development and manufacturing facilities in theUnited States—brand or generic—Mylan is well-recognized as an innovator in transdermaldrug delivery technology. In fact, last year 65% of all generic patches dispensed in the U.S.carried the Mylan name.*

We have developed more generic transdermal patches than any company in the U.S. and allof our patches are designed with patient safety in mind. None have a bulky, liquid, gel-filledreservoir, which eliminates any concern about the dangers associated with leakage, andnone have aluminum or other metals in their backing, which may cause potential burns inMRI patients. So when you need generic transdermal patches…think Mylan.

©2009 Mylan Pharmaceuticals Inc. MYNMKT308

*IMS National Prescription Audit. 12 months ending December 2008.

Generics:Cover 12/11/09 5:45 PM Page 295

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2 Generics:Cover 12/11/09 5:45 PM Page 296

REGULATORY


Many of today’s healthcare concerns focus onthe concept of value, which can be defined asa composite of cost, quality, and access.

Expanding access through affordable healthcare insur-ance will only be possible if healthcare costs are con-tained through a focus on quality.1 Poor care qualityresults in costly errors, complications, and re-work. Con -versely, high-quality care, namely, the right treatmentat the right time, results in more cost-effective care.This emphasis on value is underscored by a lack of cor-relation between the increase in healthcare spendingin recent years and health outcomes, which is often theresult of a lack of information and tracking systems todetermine the value of different treatments.2

Greater value, therefore, can be achieved by reduc-ing costs, increasing the quality of care, and/or increas-ing access. A recent report developed as a collaborativeeffort between different healthcare stakeholders andquality organizations calls for the development of met-ric systems that allow measurement and reporting thequality, as well as the cost of care.1 A new Medicareprovision will provide $10 million annually to this endfor fiscal years 2009-2012.3 These quality metrics areexpected to help determine the value of differentapproaches to treatment and the definition of guide-

lines that maximize value in the US healthcare system.Private payers and some employer groups are alsodeveloping their own quality improvement initiatives,or are incorporating initiatives developed by qualityorganizations.4

The Centers for Medicare & Medicaid Services’(CMS) Physician Quality Reporting Initiative (PQRI)represents the first step toward a value-based system.PQRI is a voluntary pay-for-reporting system, in whichparticipating professionals can earn a bonus paymentfor reporting to CMS on clinical quality measures spe-cific to their practice.5 The information collectedthrough this program will allow CMS to measure thequality of care and, in time, could lead to the establish-ment of a pay-for-performance (P4P) system.

Employers and private payers are also increasing theirfocus on value.6,7 The rise in healthcare insurance premi-ums has made employers consider quality measures intheir insurance purchasing decisions, and in turn, morehealthcare plans are seeking accreditation by nationalquality organizations, such as the National Committeefor Quality Assurance (NCQA) and others.8

Current Quality Improvement EnvironmentToday’s health quality organizations and initiatives

are fragmented, with no definite leaders. Unlike othercountries that have a more centralized system (eg, UK’sNational Institute for Health and Clinical Excellence is

Background: The increase in healthcare cost without direct improvements in health outcomes, coupledwith a desire to expand access to the large uninsured population, has underscored the importance ofquality initiatives and organizations that provide more affordable healthcare by maximizing value. Objectives: To determine the knowledge of managed care organizations about quality organizationsand initiatives and to identify potential opportunities in which pharmaceutical companies could collab-orate with health plans in the development and implementation of quality initiatives.Methods: We conducted a survey of 36 pharmacy directors and 15 medical directors of different plansduring a Managed Care Network meeting in 2008. The represented plans cover almost 74 million livesin commercial, Medicare, and Medicaid programs, or a combination of them.

Results: The responses show limited knowledge among pharmacy and medical directors about current quality organiza-tions and initiatives, except for quality organizations that provide health plan quality accreditation. The results also reveal anopportunity for pharmaceutical companies to collaborate with private health plans in the development of quality initiatives,especially those related to drug utilization, such as patient adherence and education and correct drug utilization. Conclusion: Our survey shows clearly that today’s focus for managed care organizations is mostly limited to the organiza-tions that provide health plan quality accreditation, with less focus on other organizations. [AHDB. 2009;2(7):297-304.]

Dr Fernandez-Lopez is Assistant Director and Ms Lennert isDirector, Xcenda, Palm Harbor, FL.

Quality Improvement Initiatives: The MissedOpportunity for Health PlansSara Fernandez-Lopez, PhD; Barbara Lennert, RN, BSN, MAOM

Barbara Lennert

Lennert:Cover 12/11/09 5:00 PM Page 297

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the clear leader in developing quality measures and clin-ical guidelines), in the United States the variety of qual-ity initiatives and organizations have different goals andmissions and focus on different stakeholders (Figure 1).

At the federal level, CMS and the Agency forHealthcare Research and Quality (AHRQ) extendtheir quality measures and improvement efforts to allsegments of the healthcare system through differentinitiatives. Other organizations focus their qualitymeasures and improvement initiatives in 1 or 2 seg-ments. For example, the Leapfrog Group andCheckPoint provide hospital ratings exclusively,whereas Bridges to Excellence focuses on physicianquality measures. HealthGrades and different state and

regional quality initiatives, as well as individual healthplans, develop their own quality measures for bothtypes of providers—physicians and hospitals. Finally,the NCQA and URAC (formerly Utilization ReviewAccreditation Commission) focus on rating the qualityof healthcare plans and pharmacy benefit management(PBM) organizations. Despite this fragmentation, qual-ity organizations interact and participate in eachother’s development of quality metrics and guidelines.

Two organizations stand out for specific segments. Forhealth plans, the NCQA, with its accreditation and itsHealthcare Effectiveness Data and Information Set(HEDIS) rating, represents the most followed organiza-tion, because employers often consider it the decisionfactor for their choice of insurance plan. For providers,the National Quality Forum (NQF) is gaining accept-ance as the reference for developing national standardsof care at the physician level, because many of theirquality metrics are part of CMS’s PQRI initiative.

Payers’ Knowledge of Quality OrganizationsTo determine the knowledge of healthcare plan deci-

sion makers about different quality improvement organ-izations and initiatives, we surveyed medical and phar-macy directors of health plans. The survey wasconducted live during a single session of the March 2008Managed Care Network (MCN) meeting of more than100 leading medical and pharmacy directors, represent-ing more than 150 million covered lives. The surveycaptured responses from 16 medical directors and 35pharmacy directors, representing 52 health plans cover-ing almost 74 million lives in commercial, Medicare,and Medicaid programs, or in a combination of them.

The managed care organizations (MCOs) represent-ed in the survey included regional and national plans,as well as small plans (less than 200,000 lives) and largeplans (more than 10 million lives). All participants (n= 51) responded to all questions asked during the ses-sion. Because 1 participant did not specify his/her jobfunction, there is a discrepancy between the number ofmedical and pharmacy directors present and the num-ber of health plans represented.

The survey was organized into 5 sections aimed todetermine (1) pharmacy and medical directors’ level ofknowledge about different quality organizations; (2)MCOs’ current collaboration/accreditation with quali-ty organizations; (3) level of influence of different qual-ity organizations in quality initiatives at MCOs; (4)MCOs’ interest in learning more about quality organi-zations and initiatives; and (5) MCOs’ openness toaccept pharmaceutical companies as potential partners

KEY POINTS Quality metrics have the potential to increase the

value of the US healthcare system by reducing costsand increasing access to quality care.

The goal of this survey was to evaluate the extent ofknowledge of medical and pharmacy directors ofcurrent healthcare-related quality improvementinitiatives.

Participants had limited knowledge of currentquality organizations and initiatives, except for thosethat offer quality accreditation to health plans andpharmacy benefit management organizations.

This finding, however, presents an opportunity forpharmaceutical companies to collaborate withprivate health plans to develop quality initiatives,especially for drug utilization.

Figure 1 Significant Quality Organizations and Their Segment of Focus

Hospitals Medical groups Health plans Other

• CMS: HospitalQuality Alliance

• JCAHO• HealthGrades• CheckPoint• Leapfrog Group• State/regionalQI collaboratives

• Health plans

• CMS: PQRI• NQF• HealthGrades• Bridges toExcellence

• State/regionalQI collaboratives

• NCQA certifica-tion programs

• Health plans

• CMS• NCQA accredita-tion and HEDIS

• URAC• eValue8

• CMS: HomeHealth Compare

• CMS: NursingHome Compare

• PharmacyQuality Alliance

CMS indicates Centers for Medicare & Medicaid Services; JCAHO, JointCommission on the Accreditation of Healthcare Organizations; NCQA,National Committee for Quality Assurance; NQF, National Quality Forum;PQRI, Physician Quality Reporting Initiative; QI, quality improvement.


Quality Improvement Initiatives


in quality improvement initiatives. In the first part of the survey, participants were asked

to rate their knowledge about different quality organiza-tions. Table 1 (page 300) lists the public and privateorganizations covered in the first 3 sections of the survey.

Responses show that 92% of participants had highor very high knowledge of the NCQA (Figure 2). Thisis clearly in line with the NCQA’s focus on health planaccreditation and HEDIS ratings and the influencethey have on employers’ choice of insurance. However,their knowledge of URAC (also providing qualityaccreditations for health plans and PBM organizations)was more varied: 42% of respondents had little or noknowledge about it (Figure 2).

Knowledge about other quality organizations includ-ed in the survey was limited. For any of those organiza-tions, more than 70% of respondents had low or noknowledge, with the exception of AHRQ, with only30% of respondents showing no or little knowledge.This lack of knowledge about quality initiatives repre-sents a missed opportunity for MCOs to include someof these measures in their programs.

MCOs’ Collaboration with Quality OrganizationsMCOs’ interaction with each quality organization is

different. Both NCQA and URAC issue health planaccreditations, whereas the relationship of MCOs withother quality organizations is more collaborative. Thelevel of interaction varies as shown in the survey results(Figure 3). NCQA was the organization with whomMCOs had the strongest relationship, with 74% of therespondents being or planning to be accredited by it.Furthermore, 34% of the plans were currently partici-pating in other programs offered by NCQA. This againshows a great difference with URAC, with only 30% ofplans being or seeking accreditation from URAC.

To further understand the reasons behind some ofour observations, in January 2009 we conducted a fol-low-up online survey of the MCN meeting attendeeson why the NCQA and URAC where best known andmost referenced for quality initiatives. Many respon-dents commented that the NCQA is seen as almost“mandatory or expected,” and sometimes listed as arequirement from employers to consider a health plan.Some respondents commented on the NCQA accredi-tation requirement by Medicare and some Medicaidstate programs. Respondents who chose to seek accred-itation from URAC said that they did so mainlybecause of the lower cost of the accreditation processand the more realistic expectations of the accreditationprogram for managed care plans. For pharmacy benefit

managers and utilization management quality pro-grams, URAC seems to be the first choice, given itsrecognized brand name and experience in this arena.

MCOs’ level of collaboration with any of the otherquality organizations was very low, with less than 10% ofthe plans participating in any quality initiatives. Thereasons for the low participation may be related to therelatively low knowledge of other organizations, as wellas the limited health plans resources dedicated to quali-ty programs. Respondents commented on the cost and

NCQA URAC AHRQ IHI ICSI NQF PQRI PQA HQA

AHRQ indicates Agency for Healthcare Research and Quality; HQA, HospitalQuality Alliance; ICSI, Institute for Clinical Systems Improvement; IHI, Institutefor Healthcare Improvement; NCQA, National Committee for Quality Assurance;NQF, National Quality Forum; PQA, Professional Quality Assurance; PQRI,Physician Quality Reporting Initiative.

Figure 2 Level of Knowledge of Pharmacy/Medical Directors ofDifferent Quality Organizations

100

90

80

70

60

50

40

30

20

10

0

High/very high Moderate Low/none

Quality organizations/initiatives

Respondents, %

NCQA URAC AHRQ PQRI IHI NQF ICSI PQA HQA


Figure 3 Health Plans Collaborating with Quality Organizations

Note: For NCQA and URAC, the nature of the collaboration is defined ashealth plan being accredited or seeking accreditation by NCQA and/or URAC.

100

80

60

40

20

0

Respondents, % 74%

28% 26%19%

8% 6% 4% 4% 4%


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Table 1 Organizations Covered During the First 3 Sections of the Survey

Organization What is it? Mission What does it do? Stakeholders Comments

AHRQwww.ahrq.gov

Agency in theDepartment ofHealth and HumanServices responsiblefor healthcare quality research

To improve the quality,safety, efficiency, andeffectiveness of health-care for all Americans

Sponsors/conductsresearch with evi-dence-based infor-mation on healthcarequality and outcomes,including compara-tive effectiveness oftreatments

Hospitals; providers;patients; federal,state, and local policymakers; payers; health officials; academia

Formerly Agency forHealth Care Policyand ResearchAmerican Recoveryand Reinvestment Actof 2009 designated$300 million for com-parative effectivenessresearch

HQA www.hospitalqualityaliance.org

National public–private collabora tionto promote reportingon hospital quality of care

To facilitate continuousimprovement in patientcare through: Implementing hospitalcare quality, cost, andvalue measuresDeveloping and usingmeasure reporting inhospitals nationwide Publicly sharing hospitalperformance information

Runs Hospital Compare website(www.hospitalcompare.hhs.gov), withperformance infor -mation on >4000hospitals to help consumers assess hospital quality/valueto make informeddecisions

Consumer represen-tatives, physician/nursing organizations,employers, payers,oversight organiza-tions (eg, NQF), government agencies(eg, AHRQ)

ICSIwww.icsi.org

Independent health-care collaborativecomprised of 37 medical groups repre-senting about 85% ofMinnesota physicians

To champion healthcarequality and accelerateimprovement in thevalue of healthcaredelivered to the popula-tions served by ICSI

Develops healthcareguidelines and modelsthat are recognizedbeyond Minnesota

Providers, medicalgroups

NCQA www.ncqa.org

Private, not-for-profit organizationfor healthcare quality improvement

To transform healthcarequality through measure-ment, transparency, and accountability

Provides quality rec-ommendations tohealth plans; NCQAaccreditation recog-nized by employers,regulators, and healthplans as an importantreference in evaluat-ing healthcare quality

Employers, providers,public policy groups,consumer groups,health systems

Also provides accreditation toproviders throughparticipation in voluntary programs

NQF www.qualityforum.org

Not-for-profit mem-bership organizationfor developing andimplementing anational strategy forhealthcare qualitymeasurement andreporting

To improve the quality ofAmerican healthcare by: Setting national per -formance improvementpriorities and goalsEndorsing national standards for measuring/reporting on performance Promoting national goalsthrough education andoutreach programs

Consensus standardsendorsed by the NQFare often used by gov-ernment agencies likeCMS for measuringhealthcare quality

Consumers, publicand private payers,providers, employers,accrediting bodies(eg, NCQA)

PQAwww.pqaalliance.org

Collaborative initiative focused on improvinghealthcare quality at the pharmacy/pharmacist level

To improve healthcarequality and patient safe-ty in collaboration withkey stakeholders to helpthem make informedchoices, improve out-comes, and stimulatedevelopment of newpayment models

Collects pharmacyperformance data andreports findings toconsumers, pharma-cists, employers,health insuranceplans, other health-care decision makers

Pharmacy/pharmacistassociations, CMS,manufacturers

Continued




resources needed for quality collaboration/accreditation,and the need to limit themselves to what was required bytheir clients (large employers and employer groups) andstandards, mainly NCQA and sometimes URAC.

Influence of Quality Organizations on Healthcare PlansWe also asked pharmacy and medical directors to

identify which quality organizations most influencedtheir MCOs’ quality improvement programs. Again,NCQA had the greatest influence, with URAC a dis-tant second (73% and 12%, respectively). No otherorganization had significant influence on MCOs’ qual-ity improvement priorities: 8% of plans indicated noinfluence from these external organizations and/ordepend on internal decisions for setting qualityimprovement priorities (Figure 4).

MCOs’ Interest in More InformationThe next part of the survey aimed to determine the

level of interest from healthcare plans to learn moreabout these quality organizations. Although somerespondents did not think they missed opportunities bynot participating in quality programs, most of themthought they lost some benefits. The main missed oppor-tunities cited were (1) the chance to benchmark them-selves against the competition and (2) the chance toenhance their clinical and service outcomes (Figure 5).

The level of interest of medical and pharmacy direc-tors in learning more about various organizations andinitiatives is described in Table 2.

URAC’s PBM accreditation standard garnered themost interest, with 34% of respondents expressinghigh/very high interest in learning more about it. Andmore than 30% of respondents showed high/very highlevel of interests in Pharmacy Quality Alliance (alsorelated to quality of pharmacy programs), AHRQ, andNQF. The other organizations were less interesting to

learn about, including the NCQA, probably becauseplans already know about it.

We also assessed the level of interest in additionalquality programs and/or organizations. Guidelinesdeveloped by professional specialty organizations andP4P programs at other MCOs were the areas of maininterest, with no or low interest in other initiatives,such as collaborations with state and regional pro-grams, foreign healthcare agencies, or quality measuresfor other healthcare sectors (Figure 6).

Pharmaceutical Companies as Partners in QualityWhen asked if value-added programs from pharma-

ceutical companies supported the quality improvementinitiatives of their organizations, the large majority ofresponses were negative (Figure 7). Pharmacy directorswere more negative in their responses compared withmedical directors (71% disagreed/strongly disagreed vs42%, respectively). In the January follow-up survey, the

Organization What is it? Mission What does it do? Stakeholders Comments

URAC www.urac.org

Independent, non-profit organizationpromotes healthcarequality throughaccreditation andcertification programs

To promote continuousimprovement in quality/efficiency of healthcaremanagement

Administers accredi-tation programs fromboard accreditation to specific functionsfor various healthcarestakeholders (eg, hos-pitals, HMOs, PPOs,third-party adminis-trators, providergroups)

Consumers,providers, employers,regulators, industryexperts

Formerly theUtilization ReviewAccreditationCommission Originally founded toaccredit health plans’utilization review programs The scope of accredi-tation categories/ eligible organizationshas since expanded

AHRQ indicates Agency for Healthcare Quality and Research; CMS, Centers for Medicare & Medicaid Services; HMOs, health maintenance organizations;ICSI, Institute for Clinical Systems Improvement; NCQA, National Committee for Quality Assurance; NQF, National Quality Forum; PPOs, preferredprovider organizations; PQA, Professional Quality Assurance.

Respondents, %

Figure 4 Medical and Pharmacy Directors’ Identification of theQuality Organization that Most Influenced Their QualityImprovement Plans

NCQA URAC Other/ AHRQ IHI NQF ICSI PQA HQAinternaldecisions

Quality organizations

100

80

60

40

20

0

73%

12%8% 4% 2% 2%

Table 1 Continued


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reasons for these negative responses included a prefer-ence for internal quality programs without externalinfluence, skepticism from health plans on pharmaceu-tical company involvement with these types of initia-tives, and the complaint that many of these programsseem to be geared toward a particular branded productrather than disease states.

However, even though pharmaceutical companieswere mainly not considered as quality improvement

partners, 36% of MCO directors express moderate tovery high interest in getting more support and partner-ship from pharmaceutical companies. Specifically,pharmaceutical companies were viewed as more valu-able in providing support in patient compliance/adher-ence programs, and in appropriate drug utilization pro-grams (Figure 8).

Finally, we wanted to know how some of the largerpharmaceutical companies were rated for their currentefforts to support quality improvement initiatives atMCOs. Novartis was the clear leader, with 25% of theresponses, followed by GlaxoSmithKline with 19% of theresponses (Figure 9). When asked in the follow-up sur-vey about what made those companies’ support programssuperior to others, the majority of respondents noted thefocus on disease rather than a specific drug, the quality ofthe programs, the availability of nonbranded educationalmaterials, and the flexibility of the support programs tobe adapted to the specific payer quality program.

ConclusionThe high increase in healthcare costs in the past

decade is starting to build a focus on quality as an inte-gral part of addressing cost-containment without low-ering health outcomes. By creating their own qualitymetrics and systems that allow the development ofclinical guidelines, and by collaboration with externalquality improvement organizations, health plans canmore efficiently allocate their resources to maximize

100

80

60

40

20

0

Respondents, %

NQF URAC- AHRQ PQA ICSI URAC PQRI NCQA IHI HQAPBM


High/very high Moderate Low/none

Figure 5 Level of Interest of Pharmacy/Medical Directors to Learn about Quality Organizations/Initiatives

Table 2 Additional Quality Organizations/Initiatives ofPotential Interest for MCOs

Organizations/initiatives ExampleP4P programs fromother MCOs

—

QI guidelines fromspecialty societies

Guidelines developed andendorsed by the AmericanCollege of Cardiology

Foreign healthcareassociations

National Institute for Healthand Clinical Excellence

State/regional QI collaboratives

Wisconsin Collaborative forHealthcare Quality

QI guidelines fromadvocacy groups

Guidelines developed andendorsed by the AmericanHeart Association

QI in other healthcaresectors

QI measures for home care

MCOs indicates managed care organizations; P4P, pay for perform-ance; QI, quality improvement.

Respondents, %

50

40

30

20

10

0P4P

programsfrom otherMCOs

QI guide-lines fromspecialtysocieties

Foreignhealthcareagencies

State/regional QIcollabora-tions

QI guide-lines fromadvocacygroups

Other QI in otherhealthcaresectors

MCOs indicates managed care organizations; P4P, pay for performance; QI,quality improvement.

Figure 6 Medical/Pharmacy Directors’ Identification of QualityOrganizations of Interest




health outcomes for their members. Our survey showsclearly that today’s focus for MCOs is mostly limited tothe organizations that provide health plan qualityaccreditation, such as NCQA or URAC, with lessfocus on other organizations. By not collaborating withthese organizations, health plans may be missing oppor-tunities to develop and adapt already existing qualitymeasures and clinical guidelines for the benefit of theirhealth plan needs.

Our survey also suggests an opportunity for pharma-ceutical companies to increase their relationships withhealth plans by collaborating on quality improvementinitiatives, such as patient adherence and compliance,drug utilization, and patient education. To be success-ful in such collaboration, pharmaceutical companiesshould develop evidence-based programs focused on aspecific disease rather than a specific product, and offerflexible programs that could be adapted to each healthplan’s need. ■

References1. O’Kane M, Corrigan J, Foote SM, et al. Crossroads in quality. Health Aff(Millwood). 2008;27:749-758.2. Wennberg JE, Fisher ES, Goodman DC, et al. Tracking the care of patients withsevere chronic illness: The Dartmouth Atlas of Health Care 2008. April 2008.www.dartmouthatlas.org/atlases/2008_Chronic_Care_Atlas.pdf. Accessed April20, 2009.3. Social Secruity Act PL 110-275, §183(a)(1), added §1890, effective July 15,2008. Contract with a consensus-based entity regarding performance measure-

ment. www.qualityforum.org/docs/senate_07_09_08.pdf. Accessed April 20, 2009.4. Massachusetts employers and health plans continue to support quality care byrewarding physicians through Bridges to Excellence programs. September 25, 2007.www.bridgestoexcellence.org/Content/ContentDisplay.aspx?ContentID=97.Accessed April 20, 2009.5. Centers for Medicare & Medicaid Services. Physician quality reporting initia-tive. www.cms.hhs.gov/pqri/. Accessed April 20, 2009.6. National Business Coalition on Health. Voices of value-based purchasing:health care leaders reflect on 15 years of leadership. 2008. www.nbch.org/documents/voices.pdf. Accessed April 20, 2009.7. Lo Sasso AT, Perloff L, Schield J, et al. Beyond cost: “responsible purchasing” ofmanaged care by employers. Health Aff (Millwood). 1999;18:212-223.8. National Committee for Quality Assurance. The State of Health Care Quality,2007. Page 4. 2007. www.ncqa.org/Portals/0/Publications/Resource%20Library/SOHC/SOHC_07.pdf. Accessed April 20, 2009

Disagree/strongly disagreeNeutralAgree/strongly agree

Figure 7 Response to Statement, “PharmaceuticalCompanies Support the QI Initiatives of myOrganization”

QI indicates quality improvement.

62%

19%

19%

Patient compliance/adherence

Appropriate drug utilization

Patient education

NCQA/HEDIS support

Disease management

Physician education

Other

Pharmacist education

0 5 10 15 20 25 30 35Respondents, %

HEDIS indicates Healthcare Effectiveness Data and Information Set; NCQA,National Committee for Quality Assurance.

Figure 8 Areas Where Pharmaceutical Companies’ Support IsMost Likely to Be Accepted

Novartis

GlaxoSmithKline

Other

sanofi-aventis

Merck

Pfizer

LillyJ&J/Ortho-

McNeil JanssenWyeth

Figure 9 Pharmaceutical Companies with the Best Value-Added Programs to Support MCOs’ QI Initiatives

0 5 10 15 20 25 30Respondents, %

MCOs indicates managed care organizations; QI, quality improvement.

Stakeholder perspective next page


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PAYERS: Performance with quality standards hasshown steady improvement over the years, but onethat has continued to lag is medication adherence.Best results have been seen in medications whoseadherence has been highlighted in a specific qualitystandard. For example, the NCQA’s antidepressantdrug management measure assesses patient adherenceat 12 weeks and at 6 months. Medication adherenceis strongly correlated with improved outcomes indepression, but for most drugs adherence is not rou-tinely included in quality standards.

Payers and quality organizations should considerwhat impact a national quality standard for medicationadherence across all patients for all drugs would haveon stimulating collaborative and competitive effortsamong all stakeholders. This single standard couldbecome one of the most important metrics for payers indeciding which healthcare companies provide the bestsupport for ensuring that their employees get well byadhering to their therapy. It could also catalyze collab-oration between the industry and payers to develop,test, and implement innovative solutions to medica-tion adherence beyond the current programs that most-ly involve written communication to plan members,reinforcing the importance of adherence.

PHARMACEUTICAL COMPANIES: Poor med -ication adherence continues to be a major concernand opportunity for the pharmaceutical industry. Theindustry recognizes that the value a product demon-strates in a controlled clinical trial will not be trans-lated in the real-world setting if patients do notadhere to their medication regimen. Drug companiesface misperceptions of the value of their products iftreatment failure is caused by poor patient adherencerather than by underperformance of the drug. Theindustry has a strong vested interest in doing any-thing possible to support medication adherence andthe safe and appropriate use of their products.Improved adherence presents an opportunity notonly to improve health outcomes but also to improverevenues essential for continued investment inresearch and development of innovative medicines.

The industry appreciates the complexity of this issueand realizes that improving medication adherence canonly be achieved by fully leveraging each stakeholder—health plans, pharmacy benefit managers (PBMs),employers, healthcare professionals, and patients and

their families. The industry faces many obstacles inaddressing this complex issue, including payers’ reluc-tance to work with it, requests for only unbranded dis-ease-specific programs rather than programs developedfor a specific product, complex legal agreements, andvarying interpretations between what is defined as mar-keting versus as a component of a disease/patient man-agement program.

Reluctance to accept industry support for product-specific patient support programs is severely limitingthe competition and innovation needed to addressadherence. The industry conducts more marketresearch on professionals who prescribe their prod-ucts and on patients who depend on their products toimprove their well-being than on any other entity.That research helps to develop beneficial programsfor patients and family members that improve theirunderstanding of their medical condition and med-ication, but because they are brand-specific, theseprograms are often shunned by stakeholders whocould be playing a greater role in increasing theirmembers’ awareness of these resources. To recreatewhat a drug company can do to build customized sup-port programs for patients with more than 10,000pharmaceuticals on the market is not practical forany payer, health plan, or PBM. Payers, providers,and patients could benefit from industry support.

The use of technology, interactive patient educa-tion, and patient education customized to addressspecific patient groups based on specific demograph-ics are critical contributions the industry could maketo improve product-specific patient education andmedication adherence programs.

Not enough is being done to support high-quality,effective patient education designed to improveadherence. To gain dramatic improvement, collabo-rative efforts are needed that enable the industry tocreatively design product-specific programs forpatients in addition to unbranded education. Payerinput into the design and content would allow formutually acceptable brand-specific patient supportand education, free of bias and nonpromotional.

Jeffrey A. Bourret, MS, RPh, FASHPSenior Director, Customer Marketing & Innovation,

US Specialty CustomersPfizer Specialty Care Business Unit, Collegeville, PA

STAKEHOLDER PERSPECTIVEThe Missing Quality Standard for Medication Adherence


The Return to Deep Science:Pharmaceutical Research &Development in a Value-BasedHealthcare System

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Impact of Market Trends on Drug Pipelines: The Need for Value-Based R&DAHDBonline.com/Deep-Science.aspx

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Impact of Market Trends on Drug Pipelines: The Need for Value-Based R&DAHDBonline.com/Deep-Science.aspxMathew Sarnes, PharmDVice PresidentManaged Markets DivisionXcenda

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CLINICAL


Allergic rhinitis (AR) has a significant detri-mental effect on a patient’s quality of life(QoL), affecting sleep, normal daily activities,

and work.1-4 Stempel and Woolf estimated that the 50million Americans with AR spend more than $6 bil-lion annually on prescription and nonprescriptionmedications to relieve AR symptoms.5,6 Despite a grow-ing body of literature on the effect of AR on QoL, thereis a paucity of studies that use QoL findings to assessthe cost-effectiveness of various agents used to treatAR. The recent US Food and Drug Administration(FDA) approval of the second-generation antihista-

mine (SGA) levocetirizine, and the lack of studies thatcompare the cost-effectiveness of oral AR treatmentsin terms of QoL led to the present analysis.

Although estimates of economic impact vary widely,AR clearly has important economic implications formanaged care, employers, and patients. Specifically,estimates of the direct costs to US payers range from$1.4 billion to $6 billion annually.5,7,8 These estimatesmay be low, however, because they exclude substantialspending on over-the-counter (OTC) allergy medica-tions, a cost that is largely borne by the patient.5 Inaddition, indirect costs realized by employers throughpresenteeism and absenteeism represent a significantburden. When these indirect costs are considered inconjunction with direct healthcare costs, allergies areranked as the fifth most expensive chronic conditionfor employers.9

Lack of rigorous economic evidence has not slowedthe adoption of newer SGAs, which are among the

Background: Allergic rhinitis causes significant economic losses and substantial reductions in quality oflife. Improving a patient’s symptoms can therefore enhance the patient’s quality of life.Objective: To measure the relative cost-effectiveness of prescription second-generation antihistamines(levocetirizine, desloratadine, and fexofenadine) and montelukast based on their impact on quality oflife in patients with uncomplicated allergic rhinitis. Methods: A retrospective, cost-effectiveness model was constructed using 1-year costs to managedcare payers and using the Rhinoconjunctivitis Quality of Life Questionnaire to measure the quality of lifein patients taking prescription second-generation antihistamines or montelukast for the treatment ofallergic rhinitis. Clinical trial results for levocetirizine, desloratadine, fexofenadine (brand and generic), ormontelukast were combined as standardized mean differences to create a pooled effectiveness meas-

ure. The costs of prescription drugs and physician office visits for allergic rhinitis were used as direct costs measures. Sensitivitywas assessed by a Monte Carlo simulation run 1000 times. Results: All the drugs in the study showed significant improvement in quality of life, with levocetirizine showing the greatestimprovement. The incremental cost-effectiveness of levocetirizine dominated montelukast (incremental cost-effective ratio,–1317; 95% confidence interval, –7471, –212). The incremental cost-effectiveness favored levocetirizine compared withdesloratadine and branded fexofenadine.Conclusion: There are significant differences in the cost-effectiveness of various oral prescription agents with regard toimproving quality of life of patients with allergic rhinitis. [AHDB. 2009;2(7):309-316].

Ms Saverno is a graduate student in Pharmaceutical Economics,Policy, and Outcomes, University of Arizona College ofPharmacy, Tucson; Dr Seal is Senior Director, sanofi-aventis,Bridgewater, NJ; Dr Goodman is Assistant Professor,University of Utah College of Pharmacy, Salt Lake City; Dr Meyer is Associate Director, Xcenda, Palm Harbor, FL.

Economic Evaluation of Quality-of-LifeImprovement with Second-GenerationAntihistamines and Montelukast in Patients with Allergic RhinitisKim R. Saverno, RPh; Brian Seal, PhD; Michael J. Goodman, PhD; Kellie Meyer, PharmD

Kellie Meyer

Meyer:Cover 12/11/09 5:04 PM Page 309

CLINICAL


most widely prescribed medications in the UnitedStates. SGAs have the advantage of fewer side effects,including less sedation, than older antihistamines,10

making them more acceptable to many patients. Thepurpose of this study was to estimate the comparativecost-effectiveness of QoL improvements associated withmajor prescription agents used for AR management.

To date, no cost-effectiveness studies have comparedindividual SGAs to one another or to alternative oralAR treatments based on QoL improvements. One cost-effectiveness study compared SGAs with older, first-generation antihistamines that produced a significantsedating effect.10 However, current treatment patternscall for more advanced modeling that directly com-pares economic outcomes of treatment patterns withnewer agents.

A recent study by some of the present authors com-pared the cost-effectiveness of SGAs to one another andto alternative AR treatments based on clinical symptomimprovement.11 Our current analysis builds on that studyby assessing the cost-effectiveness of levocetirizine rela-tive to other prescription SGAs and the widely usedleukotriene receptor antagonist montelukast in terms ofQoL improvements reported by clinical trials. The pres-ent study was conducted from the perspective of pre-

scription benefit managers from US health plans; there-fore, OTC products were not included.

MethodsWe used a decision-analytic cost-effectiveness model

developed from the perspective of managed care deci-sion makers and using costs over a 1-year time period.US payers typically do not include OTC products intheir benefit design; therefore, our treatment compara-tors were limited to prescription products, including theSGAs levocetirizine, desloratadine, and fexofenadine,and the leukotriene receptor antagonist montelukast,which is also FDA approved for AR treatment.

The study population included patients with ARwho had been treated with an SGA monotherapy orwith montelukast. Although combination therapy withan SGA and montelukast is sometimes used for ARsymptoms, combination therapy was excluded in thisanalysis, because clinical trial evidence supporting suchcombination therapy is limited, which would limit thegeneralizability of our findings. Patients with asthmarequiring daily corticosteroid treatment were excluded,to preserve homogeneity of the population.

The Rhinoconjunctivitis Quality of Life Question -naire (RQLQ) was selected for our model, because it isspecific to AR, widely used, validated, and has a specif-ic clinical interpretation.1,2,12-14 The RQLQ includes 28items on 7 disease-specific domains: activity limita-tions, practical problems, nonrespiratory symptoms,nasal symptoms, eye symptoms, emotional function,and sleep. The outcome measure in our model was thecomposite of all 28 items.

We conducted a MEDLINE search to identify eligi-ble articles between January 1950 and May 2007, usingthe comparator names levocetirizine, fexofenadine, deslo-ratadine, and montelukast in combination with theterms RQLQ, QoL, and Rhinoconjunctivitis Quality ofLife Questionnaire. Additional studies were identified bysearching the references listed in these studies. Eligiblestudies had to (1) include monotherapy with an FDA-approved dose of one of the model comparator agents;(2) be randomized, blinded, and placebo-controlled;(3) exclude patients with asthma requiring daily corti-costeroids; and (4) include RQLQ as an outcome.Study length had to be 14 to 90 days. Patients’ age hadto be 11 years or older. A total of 12 studies wereincluded in the analysis.15-26

For each study, the standardized mean difference(SMD) between the comparator and placebo was calcu-lated as a ratio of the RQLQ outcome to the standarddeviation (see Goodman and colleagues11). To convert

KEY POINTS Despite a growing understanding of the effect of

allergic rhinitis on quality of life, few studies haveassessed the cost-effectiveness of various agents forthis condition based on quality-of-life improvements.

This study compared the cost-effectiveness oflevocetirizine and other prescription second-generation antihistamines and the widely usedleukotriene receptor antagonist montelukast in termsof quality-of-life improvements.

It shows that levocetirizine is a cost-effective optionand offers clinically meaningful improvement inquality of life.

Levocetirizine is cost-effective compared withmontelukast and its cost-effective ratios arefavorable compared with the other comparators inthis analysis.

The present study was conducted from theperspective of prescription benefit managersfrom US health plans; therefore, OTC productswere not included.


Quality of Life in Patients with Allergic Rhinitis


the pooled SMD into a usable measure for the cost-effective ratio, the baseline mean and standard devia-tion of the RQLQ for placebo and the comparator werecombined. Using the baseline mean and the standarddeviation as the untreated standard, the mean marginalRQLQ score, assuming treatment with each comparatorafter removing the effect of placebo observed in the tri-als, was calculated as the baseline mean plus the SMDmultiplied by the standard deviation.

A clinically relevant improvement was defined as a0.5-point reduction from baseline in marginal RQLQscore—after removing the effect of placebo—whichwas used as the threshold for clinically relevantimprovement. In contrast, Juniper and colleagues’ def-inition does not remove the effect of placebo.1 Our def-inition, although conservative, is consistent with thestandards for cost-effectiveness analysis. The propor-tion of the population 0.5 points below the baselinemean was calculated using standard formulas for com-puting the area under the normal curve. The probabil-ity of clinically relevant improvement was defined asthe marginal difference in the proportion of the popu-lation below the threshold for clinically relevantimprovement.11

Drug costs were calculated as the expected days oftherapy in a year multiplied by the daily wholesaleacquisition cost.27 The model assumed 90 days of ther-apy for a calendar year. Medical costs for allergy-relat-ed physician office visits were calculated from an analy-sis of the proprietary PharMetrics dataset for a 1-yearperiod for each model comparator agent. Medical costswere inflated to 2007 dollars, using the Bureau of LaborStatistics.28

Because levocetirizine was not available in theUnited States when the PharMetrics data were cap-tured, its costs were imputed using a linear fit of theRQLQ effect size to the physician’s office visit costs forthe other model comparator agents, based on a simplelinear regression. Indirect costs, such as productivity,were not included, because they were not assessed inthe original trials used for our analysis, and because themodel’s perspective was that of a third-party payer.

The comparative cost-effectiveness of the agentswas calculated as the ratio of costs to the probability ofclinically relevant improvement. Incremental cost-effective ratio (ICER) between agents was evaluated asthe ratio of difference in cost to difference in probabil-ity of clinically relevant improvement for any alterna-tive therapy relative to levocetirizine.

A Monte Carlo simulation, which varied the totalcost by ±10%, was used to obtain 95% confidence

interval (CI) values. The effectiveness measure (SMD)for each product varied within the 95% CI range forthe pooled SMD across each comparator. Randomdraws were run 1000 times (using Microsoft Excel2003, Service Pack 2). Exact 95% CI values for thecost-effective ratios were calculated as the 26th and974th ordered values in the simulation.

Significance for a cost-effective ratio was defined by aCI that did not overlap the point estimate; significancefor an ICER was defined as a CI that did not overlap 0.0.

Results Effects on Quality of Life

Table 1 compares the mean QoL effect size for eachcomparator agent versus placebo. All comparatorswere significantly better than placebo in improvingQoL.15-26 Levocetirizine demonstrated greater QoLimprovement (–0.418; 95% CI, –0.573, –0.262), asmeasured by the pooled RQLQ SMD, than deslorata-dine (–0.360; 95% CI, –0.539, –0.180), montelukast(–0.213; 95% CI, –0.267, –0.159), or fexofenadine(–0.201; 95% CI, –0.301, –0.101).

Table 2 summarizes the annual drug and medicalexpenditures for each comparator, as well as eachagent’s efficacy, expressed as the probability of a clini-cally relevant improvement in RQLQ. The medicalcosts for AR physician office visits were highest formontelukast. Annual AR drug costs, assuming 90 daysof therapy, ranged from $168 to $275. Column 5 ofTable 2 translates the SMDs into a probability of clini-cally relevant improvement. Applying these probabil-ity estimates to a population of 10,000 AR patients,levocetirizine would lead to clinically relevantimprovement in an additional 810 patients comparedwith montelukast, or 231 additional patients comparedwith desloratadine.

Cost-EffectivenessTable 3 outlines the results of this study. Levocet -

Table 1 Mean QoL Effect Sizes Based on RQLQ

Comparator Mean effect size vs placebo

Desloratadine –0.360 (95% CI, –0.539, –0.180)

Fexofenadinea –0.201(95% CI, –0.301, –0.101)

Levocetirizine –0.418 (95% CI, –0.573, –0.262)

Montelukast –0.213 (95% CI, –0.267, –0.159)aStudies for brand and generic fexofenadine were used to calculate themean effect. CI indicates confidence interval; RQLQ, Rhinoconjunctivitis Qualityof Life Questionnaire.


CLINICAL


irizine had the lowest average cost ($3255) for a clini-cally relevant RQLQ improvement, followed by deslo-ratadine ($4165). Montelukast had the highest cost($7871) per clinically relevant RQLQ improvement andlower efficacy compared with the other comparators.

Negative ICERs (Table 3) can reflect either lowercost and higher effectiveness or higher cost and lowereffectiveness, which are generally reported as “domi-nated.” All the comparators in this study are less effec-tive in terms of RQLQ improvement than levoceti-rizine. Generic fexofenadine is less costly thanlevocetirizine but results in lower RQLQ improvement.The other comparators have lower RQLQ improve-ment and are more costly than levocetirizine.

The statistical significance of the ICERs is shownwith CI values. The wide CI values reflect the relative-ly small sample sizes and the resulting large variation inthe RQLQ measures in the Monte Carlo simulation.Only the comparison between levocetirizine and mon-telukast is significant (95% CI, –7471, –212). Becausethe CIs overlapped zero for the other comparators,another way to understand ICERs is to examine howmany times the simulated ICER is negative, which indi-cates that levocetirizine dominated the comparator inthat simulation. The number of negative ICERs of 1000simulations is 601 for desloratadine, 273 for generic fex-ofenadine, 644 for branded fexofenadine, and 993 formontelukast. In the case of desloratadine, negativeICERs indicate that 60% of the time levocetirizine hasgreater RQLQ improvement and is less costly.

When the ICERs are positive, a tradeoff is requiredbetween cost and effectiveness. The tradeoff for a posi-tive ICER is between lower cost and lower effectiveness

Table 2 Model Inputs: Probability of QoL Improvement (Efficacy) Based on RQLQ Values

Treatment armAnnual drug

cost, $Annual medical

cost, $ Total cost, $

Marginal probability of a clinically significant

RQLQ improvement, %a

Probability of a clinicallysignificant RQLQ improvement, %a

Levocetirizine 203 322 525 16.1 49.1

Desloratadine 249 326 575 13.8 46.8

Fexofenadine(generic)

168 326 494 7.6 40.6

Fexofenadine(brand)

216 326 542 7.6 40.6

Montelukast 275 356 631 8.0 41.0aAt baseline, assuming a normal distribution, 33% of the sample had RQLQ values below the threshold for clinically significant improvement (0.5points difference). Column 6 shows the proportion of the population with a mean below the threshold after treatment. Column 5 shows the mar-ginal effect given treatment with the target drug (the last column minus 33%). Column 5 was used in the cost-effectiveness analysis calculations.RQLQ indicates Rhinoconjunctivitis Quality of Life Questionnaire.

Table 3 Cost-Effectiveness Ratios

Treatment armCE ratio, cost per patient with clinically

significant improvement, $ ICER, $a

Levocetirizine 3255 (95% CI, 2293, 5238) —

Desloratadine 4165 (95% CI, 2704, 8167) –2189 (95% CI, –10,138, 17,275)

Fexofenadine (generic) 6535 (95% CI, 4183, 12,866) 361 (95% CI, –1166, 3574)

Fexofenadine (brand) 7168 (95% CI, 4625, 13,770) –198 (95% CI, –3241, 1186)

Montelukast 7871 (95% CI, 5990, 10,721) –1317 (95% CI, –7471, –212)aNegative ICERs are dominated.CE indicates cost-effective; CI, confidence interval; ICERs, incremental cost-effective ratios.

When the ICERs are positive, a tradeoff isrequired between cost and effectiveness.




for one product compared with higher cost, as well asgreater clinical benefit for the other. For example, thepositive ICER for generic fexofenadine (Table 3)reflects its lower cost and lower impact on RQLQ com-pared with the greater clinical benefit of levocetirizine.Decision makers will need to weigh the additional clin-ical benefit against the additional cost.

Discussion The 4 model comparators vary substantially in their

ability to improve QoL for patients with uncomplicat-ed AR. This variation, combined with significant vari-ation in the costs of the comparators, make this cost-effectiveness analysis important for formulary decisionmakers, clinicians treating AR, and patients undergo-ing treatment. The results favor levocetirizine, whichhas the lowest average cost-effective ratio.

To our knowledge, this is the first published analysisof the cost per patient with clinically relevant improve-ment in RQLQ of the individual SGAs and the onlyleukotriene receptor antagonist indicated for the treat-ment of AR. This is surprising given the prevalenceand the large economic impact of AR in direct andindirect costs. Sullivan and colleagues noted that thelack of a standard outcome measure across AR studiescould contribute to the scant number of studies aboutcost-effectiveness of AR therapies.29

The effectiveness measure in the present study isimportant clinically and is consistent with the need foreconomic decisions that focus on QoL.30 The choice touse the RQLQ as the basis of our cost-effectivenessmodel was based on several factors. The RQLQ is repro-ducible, can assess the impact of treatment over multi-ple dimensions, and has a strict clinical interpretationthat has been validated in many studies.1,12-14 Ourresults, however, are conservative. To make the denom-inator of the cost-effectiveness ratio consistent withstandards in economic modeling, we removed the effectobserved for placebo from the calculation of clinicallyrelevant improvement. This reduces the number of per-sons in a population whom we classify as having clini-cally relevant improvement. A change that is smallerthan the clinically relevant threshold may neverthelessrepresent meaningful improvement in symptom relieffor many patients. An alternative measure, the numberneeded to treat to achieve 1 person with improvement,has been suggested for interpreting the RQLQ.31

Our analysis was designed specifically to assess thecost-effectiveness of levocetirizine relative to other oralprescription medications for the management of ARsymptoms, where effectiveness is defined as clinically

relevant improvement in RQLQ. Our model indicatesthat levocetirizine has greater RQLQ improvementand is less costly than montelukast for the managementof AR in patients without asthma who require dailycorticosteroids. However, because the 95% CI of theICERs comparing levocetirizine with the other com-parators cross zero, levocetirizine does not have com-plete dominance over the SGA comparators.

The 95% CI of the ICER comparing levocetirizinewith desloratadine was wide (–$10,138 and $17,275,respectively; Table 3) for 2 reasons. First, only 2 trialshad usable data for changes in RQLQ for levocetirizine,and only 1 study for desloratadine. With such few stud-ies, the resulting variability from the SMD in RQLQscore was large. Second, the difference in probability ofa clinically relevant improvement between the 2 drugswas small (16.1% and 13.8%, respectively). When thedenominator in an ICER is a probability, a small differ-ence between the 2 comparators leads to very large CIestimates. As additional comparator-specific informa-tion on QoL becomes available, the precision of theseestimates will be increased and judgments about theirrelative effectiveness and cost-effectiveness willbecome more accurate.

Overall, the ICER CI values were very wide, whichagain reflects the lack of multiple studies for the com-parators. For example, the variation for montelukast issmaller than for desloratadine, because there are moremontelukast trials with RQLQ data. Although theresults are valid for the specific sample sizes, the rela-tively small number of studies results in CI values thatmight have obscured effects of clinical significance forimproved QoL.32

Several prescription and OTC medications areapproved for the relief of AR symptoms, includingnasal corticosteroids, antihistamines, decongestants,and leukotriene receptor antagonists. Although the useof these agents and combination therapy is common forAR management, it was unreasonable to include allthese options in our analysis, because of the lack ofRQLQ outcomes data and because of the sheer number

Several prescription and OTC medications are approved for the relief of AR symptoms,including nasal corticosteroids, antihistamines,decongestants, and leukotriene receptorantagonists.


CLINICAL


of potential comparators. We therefore opted toinclude comparators available only by prescription,because our goal was to address issues relevant to pre-scription drug benefit managers. Many health plans donot reimburse for OTC medications.33

Our model included direct costs only, specificallydrug costs and outpatient physician office visit costs forAR. The literature indicates that a sizable amount ofthe economic burden associated with AR is because oflost productivity from absenteeism and presenteeism.34

An employee survey showed that employees with ARwere absent roughly 3.6 days annually due to this con-dition and lost 2.3 hours per workday in productivitywhen symptoms were present. In our analysis, indirectcosts were excluded due to lack of data substantiatingdifferences in indirect costs between individual modelcomparators, which may be related to the short dura-tion of most AR clinical trials. Other costs notaccounted for in our model include costs associatedwith lack of effectiveness and adverse events.

LimitationsSeveral potential limitations of this study warrant dis-

cussion. Our rigorous inclusion criteria might have led tounintended bias. For example, Meltzer and colleaguesonly reported on the significance of a single RQLQdomain, so this study was not included in our analysis.35

In addition, the AR patient population is broad,ranging from young children to the elderly and fromrelatively healthy patients to patients with severe res-piratory conditions. Our decision to exclude clinicaltrials that enrolled children younger than 11 years oldor AR patients with concomitant asthma treated withdaily corticosteroids does not accurately reflect theoverall population with AR. It is estimated that nearly40% of individuals with allergies have asthma.36

Furthermore, 60% to 78% of individuals with asthmahave AR.36 Montelukast is FDA-approved for the man-agement of asthma and AR, whereas the SGAs are notapproved for the treatment of asthma.37-40 Therefore, wechose to eliminate studies involving patients with asth-ma requiring daily corticosteroids so as to not bias theresults with respect to montelukast. About 40% of in -dividuals younger than age 12 suffer from AR.6

Therefore, although our results are robust to the gener-al population, specific subpopulations are not repre-sented, and the cost-effectiveness in the young and inthose with significant comorbidities remains to beexamined in future research.

We also did not include OTC SGAs, such as lorata-dine and cetirizine, in our analysis. We believe that thisis justified, because the audience for this study is healthplan decision makers. Historically, when drugs havebeen moved to an OTC status, this typically hasremoved them from coverage by managed care.41

Therefore, our intended audience is served by thisexclusion. In addition, cost and QoL data are not avail-able for all OTC agents.

We only included physician office visits and ARdrug costs, and excluded costs for emergency depart-ment visits or hospitalizations. Patients with AR with-out asthma are unlikely to be hospitalized, visit theemergency department, or use additional drugs.

There may be some limitations to using thePharMetrics database to obtain the cost inputs for theanalysis. For example, diagnosis codes from claims arebased on payment rather than on clinical practice.Therefore, diagnoses from claims data may be less spe-cific than diagnoses or narrative in a medical record.This limitation, however, is offset by the coding biasbeing consistent across all comparators. In addition,the PharMetrics data contain few elderly patients;however, as with the coding bias noted, this shouldresult in a consistent effect across all comparators.

We also did not separate seasonal and perennial AR.All the agents included in our analysis have an indica-tion for both seasonal and perennial AR, except forfexofenadine, which is only indicated for seasonal AR.In addition, the availability of the clinical trial datawould have been limited if we separated our analysis byseasonal and perennial AR, potentially reducing therobustness of the QoL estimates.

Finally, we did not formally analyze statistical het-erogeneity in our calculation of comparative effective-ness. Because our goal was to model the economicsrather than conduct a full-fledged meta-analysis ofcomparative effectiveness of AR medications, it wasbeyond this study’s scope to rigorously exclude studiesthat might introduce heterogeneity. Estimates derivedfrom a full meta-analysis would provide tighter CI val-ues for effectiveness measures, but they would also limitthe generalizability of the results.

ConclusionOur analysis shows that levocetirizine is a cost-

Our analysis shows that levocetirizine is a cost-effective option for the treatment of ARthat produces clinically meaningful improve-ment in QoL based on the RQLQ.




effective option for the treatment of AR that producesclinically meaningful improvement in QoL based onthe RQLQ. Levocetirizine is cost-effective comparedwith montelukast, and its cost-effective ratios arefavorable compared with the other comparators in thisanalysis. Further research is warranted to assesspatients with AR and comorbid asthma who requiredaily cortico steroids and in younger populations, aswell as to address the effect of different therapies onindirect costs of AR.

AcknowledgmentsLaurie Kozbelt and Jeanne Hawkins of Xcenda, LLC, Palm

Harbor, FL, provided technical assistance in conducting thisstudy and in preparing this manuscript.

Disclosure StatementThis study was funded by UCB, Inc, and sanofi-aventis US,

LLC. Ms Saverno and Dr Goodman were employed and Dr Meyeris currently employed by Xcenda, which provides consulting servicesto various pharmaceutical companies, including UCB and sanofi-aventis. Dr Seal is employed by sanofi-aventis. ■

References1. Juniper EF, Guyatt GH, Griffith LE, Ferrie PJ. Interpretation of rhinoconjunctivi-tis quality of life questionnaire data. J Allergy Clin Immunol. 1996;98:843-845.2. Juniper EF, O’Byrne PM, Guyatt GH, et al. Development and validation of a ques-tionnaire to measure asthma control. Eur Respir J. 1999;14:902-907.3. Nathan RA. The burden of allergic rhinitis. Allergy Asthma Proc. 2007;28:3-9.4. Schoenwetter WF, Dupclay L Jr, Appajosyula S, et al. Economic impact and qual-ity-of-life burden of allergic rhinitis. Curr Med Res Opin. 2004;20:305-317.5. Stempel DA, Woolf R. The cost of treating allergic rhinitis. Curr Allergy AsthmaRep. 2002;2:223-230.6. American Academy of Allergy, Asthma, and Immunology. Allergy statistics.www.aaaai.org/media/resources/media_kit/allergy_statistics.stm. Accessed January22, 2008.7. Malone DC, Lawson KA, Smith DH, et al. A cost of illness study of allergic rhini-tis in the United States. J Allergy Clin Immunol. 1997;99(1 pt 1):22-27.8. Reed SD, Lee TA, McCrory DC. The economic burden of allergic rhinitis: a crit-ical evaluation of the literature. Pharmacoeconomics. 2004;22:345-361.9. Goetzel RZ, Long SR, Ozminkowski RJ, et al. Health, absence, disability, and pre-senteeism cost estimates of certain physical and mental health conditions affectingU.S. employers. J Occup Environ Med. 2004;46:398-412.10. Sullivan PW, Nichol MB. The economic impact of payer policies after the Rx-to-OTC switch of second-generation antihistamines. Value Health. 2004;7:402-412.11. Goodman MJ, Jhaveri M, Saverno K, et al. Cost-effectiveness of second-genera-tion antihistamines and montelukast in relieving nasal symptoms of allergic rhinitis.Am Health Drug Benefits. 2008;1(8):26-34.12. Juniper EF, Guyatt GH. Development and testing of a new measure of health sta-tus for clinical trials in rhinoconjunctivitis. Clin Exp Allergy. 1991;21:77-83.13. Juniper EF, Thompson AK, Roberts JN. Can the standard gamble and rating scalebe used to measure quality of life in rhinoconjunctivitis? Comparison with the RQLQand SF-36. Allergy. 2002;57:201-206.14. Juniper EF, Rohrbaugh T, Meltzer EO. A questionnaire to measure quality of lifein adults with nocturnal allergic rhinoconjunctivitis. J Allergy Clin Immunol. 2003;111:484-490.

15. Bachert C, Bousquet J, Canonica GW, et al. Levocetirizine improves quality oflife and reduces costs in long-term management of persistent allergic rhinitis. JAllergy Clin Immunol. 2004;114:838-844.16. Lombardo G, Quattrocchi P, Lombardo GR, et al. Concomitant levocetirizineand montelukast in the treatment of seasonal allergic rhinitis: influence on clinicalsymptoms. IT J Allergy Clin Immunol. 2006;16:63-68.17. Meltzer EO, Casale TB, Nathan RA, Thompson AK. Once-daily fexofenadineHCl improves quality of life and reduces work and activity impairment in patientswith seasonal allergic rhinitis. Ann Allergy Asthma Immunol. 1999;83:311-317.18. Meltzer EO, Malmstrom K, Lu S, et al. Concomitant montelukast and loratadineas treatment for seasonal allergic rhinitis: a randomized, placebo-controlled clinicaltrial. J Allergy Clin Immunol. 2000;105:917-922.19. Nayak AS, Philip G, Lu S, et al. Efficacy and tolerability of montelukast aloneor in combination with loratadine in seasonal allergic rhinitis: a multicenter, ran-domized, double-blind, placebo-controlled trial performed in the fall. Ann AllergyAsthma Immunol. 2002;88:592-600.20. Okubo K, Gotoh M, Shimada K, et al. Fexofenadine improves the quality of lifeand work productivity in Japanese patients with seasonal allergic rhinitis during thepeak cedar pollinosis season. Int Arch Allergy Immunol. 2005;136:148-154.21. Patel P, Philip G, Yang W, et al. Randomized, double-blind, placebo-controlledstudy of montelukast for treating perennial allergic rhinitis. Ann Allergy AsthmaImmunol. 2005;95:551-557.22. Philip G, Malmstrom K, Hampel FC, et al. Montelukast for treating seasonalallergic rhinitis: a randomized, double-blind, placebo-controlled trial performed inthe spring. Clin Exp Allergy. 2002;32:1020-1028.23. Pradalier A, Neukirch C, Dreyfus I, Devillier P. Desloratadine improves quality oflife and symptom severity in patients with allergic rhinitis. Allergy. 2007;62:1331-1334.24. Tanner LA, Reilly M, Meltzer EO, et al. Effect of fexofenadine HCl on quality oflife and work, classroom, and daily activity impairment in patients with seasonalallergic rhinitis. Am J Manag Care. 1999;5(suppl):S235-S247.25. van Adelsberg J, Philip G, Pedinoff AJ, et al. Montelukast improves symptoms ofseasonal allergic rhinitis over a 4-week treatment period. Allergy. 2003;58:1268-1276.26. van Adelsberg J, Philip G, LaForce CF, et al. Randomized controlled trial evalu-ating the clinical benefit of montelukast for treating spring seasonal allergic rhinitis.Ann Allergy Asthma Immunol. 2003;90:214-222.27. RED BOOK for Windows. Volume 46; 2007. [Requires password to access online.]28. US Department of Labor, Bureau of Labor Statistics. Consumer price index.US medical care, 1982-84=100-CUUR0000SAM. http://data.bls.gov/cgi-bin/surveymost?cu. Accessed January 22, 2008.29. Sullivan PW, Follin SL, Nichol MB. Transitioning the second-generation anti-histamines to over-the-counter status. A cost-effectiveness analysis. Med Care. 2003;41:1382-1395.30. Gold MR. Cost-effectiveness in Health and Medicine. New York, NY: OxfordUniversity; 1996.31. Guyatt GH, Juniper EF, Walter SD, et al. Interpreting treatment effects in ran-domised trials. BMJ. 1998;316:690-693.32. Kirk RE. Practical significance: a concept whose time has come. Educ PsycholMeas. 1996;56:746-759.33. Hay JW, Leahy M. Cost and utilization impacts of oral antihistamines in theCalifornia Medi-Cal program. Value Health. 2005;8:506-516.34. Lamb CE, Ratner PH, Johnson CE, et al. Economic impact of workplace pro-ductivity losses due to allergic rhinitis compared with select medical conditions inthe United States from an employer perspective. Curr Med Res Opin. 2006;22:1203-1210.35. Meltzer EO, Jalowayski AA, Vogt K, et al. Effect of desloratadine therapy onsymptom scores and measures of nasal patency in seasonal allergic rhinitis: resultsof a single-center, placebo-controlled trial. Ann Allergy Asthma Immunol. 2006;96:363-368.36. Crown WH, Olufade A, Smith MW, Nathan R. Seasonal versus perennial aller-gic rhinitis: drug and medical resource use patterns. Value Health. 2003;6:448-456.37. Clarinex [package insert]. Kenilworth, NJ: Schering Co; 2005.38. Xyzal [package insert]. Smyrna, GA: UCB; 2007.39. Singulair [package insert]. Whitehouse Station, NJ: Merck & Co; 2007.40. Allegra [package insert]. Bridgewater, NJ: sanofi-aventis US; 2008.41. Sullivan PW, Nair KV, Patel BV. The effect of the Rx-to-OTC switch of lorata-dine and changes in prescription drug benefits on utilization and cost of therapy. AmJ Manag Care. 2005;11:374-382.

Stakeholder Perspective next page


CLINICAL


Allergic rhinitis can be a very devastating chroniccondition, affecting patients’ ability to work produc-tively, hamper their desire for recreation activities,and even prevent a restful sleep. The present articleby Meyer and colleagues focuses on quality-of-life(QoL) issues that patients with allergic rhinitis maystruggle with on a daily basis. The article also makesa comparison between the second-generation nonse-dating antihistamines and montelukast as alterna-tives for the treatment of this disease.

The good thing is that many safe and effectivepharmaceutical products are available that work wellfor the treatment of the symptoms associated withallergic rhinitis, allowing patients to have normal, pro-ductive, and active lives. The many pharmaceuticalproducts available work in a number of ways, includingoral systemic products and nasally inhaled products.

PAYERS: Payers will typically have copay incen-tives for patients to use medications that may be avail-able as generics, or even older products, such as someof the first-generation nonsedating antihistamines thatare available over the counter (OTC) and providerelief from the symptoms of allergic rhinitis. Thesesame copay incentives may also apply for nasallyinhaled products that may be more attractive than thecopay a patient may have for second-generationnonsedating antihistamines or for montelukast.

PATIENTS: Patients can take advantage of inex-pensive products for this condition or reduced copaysand often have good results in getting symptomaticrelief and increased QoL, while avoiding having todeal with a cost difficulty for their medication.

Patients working closely with their physician canreach the best decision of what type of medicationwill enable them to have their best response to thetreatment and enhance their ongoing QoL.

PROVIDERS: Physicians have a large arsenal ofmedications available to combat allergic rhinitis andoften may not be driven to use the more expensivesecond-generation nonsedating antihistamines ormontelukast, unless a patient is unable to get symp-tomatic relief from first-line products, or the patienthas had an adverse reaction to a systemic or a nasal-ly inhaled medication.

CARE STRATEGY: The care strategy that allstakeholders have to consider involves far more thanjust limiting the decision to a choice among the sec-ond-generation nonsedating antihistamines. Stake -holders—including providers, patients, and payers—can have a profound effect on the patient’s well-beingby working together to use proven clinical guidelinesand medication choices according to the best interestof each patient. This allows the optimization ofpatients’ QoL, while also focusing on the best overalltreatment cost, whether using an OTC agent forthose who are able to take advantage of theseoptions, prescription medications, or a second-gener-ation nonsedating antihistamine or montelukast, ifthat is determined to be the best treatment for theindividual patient.

Paul Anthony Polansky, BSPharm, MBAExecutive VP & Chief Pharmacy Officer

Sanovia Corporation, Philadelphia, PA

STAKEHOLDER PERSPECTIVEAllergic Rhinitis: A Serious Condition with Many Safe and EffectivePharmaceutical Options


Partnership. People. Programs. Passion. The Flexibility You Need. The Integrity You Deserve.

| M A N A G E D M A R K E T S Leaders in Business. Partners in Care.

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VOL. 2 NO. 7

EXECUTIVE SUMMARIES

318 AMERICAN HEALTH & DRUG BENEFITS November/December 2009

Allergic rhinitis has a significant effect on the patient’squality of life (QoL), in addition to the economic cost toemployers and the healthcare system, but few studieshave assessed the cost-effectiveness of various agents forthis condition based on QoL improvements. That was theexact goal of this retrospective analysis. The authors con-structed a cost-effectiveness model based on 1-year coststo managed care payers and the RhinoconjunctivitisQuality of Life Questionnaire to measure the QoL inpatients taking prescription second-generation antihista-mines or montelukast for the treatment of allergic rhini-

tis. Results showed that all these agents had significantimprovement in QoL, with levocetirizine showing thegreatest improvement. However, the authors did notinclude in their analysis over-the counter (OTC) second-generation agents, such as loratadine or cetirizine, in partbecause their analysis was directed at decision makers inhealth plans, who do not include OTC agents in theirbenefit plans. Historically, when drugs have been movedto an OTC status, this typically has removed them fromcoverage by managed care plans. In addition, cost andQoL data are not available for all OTC agents.

Economic Evaluation of Quality-of-Life Improvement with Second-Generation Antihistamines and Montelukast in Patients with Allergic RhinitisKim R. Saverno, RPh; Brian Seal, PhD; Michael J. Goodman, PhD; Kellie Meyer, PharmD

Approximately 26 million Americans have chronickidney disease (CKD) and about 66% of all new cases ofCKD are caused by diabetes or hypertension. The find-ings from this study involving 31,917 patients withCKD show that contrary to common perceptions inmanaged care, patients who are newly diagnosed withCKD retain their health plans for many years. On aver-age, patients with CKD plus diabetes or hypertensionremained enrolled in their health plans slightly longerthan patients with CKD only. The largest number of

claims was for inpatient medical costs, followed by phar-macy and laboratory services. Mean annual directhealthcare costs were higher for patients with CKD plusdiabetes ($20,165) or CKD plus hypertension ($17,612)compared with those with CKD only ($9390). Themean annual total medical costs were $22,444 for CKDplus diabetes, $19,667 for CKD plus hypertension, and$10,170 for patients with CKD only. Therefore, earlyintervention to prevent or delay the progression fromdiabetes or hypertension to CKD can also reduce costs.

Health Plan Retention and Pharmacy Costs of Newly DiagnosedPatients with CKD in a Managed Care PopulationMaureen Kubacki, PharmD, MBA; Chureen Carter, PharmD, MS; Alan D.L. Herrera, PharmD; Jim Wang, PhD; Janice M. Lopez,PharmD; Catherine T. Piech, MBA

Quality metrics have the potential to increase thevalue of the US healthcare system by reducing costsand increasing access to quality care. A recent survey ofmedical and pharmacy directors in managed care plansevaluated the extent of knowledge of these experts ofavailable health-related quality improvement initia-tives undertaken by different organizations. Surveyresults show that medical and pharmacy directors havelimited knowledge of current quality organizations/ini-tiatives, except for the 2 organizations that offer quali-

ty accreditation to health plans or to pharmacy benefitmanagement organizations—NCQA and URAC. Thisfinding, the authors suggest, presents an opportunity forpharmaceutical companies to collaborate with privatehealth plans to develop quality initiatives, especiallyfor drug utilization. They note that to collaborate withhealth plans successfully, pharmaceutical companiesshould develop evidence-based programs that arefocused on a specific disease state rather than on a spe-cific product.

Quality Improvements Initiatives: The Missed Opportunity for Health PlansSara Fernandez-Lopez, PhD; Barbara Lennert, RN, BSN, MAOM

ExecSummary:Cover 12/11/09 4:30 PM Page 318

Brief Summary of Prescribing InformationINDICATIONS AND USAGEAGGRENOX® (aspirin/extended-release dipyridamole) is indicated to reduce the risk of stroke in patients who have had transient isch-emia of the brain or completed ischemic stroke due to thrombosis.CONTRAINDICATIONS AGGRENOX is contraindicated in patients with hypersensitivity to dipyridamole, aspirin or any of the other product components.Allergy: Aspirin is contraindicated in patients with known allergy to nonsteroidal anti-inflammatory drug products and in patients with the syndrome of asthma, rhinitis, and nasal polyps. Aspirin may cause severe urticaria, angioedema or bronchospasm (asthma).Reye’s Syndrome: Aspirin should not be used in children or teenagers for viral infections, with or without fever, because of the risk of Reye’s syndrome with concomitant use of aspirin in certain viral illnesses.WARNINGSAlcohol Warning: Patients who consume three or more alcoholic drinks every day should be counseled about the bleeding risks involved with chronic, heavy alcohol use while taking aspirin.Coagulation Abnormalities: Even low doses of aspirin can inhibit platelet function leading to an increase in bleeding time. This can adversely affect patients with inherited or acquired (liver disease or vitamin K deficiency) bleeding disorders.Gastrointestinal (GI) Side Effects: GI side effects include stomach pain, heartburn, nausea, vomiting, and gross GI bleeding. Although minor upper GI symptoms, such as dyspepsia, are common and can occur anytime during therapy, physicians should remain alert for signs of ulceration and bleeding, even in the absence of previous GI symptoms. Physicians should inform patients about the signs and symptoms of GI side effects and what steps to take if they occur.Peptic Ulcer Disease: Patients with a history of active peptic ulcer disease should avoid using aspirin, which can cause gastric mucosal irritation, and bleeding.Pregnancy: AGGRENOX can cause fetal harm when administered to a pregnant woman. Maternal aspirin use during later stages of pregnancy may cause low birth weight, increased incidence for intracranial hemorrhage in premature infants, stillbirths and neonatal death. Because of the above and because of the known effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on the fetal cardiovas-cular system (closure of the ductus arteriosus), AGGRENOX should be avoided in the third trimester of pregnancy. Aspirin has been shown to be teratogenic in rats (spina bifida, exencephaly, microphthalmia and coelosomia) and rabbits (congested fetuses, agenesis of skull and upper jaw, generalized edema with malformation of the head, and diaphanous skin) at oral doses of 330 mg/kg/day and 110 mg/kg/day, respectively. These doses, which also resulted in a high resorption rate in rats (63% of implanta-tions versus 5% in controls), are, on a mg/m2 basis, about 66 and 44 times, respectively, the dose of aspirin contained in the maximum recommended daily human dose of AGGRENOX. Reproduction studies with dipyridamole have been performed in mice, rabbits and rats at oral doses of up to 125 mg/kg, 40 mg/kg and 1000 mg/kg, respectively (about 11⁄2, 2 and 25 times the maximum recommended daily human oral dose, respectively, on a mg/m2 basis) and have revealed no evidence of harm to the fetus due to dipyridamole. When 330 mg aspirin/kg/day was combined with 75 mg dipyridamole/kg/day in the rat, the resorption rate approached 100%, indicating potentiation of aspirin-related fetal toxicity. There are no adequate and well-controlled studies in pregnant women. If AGGRENOX is used during preg-nancy, or if the patient becomes pregnant while taking AGGRENOX, the patient should be apprised of the potential hazard to the fetus.PRECAUTIONSGeneralAGGRENOX is not interchangeable with the individual components of aspirin and Persantine® Tablets.Coronary Artery Disease: Dipyridamole has a vasodilatory effect and should be used with caution in patients with severe coronary artery disease (e.g., unstable angina or recently sustained myocardial infarction). Chest pain may be aggravated in patients with underly-ing coronary artery disease who are receiving dipyridamole.For stroke or TIA patients for whom aspirin is indicated to prevent recurrent myocardial infarction (MI) or angina pectoris, the aspirin in this product may not provide adequate treatment for the cardiac indications.Hepatic Insufficiency: Elevations of hepatic enzymes and hepatic failure have been reported in association with dipyridamole administration. Hypotension: Dipyridamole should be used with caution in patients with hypotension since it can produce peripheral vasodilation.Renal Failure: Avoid aspirin in patients with severe renal failure (glomerular filtration rate less than 10 mL/minute).Risk of Bleeding: In ESPS2 the incidence of gastrointestinal bleeding was 68 patients (4.1%) in the AGGRENOX group, 36 patients (2.2%) in the extended-release dipyridamole group, 52 patients (3.2%) in the aspirin group, and 34 patients (2.1%) in the placebo groups. The incidence of intracranial hemorrhage was 9 patients (0.6%) in the AGGRENOX group, 6 patients (0.5%) in the extended-release dipyridamole group, 6 patients (0.4%) in the aspirin group and 7 patients (0.4%) in the placebo groups.Laboratory TestsAspirin has been associated with elevated hepatic enzymes, blood urea nitrogen and serum creatinine, hyperkalemia, proteinuria and prolonged bleeding time.Dipyridamole has been associated with elevated hepatic enzymes.Drug InteractionsNo pharmacokinetic drug-drug interaction studies were conducted with the AGGRENOX formulation. The following information was obtained from the literature.Adenosine: Dipyridamole has been reported to increase the plasma levels and cardiovascular effects of adenosine. Adjustment of adenosine dosage may be necessary.Angiotensin Converting Enzyme (ACE) Inhibitors: Due to the indirect effect of aspirin on the renin-angiotensin conversion pathway, the hyponatremic and hypotensive effects of ACE inhibitors may be diminished by concomitant administration of aspirin. Acetazolamide: Concurrent use of aspirin and acetazolamide can lead to high serum concentrations of acetazolamide (and toxicity) due to competition at the renal tubule for secretion.Anticoagulant Therapy (heparin and warfarin): Patients on anticoagulation therapy are at increased risk for bleeding because of drug-drug interactions and effects on platelets. Aspirin can displace warfarin from protein binding sites, leading to prolongation of both the prothrombin time and the bleeding time. Aspirin can increase the anticoagulant activity of heparin, increasing bleeding risk.Anticonvulsants: Salicylic acid can displace protein-bound phenytoin and valproic acid, leading to a decrease in the total concentration of phenytoin and an increase in serum valproic acid levels. Beta Blockers: The hypotensive effects of beta blockers may be diminished by the concomitant administration of aspirin due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.Cholinesterase Inhibitors: Dipyridamole may counteract the anticholinesterase effect of cholinesterase inhibitors, thereby potentially aggravating myasthenia gravis. Diuretics: The effectiveness of diuretics in patients with underlying renal or cardiovascular disease may be diminished by the con-comitant administration of aspirin due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.Methotrexate: Salicylate can inhibit renal clearance of methotrexate, leading to bone marrow toxicity, especially in the elderly or renal impaired.Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): The concurrent use of aspirin with other NSAIDs may increase bleeding or lead to decreased renal function.Oral Hypoglycemics: Moderate doses of aspirin may increase the effectiveness of oral hypoglycemic drugs, leading to hypoglycemia.Uricosuric Agents (probenecid and sulfinpyrazone): Salicylates antagonize the uricosuric action of uricosuric agents.Carcinogenesis, Mutagenesis, Impairment of FertilityIn studies in which dipyridamole was administered in the feed to mice (up to 111 weeks in males and females) and rats (up to 128 weeks in males and up to 142 weeks in females), there was no evidence of drug-related carcinogenesis. The highest dose administered in these studies (75 mg/kg/day) was, on a mg/m2 basis, about equivalent to the maximum recommended daily human oral dose (MRHD) in mice and about twice the MRHD in rats. Combinations of dipyridamole and aspirin (1:5 ratio) tested negative in the Ames test, in vivo chromosome aberration tests (in mice and hamsters), oral micronucleus tests (in mice and hamsters) and oral dominant lethal test (in mice). Aspirin, alone, induced chromo-some aberrations in cultured human fibroblasts. Mutagenicity tests of dipyridamole alone with bacterial and mammalian cell systems were negative.Combinations of dipyridamole and aspirin have not been evaluated for effects on fertility and reproductive performance. There was no evidence of impaired fertility when dipyridamole was administered to male and female rats at oral doses up to 500 mg/kg/day (about 12 times the MRHD on a mg/m2 basis). A significant reduction in number of corpora lutea with consequent reduction in implantations and live fetuses was, however, observed at 1250 mg/kg (more than 30 times the MRHD on a mg/m2 basis). Aspirin inhibits ovulation in rats.PregnancyTeratogenic Effects: Pregnancy Category D (see WARNINGS)Labor and DeliveryAspirin can result in excessive blood loss at delivery as well as prolonged gestation and prolonged labor. Because of these effects on the mother and because of adverse fetal effects seen with aspirin during the later stages of pregnancy (see WARNINGS, Pregnancy), AGGRENOX should be avoided in the third trimester of pregnancy and during labor and delivery.Nursing MothersBoth dipyridamole and aspirin are excreted in human milk. Caution should be exercised when AGGRENOX is administered to a nursing woman.Pediatric UseSafety and effectiveness of AGGRENOX in pediatric patients have not been studied. Due to the aspirin component, use of this product in the pediatric population is not recommended (see CONTRAINDICATIONS).ADVERSE REACTIONSA 24-month, multicenter, double-blind, randomized study (ESPS2) was conducted to compare the efficacy and safety of AGGRENOX with placebo, extended-release dipyridamole alone and aspirin alone. The study was conducted in a total of 6602 male and female patients who had experienced a previous ischemic stroke or transient ischemia of the brain within three months prior to randomization. T

Table 1: Incidence of Adverse Events in ESPS2* Individual Treatment GroupBody System/Preferred Term AGGRENOX ER-DP Alone ASA Alone PlaceboTotal Number of Patients 1650 1654 1649 1649Total Number (%) of Patients With at Least One On-Treatment Adverse Event 1319 (79.9%) 1305 (78.9%) 1323 (80.2%) 1304 (79.1%)Central & Peripheral Nervous System Disorders Headache 647 (39.2%) 634 (38.3%) 558 (33.8%) 543 (32.9%) Convulsions 28 (1.7%) 15 (0.9%) 28 (1.7%) 26 (1.6%)Gastro-Intestinal System Disorders Dyspepsia 303 (18.4%) 288 (17.4%) 299 (18.1%) 275 (16.7%) Abdominal Pain 289 (17.5%) 255 (15.4%) 262 (15.9%) 239 (14.5%) Nausea 264 (16.0%) 254 (15.4%) 210 (12.7%) 232 (14.1%) Diarrhea 210 (12.7%) 257 (15.5%) 112 (6.8%) 161 (9.8%) Vomiting 138 (8.4%) 129 (7.8%) 101 (6.1%) 118 (7.2%) Hemorrhage Rectum 26 (1.6%) 22 (1.3%) 16 (1.0%) 13 (0.8%) Melena 31 (1.9%) 10 (0.6%) 20 (1.2%) 13 (0.8%) Hemorrhoids 16 (1.0%) 13 (0.8%) 10 (0.6%) 10 (0.6%) GI Hemorrhage 20 (1.2%) 5 (0.3%) 15 (0.9%) 7 (0.4%)Body as a Whole - General Disorders Pain 105 (6.4%) 88 (5.3%) 103 (6.2%) 99 (6.0%) Fatigue 95 (5.8%) 93 (5.6%) 97 (5.9%) 90 (5.5%) Back Pain 76 (4.6%) 77 (4.7%) 74 (4.5%) 65 (3.9%) Accidental Injury 42 (2.5%) 24 (1.5%) 51 (3.1%) 37 (2.2%) Malaise 27 (1.6%) 23 (1.4%) 26 (1.6%) 22 (1.3%) Asthenia 29 (1.8%) 19 (1.1%) 17 (1.0%) 18 (1.1%) Syncope 17 (1.0%) 13 (0.8%) 16 (1.0%) 8 (0.5%)Psychiatric Disorders Amnesia 39 (2.4%) 40 (2.4%) 57 (3.5%) 34 (2.1%) Confusion 18 (1.1%) 9 (0.5%) 22 (1.3%) 15 (0.9%) Anorexia 19 (1.2%) 17 (1.0%) 10 (0.6%) 15 (0.9%) Somnolence 20 (1.2%) 13 (0.8%) 18 (1.1%) 9 (0.5%)Musculoskeletal System Disorders Arthralgia 91 (5.5%) 75 (4.5%) 91 (5.5%) 76 (4.6%) Arthritis 34 (2.1%) 25 (1.5%) 17 (1.0%) 19 (1.2%) Arthrosis 18 (1.1%) 22 (1.3%) 13 (0.8%) 14 (0.8%) Myalgia 20 (1.2%) 16 (1.0%) 11 (0.7%) 11 (0.7%)Respiratory System Disorders Coughing 25 (1.5%) 18 (1.1%) 32 (1.9%) 21 (1.3%) Upper Respiratory Tract Infection 16 (1.0%) 9 (0.5%) 16 (1.0%) 14 (0.8%)Cardiovascular Disorders, General Cardiac Failure 26 (1.6%) 17 (1.0%) 30 (1.8%) 25 (1.5%)Platelet, Bleeding & Clotting Disorders Hemorrhage NOS 52 (3.2%) 24 (1.5%) 46 (2.8%) 24 (1.5%) Epistaxis 39 (2.4%) 16 (1.0%) 45 (2.7%) 25 (1.5%) Purpura 23 (1.4%) 8 (0.5%) 9 (0.5%) 7 (0.4%)Neoplasm Neoplasm NOS 28 (1.7%) 16 (1.0%) 23 (1.4%) 20 (1.2%)Red Blood Cell Disorders Anemia 27 (1.6%) 16 (1.0%) 19 (1.2%) 9 (0.5%)*Reported by ≥1% of patients during AGGRENOX treatment where the incidence was greater than in those treated with placebo.Note: ER-DP = extended-release dipyridamole 200 mg; ASA = aspirin 25 mg. The dosage regimen for all treatment groups is BID. NOS = not otherwise specified.Discontinuation due to adverse events in ESPS2 was 25% for AGGRENOX, 25% for extended-release dipyridamole, 19% for aspirin, and 21% for placebo (refer to Table 2).Table 2: Incidence of Adverse Events that Led to the Discontinuation of Treatment: Adverse Events with an Incidence of ≥1% in the AGGRENOX group Treatment Groups AGGRENOX ER-DP ASA PlaceboTotal Number of Patients 1650 1654 1649 1649Patients with at least one Adverse Eventthat led to treatment discontinuation 417 (25%) 419 (25%) 318 (19%) 352 (21%) Headache 165 (10%) 166 (10%) 57 (3%) 69 (4%) Dizziness 85 (5%) 97 (6%) 69 (4%) 68 (4%) Nausea 91 (6%) 95 (6%) 51 (3%) 53 (3%) Abdominal Pain 74 (4%) 64 (4%) 56 (3%) 52 (3%) Dyspepsia 59 (4%) 61 (4%) 49 (3%) 46 (3%) Vomiting 53 (3%) 52 (3%) 28 (2%) 24 (1%) Diarrhea 35 (2%) 41 (2%) 9 (<1%) 16 (<1%) Stroke 39 (2%) 48 (3%) 57 (3%) 73 (4%) Transient Ischemic Attack 35 (2%) 40 (2%) 26 (2%) 48 (3%) Angina Pectoris 23 (1%) 20 (1%) 16 (<1%) 26 (2%)Note: ER-DP = extended-release dipyridamole 200 mg; ASA = aspirin 25 mg. The dosage regimen for all treatment groups is BID.Other adverse events:Adverse reactions that occurred in less than 1% of patients treated with AGGRENOX in the ESPS2 study and that were medically judgedto be possibly related to either dipyridamole or aspirin are listed below (see WARNINGS). Body as a Whole: Allergic reaction, fever.Cardiovascular: Hypotension. Central Nervous System: Coma, dizziness, paresthesia, cerebral hemorrhage, intracranial hemorrhage,subarachnoid hemorrhage. Gastrointestinal: Gastritis, ulceration and perforation. Hearing and Vestibular Disorders: Tinnitus, and deaf-ness. Patients with high frequency hearing loss may have difficulty perceiving tinnitus. In these patients, tinnitus cannot be used as a clinical indicator of salicylism. Heart Rate and Rhythm Disorders: Tachycardia, palpitation, arrhythmia, supraventricular tachycardia. Liver and Biliary System Disorders: Cholelithiasis, jaundice, hepatic function abnormal. Metabolic & Nutritional Disorders: Hypergly-cemia, thirst. Platelet, Bleeding and Clotting Disorders: Hematoma, gingival bleeding. Psychiatric Disorders: Agitation. Reproductive: Uterine hemorrhage. Respiratory: Hyperpnea, asthma, bronchospasm, hemoptysis, pulmonary edema. Special Senses Other Disor-ders: Taste loss. Skin and Appendages Disorders: Pruritus, urticaria. Urogenital: Renal insufficiency and failure, hematuria. Vascular(Extracardiac) Disorders: Flushing.The following is a list of additional adverse reactions that have been reported either in the literature or are from postmarketing spontane-ous reports for either dipyridamole or aspirin. Body as a Whole: Hypothermia, chest pain. Cardiovascular: Angina pectoris. Central Nervous System: Cerebral edema. Fluid and Electrolyte: Hyperkalemia, metabolic acidosis, respiratory alkalosis, hypokalemia. Gastro-intestinal: Pancreatitis, Reye’s syndrome, hematemesis. Hearing and Vestibular Disorders: Hearing loss. Hypersensitivity: Acute anaphy-laxis, laryngeal edema. Liver and Biliary System Disorders: Hepatitis, hepatic failure. Musculoskeletal: Rhabdomyolysis. Metabolic &Nutritional Disorders: Hypoglycemia, dehydration. Platelet, Bleeding and Clotting Disorders: Prolongation of the prothrombin time, dis-seminated intravascular coagulation, coagulopathy, thrombocytopenia. Reproductive: Prolonged pregnancy and labor, stillbirths, lowerbirth weight infants, antepartum and postpartum bleeding. Respiratory: Tachypnea, dyspnea. Skin and Appendages Disorders: Rash,alopecia, angioedema, Stevens-Johnson syndrome, pruritus, urticaria, skin hemorrhages such as bruising, ecchymosis, and hematoma.Urogenital: Interstitial nephritis, papillary necrosis, proteinuria. Vascular (Extracardiac Disorders): Allergic vasculitis.The following is a list of additional adverse events that have been reported either in the literature or are from postmarketing spontaneousreports for either dipyridamole or aspirin. The causal relationship of these adverse events has not been established: anorexia, aplasticanemia, pancytopenia, thrombocytosis.Laboratory ChangesOver the course of the 24-month study (ESPS2), patients treated with AGGRENOX showed a decline (mean change from baseline) in hemoglobin of 0.25 g/dL, hematocrit of 0.75%, and erythrocyte count of 0.13x106/mm3.OVERDOSAGEBecause of the dose ratio of dipyridamole to aspirin, overdosage of AGGRENOX is likely to be dominated by signs and symptoms ofdipyridamole overdose. In case of real or suspected overdose, seek medical attention or contact a Poison Control Center immediately.Careful medical management is essential.DOSAGE AND ADMINISTRATIONThe recommended dose of AGGRENOX capsules is one capsule given orally twice daily, one in the morning and one in the evening. Thecapsules should be swallowed whole without chewing. AGGRENOX capsules may be administered with or without food.Alternative Regimen in Case of Intolerable Headaches: In the event of intolerable headaches during initial treatment, switch to one capsule at bedtime and low-dose aspirin in the morning. Because there are no outcome data with this regimen and headaches become less of a problem as treatment continues, patients should return to the usual regimen as soon as possible, usually within one week.AGGRENOX is not interchangeable with the individual components of aspirin and Persantine® Tablets.Marketed by: Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT 06877 USAManufactured by: Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, GermanyLicensed from: Boehringer Ingelheim International GmbH © Copyright Boehringer Ingelheim International GmbH 2007ALL RIGHTS RESERVED Patent No. 6,015,577 42633/US/7 AG/BS/42633 AG49262

R l

Brief Summary of Prescribing InformationINDICATIONS AND USAGEAGGRENOX® (aspirin/extended-release dipyridamole) is indicated to reduce the risk of stroke in patients who have had transient ischemiaof the brain or completed ischemic stroke due to thrombosis.CONTRAINDICATIONSAGGRENOX (aspirin/extended-release dipyridamole) is contraindicated in patients with hypersensitivity to dipyridamole, aspirin or any of theother product components.Allergy: Aspirin is contraindicated in patients with known allergy to nonsteroidal anti-inflammatory drug products and in patients with thesyndrome of asthma, rhinitis, and nasal polyps. Aspirin may cause severe urticaria, angioedema or bronchospasm (asthma).Reye’s Syndrome: Aspirin should not be used in children or teenagers for viral infections, with or without fever, because of the risk of Reye’ssyndrome with concomitant use of aspirin in certain viral illnesses.WARNINGSAlcohol Warning: Patients who consume three or more alcoholic drinks every day should be counseled about the bleeding risks involvedwith chronic, heavy alcohol use while taking aspirin.Coagulation Abnormalities: Even low doses of aspirin can inhibit platelet function leading to an increase in bleeding time. This canadversely affect patients with inherited or acquired (liver disease or vitamin K deficiency) bleeding disorders.Gastrointestinal (GI) Side Effects: GI side effects include stomach pain, heartburn, nausea, vomiting, and gross GI bleeding. Althoughminor upper GI symptoms, such as dyspepsia, are common and can occur anytime during therapy, physicians should remain alert for signsof ulceration and bleeding, even in the absence of previous GI symptoms. Physicians should inform patients about the signs and symptomsof GI side effects and what steps to take if they occur.Peptic Ulcer Disease: Patients with a history of active peptic ulcer disease should avoid using aspirin, which can cause gastric mucosalirritation, and bleeding.Pregnancy: AGGRENOX can cause fetal harm when administered to a pregnant woman. Maternal aspirin use during later stages ofpregnancy may cause low birth weight, increased incidence for intracranial hemorrhage in premature infants, stillbirths and neonatal death.Because of the above and because of the known effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on the fetal cardiovascular system(closure of the ductus arteriosus), AGGRENOX should be avoided in the third trimester of pregnancy.Aspirin has been shown to be teratogenic in rats (spina bifida, exencephaly, microphthalmia and coelosomia) and rabbits (congested fetuses,agenesis of skull and upper jaw, generalized edema with malformation of the head, and diaphanous skin) at oral doses of 330 mg/kg/day and110 mg/kg/day, respectively. These doses, which also resulted in a high resorption rate in rats (63% of implantations versus 5% in controls),are, on a mg/m2 basis, about 66 and 44 times, respectively, the dose of aspirin contained in the maximum recommended daily human dose ofAGGRENOX. Reproduction studies with dipyridamole have been performed in mice, rabbits and rats at oral doses of up to 125 mg/kg,40 mg/kg and 1000 mg/kg, respectively (about 11⁄2, 2 and 25 times the maximum recommended daily human oral dose, respectively, on amg/m2 basis) and have revealed no evidence of harm to the fetus due to dipyridamole. When 330 mg aspirin/kg/day was combined with75 mg dipyridamole/kg/day in the rat, the resorption rate approached 100%, indicating potentiation of aspirin-related fetal toxicity. There areno adequate and well-controlled studies in pregnant women. If AGGRENOX is used during pregnancy, or if the patient becomes pregnant whiletaking AGGRENOX, the patient should be apprised of the potential hazard to the fetus.PRECAUTIONSGeneralAGGRENOX (aspirin/extended-release dipyridamole) is not interchangeable with the individual components of aspirinand Persantine® Tablets.Coronary Artery Disease: Dipyridamole has a vasodilatory effect and should be used with caution in patients with severe coronary arterydisease (e.g., unstable angina or recently sustained myocardial infarction). Chest pain may be aggravated in patients with underlying coronaryartery disease who are receiving dipyridamole.For stroke or TIA patients for whom aspirin is indicated to prevent recurrent myocardial infarction (MI) or angina pectoris, the aspirin in thisproduct may not provide adequate treatment for the cardiac indications.Hepatic Insufficiency: Elevations of hepatic enzymes and hepatic failure have been reported in association with dipyridamole administration.Hypotension: Dipyridamole should be used with caution in patients with hypotension since it can produce peripheral vasodilation.Renal Failure: Avoid aspirin in patients with severe renal failure (glomerular filtration rate less than 10 mL/minute).Risk of Bleeding: In ESPS2 the incidence of gastrointestinal bleeding was 68 patients (4.1%) in the AGGRENOX group, 36 patients (2.2%)in the extended-release dipyridamole group, 52 patients (3.2%) in the aspirin group, and 34 patients (2.1%) in the placebo groups.The incidence of intracranial hemorrhage was 9 patients (0.6%) in the AGGRENOX group, 6 patients (0.5%) in the extended-releasedipyridamole group, 6 patients (0.4%) in the aspirin group and 7 patients (0.4%) in the placebo groups.Laboratory TestsAspirin has been associated with elevated hepatic enzymes, blood urea nitrogen and serum creatinine, hyperkalemia, proteinuria andprolonged bleeding time.Dipyridamole has been associated with elevated hepatic enzymes.Drug InteractionsNo pharmacokinetic drug-drug interaction studies were conducted with the AGGRENOX formulation. The following information was obtainedfrom the literature.Adenosine: Dipyridamole has been reported to increase the plasma levels and cardiovascular effects of adenosine. Adjustment of adenosinedosage may be necessary.Angiotensin Converting Enzyme (ACE) Inhibitors: Due to the indirect effect of aspirin on the renin-angiotensin conversion pathway, thehyponatremic and hypotensive effects of ACE inhibitors may be diminished by concomitant administration of aspirin.Acetazolamide: Concurrent use of aspirin and acetazolamide can lead to high serum concentrations of acetazolamide (and toxicity) due tocompetition at the renal tubule for secretion.Anticoagulant Therapy (heparin and warfarin): Patients on anticoagulation therapy are at increased risk for bleeding because of drug-druginteractions and effects on platelets. Aspirin can displace warfarin from protein binding sites, leading to prolongation of both the prothrombintime and the bleeding time. Aspirin can increase the anticoagulant activity of heparin, increasing bleeding risk.Anticonvulsants: Salicylic acid can displace protein-bound phenytoin and valproic acid, leading to a decrease in the total concentration ofphenytoin and an increase in serum valproic acid levels.Beta Blockers: The hypotensive effects of beta blockers may be diminished by the concomitant administration of aspirin due to inhibition ofrenal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.Cholinesterase Inhibitors: Dipyridamole may counteract the anticholinesterase effect of cholinesterase inhibitors, thereby potentiallyaggravating myasthenia gravis.Diuretics: The effectiveness of diuretics in patients with underlying renal or cardiovascular disease may be diminished by the concomitantadministration of aspirin due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.Methotrexate: Salicylate can inhibit renal clearance of methotrexate, leading to bone marrow toxicity, especially in the elderly or renal impaired.Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): The concurrent use of aspirin with other NSAIDs may increase bleeding or lead to decreasedrenal function.Oral Hypoglycemics: Moderate doses of aspirin may increase the effectiveness of oral hypoglycemic drugs, leading to hypoglycemia.Uricosuric Agents (probenecid and sulfinpyrazone): Salicylates antagonize the uricosuric action of uricosuric agents.Carcinogenesis, Mutagenesis, Impairment of FertilityIn studies in which dipyridamole was administered in the feed to mice (up to 111 weeks in males and females) and rats (up to 128 weeks inmales and up to 142 weeks in females), there was no evidence of drug-related carcinogenesis. The highest dose administered in these studies(75 mg/kg/day) was, on a mg/m2 basis, about equivalent to the maximum recommended daily human oral dose (MRHD) in mice and abouttwice the MRHD in rats.Combinations of dipyridamole and aspirin (1:5 ratio) tested negative in the Ames test, in vivo chromosome aberration tests (in mice andhamsters), oral micronucleus tests (in mice and hamsters) and oral dominant lethal test (in mice). Aspirin, alone, induced chromosomeaberrations in cultured human fibroblasts. Mutagenicity tests of dipyridamole alone with bacterial and mammalian cell systems were negative.Combinations of dipyridamole and aspirin have not been evaluated for effects on fertility and reproductive performance. There was noevidence of impaired fertility when dipyridamole was administered to male and female rats at oral doses up to 500 mg/kg/day (about 12 timesthe MRHD on a mg/m2 basis). A significant reduction in number of corpora lutea with consequent reduction in implantations and live fetuseswas, however, observed at 1250 mg/kg (more than 30 times the MRHD on a mg/m2 basis). Aspirin inhibits ovulation in rats.PregnancyTeratogenic Effects: Pregnancy Category D (see WARNINGS)Labor and DeliveryAspirin can result in excessive blood loss at delivery as well as prolonged gestation and prolonged labor. Because of these effects on themother and because of adverse fetal effects seen with aspirin during the later stages of pregnancy (see WARNINGS, Pregnancy),AGGRENOX should be avoided in the third trimester of pregnancy and during labor and delivery.Nursing MothersBoth dipyridamole and aspirin are excreted in human milk. Caution should be exercised when AGGRENOX is administered to a nursing woman.Pediatric UseSafety and effectiveness of AGGRENOX in pediatric patients have not been studied. Due to the aspirin component, use of this product in thepediatric population is not recommended (see CONTRAINDICATIONS).ADVERSE REACTIONSA 24-month, multicenter, double-blind, randomized study (ESPS2) was conducted to compare the efficacy and safety of AGGRENOX(aspirin/extended-release dipyridamole) with placebo, extended-release dipyridamole alone and aspirin alone. The study was conducted in atotal of 6602 male and female patients who had experienced a previous ischemic stroke or transient ischemia of the brain within three monthsprior to randomization.Table 1 presents the incidence of adverse events that occurred in 1% or more of patients treated with AGGRENOX where the incidence was alsogreater than in those patients treated with placebo. There is no clear benefit of the dipyridamole/aspirin combination over aspirin with respect to safety.

Table 1: Incidence of Adverse Events in ESPS2*Individual Treatment Group

Body System/Preferred Term AGGRENOX ER-DP Alone ASA Alone PlaceboTotal Number of Patients 1650 1654 1649 1649Total Number (%) of Patients With at LeastOne On-Treatment Adverse Event 1319 (79.9%) 1305 (78.9%) 1323 (80.2%) 1304 (79.1%)Central & Peripheral Nervous System Disorders

Headache 647 (39.2%) 634 (38.3%) 558 (33.8%) 543 (32.9%)Convulsions 28 (1.7%) 15 (0.9%) 28 (1.7%) 26 (1.6%)

Gastro-Intestinal System DisordersDyspepsia 303 (18.4%) 288 (17.4%) 299 (18.1%) 275 (16.7%)Abdominal Pain 289 (17.5%) 255 (15.4%) 262 (15.9%) 239 (14.5%)Nausea 264 (16.0%) 254 (15.4%) 210 (12.7%) 232 (14.1%)Diarrhea 210 (12.7%) 257 (15.5%) 112 (6.8%) 161 (9.8%)Vomiting 138 (8.4%) 129 (7.8%) 101 (6.1%) 118 (7.2%)Hemorrhage Rectum 26 (1.6%) 22 (1.3%) 16 (1.0%) 13 (0.8%)Melena 31 (1.9%) 10 (0.6%) 20 (1.2%) 13 (0.8%)Hemorrhoids 16 (1.0%) 13 (0.8%) 10 (0.6%) 10 (0.6%)GI Hemorrhage 20 (1.2%) 5 (0.3%) 15 (0.9%) 7 (0.4%)

Body as a Whole - General DisordersPain 105 (6.4%) 88 (5.3%) 103 (6.2%) 99 (6.0%)Fatigue 95 (5.8%) 93 (5.6%) 97 (5.9%) 90 (5.5%)Back Pain 76 (4.6%) 77 (4.7%) 74 (4.5%) 65 (3.9%)Accidental Injury 42 (2.5%) 24 (1.5%) 51 (3.1%) 37 (2.2%)Malaise 27 (1.6%) 23 (1.4%) 26 (1.6%) 22 (1.3%)Asthenia 29 (1.8%) 19 (1.1%) 17 (1.0%) 18 (1.1%)Syncope 17 (1.0%) 13 (0.8%) 16 (1.0%) 8 (0.5%)

Psychiatric DisordersAmnesia 39 (2.4%) 40 (2.4%) 57 (3.5%) 34 (2.1%)Confusion 18 (1.1%) 9 (0.5%) 22 (1.3%) 15 (0.9%)Anorexia 19 (1.2%) 17 (1.0%) 10 (0.6%) 15 (0.9%)Somnolence 20 (1.2%) 13 (0.8%) 18 (1.1%) 9 (0.5%)

Musculoskeletal System DisordersArthralgia 91 (5.5%) 75 (4.5%) 91 (5.5%) 76 (4.6%)Arthritis 34 (2.1%) 25 (1.5%) 17 (1.0%) 19 (1.2%)Arthrosis 18 (1.1%) 22 (1.3%) 13 (0.8%) 14 (0.8%)Myalgia 20 (1.2%) 16 (1.0%) 11 (0.7%) 11 (0.7%)

Respiratory System DisordersCoughing 25 (1.5%) 18 (1.1%) 32 (1.9%) 21 (1.3%)Upper Respiratory Tract Infection 16 (1.0%) 9 (0.5%) 16 (1.0%) 14 (0.8%)

Cardiovascular Disorders, GeneralCardiac Failure 26 (1.6%) 17 (1.0%) 30 (1.8%) 25 (1.5%)

Platelet, Bleeding & Clotting DisordersHemorrhage NOS 52 (3.2%) 24 (1.5%) 46 (2.8%) 24 (1.5%)Epistaxis 39 (2.4%) 16 (1.0%) 45 (2.7%) 25 (1.5%)Purpura 23 (1.4%) 8 (0.5%) 9 (0.5%) 7 (0.4%)

NeoplasmNeoplasm NOS 28 (1.7%) 16 (1.0%) 23 (1.4%) 20 (1.2%)

Red Blood Cell DisordersAnemia 27 (1.6%) 16 (1.0%) 19 (1.2%) 9 (0.5%)

*Reported by ≥1% of patients during AGGRENOX treatment where the incidence was greater than in those treated with placebo.Note: ER-DP = extended-release dipyridamole 200 mg; ASA = aspirin 25 mg. The dosage regimen for all treatment groups is BID.

NOS = not otherwise specified.Discontinuation due to adverse events in ESPS2 was 25% for AGGRENOX, 25% for extended-release dipyridamole, 19% for aspirin, and21% for placebo (refer to Table 2).Table 2: Incidence of Adverse Events that Led to the Discontinuation of Treatment:

Adverse Events with an Incidence of ≥1% in the AGGRENOX groupTreatment Groups

AGGRENOX ER-DP ASA PlaceboTotal Number of Patients 1650 1654 1649 1649Patients withat least one AdverseEventthat led to treatment discontinuation 417 (25%) 419 (25%) 318 (19%) 352 (21%)

Headache 165 (10%) 166 (10%) 57 (3%) 69 (4%)Dizziness 85 (5%) 97 (6%) 69 (4%) 68 (4%)Nausea 91 (6%) 95 (6%) 51 (3%) 53 (3%)Abdominal Pain 74 (4%) 64 (4%) 56 (3%) 52 (3%)Dyspepsia 59 (4%) 61 (4%) 49 (3%) 46 (3%)Vomiting 53 (3%) 52 (3%) 28 (2%) 24 (1%)Diarrhea 35 (2%) 41 (2%) 9 (<1%) 16 (<1%)Stroke 39 (2%) 48 (3%) 57 (3%) 73 (4%)Transient Ischemic Attack 35 (2%) 40 (2%) 26 (2%) 48 (3%)Angina Pectoris 23 (1%) 20 (1%) 16 (<1%) 26 (2%)

Note: ER-DP = extended-release dipyridamole 200 mg; ASA = aspirin 25 mg. The dosage regimen for all treatment groups is BID.Other adverse events:Adverse reactions that occurred in less than 1% of patients treated with AGGRENOX in the ESPS2 study and that were medically judged to bepossibly related to either dipyridamole or aspirin are listed below (see WARNINGS). Body as a Whole: Allergic reaction, fever.Cardiovascular: Hypotension. Central Nervous System: Coma, dizziness, paresthesia, cerebral hemorrhage, intracranial hemorrhage,subarachnoid hemorrhage. Gastrointestinal: Gastritis, ulceration and perforation. Hearing and Vestibular Disorders: Tinnitus, and deafness.Patients with high frequency hearing loss may have difficulty perceiving tinnitus. In these patients, tinnitus cannot be used as a clinicalindicator of salicylism. Heart Rate and Rhythm Disorders: Tachycardia, palpitation, arrhythmia, supraventricular tachycardia. Liver and BiliarySystem Disorders: Cholelithiasis, jaundice, hepatic function abnormal. Metabolic & Nutritional Disorders: Hyperglycemia, thirst. Platelet,Bleeding and Clotting Disorders: Hematoma, gingival bleeding. Psychiatric Disorders: Agitation. Reproductive: Uterine hemorrhage.Respiratory: Hyperpnea, asthma, bronchospasm, hemoptysis, pulmonary edema. Special Senses Other Disorders: Taste loss. Skin andAppendages Disorders: Pruritus, urticaria. Urogenital: Renal insufficiency and failure, hematuria. Vascular (Extracardiac) Disorders: Flushing.The following is a list of additional adverse reactions that have been reported either in the literature or are from postmarketing spontaneousreports for either dipyridamole or aspirin. Body as a Whole: Hypothermia, chest pain. Cardiovascular: Angina pectoris. Central Nervous System:Cerebral edema. Fluid and Electrolyte: Hyperkalemia, metabolic acidosis, respiratory alkalosis, hypokalemia. Gastrointestinal: Pancreatitis,Reye’s syndrome, hematemesis. Hearing and Vestibular Disorders: Hearing loss. Hypersensitivity: Acute anaphylaxis, laryngeal edema. Liverand Biliary System Disorders: Hepatitis, hepatic failure. Musculoskeletal: Rhabdomyolysis. Metabolic & Nutritional Disorders: Hypoglycemia,dehydration. Platelet, Bleeding and Clotting Disorders: Prolongation of the prothrombin time, disseminated intravascular coagulation,coagulopathy, thrombocytopenia. Reproductive: Prolonged pregnancy and labor, stillbirths, lower birth weight infants, antepartum andpostpartum bleeding. Respiratory: Tachypnea, dyspnea. Skin and Appendages Disorders: Rash, alopecia, angioedema, Stevens-Johnsonsyndrome, pruritus, urticaria, skin hemorrhages such as bruising, ecchymosis, and hematoma. Urogenital: Interstitial nephritis, papillarynecrosis, proteinuria. Vascular (Extracardiac Disorders): Allergic vasculitis.The following is a list of additional adverse events that have been reported either in the literature or are from postmarketing spontaneousreports for either dipyridamole or aspirin. The causal relationship of these adverse events has not been established: anorexia, aplastic anemia,pancytopenia, thrombocytosis.Laboratory ChangesOver the course of the 24-month study (ESPS2), patients treated with AGGRENOX showed a decline (mean change from baseline) inhemoglobin of 0.25 g/dL, hematocrit of 0.75%, and erythrocyte count of 0.13x106/mm3.OVERDOSAGEBecause of the dose ratio of dipyridamole to aspirin, overdosage of AGGRENOX (aspirin/extended-release dipyridamole) is likely to bedominated by signs and symptoms of dipyridamole overdose. In case of real or suspected overdose, seek medical attention or contact aPoison Control Center immediately. Careful medical management is essential.DOSAGE AND ADMINISTRATIONThe recommended dose of Aggrenox® (aspirin/extended-release dipyridamole) capsules is one capsule given orally twice daily, one in themorning and one in the evening. The capsules should be swallowed whole without chewing. AGGRENOX capsules may be administered withor without food.Alternative Regimen in Case of Intolerable Headaches: In the event of intolerable headaches during initial treatment, switch to onecapsule at bedtime and low-dose aspirin in the morning. Because there are no outcome data with this regimen and headaches become less of aproblem as treatment continues, patients should return to the usual regimen as soon as possible, usually within one week.AGGRENOX is not interchangeable with the individual components of aspirin and Persantine® Tablets.Marketed by: Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT 06877 USAManufactured by: Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, GermanyLicensed from: Boehringer Ingelheim International GmbH © Copyright Boehringer Ingelheim International GmbH 2007ALL RIGHTS RESERVED Patent No. 6,015,577 42633/US/7 AG/BS/42633

Rx only

AG49265


Copyright © 2009, Boehringer Ingelheim Pharmaceuticals, Inc. All rights reserved. Printed in the U.S.A. (08/09) AG66794

Please see reverse side for Brief Summary of Prescribing Information.

Pick the TIA or ischemic stroke patients out of the crowd.

AGGRENOX may be right for many of them.

Important Safety InformationAggrenox® (aspirin/extended-release dipyridamole) 25 mg/200 mg capsules is indicated to reduce the risk of stroke in patients who have had transient ischemia of the brain or completed ischemic stroke due to thrombosis. In ESPS 2, the most common adverse event with AGGRENOX was headache (39.2% vs. 32.9% with placebo), which was more frequent at the onset of therapy but diminished over time. Bleeding (including GI and intracranial bleeding) was comparable to aspirin (8.7% vs. 8.2%) and higher than placebo (8.7% vs. 4.5%). GI side effects (such as dyspepsia, stomach pain, heartburn, nausea, and vomiting) were other common adverse events.

AGGRENOX contains aspirin. Patients who consume three or more alcoholic drinks every day should be counseled about the bleeding risks associated with chronic, heavy alcohol use while taking aspirin. Even low doses of aspirin can increase bleeding time, which can adversely affect patients with bleeding disorders. Patients with a history of active peptic ulcer disease should avoid using aspirin. Aspirin should be avoided in the third trimester of pregnancy. Aspirin is contraindicated in patients with known allergy to nonsteroidal anti-infl ammatory drug products and in patients with the syndrome of asthma, rhinitis, and nasal polyps occurring in combination.Reference: 1. Diener H-C, Cunha L, Forbes C, et al. European Stroke Prevention Study 2: dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci. 1996;143:1-13.

afety Information

CHOOSE AGGRENOX FOR SECONDARY STROKE RISK REDUCTION THAT MAY BE RIGHT FOR MANY PATIENTS.

AGGRENOX has been shown to be twice as effective as low-dose aspirin when compared to placebo.1

• In ESPS 2, relative risk reductions were 37.0% for AGGRENOX vs placebo; 18.1% for aspirin vs placebo; 23.1% for AGGRENOX vs aspirin alone

ESPS 2 = European Stroke Prevention Study 2.

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November/December 2009, Vol 2, No 7

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