January 2009, Vol 2, No 1 by Dalia Buffery

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™ JANUARY 2009

VOLUME 2, NUMBER 1

EDITORIAL

Healthcare Innovation Viability: On the Edge of a Knife Robert E. Henry

Why Financial Incentives Aren’t Enough to Move the Needle on Compliance Emily Cox, PhD BUSINESS ™

Partial Compliance with Antipsychotics Increases Mental Health Hospitalizations in Schizophrenic Patients: Analysis of a National Managed Care Database Chris M. Kozma, PhD; Peter J. Weiden, MD Stakeholder Perspective by Paul Anthony Polansky, BSPharm, MBA

Alzheimer’s Disease: A Healthcare Burden of Epidemic Proportion T.S. Dharmarajan, MD, FACP, AGSF; Srinivas G. Gunturu, MD Stakeholder Perspective by Jeffrey Januska, PharmD DEPARTMENTS ◆ Generic Drug Trends ◆ AHA Meeting Highlights

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

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

PROCRIT Indication

Additional Important Safety Information

PROCRIT is indicated for the treatment of anemia due to the effect of concomitantly administered chemotherapy based on studies that have shown a reduction in the need for RBC transfusions in patients with metastatic, non-myeloid malignancies receiving chemotherapy for a minimum of 2 months. Studies to determine whether PROCRIT increases mortality or decreases progression-free/recurrence-free survival are ongoing. • PROCRIT is not indicated for use in patients receiving hormonal agents, therapeutic biologic products, or radiotherapy unless receiving concomitant myelosuppressive chemotherapy. • PROCRIT is not indicated for patients receiving myelosuppressive therapy when the anticipated outcome is cure due to the absence of studies that adequately characterize the impact of PROCRIT on progression-free and overall survival (see WARNINGS: Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence). • PROCRIT is not indicated for the treatment of anemia in cancer patients due to other factors such as iron or folate deficiencies, hemolysis, or gastrointestinal bleeding (see PRECAUTIONS: Lack or Loss of Response). • PROCRIT use has not been demonstrated in controlled clinical trials to improve symptoms of anemia, quality of life, fatigue, or patient well-being.

• Patients with chronic renal failure experienced greater risks for death and serious cardiovascular events (including myocardial infarction, stroke, congestive heart failure, and hemodialysis vascular access thrombosis) when administered ESAs to target higher versus lower hemoglobin levels (13.5 vs.11.3 g/dL; 14 vs. 10 g/dL) in two clinical studies; these risks also increased in controlled clinical trials of patients with cancer. A rate of hemoglobin rise of >1 g/dL over 2 weeks may contribute to these risks. • PROCRIT therapy should not be initiated at hemoglobin levels 10 g/dL. • The dose of PROCRIT should be titrated for each patient to achieve and maintain the lowest hemoglobin level sufficient to avoid the need for blood transfusion. • When the hemoglobin reaches a level needed to avoid transfusion or, increases by more than 1 g/dL in a 2-week period, the PROCRIT dose should be reduced by 25%. Withhold the dose of PROCRIT if the hemoglobin exceeds a level needed to avoid transfusion. Restart dose at 25% below the previous dose when the hemoglobin approaches a level where transfusions may be required. Discontinue if after 8 weeks of therapy there is no response as measured by hemoglobin levels or if transfusions are still required. • Monitor hemoglobin regularly during therapy, weekly until hemoglobin becomes stable. • Cases of pure red cell aplasia (PRCA) and of severe anemia, with or without other cytopenias, associated with neutralizing antibodies to erythropoietin have been reported in patients treated with PROCRIT; predominantly in patients with chronic renal failure receiving PROCRIT by subcutaneous administration. If any patient develops a sudden loss of response to PROCRIT, accompanied by severe anemia and low reticulocyte count, and anti-erythropoietin antibody-associated anemia is suspected, withhold PROCRIT and other erythropoietic proteins. Contact ORTHO BIOTECH (1-888-2ASKOBI or 1-888-227-5624) to perform assays for binding and neutralizing antibodies. If erythropoietin antibody-mediated anemia is confirmed, PROCRIT should be permanently discontinued and patients should not be switched to other erythropoietic proteins. • The safety and efficacy of PROCRIT therapy have not been established in patients with a known history of a seizure disorder or underlying hematologic disease (e.g., sickle cell anemia, myelodysplastic syndromes, or hypercoagulable disorders). • In some female patients, menses have resumed following PROCRIT therapy; the possibility of pregnancy should be discussed and the need for contraception evaluated. • Prior to and regularly during PROCRIT therapy monitor iron status; transferrin saturation should be 20% and ferritin should be 100 ng/mL. During therapy absolute or functional iron deficiency may develop and all patients will eventually require supplemental iron to adequately support erythropoiesis stimulated by PROCRIT. • Treatment of patients with grossly elevated serum erythropoietin levels (e.g., >200 mUnits/mL) is not recommended. • During PROCRIT therapy, blood pressure should be monitored carefully and aggressively managed, particularly in patients with an underlying history of hypertension or cardiovascular disease. • Seizures in PROCRIT-treated patients have been reported in the context of a significant increase in hemoglobin from baseline; increases in blood pressure were not always observed; and patients may have had other underlying central nervous system pathology. • The most commonly reported side effects (>10%) for PROCRIT in clinical trials were pyrexia, diarrhea, nausea, vomiting, edema, asthenia, fatigue, shortness of breath, paresthesia, and upper respiratory infection.

Important Safety Information WARNINGS: INCREASED MORTALITY, SERIOUS CARDIOVASCULAR and THROMBOEMBOLIC EVENTS, and INCREASED RISK OF TUMOR PROGRESSION OR RECURRENCE Renal failure: Patients experienced greater risks for death and serious cardiovascular events when administered erythropoiesis-stimulating agents (ESAs) to target higher versus lower hemoglobin levels (13.5 vs. 11.3 g/dL; 14 vs. 10 g/dL) in two clinical studies. Individualize dosing to achieve and maintain hemoglobin levels within the range of 10 to 12 g/dL. Cancer: • ESAs shortened overall survival and/or increased the risk of tumor progression or recurrence in some clinical studies in patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers (see WARNINGS: Table 1). • To decrease these risks, as well as the risk of serious cardio- and thrombovascular events, use the lowest dose needed to avoid red blood cell transfusion. • Use ESAs only for treatment of anemia due to concomitant myelosuppressive chemotherapy. • ESAs are not indicated for patients receiving myelosuppressive therapy when the anticipated outcome is cure. • Discontinue following the completion of a chemotherapy course. Perisurgery: PROCRIT® (Epoetin alfa) increased the rate of deep venous thromboses in patients not receiving prophylactic anticoagulation. Consider deep venous thrombosis prophylaxis.

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

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

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

BRIEF SUMMARY OF PROCRIT® PRESCRIBING INFORMATION FOR THE TREATMENT OF ANEMIA IN CANCER PATIENTS ON CHEMOTHERAPY PROCRIT® (Epoetin alfa) FOR INJECTION FOR FULL PRESCRIBING INFORMATION FOR ALL INDICATIONS, REFER TO THE PHYSICIANS’ DESK REFERENCE® WARNINGS: INCREASED MORTALITY, SERIOUS CARDIOVASCULAR and THROMBOEMBOLIC EVENTS, and INCREASED RISK OF TUMOR PROGRESSION OR RECURRENCE Renal failure: Patients experienced greater risks for death and serious cardiovascular events when administered erythropoiesis-stimulating agents (ESAs) to target higher versus lower hemoglobin levels (13.5 vs. 11.3 g/dL; 14 vs. 10 g/dL) in two clinical studies. Individualize dosing to achieve and maintain hemoglobin levels within the range of 10 to 12 g/dL. Cancer: • ESAs shortened overall survival and/or increased the risk of tumor progression or recurrence in some clinical studies in patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers (see WARNINGS: Table 1). • To decrease these risks, as well as the risk of serious cardio- and thrombovascular events, use the lowest dose needed to avoid red blood cell transfusion. • Use ESAs only for treatment of anemia due to concomitant myelosuppressive chemotherapy. • ESAs are not indicated for patients receiving myelosuppressive therapy when the anticipated outcome is cure. • Discontinue following the completion of a chemotherapy course. Perisurgery: PROCRIT® increased the rate of deep venous thromboses in patients not receiving prophylactic anticoagulation. Consider deep venous thrombosis prophylaxis. (See WARNINGS: Increased Mortality, Serious Cardiovascular and Thromboembolic Events, WARNINGS: Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence, INDICATIONS AND USAGE, and DOSAGE AND ADMINISTRATION in full Prescribing Information.) INDICATIONS AND USAGE PROCRIT® is indicated for the treatment of anemia due to the effect of concomitantly administered chemotherapy based on studies that have shown a reduction in the need for RBC transfusions in patients with metastatic, non-myeloid malignancies receiving chemotherapy for a minimum of 2 months. Studies to determine whether PROCRIT® increases mortality or decreases progression-free/recurrence-free survival are ongoing. • PROCRIT® is not indicated for use in patients receiving hormonal agents, therapeutic biologic products, or radiotherapy unless receiving concomitant myelosuppressive chemotherapy. • PROCRIT® is not indicated for patients receiving myelosuppressive therapy when the anticipated outcome is cure due to the absence of studies that adequately characterize the impact of PROCRIT® on progressionfree and overall survival (see WARNINGS: Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence). • PROCRIT ® is not indicated for the treatment of anemia in cancer patients due to other factors such as iron or folate deficiencies, hemolysis, or gastrointestinal bleeding (see PRECAUTIONS: Lack or Loss of Response). • PROCRIT ® use has not been demonstrated in controlled clinical trials to improve symptoms of anemia, quality of life, fatigue, or patient well-being. CONTRAINDICATIONS PROCRIT® is contraindicated in patients with: 1. Uncontrolled hypertension. 2. Known hypersensitivity to mammalian cell-derived products. 3. Known hypersensitivity to Albumin (Human). WARNINGS Pediatrics Risk in Premature Infants The multidose preserved formulation contains benzyl alcohol. Benzyl alcohol has been reported to be associated with an increased incidence of neurological and other complications in premature infants which are sometimes fatal. Adults Increased Mortality, Serious Cardiovascular and Thromboembolic Events Patients with chronic renal failure experienced greater risks for death and serious cardiovascular events when administered erythropoiesis-stimulating agents (ESAs) to target higher versus lower hemoglobin levels (13.5 vs. 11.3 g/dL; 14 vs. 10 g/dL) in two clinical studies. Patients with chronic renal failure and an insufficient hemoglobin response to ESA therapy may be at even greater risk for cardiovascular events and mortality than other patients. PROCRIT® and other ESAs increased the risks for death and serious cardiovascular events in controlled clinical trials of patients with cancer. These events included myocardial infarction, stroke, congestive heart failure, and hemodialysis vascular access thrombosis. A rate of hemoglobin rise of > 1 g/dL over 2 weeks may contribute to these risks. In a randomized prospective trial, 1432 anemic chronic renal failure patients who were not undergoing dialysis were assigned to Epoetin alfa (rHuEPO) treatment targeting a maintenance hemoglobin concentration of 13.5 g/dL or 11.3 g/dL. A major cardiovascular event (death, myocardial infarction, stroke, or hospitalization for congestive heart failure) occurred among 125 (18%) of the 715 patients in the higher hemoglobin group compared to 97 (14%) among the 717 patients in the lower hemoglobin group (HR 1.3, 95% CI: 1.0, 1.7, p = 0.03). Increased risk for serious cardiovascular events was also reported from a randomized, prospective trial of 1265 hemodialysis patients with clinically evident cardiac disease (ischemic heart disease or congestive heart failure). In this trial, patients were assigned to PROCRIT® treatment targeted to a maintenance hematocrit of either 42 ± 3% or 30 ± 3%. Increased mortality was observed in 634 patients randomized to a target hematocrit of 42% [221 deaths (35% mortality)] compared to 631 patients targeted to remain at a hematocrit of 30% [185 deaths (29% mortality)]. The reason for the increased mortality observed in this study is unknown, however, the incidence of non-fatal myocardial infarctions (3.1% vs. 2.3%), vascular access thromboses (39% vs. 29%), and all other thrombotic events (22% vs. 18%) were also higher in the group randomized to achieve a hematocrit of 42%. An increased incidence of thrombotic events has also been observed in patients with cancer treated with erythropoietic agents. In a randomized controlled study (referred to as Cancer Study 1 - the ‘BEST’ study) with another ESA in 939 women with metastatic breast cancer receiving chemotherapy, patients received either weekly Epoetin alfa or placebo for up to a year. This study was designed to show that survival was superior when an ESA was administered to prevent anemia (maintain hemoglobin levels between 12 and 14 g/dL or hematocrit between 36% and 42%). The study was terminated prematurely when interim results demonstrated that a higher mortality at 4 months (8.7% vs. 3.4%) and a higher rate of fatal thrombotic events (1.1% vs. 0.2%) in the first 4 months of the study were observed among patients treated with Epoetin alfa. Based on Kaplan-Meier estimates, at the time of study termination, the 12-month survival was lower in the Epoetin alfa group than in the placebo group (70% vs. 76%; HR 1.37, 95% CI: 1.07, 1.75; p = 0.012). A systematic review of 57 randomized controlled trials (including Cancer Studies 1 and 5 - the ‘BEST’ and ‘ENHANCE’ studies) evaluating 9353 patients with cancer compared ESAs plus red blood cell transfusion with red blood cell transfusion alone for prophylaxis or treatment of anemia in cancer patients with or without concurrent antineoplastic therapy. An increased relative risk of thromboembolic events (RR 1.67, 95% CI: 1.35, 2.06; 35 trials and 6769 patients) was observed in ESA-treated patients. An overall survival hazard ratio of 1.08 (95% CI: 0.99, 1.18; 42 trials and 8167 patients) was observed in ESA-treated patients. An increased incidence of deep vein thrombosis (DVT) in patients receiving Epoetin alfa undergoing surgical orthopedic procedures has been observed (see ADVERSE REACTIONS, Surgery Patients: Thrombotic/Vascular Events in full Prescribing Information). In a randomized controlled study (referred to as the ‘SPINE’ study), 681 adult patients, not receiving prophylactic anticoagulation and undergoing spinal surgery, received either 4 doses of 600 U/kg Epoetin alfa (7, 14, and 21 days before surgery, and the day of surgery) and standard of care (SOC) treatment, or SOC treatment alone. Preliminary analysis showed a higher incidence of DVT,

determined by either Color Flow Duplex Imaging or by clinical symptoms, in the Epoetin alfa group [16 patients (4.7%)] compared to the SOC group [7 patients (2.1%)]. In addition, 12 patients in the Epoetin alfa group and 7 patients in the SOC group had other thrombotic vascular events. Deep venous thrombosis prophylaxis should be strongly considered when ESAs are used for the reduction of allogeneic RBC transfusions in surgical patients (see BOXED WARNINGS and DOSAGE AND ADMINISTRATION in full Prescribing Information). Increased mortality was also observed in a randomized placebo-controlled study of PROCRIT® in adult patients who were undergoing coronary artery bypass surgery (7 deaths in 126 patients randomized to PROCRIT® versus no deaths among 56 patients receiving placebo). Four of these deaths occurred during the period of study drug administration and all four deaths were associated with thrombotic events. ESAs are not approved for reduction of allogeneic red blood cell transfusions in patients scheduled for cardiac surgery. Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence Erythropoiesis-stimulating agents resulted in decreased locoregional control/progression-free survival and/or overall survival (see Table 1). These findings were observed in studies of patients with advanced head and neck cancer receiving radiation therapy (Cancer Studies 5 and 6), in patients receiving chemotherapy for metastatic breast cancer (Cancer Study 1) or lymphoid malignancy (Cancer Study 2), and in patients with non-small cell lung cancer or various malignancies who were not receiving chemotherapy or radiotherapy (Cancer Studies 7 and 8). Table 1: Randomized, Controlled Trials with Decreased Survival and/or Decreased Locoregional Control Adverse Achieved Outcome for Hemoglobin Hemoglobin Primary ESA-containing Study / Tumor / (n) Target (Median Q1,Q3) Endpoint Arm Chemotherapy Cancer Study 1 Metastatic breast 12-14 g/dL 12.9 g/dL 12-month overall Decreased 12-month cancer (n=939) 12.2, 13.3 g/dL survival survival Cancer Study 2 Lymphoid 13-15 g/dL (M) 11.0 g/dL Proportion of Decreased overall malignancy (n=344) 13-14 g/dL (F) 9.8, 12.1 g/dL patients achieving survival a hemoglobin response Cancer Study 3 Early breast 12.5-13 g/dL 13.1 g/dL Relapse-free and Decreased 3 yr. cancer (n=733) 12.5, 13.7 g/dL overall survival relapse-free and overall survival Cancer Study 4 Cervical Cancer 12-14 g/dL 12.7 g/dL Progression-free Decreased 3 yr. (n=114) 12.1, 13.3 g/dL and overall survival progression-free and locoregional and overall survival control and locoregional control Radiotherapy Alone Cancer Study 5 Head and neck ≥15 g/dL (M) Not available Locoregional Decreased 5-year cancer (n=351) ≥14 g/dL (F) progression-free locoregional survival progression-free survival Decreased overall survival Cancer Study 6 Head and neck 14-15.5 g/dL Not available Locoregional Decreased cancer (n=522) disease control locoregional disease control No Chemotherapy or Radiotherapy Cancer Study 7 Non-small cell 12-14 g/dL Not available Quality of life Decreased overall lung cancer (n=70) survival Cancer Study 8 Non-myeloid 12-13 g/dL 10.6 g/dL RBC transfusions Decreased overall malignancy (n=989) 9.4, 11.8 g/dL survival

Decreased overall survival: Cancer Study 1 (the ‘BEST’ study) was previously described (see WARNINGS: Increased Mortality, Serious Cardiovascular and Thromboembolic Events). Mortality at 4 months (8.7% vs. 3.4%) was significantly higher in the Epoetin alfa arm. The most common investigator-attributed cause of death within the first 4 months was disease progression; 28 of 41 deaths in the Epoetin alfa arm and 13 of 16 deaths in the placebo arm were attributed to disease progression. Investigator assessed time to tumor progression was not different between the two groups. Survival at 12 months was significantly lower in the Epoetin alfa arm (70% vs. 76%, HR 1.37, 95% CI: 1.07, 1.75; p = 0.012). Cancer Study 2 was a Phase 3, double-blind, randomized (darbepoetin alfa vs. placebo) study conducted in 344 anemic patients with lymphoid malignancy receiving chemotherapy. With a median follow-up of 29 months, overall mortality rates were significantly higher among patients randomized to darbepoetin alfa as compared to placebo (HR 1.36, 95% CI: 1.02, 1.82). Cancer Study 7 was a Phase 3, multicenter, randomized (Epoetin alfa vs. placebo), double-blind study, in which patients with advanced non-small cell lung cancer receiving only palliative radiotherapy or no active therapy were treated with Epoetin alfa to achieve and maintain hemoglobin levels between 12 and 14 g/dL. Following an interim analysis of 70 of 300 patients planned, a significant difference in survival in favor of the patients on the placebo arm of the trial was observed (median survival 63 vs. 129 days; HR 1.84; p = 0.04). Cancer Study 8 was a Phase 3, double-blind, randomized (darbepoetin alfa vs. placebo), 16-week study in 989 anemic patients with active malignant disease, neither receiving nor planning to receive chemotherapy or radiation therapy. There was no evidence of a statistically significant reduction in proportion of patients receiving RBC transfusions. The median survival was shorter in the darbepoetin alfa treatment group (8 months) compared with the placebo group (10.8 months); HR 1.30, 95% CI: 1.07, 1.57. Decreased progression-free survival and overall survival: Cancer Study 3 (the ‘PREPARE’ study) was a randomized controlled study in which darbepoetin alfa was administered to prevent anemia conducted in 733 women receiving neo-adjuvant breast cancer treatment. After a median follow-up of approximately 3 years, the survival rate (86% vs. 90%, HR 1.42, 95% CI: 0.93, 2.18) and relapse-free survival rate (72% vs. 78%, HR 1.33, 95% CI: 0.99, 1.79) were lower in the darbepoetin alfatreated arm compared to the control arm. Cancer Study 4 (protocol GOG 191) was a randomized controlled study that enrolled 114 of a planned 460 cervical cancer patients receiving chemotherapy and radiotherapy. Patients were randomized to receive Epoetin alfa to maintain hemoglobin between 12 and 14 g/dL or to transfusion support as needed. The study was terminated prematurely due to an increase in thromboembolic events in Epoetin alfa-treated patients compared to control (19% vs. 9%). Both local recurrence (21% vs. 20%) and distant recurrence (12% vs. 7%) were more frequent in Epoetin alfa-treated patients compared to control. Progression-free survival at 3 years was lower in the Epoetin alfa-treated group compared to control (59% vs. 62%, HR 1.06, 95% CI: 0.58, 1.91). Overall survival at 3 years was lower in the Epoetin alfa-treated group compared to control (61% vs. 71%, HR 1.28, 95% CI: 0.68, 2.42). Cancer Study 5 (the ‘ENHANCE’ study) was a randomized controlled study in 351 head and neck cancer patients where Epoetin beta or placebo was administered to achieve target hemoglobin of 14 and 15 g/dL for women and men, respectively. Locoregional progression-free survival was significantly shorter in patients receiving Epoetin beta (HR 1.62, 95% CI: 1.22, 2.14; p = 0.0008) with a median of 406 days Epoetin beta vs. 745 days placebo. Overall survival was significantly shorter in patients receiving Epoetin beta (HR 1.39, 95% CI: 1.05, 1.84; p = 0.02).

PROCRIT ® (Epoetin alfa) FOR INJECTION

Decreased locoregional control: Cancer Study 6 (DAHANCA 10) was conducted in 522 patients with primary squamous cell carcinoma of the head and neck receiving radiation therapy randomized to darbepoetin alfa with radiotherapy or radiotherapy alone. An interim analysis on 484 patients demonstrated that locoregional control at 5 years was significantly shorter in patients receiving darbepoetin alfa (RR 1.44, 95% CI: 1.06, 1.96; p = 0.02). Overall survival was shorter in patients receiving darbepoetin alfa (RR 1.28, 95% CI: 0.98, 1.68; p = 0.08). Pure Red Cell Aplasia Cases of pure red cell aplasia (PRCA) and of severe anemia, with or without other cytopenias, associated with neutralizing antibodies to erythropoietin have been reported in patients treated with PROCRIT®. This has been reported predominantly in patients with chronic renal failure (CRF) receiving PROCRIT® by subcutaneous administration. Any patient who develops a sudden loss of response to PROCRIT®, accompanied by severe anemia and low reticulocyte count, should be evaluated for the etiology of loss of effect, including the presence of neutralizing antibodies to erythropoietin (see PRECAUTIONS: Lack or Loss of Response). If anti-erythropoietin antibody-associated anemia is suspected, withhold PROCRIT® and other erythropoietic proteins. Contact ORTHO BIOTECH at 1 888 2ASK OBI (1-888-227-5624) to perform assays for binding and neutralizing antibodies. PROCRIT® should be permanently discontinued in patients with antibody-mediated anemia. Patients should not be switched to other erythropoietic proteins as antibodies may cross-react (see ADVERSE REACTIONS: Immunogenicity). Albumin (Human) PROCRIT® contains albumin, a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin. PRECAUTIONS The parenteral administration of any biologic product should be attended by appropriate precautions in case allergic or other untoward reactions occur (see CONTRAINDICATIONS). In clinical trials, while transient rashes were occasionally observed concurrently with PROCRIT® therapy, no serious allergic or anaphylactic reactions were reported (see ADVERSE REACTIONS in full Prescribing Information for more information regarding allergic reactions). The safety and efficacy of PROCRIT® therapy have not been established in patients with a known history of a seizure disorder or underlying hematologic disease (eg, sickle cell anemia, myelodysplastic syndromes, or hypercoagulable disorders). In some female patients, menses have resumed following PROCRIT® therapy; the possibility of pregnancy should be discussed and the need for contraception evaluated. Hematology: Exacerbation of porphyria has been observed rarely in patients with CRF treated with PROCRIT®. However, PROCRIT® has not caused increased urinary excretion of porphyrin metabolites in normal volunteers, even in the presence of a rapid erythropoietic response. Nevertheless, PROCRIT® should be used with caution in patients with known porphyria. In preclinical studies in dogs and rats, but not in monkeys, PROCRIT® therapy was associated with subclinical bone marrow fibrosis. Bone marrow fibrosis is a known complication of CRF in humans and may be related to secondary hyperparathyroidism or unknown factors. The incidence of bone marrow fibrosis was not increased in a study of adult patients on dialysis who were treated with PROCRIT® for 12 to 19 months, compared to the incidence of bone marrow fibrosis in a matched group of patients who had not been treated with PROCRIT®. Cancer patients should have hemoglobin measured once a week until hemoglobin has been stabilized, and measured periodically thereafter. Lack or Loss of Response: If the patient fails to respond or to maintain a response to doses within the recommended dosing range, the following etiologies should be considered and evaluated: 1. Iron deficiency: Virtually all patients will eventually require supplemental iron therapy (see IRON EVALUATION); 2. Underlying infectious, inflammatory, or malignant processes; 3. Occult blood loss; 4. Underlying hematologic diseases (ie, thalassemia, refractory anemia, or other myelodysplastic disorders); 5. Vitamin deficiencies: Folic acid or vitamin B12; 6. Hemolysis; 7. Aluminum intoxication; 8. Osteitis fibrosa cystica; 9. Pure Red Cell Aplasia (PRCA) or anti-erythropoietin antibody-associated anemia: In the absence of another etiology, the patient should be evaluated for evidence of PRCA and sera should be tested for the presence of antibodies to erythropoietin (see WARNINGS: Pure Red Cell Aplasia). Iron Evaluation: During PROCRIT® therapy, absolute or functional iron deficiency may develop. Functional iron deficiency, with normal ferritin levels but low transferrin saturation, is presumably due to the inability to mobilize iron stores rapidly enough to support increased erythropoiesis. Transferrin saturation should be at least 20% and ferritin should be at least 100 ng/mL. Prior to and during PROCRIT® therapy, the patient’s iron status, including transferrin saturation (serum iron divided by iron binding capacity) and serum ferritin, should be evaluated. Virtually all patients will eventually require supplemental iron to increase or maintain transferrin saturation to levels which will adequately support erythropoiesis stimulated by PROCRIT®. Drug Interaction: No evidence of interaction of PROCRIT® with other drugs was observed in the course of clinical trials. Carcinogenesis, Mutagenesis, and Impairment of Fertility: Carcinogenic potential of PROCRIT® has not been evaluated. PROCRIT® does not induce bacterial gene mutation (Ames Test), chromosomal aberrations in mammalian cells, micronuclei in mice, or gene mutation at the HGPRT locus. In female rats treated IV with PROCRIT®, there was a trend for slightly increased fetal wastage at doses of 100 and 500 Units/kg. Pregnancy Category C: PROCRIT® has been shown to have adverse effects in rats when given in doses 5 times the human dose. There are no adequate and well-controlled studies in pregnant women. PROCRIT® should be used during pregnancy only if potential benefit justifies the potential risk to the fetus. In studies in female rats, there were decreases in body weight gain, delays in appearance of abdominal hair, delayed eyelid opening, delayed ossification, and decreases in the number of caudal vertebrae in the F1 fetuses of the 500 Units/kg group. In female rats treated IV, there was a trend for slightly increased fetal wastage at doses of 100 and 500 Units/kg. PROCRIT® has not shown any adverse effect at doses as high as 500 Units/kg in pregnant rabbits (from day 6 to 18 of gestation). Nursing Mothers: Postnatal observations of the live offspring (F1 generation) of female rats treated with PROCRIT® during gestation and lactation revealed no effect of PROCRIT® at doses of up to 500 Units/kg. There were, however, decreases in body weight gain, delays in appearance of abdominal hair, eyelid opening, and decreases in the number of caudal vertebrae in the F1 fetuses of the 500 Units/kg group. There were no PROCRIT®-related effects on the F2 generation fetuses. It is not known whether PROCRIT® is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PROCRIT® is administered to a nursing woman. Pediatric Use: See WARNINGS: Pediatrics Pediatric Cancer Patients on Chemotherapy: The safety and effectiveness of PROCRIT® were evaluated in a randomized, double-blind, placebo-controlled, multicenter study (see CLINICAL EXPERIENCE, Weekly (QW) Dosing, Pediatric Patients in full Prescribing Information). Geriatric Use: Insufficient numbers of patients age 65 or older were enrolled in clinical studies of PROCRIT® for the treatment of anemia associated with pre-dialysis chronic renal failure, cancer chemotherapy, and Zidovudine-treatment of HIV infection to determine whether they respond differently from younger subjects. Information for Patients Patients should be informed of the increased risks of mortality, serious cardiovascular events, thromboembolic events, and increased risk of tumor progression or recurrence (see WARNINGS). In those situations in which the physician determines that a patient or their caregiver can safely and effectively administer PROCRIT® at home,

instruction as to the proper dosage and administration should be provided. Patients should be instructed to read the PROCRIT® Medication Guide and Patient Instructions for Use and should be informed that the Medication Guide is not a disclosure of all possible side effects. Patients should be informed of the possible side effects of PROCRIT® and of the signs and symptoms of allergic drug reaction and advised of appropriate actions. If home use is prescribed for a patient, the patient should be thoroughly instructed in the importance of proper disposal and cautioned against the reuse of needles, syringes, or drug product. A puncture-resistant container should be available for the disposal of used syringes and needles, and guidance provided on disposal of the full container. Hypertension: Hypertension, associated with a significant increase in hemoglobin, has been noted rarely in patients treated with PROCRIT®. Nevertheless, blood pressure in patients treated with PROCRIT® should be monitored carefully, particularly in patients with an underlying history of hypertension or cardiovascular disease. Seizures: In double-blind, placebo-controlled trials, 3.2% (n = 2/63) of patients treated with PROCRIT® TIW and 2.9% (n = 2/68) of placebo-treated patients had seizures. Seizures in 1.6% (n = 1/63) of patients treated with PROCRIT® TIW occurred in the context of a significant increase in blood pressure and hematocrit from baseline values. However, both patients treated with PROCRIT® also had underlying CNS pathology which may have been related to seizure activity. In a placebo-controlled, double-blind trial utilizing weekly dosing with PROCRIT®, 1.2% (n = 2/168) of safetyevaluable patients treated with PROCRIT® and 1% (n = 1/165) of placebo-treated patients had seizures. Seizures in the patients treated with weekly PROCRIT® occurred in the context of a significant increase in hemoglobin from baseline values however significant increases in blood pressure were not seen. These patients may have had other CNS pathology. Thrombotic Events: In double-blind, placebo-controlled trials, 3.2% (n = 2/63) of patients treated with PROCRIT® TIW and 11.8% (n = 8/68) of placebo-treated patients had thrombotic events (eg, pulmonary embolism, cerebrovascular accident), (see WARNINGS: Increased Mortality, Serious Cardiovascular and Thromboembolic Events). In a placebo-controlled, double-blind trial utilizing weekly dosing with PROCRIT®, 6.0% (n = 10/168) of safetyevaluable patients treated with PROCRIT® and 3.6% (n = 6/165) (p = 0.444) of placebo-treated patients had clinically significant thrombotic events (deep vein thrombosis requiring anticoagulant therapy, embolic event including pulmonary embolism, myocardial infarction, cerebral ischemia, left ventricular failure and thrombotic microangiopathy). A definitive relationship between the rate of hemoglobin increase and the occurrence of clinically significant thrombotic events could not be evaluated due to the limited schedule of hemoglobin measurements in this study. The safety and efficacy of PROCRIT® were evaluated in a randomized, double-blind, placebo-controlled, multicenter study that enrolled 222 anemic patients ages 5 to 18 receiving treatment for a variety of childhood malignancies. Due to the study design (small sample size and the heterogeneity of the underlying malignancies and of anti-neoplastic treatments employed), a determination of the effect of PROCRIT® on the incidence of thrombotic events could not be performed. In the PROCRIT® arm, the overall incidence of thrombotic events was 10.8% and the incidence of serious or life-threatening events was 7.2%. ADVERSE REACTIONS Immunogenicity As with all therapeutic proteins, there is the potential for immunogenicity. Neutralizing antibodies to erythropoietin, in association with PRCA or severe anemia (with or without other cytopenias), have been reported in patients receiving PROCRIT® (see WARNINGS: Pure Red Cell Aplasia) during post-marketing experience. There has been no systematic assessment of immune responses, i.e., the incidence of either binding or neutralizing antibodies to PROCRIT®, in controlled clinical trials. Where reported, the incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies across products within this class (erythropoietic proteins) may be misleading. Adverse Experiences Reported in Clinical Trials In double-blind, placebo-controlled studies of up to 3 months duration involving 131 cancer patients, adverse events with an incidence > 10% in either patients treated with PROCRIT® or placebo-treated patients were as indicated below: Percent of Patients Reporting Event

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

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

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

Although some statistically significant differences between patients being treated with PROCRIT® and placebotreated patients were noted, the overall safety profile of PROCRIT® appeared to be consistent with the disease process of advanced cancer. During double-blind and subsequent open-label therapy in which patients (n = 72 for total exposure to PROCRIT®) were treated for up to 32 weeks with doses as high as 927 Units/kg, the adverse experience profile of PROCRIT® was consistent with the progression of advanced cancer. Three hundred thirty-three (333) cancer patients enrolled in a placebo-controlled double-blind trial utilizing Weekly dosing with PROCRIT® for up to 4 months were evaluable for adverse events. The incidence of adverse events was similar in both the treatment and placebo arms. OVERDOSAGE The expected manifestations of PROCRIT® overdosage include signs and symptoms associated with an excessive and/or rapid increase in hemoglobin concentration, including any of the cardiovascular events described in WARNINGS and listed in ADVERSE REACTIONS in full Prescribing Information. Patients receiving an overdosage of PROCRIT® should be monitored closely for cardiovascular events and hematologic abnormalities. Polycythemia should be managed acutely with phlebotomy, as clinically indicated. Following resolution of the effects due to PROCRIT® overdosage, reintroduction of PROCRIT® therapy should be accompanied by close monitoring for evidence of rapid increases in hemoglobin concentration (>1 gm/dL per 14 days). In patients with an excessive hematopoietic response, reduce the PROCRIT® dose in accordance with the recommendations described in DOSAGE AND ADMINISTRATION in full Prescribing Information.

PROCRIT ® (Epoetin alfa) FOR INJECTION DOSAGE AND ADMINISTRATION IMPORTANT: See BOXED WARNINGS and WARNINGS: Increased Mortality, Serious Cardiovascular and Thromboembolic Events. Prior to initiating treatment with PROCRIT® a hemoglobin should be obtained to establish that it is >10 to ≤ 13 g/dL. The recommended dose of PROCRIT® is 300 Units/kg/day subcutaneously for 10 days before surgery, on the day of surgery, and for 4 days after surgery. An alternate dose schedule is 600 Units/kg PROCRIT® subcutaneously in once weekly doses (21, 14, and 7 days before surgery) plus a fourth dose on the day of surgery. All patients should receive adequate iron supplementation. Iron supplementation should be initiated no later than the beginning of treatment with PROCRIT® and should continue throughout the course of therapy. Deep venous thrombosis prophylaxis should be strongly considered (see BOXED WARNINGS). PREPARATION AND ADMINISTRATION OF PROCRIT® 1. Do not shake. It is not necessary to shake PROCRIT®. Prolonged vigorous shaking may denature any glycoprotein, rendering it biologically inactive. 2. Protect the solution from light. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use any vials exhibiting particulate matter or discoloration. 3. Using aseptic techniques, attach a sterile needle to a sterile syringe. Remove the flip top from the vial containing PROCRIT®, and wipe the septum with a disinfectant. Insert the needle into the vial, and withdraw into the syringe an appropriate volume of solution. 4. Single-dose: 1 mL vial contains no preservative. Use one dose per vial; do not re-enter the vial. Discard unused portions. Multidose: 1 mL and 2 mL vials contain preservative. Store at 2° to 8°C after initial entry and between doses. Discard 21 days after initial entry. 5. Do not dilute or administer in conjunction with other drug solutions. However, at the time of SC administration, preservative-free PROCRIT® from single-use vials may be admixed in a syringe with bacteriostatic 0.9% sodium chloride injection, USP, with benzyl alcohol 0.9% (bacteriostatic saline) at a 1:1 ratio using aseptic technique. The benzyl alcohol in the bacteriostatic saline acts as a local anesthetic which may ameliorate SC injection site discomfort. Admixing is not necessary when using the multidose vials of PROCRIT® containing benzyl alcohol.

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

EDITORIAL BOARD

CLINICAL EDITOR

HEALTH OUTCOMES RESEARCH

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

Gordon M. Cummins, MS Director, IntegriChain

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

Kavita V. Nair, PhD Associate Professor, School of Pharmacy University of Colorado at Denver

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

Gary M. Owens, MD President, Gary Owens Associates Glen Mills, PA

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

Timothy S. Regan, BPharm, RPh Executive Director, Xcenda Palm Harbor, FL

PHARMACY & SPECIALTY PRODUCTS

BUSINESS/GOVERNEMENT EDITOR

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

David Williams Milliman, Windsor, CT CLINICAL RESEARCH

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

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

MANGED CARE & GOVERNEMENT AFFAIRS

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

POLICY & PUBLIC HEALTH

Joseph R. Antos, PhD American Enterprise Institute for Public Policy Research, Washington, DC

MANAGED MARKETS

Samuel M. Silver, MD, PhD, FACP Professor, Internal Medicine Director, Cancer Center Network Division of Hematology/Oncology Assistant Dean for Research University of Michigan Health Systems Michael A. Weber, MD Professor of Medicine Department of Medicine (Cardiology) State University of New York Downstate College of Medicine, NY EMPLOYERS

Alberto M. Colombi, MD, MPH Corporate Medical Director PPG Industries, Inc., Pittsburgh, PA Wayne M. Lednar, MD, PhD Global Chief Medical Officer Director, Integrated Health Services DuPont, Wilmington, DE Arthur F. Shinn, PharmD, FASCP President, Managed Pharmacy Consultants, LLC, Lakewood, FL

Jeffrey A. Bourret, MS, RPh, FASHP Executive Director, Customer-Centric Strategy and Innovation, Healthcare Systems Marketing Wyeth Pharmaceuticals, Collegeville, PA Charles E. Collins, Jr, MS, MBA Associate Director, Managed Markets Marketing, Boehringer-Ingelheim, Ridgefield, CT PATIENT ADVOCACY

Alex Hathaway, MD, MPH, FACPM Senior Medical Policy Advisor Government Programs GlaxoSmithKline, Philadelphia, PA J. Warren Salmon, PhD Professor of Health Policy & Administration School of Public Health, Univ. of Illinois at Chicago

William E. Fassett, BSPharm, MBA, PhD Professor of Pharmacy Law & Ethics Vice Chair, Department of Pharmacotherapy College of Pharmacy, Washington State REIMBURSEMENT POLICY Univ., Spokane, WA Grant D. Lawless, BSPharm, MD, FACP Executive Director for Payor Relations PERSONALIZED MEDICINE Corporate Account Wayne A. Rosenkrans, Jr, PhD Amgen, Thousand Oaks, CA Chairman and President, Personalized Medicine Coalition, Distinguished Fellow, Michael Schaffer, PharmD, MBA MIT Center for Biomedical Innovation, Director, Pharmacy Programs Chief Application Officer Sanovia Co., Philadelphia, PA SchiTech Strategies, Washington, DC RESEARCH & DEVELOPMENT PHARMACOECONOMICS

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

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

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

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

PHARMACY BENEFIT DESIGN HEALTH INFORMATION TECHNOLOGY

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

VOL. 2

NO. 1

Jan Berger, MD, MJ President, Health Intelligence Partners Joel V. Brill, MD Chief Medical Officer, Predictive Health, LLC, Phoenix, AZ

www.AHDBonline.com

JANUARY 2009

VOLUME 2, NUMBER 1

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EDITORIAL

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

Healthcare Innovation Viability: On the Edge of a Knife Robert E. Henry

Why Financial Incentives Aren’t Enough to Move the Needle on Compliance Emily Cox, PhD

National Account Manager Cristopher Pires Cristopher@engagehc.com 732-992-1896

BUSINESS

Prescription Copay Reduction Program for Diabetic Employees: Impact on Medication Compliance and Healthcare Costs and Utilization

Editorial Director Dalia Buffery dalia@AHDBonline.com 732-992-1889

Kavita V. Nair, PhD; Kerri Miller, PharmD, BCPS; Joseph Saseen, PharmD, FCCP, BCPS; Pamela Wolfe, MS; Richard Read Allen, MS; Jinhee Park, CPhil, MA, MS Stakeholder Perspective by Geoffrey P. Cole, MD, MBA

Associate Editor Dawn Lagrosa 732-992-1892

CLINICAL

Partial Compliance with Antipsychotics Increases Mental Health Hospitalizations in Schizophrenic Patients: Analysis of a National Managed Care Database

President Brian F. Tyburski brian@engagehc.com Editor-in-Chief Robert E. Henry rhenry@AHDBonline.com 732-992-1885

Alzheimer’s Disease: A Healthcare Burden of Epidemic Proportion

Mission Statement

T.S. Dharmarajan, MD, FACP, AGSF; Srinivas G. Gunturu, MD Stakeholder Perspective by Jeffrey Januska, PharmD

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

Continued on page 8 American Health & Drug Benefits is included in the following indexing and database services: CINAHL: Cumulative Index to Nursing and Allied Health Literature EBSCO: EBSCO research databases

Senior Production Manager Lynn Hamilton Business Manager Blanche Marchitto

Chris M. Kozma, PhD; Peter J. Weiden, MD Stakeholder Perspective by Paul Anthony Polansky, BSPharm, MBA

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

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

Contact Information: For reprints, subscription information, and editorial queries, please contact: editorial@AHDBonline.com T: 732-992-1880 F: 732-992-1881

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Continued DEPARTMENTS

GENERIC DRUG TRENDS Recent Slowdown in National Health Expenditures Attributed to Growing Use of Generics Dalia Buffery, MA, ABD

AHA MEETING HIGHLIGHTS Cost-Sharing Strategies Decrease Adherence to Statin Therapy By Alice Goodman

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Permission requests to reprint all or part of any article published in this journal should be addressed to REPRINT PERMISSIONS DEPARTMENT, Engage Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205A, Monroe Township, NJ 08831.

The ideas and opinions expressed in American Health & Drug Benefits do not necessarily reflect those of the Editorial Board, the Editors, or the Publisher. Publication of an advertisement or other product mentioned in American Health & Drug Benefits should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturers about any features or limitations of products mentioned. Neither the Editors nor the Publisher assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication.

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American Health & Drug Benefits, ISSN 1942-2962 (print); ISSN 1942-2970 (online), is published 12 times a year by Engage Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205A, Monroe Township, NJ 08831. Copyright © 2009 by Engage Healthcare Communications, LLC. All rights reserved. American Health & Drug Benefits and The Peer-Reviewed Forum for Evidence in Benefit Design are trademarks of Engage Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher. Printed in the United States of America. Address all editorial correspondence to: editorial@AHDBonline.com, Telephone: 732-992-1889. Fax: 732-9921881. American Health & Drug Benefits, 241 Forsgate Drive, Suite 205A, Monroe Township, NJ 08831.

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145,827 lives touched by Lilly assistance programs

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If it matters to patients, it matters to us. That’s why Eli Lilly and Company is committed to providing the programs, services, and manpower that help you deliver positive outcomes for the patients under your care. And while health care may be a numbers game, we’re interested in the one number that matters most.

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FROM THE EDITOR

Healthcare Innovation Viability: On the Edge of a Knife

n October 10, 2008, we convened the First Annual American Health & Drug Benefits Summit on Healthcare Stakeholder Integration—The Return to Deep Science: Pharmaceutical Research & Development in a Value-Based Healthcare System. The proceedings are published in a special supplement accompanying this issue of the journal. The summit brought together leaders from many sectors to evaluate the prospects for the future of healthcare innovation, which is fundamental to the viability of the healthcare system. Consensus across all stakeholder lines is the ultimate purpose of AHDB. The summit was convened to allow a multidisciplinary faculty to present a composite picture of the state of drug discovery and development. The top-heavy resources of healthcare are making it increasingly difficult to balance the process of care. As all aspects of medicine become increasingly complex, it becomes correspondingly harder for all stakeholders to work collaboratively. The trend has often been one where each party tries to impose its agenda on the healthcare system unilaterally, an approach that is not working. Thus, the very divergent nature of the summit’s presentations imparted a picture of unity to the entire healthcare community—clinical, business, and regulatory—to help guide all parties toward a strategy that makes possible new and productive drug therapies for diseases most in need of innovation.

The summit was another step toward healthcare system viability, based on the premise that all stakeholders must regard the others as possessing answers, not obstacles, to their interests. Innovation is facing many obstacles today; the market for new drug discovery and development has become risk adverse to an extreme. Some pharmaceutical manufacturers have reacted to this market condition by retreating from real innovation. Payers, meanwhile, must make sense of new drugs coming before

AMERICAN HEALTH & DRUG BENEFITS

January 2009

their Pharmacy & Therapeutics Committees. They and the purchasers funding health and drug plans have hard decisions to make: Should formularies and benefit designs stress short-term cost-saving or quality? If the latter, how will quality and value be measured? What are the governing dynamics that will incentivize pharma to pursue needed innovations? And, what, in turn, will be the response by payers, providers, patients, purchasers, and regulatory agencies? Will innovation be rewarded? The summit’s presentations covered a powerful range of inquiry that explored the confluence of forces that comprises the environment in which pharmaceutical research and development (R&D) takes place. Like the rest of the healthcare system, R&D is undergoing great changes to stay viable and provide medications relevant to patient needs. The presenters sought answers for the preservation of the great institution of drug discovery and development through a collegial sharing of stakeholder needs, data, and propositions. Each group benefited from understanding the incentives and conditions of the other groups. They appreciated that what is needed to ensure success is to understand the new “rules of engagement” between stakeholders, and to work together in common purpose to heal patients in need. The summit was another step toward healthcare system viability, based on the premise that all stakeholders must regard the others as possessing answers, not obstacles, to their interests. The remarkable findings from the summit showcased in the supplement confirm the belief that collegiality turns insular, contentious debate into a civilized and productive examination of how to organize resources into a process that produces new valuebased medicines that serve patients’ needs. ■

Robert E. Henry Editor-in-Chief

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JOIN AHDB PEER REVIEW American Health & Drug Benefits (AHDB) is looking for medical and pharmacy directors, P & T Committee members, and other experts in benefit design who are interested in joining our peer reviewers and assist in maintaining the high quality of articles published in the journal. You will be asked to review at least 1 or 2 articles per year in your area of expertise. Reviewers’ names will be published in AHDB at the end of the year. Reviewers should have at least 1 area of expertise in a health-related field for which they feel qualified to assess the content and quality of manuscripts submitted for publication in AHDB.

Articles fall into 3 main areas related to healthcare: Regulatory, Business, and Clinical. These main categories are represented from the different vantage points of all stakeholders in healthcare and are divided into many subcategories, including (but not limited to): • Administration/Management • Benefit design • Disease management/state (eg, asthma, infectious diseases, pain management, schizophrenia) • Drug therapy (including biologics, generics) • Drug utilization • Employer benefits • Finance/economics • Health information technology • Health policy/reform • Patient education/initiatives/quality-of-life issues • Pharmacoeconomics: cost-benefit analysis, cost-effectiveness • Pharmacy management: pharmacology, specialty pharmacy, pharmacy benefits • Reimbursement: Medicare/Medicaid, health insurance, prior authorization • Research: methods, study design, data collection/analysis

To become a peer reviewer, please complete the form below and fax to: 732-992-1881 or e-mail to editorial@ahdbonline.com Reviewer Information _______________________________________________________________________________________ First Name Last Name Credentials _______________________________________________________________________________________ Title Company _______________________________________________________________________________________ Address _______________________________________________________________________________________ E-mail Phone

EDITORIAL

Why Financial Incentives Aren’t Enough to Move the Needle on Compliance Emily Cox, PhD

ell established is the fact that prescription copayments (ie, the price paid by members) and how they are structured play a role in influencing the demand for prescription medications.1,2 Many plan sponsors are banking on the tenet of price responsiveness by lowering copayments to increase utilization of select chronic therapies. But is lowering copayment, or financial incentives in general, the answer to achieving the desired behaviors when it comes to prescription utilization (ie, compliance with therapy and use of the most cost-effective agent within a therapeutic class)?

It means that financial incentives are not the sole solution to influencing patient behavior. Important psychological principles are also at play in shaping decisions about consumption of pharmaceutical products. Let us examine this by starting with some basics. The metric economists use to represent the relationship between price and demand is called “price elasticity of demand” and is expressed as the relative change in quantity demanded over relative changes in price. When it comes to demand for prescription drugs, numerous studies have found that the price elasticity of demand is less than 1, ranging from -0.18 to -0.60, a situation referred to as “inelastic demand.” This means that the relative change in quantity demanded is always less than the relative change in price. For prescription drugs, a 10% increase in price or in copayments leads to a decrease of 1.8% to 6.0% in utilization, all else being equal. So what happens when copayments are decreased instead of increased? Classic economics would predict that copayment reductions would lead to comparable increases in compliance, which leads to better disease Dr Cox is Senior Director of Research, Research and Trend Management, Express Scripts.

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January 2009

control, which leads to better health outcomes, which results in lower healthcare costs. That is the basic premise of valuebased benefit design and the premise examined most recently by Nair and colleagues in this issue of the journal.3 Using a pre-/postresearch design (admittedly, not the strongest), they found that per member per year utilization for antidiabetes medications increased significantly by 9% in the first year—from 11.62 to 12.72. However, these gains in prescription utilization did not result in medical cost offsets 2 years after copayments had been reduced. Although not formally calculated, a back-of-theenvelope calculation of price elasticity of demand given the average change in copayment and a 3.3% marginal increase in utilization (the difference between 9.5% and 6.2%, the national trend cited by Nair and colleagues) was approximately -0.04. This is similar to elasticity estimates my colleague and I recently found for copayment reductions with statin therapy, where elasticities ranged from 0.02 and -0.02 for copayment reductions of $0 to $5 and > $15, respectively.4 These price elasticity estimates from lowering copayments are orders of magnitude smaller than estimates obtained from studies examining utilization changes from price increases. Why did we find much less price sensitivity (ie, smaller changes in quantity demanded) when prices decreased than when prices increased? Greater response to copayment increases than to decreases is supported by one of the most well-documented principles of behavioral economics: aversion to losses.5 Under this theory, patients have a more pronounced demand response when required to increase their contribution as opposed to when they pay less than their usual cost. And when it comes to monetary gains, it is estimated that individuals value a loss twice as great as a similar gain. So what does this mean for plan sponsors designing pharmacy benefits? It means that financial incentives are not the sole solution to influencing patient behavior. Important psychological principles—such as procrastination, expectations, social norms, and framing,6 in addition to price, side effects, and drug effectiveness—are also at play in shaping decisions about con-

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sumption of pharmaceutical products. It further means that we should recalculate the return on investment from lowering copayment strategies and consider winwin strategies for lowering member out-of-pocket costs that include use of equally effective lower-cost brands and generics, which lowers costs for both plan sponsors and members, while also increasing adherence.7 And it means that one size does not fit all in designing interventions to shape the decisions of patients. It also means that we have a lot of work to do to figure this out. â&#x2013; References 1. Mager DE, Cox ER. Relationship between generic and preferredbrand prescription-copayment differentials and generic fill rate. Am J

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Manag Care. 2007;13(6 pt 2):347-352. 2. Goldman DP, Joyce GF, Zheng Y. Prescription drug cost sharing: associations with medication and medical utilization and spending and health. JAMA. 2007;298:61-69. 3. Nair KV, Miller K, Saseen J, et al. Prescription copay reduction program for diabetic employees: its impact on medication costs, compliance, healthcare costs, and utilization. Am Health Drug Benefits. 2009;2:20-30. 4. Sedjo RL, Cox ER. Lowering copayments: impact of simvastatin patent expiration on patient adherence. Am J Manag Care. 2008;14:813-818. 5. Tversky A, Kahneman D. Loss aversion in riskless choice: a referencedependent model. Q J Econ. 1991;106:1039-1061. 6. Ariely D. Predictably Irrational: The Hidden Forces that Shape Our Decisions. New York, NY: HarperCollins; 2008. 7. Shrank WH, Hoang T, Ettner SL, et al. The implications of choice: prescribing generic or preferred pharmaceuticals improves medication adherence for chronic conditions. Arch Intern Med. 2006;166:332-337.

Winners Receive $50 Submission deadline: February 12, 2009 Winnersâ&#x20AC;&#x2122; names posted: February 16, 2009

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BUSINESS

Prescription Copay Reduction Program for Diabetic Employees: Impact on Medication Compliance and Healthcare Costs and Utilization Kavita V. Nair, PhD; Kerri Miller, PharmD, BCPS; Joseph Saseen, PharmD, FCCP, BCPS; Pamela Wolfe, MS; Richard Read Allen, MS; Jinhee Park, CPhil, MA, MS Objective: To examine the impact of a value-based benefit design on utilization and expenditures. Methods: This benefit design involved all diabetes-related drugs and testing supplies placed on the lowest copay tier for 1 employer group. The sample of diabetic members were enrolled from a 9-month preperiod and for 2 years after the benefit design was implemented. Measured outcomes included prescription drug utilization for diabetes and medical utilization. Generalized measures were used to estimate differences between years 1 and 2 and Kavita V. Nair the preperiod adjusting for age, gender, and comorbidity risk. Results: Diabetes prescription drug use increased by 9.5% in year 1 and by 5.5% in year 2, and mean adherence increased by 7% to 8% in year 1 and fell slightly in year 2 compared with the preperiod. Pharmacy expenditures increased by 47% and 53% and expenditures for diabetes services increased by 16% and 32% in years 1 and 2, respectively. Conclusion: Increases in adherence and use of diabetes medications were observed. There were no compensatory cost-savings for the employer through lower utilization of medical expenditures in the first 2 years. Adherent patients had fewer emergency department visits than nonadherent patients after the implementation of this benefit design. [AHDB. 2009;2(1):14-24.]

or employers, the underlying premise of benefit design is to provide quality healthcare services to their employees. Although the cost of providing healthcare benefits is a key consideration, employers balance this consideration against employee satisfaction and retention as well as productivity.1 The concept of a value-based benefit design (VBBD) has emerged over the past decade as a strategy to meet this objective.

Value-Based Benefit Design VBBD allows employers to adopt innovative approaches to health benefits that are designed to lower costs and encourage employees to engage in better health-promoting behaviors. Dr Nair is Associate Professor, School of Pharmacy, University of Colorado at Denver, Aurora, CO; Dr Miller is Vice President of Pharmacy Services, Great West Healthcare (now Cigna), Denver, CO; Dr Saseen is Associate Professor, University of Colorado, Denver, CO; Ms Wolfe and Mr Allen are Statisticians, University of Colorado, Denver, CO; Ms Park is Pharmacy Manager, GlaxoSmithKline, Research Triangle Park, NC.

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The National Business Coalition on Health has defined VBBD as a “set of benefits and activities that apply information and incentives to promote a change in patient or provider behavior”2 and “use plan design features to maximize the value of a high-quality benefit design.”2 Academics have further focused the definition of VBBD to a “clinically sensitive approach that is explicitly designed to mitigate the adverse health consequences of high out-of-pocket expenditures.”3 VBBD health plan strategies are gaining in popularity among employers. A nationwide survey of US employers conducted by the Midwest Business Group on Health (a nonprofit coalition of more than 90 employers) in May 2008 found that 62% of employers will waive copays or reduce the costs of certain drugs to provide financial incentives for employees to participate in disease management programs.4 Another survey of 117 employers revealed that 45% of employers are currently considering modifying their current prescription copay structure, and 16% had already reduced prescription copays for select chronic conditions.5 VBBDs in pharmacy benefits have received the most attention from employers. The most popular approach

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has been to target select chronic diseases and lower copays for drugs used to treat those diseases.6 The impetus for this VBBD stemmed from evidence that increasing cost-sharing for prescription medications can reduce the use of necessary medications and increase adverse events and associated medical utilization, such as hospital or emergency department visits.7 With this evidence, Asheville, North Carolina, launched one of the earlier forms of a prescription-centered VBBD in 1997.8 In this program, copays for diabetes medications and supplies were waived for employees of Asheville if they agreed to be counseled by trained pharmacists every 1 to 3 months about diet, exercise, medication use, blood glucose testing, and foot and eye examinations. Although prescription costs increased for the employer, mean medical costs per member decreased between $2705 and $6502 annually in all 5 years after program implementation, 53% to 75% of employees had improved hemoglobin (Hb) A1C levels, and the city saved an estimated $18,000 annually through reduced sick day use.8 The efforts of Pitney Bowes, a national organization providing various postal services, in implementing VBBDs have been widely publicized. Pitney Bowes lowered prescription copays for brand-name medications for diabetes, asthma, and hypertension to a coinsurance rate of 10% compared with previous rates of 30% and 50%.9 For patients with diabetes, nonadherence to insulin therapy decreased by two thirds, strip use increased by 27%, and the use of fixed combination oral drugs for diabetes increased by 13%.9 Most recently, Chernew and colleagues10 examined the impact on medication adherence of lower copays for angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, diabetes medications (oral and insulin based), HMGCoA reductase inhibitors (statins), and steroids.10 Copays for generic medications were reduced from $5 to $0, for preferred brand-name medications from $25 to $12.50, and for nonpreferred medications from $45 to $22.50. The authors saw a 3.8% to 6.3% increase in medication adherence for all drug classes examined, with the smallest increase for ACE inhibitors and ARBs (3.8%) and the largest increase for statins (6.3%).10 Despite the complexities of a pharmacy benefit, prescription-centered VBBDs are popular because employers believe that benefit structures should be based on a system of financial incentives that encourage the use of high-value services and discourage low-value services.11 The consensus among employers is that adherence to medications is integral to the management of chronic

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KEY POINTS ▲ Healthcare cost is a key consideration in benefit design, but

employers have to balance cost against quality of care to ensure employee satisfaction, retention, and productivity. ▲ Value-based benefit design is a relatively new strategy that

attempts to meet employers’ objectives. ▲ This study examined the impact of lower copays for diabetes

medications on pharmacy and medical utilization, medication adherence, and healthcare expenditures. ▲ The number of adherent patients increased during the

study compared with the period before study initiation. Diabetes-specific office visits and laboratory/diagnostic visits were reduced. ▲ The flip side of increased adherence was an increase in

pharmacy expenditures for diabetes medications.

diseases.12 Interventions that are very effective (eg, the use of prescription medications to treat chronic conditions) and moderate the growth of healthcare costs should be covered at lower or at no cost-sharing, whereas low-value interventions (eg, bariatric surgery) should have higher cost-sharing associated with it. Finally, the “ease” of implementing a pharmacy benefit change is also appealing to an employer. At its simplest form, employers merely have to change a pharmacy benefit rider to reflect the lower copays and communicate this change to employees. The 3 studies outlined above illustrate the emerging research in evaluating a prescription-centered VBBD. In a review of more than 100 articles, the national consulting company PricewaterhouseCoopers concluded that despite these efforts, there is a paucity of objective academic research demonstrating the true impact of a prescription-centered VBBD for employers.1 The firm called for more academic research. The goal of our research was to examine the impact of reducing prescription copays for brand-name diabetes medications and testing supplies from a 3-tier plan with $10, $20, and $40 upper-tier copays to a generic-tier copay of $10 for diabetic employees and their dependents in 1 employer group. The employer group implemented this program starting on October 1, 2005, and ending in December 2008. Our primary goal was to examine the impact of reducing prescription copays for medications for diabetes on pharmacy utilization patterns, medication adherence for diabetes medication, and medical utilization and expenditures during a 2-year period (October 1, 2005, to September 30, 2007) and to compare these results to a 9-month baseline period for 1 employer group. Our

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secondary goal was to compare prescription and medical utilization behavior between adherent and nonadherent patients in a similar manner.

Methods The study design involved a pre/post period comparison of a cohort of continuously enrolled members in the baseline and after years 1 and 2. The employer group was from the healthcare industry and represented a nationwide group. At the time of the study, there were 5427 employees, 3146 of whom had dependent coverage as well (an average of 2.23 dependents per employee), for a total of 12,443 employees and dependents. A majority of the employees (68%) were women. The mean age was 42 years, and the average length of job tenure was 7.4 years. A majority of the employees (45%) were located in Colorado, 13% were in Missouri, 6% were in California and Texas, and small percentages lived in other states. Two preferred provider organization (PPO)-based plans were offered to employees between 2005 and 2007. Plan features remained the same in all years and most features of both plans were similar. The plans differed with respect to out-of-network benefits. For PPO plan 1, in-network benefits were: 1. $500 individual and $1500 family annual deductible 2. $20 copay for office visits and preventive care 3. 20% cost-sharing for hospital services, nursing facilities, home healthcare, and hospice care 4. 20% cost-sharing for laboratory and x-ray services for inpatient services 5. 40% cost-sharing for outpatient surgery, laboratory, and x-ray services for outpatient facilities, physical therapy, and outpatient mental health visits 6. 40% cost-sharing for emergency department visits. For PPO plan 2, in-network benefits were similar to plan 1 except that: 1. Emergency department visits were at 20% cost-sharing 2. Outpatient mental health visits were 50% for 20 visits per calendar year. Pharmacy benefits were similar for both plans and consisted of an annual $100 deductible per individual or a $300 deductible per family, with copays of $10 for tier1 drugs or generics, $20 for tier-2 drugs or preferred brands, and $30 for tier-3 preferred brands. Prescription copays for mail-order drugs were $20 for tier 1, $40 for tier 2, and $80 for tier 3. The program consisted of placing all diabetes drugs and testing supplies at tier 1, so members would have access to these drugs and testing supplies for a $10 retail copay or a $20 mail-order copay. A letter was sent to all

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participants before the start of year 1 informing them of their reduced copays for brand-name diabetes medications or testing supplies. No further communication about the program was made to employees following the initial letter in year 1. The sample consisted of members who were continuously enrolled with the health plan for the 3 observation periods: • Preperiod or baseline period (January 1, 2005, to September 30, 2005) • Postperiod year 1 (October 1, 2005, to September 30, 2006) referred to as “year 1” • Postperiod year 2 (October 1, 2006, to September 30, 2007) referred to as “year 2.” Patients with diabetes were identified in the preperiod as those who met 1 of the following conditions13: • 2 outpatient visits with diabetes as the primary or secondary International Classification of Diseases, Ninth Revision (ICD-9) code of 250.xx • 1 emergency department visit with diabetes as the primary or secondary ICD-9 code • hospitalization with diabetes as the primary or secondary ICD-9 code • 2 consecutive prescriptions for any diabetes drugs. Patients with gestational diabetes, polycystic ovarian syndrome, or chronic renal failure and on dialysis as well as transplant patients and individuals with highcost conditions (such as cancer, HIV) in the baseline period were excluded.

Outcome Measures The pharmacy-based measures consisted of annual or annualized measurements per member per year (PMPY) in 3 observation periods for (1) the number of diabetes medications (any, brand, generic, single, combination, mail order); (2) number of diabetes-testing supplies; and (3) medication adherence defined as the proportion of days covered (PDC) for diabetes medications (any medications for diabetes, oral medications for diabetes, or insulin use). Individuals were classified as adherent if the PDC was greater than 80% for any diabetes medications, including oral diabetes medications and insulin.14 Individuals were classified as adherent or nonadherent in each period separately. Percent differences between year 1 and the preperiod, year 2 and the preperiod, and year 2 and year 1 were also determined for all measures. Differences in utilization of diabetes medications between adherent and nonadherent patients in each time period were examined as well. Medical outcome measures consisted of the number of diabetes-related emergency department visits, hospi-

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Table 1 Adjusted Differences in PMPY Pharmacy Utilization: Diabetes Medications and Testing Supplies Mean Preperiod vs year 1

Difference, % Preperiod vs year 2

Year 2 vs year 1

Member characteristics (N = 225)

Preperiod

Year 1

Year 2

Any diabetes prescriptions*

11.62

12.72

12.22

9 (P <.05)

Brand-name diabetes prescriptions

4.36

4.99

4.92

14 (P <.05)

Generic diabetes prescriptions†

4.70

5.19

4.90

−6

Mail-order diabetes prescriptions†

2.00

2.20

2.02

10 (P <.05)

−8

Single-entity diabetes prescriptions*

9.66

10.68

10.40

11 (P <.05)

−3

Combination-based diabetes prescriptions†

0.23

0.26

0.37

13 (P <.05)

Diabetes-testing supplies†

1.83

1.82

1.63

−1

†

5 13 (P <.05)

61 (P <.05) −11 (P <.05)

−4 −1

42 (P <.05) −10

Estimates based on a Poisson model. Estimates based on a zero-inflated Poisson model. PMPY indicates per member, per year.

†

talizations, outpatient visits, and laboratory or diagnostic visits in all 3 observation periods and the same measures for adherent and nonadherent members in each time period. Percent differences between year 1 and the preperiod, year 2 and the preperiod, and year 2 and year 1 were determined for all medical utilization measures in which a diagnosis for diabetes was present in the primary, secondary, or tertiary ICD-9 diagnosis position code. In addition, percent differences in medical utilization of diabetes services between adherent and nonadherent patients in each time period were examined. Expenditure-based measures consisted of health plan pharmacy expenditures for diabetes medications and testing supplies, member out-of-pocket costs for diabetes medications and testing supplies (to include copays and deductibles), and health plan expenditures for diabetes medical services for adherent patients (PDC *80% for any diabetes medication) and nonadherent patients (PDC <80% for any diabetes medication) in each time period. Differences in the outcome measures between each of the observation periods were adjusted for age, gender, and the RxHCC risk score.15 The RxHCC risk score was developed by the Centers for Medicare & Medicaid Services using a prescription drug risk adjustment model to tailor payments to reflect the health status of plan enrollees. The model uses particular demographic characteristics to predict the following year’s expected costs for an individual. The RxHCC diagnostic classification groups more than 15,000 ICD-9-CM diagnosis codes into 197 condition categories known as RxCCs, which are then classified into disease groups.

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Analysis Generalized estimating equations for repeated measures were used to estimate pairwise differences between the observation periods.16 For count-based variables with <25% of values equal to zero, we assumed a Poisson distribution (numbers of prescriptions, emergency department visits, and hospitalizations). For count-based variables with >25% zero values, we used a zero-inflated Poisson model (brand or generic prescription use, testing supply use, and mail-order prescription use). Medication adherence was coded as a binary variable—“yes” was “adherence of *80%” and “no” otherwise—and this outcome measure was evaluated using logistic regression. Expenditure data were evaluated by computing the period-to-period differences within a subject; the differences were approximately normally distributed. All analysis was conducted in SAS version 9.1.3. Results A total of 225 patients who were continuously enrolled for all 3 observation periods met all the inclusion criteria. Their mean age was 49 years, slightly more than half the sample were women (53.4%), and the mean risk score was 1.08. More than 50% of the patient sample had dyslipidemia (52%) and hypertension (68%); one fifth (21%) had depression. Pharmacy Utilization Pharmacy utilization of diabetes medications and testing supplies is shown in Table 1. There was a mean increase of 9% for any prescription for diabetes in year 1 and a smaller increase (95%) in year 2 compared with the preperiod. There was a 14% increase in brand-name

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Table 2 Adjusted Differences: Mean Adherence Levels and Number of Adherent Patients

Sample (N = 225) n Any diabetes 189 medication Oral diabetes 150 medication Insulin

Any diabetes medication Oral diabetes medication Insulin * †

Preperiod, %

Mean Adherence Levels* Year 1, Year 2, Preperiod vs % % year 1

Preperiod vs year 2

Year 2 vs year 1

67.34

75.08

72.77

7.74 (P <.001)

5.43 (P <.0025) −2.31 (P = .0888)

69.04

76.79

73.27

7.74 (P <.001)

4.24 (P <.0462) −3.20 (P = .0263)

55.67

63.37

63.15

7.70 (P = .0068) 7.48 (P = .0251) −0.22 (P = .9329)

Adherent Patients† Year 2, Preperiod vs n (%) year 1

Preperiod, n (%)

Year 1, n (%)

Preperiod vs year 2

Year 2 vs year 1

189

77 (40.7)

101 (53.4)

90 (47.6)

1.67 (P = .002)

1.32 (P = .110)

0.79 (P = .136)

150

64 (42.7)

85 (56.7)

77 (51.3)

1.76 (P = .003)

1.42 (P = .090)

0.81 (P = .236)

11 (20.8)

12 (22.6)

11 (20.8)

1.12 (P = .781)

1.00 (P = 1.00)

0.90 (P = .796)

Includes members who took prescriptions in all 3 observation periods. Includes members whose adherence levels were *80% in each observation period.

prescription drug use for diabetes in year 1 and a 13% increase in year 2 compared with the preperiod. Smaller increases of 10% and 4% were seen for generic diabetes prescription drugs in years 1 and 2, respectively, compared with the preperiod. There was a 10% increase in year 1, with a negligible change in year 2, in mail-order prescriptions. There was a dramatic increase in the number of combination diabetes prescriptions in year 1 and year 2 compared with the preperiod, but the mean number of combination prescriptions was less than 1.0 PMPY. The number of single-entity prescriptions for diabetes increased by 11% in year 1 and 8% in year 2 relative to the preperiod. There was a decrease in the mean number of diabetes-testing supplies in both years after the preperiod. A majority of these differences were significant (P <.05).

Medication Adherence Mean medication adherence increased by 7.74% for any medication for diabetes in year 1 but dropped by 2.31% in year 2 compared with year 1 (Table 2). Mean medication adherence increased from 67% to 75% in year 1 and dropped to 73% in year 2 for any diabetes medications. Similar increases in mean levels of medication adherence were seen for users of oral diabetes medications. However, adherence was lower for insulin users in all years (56% in the preperiod, 63% in years 1 and 2) compared with those taking oral medications, with an increase of 7.7% in year 1 but with virtually no change

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in year 2. All differences in year 1 compared with the preperiod were significant. The number of adherent patients increased for all diabetes medications and for oral diabetes medications in both years compared with the preperiod. Members were 1.67 times more likely to use any medication for diabetes in year 1 compared with the preperiod and 1.32 times more likely in year 2 compared with the preperiod. These differences were significant in year 1 compared with the preperiod. Similar increases were observed for members using oral diabetes medications. There was little change in the number of adherent members using insulin in all 3 years.

Medical Utilization Mean medical utilization showed a decrease in diabetes-specific office visits and laboratory/diagnostic visits in both years compared with the preperiod (Table 3). There was a 25% decrease in diabetes-specific emergency department visits and a 20% decrease in hospitalizations in year 2 compared with year 1. Differences comparing year 1 and year 2 with the preperiod were not significant. Expenditures There was a 47% increase in health plan–paid pharmacy expenditures for diabetes medications in year 1 and a 53% increase in year 2 compared with the preperiod (Table 4). These increases were highest for brand-

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name medication use (53% increase in year 1 and 68% in year 2 compared with the preperiod). The increase in expenditures for generic diabetes medications was much smaller compared with brand-name agents (28% in year 1 and no change in year 2 compared with the preperiod). Member out-of-pocket expenditures (including deductible amounts) decreased by 28% for all diabetes medications in year 1 and by 33% in year 2 compared with the preperiod. Large decreases were seen in member out-of-pocket costs for brand-name diabetes medications (41% in year 1 and 37% in year 2 compared with the preperiod). There was a 13% increase in member out-of-pocket expenditures for generic medications in year 1 and no change in year 2 compared with the preperiod. A majority of these differences in years 1 and 2 compared with the preperiod were significant. Despite some decreases in diabetes-related medical utilization in year 2 compared with year 1, there was a 16% increase in total medical expenditures for diabetes services in year 1 and a 32% increase in year 2 compared with the preperiod, none of which was significant.

Table 3 Adjusted Differences in PMPY Medical Utilization for Diabetes Services Preperiod vs year 1, % Year 1 Year 2

Preperiod vs year 2, %

2.88

2.39

2.45

−17

−15

0.08

0.12

0.09

−25

0.04

0.05

0.04

−20

4.01

3.69

3.57

−8

−11

−3

Sample (N = 225) Preperiod Office visits* Emergency department visits† Hospitalizations† Laboratory/ diagnostic visits*

Year 2 vs year 1, %

Estimates based on a Poisson model. Estimates based on a zero-inflated Poisson model. No comparisons were significant at the 0.05 level. PMPY indicates per member, per year. †

Table 4 Adjusted Differences in Mean PMPY Pharmacy, Medical Expenditures, and Member Out-of-Pocket Prescription Costs Preperiod, Year 1, Year 2, $ $ $ Sample (N = 225)

Preperiod vs year 1, %

Preperiod vs year 2, %

Year 2 vs year 1, %

Health plan pharmacy expenditures All diabetes medications Brand-name diabetes drugs All generic medications

888

1305

1361

47 (P <.05)

53 (P <.05)

611

936

1030

53 (P <.05)

68 (P <.05)

121

156

121

28 (P <.05)

−22

Member out-of-pocket expenditures All diabetes medications Brand-name diabetes drugs Generic diabetes drugs

267

192

180

−28 (P <.05) −33 (P <.05)

−6

142

−41 (P <.05) −37 (P <.05)

67 76 66 13 (P <.05) 0 −13 Adherent and Nonadherent Patients Health plan diabetes-specific medical expenditures Table 5 shows percent difference in the PMPY prescription utilization Office visits 425 536 606 26 (P <.05) 43 (P <.05) 13 for diabetes medication and testing Emergency 47 40 63 −15 34 58 supplies in all 3 observation periods department visits between adherent and nonadherent 401 447 473 11 18 6 patients. Adherent patients used Hospitalizations 81% more prescriptions in the Laboratory/ 230 253 313 10 36 (P <.05) 24 preperiod, 93% more in year 1, and diagnostic visits 126% more in year 2 compared with Total 1105 1277 1456 16 32 14 nonadherent patients. Similarly, Statistical tests are based on the analysis of differences between periods for each patient. they used 87% more brand-name PMPY indicates per member, per year. prescriptions in the preperiod and 122% more brand-name prescriptions in years 1 and 2 adherent patients, 122% higher in year 1, and 190% compared with nonadherent patients. Generic prehigher in year 2 compared with nonadherent patients. scription use was 113% higher in the preperiod for Mail-order prescription use for adherent patients was

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Table 5 Adjusted Differences in PMPY Pharmacy Utilization for Diabetes Drugs and Testing Supplies: Nonadherent vs Adherent Patients Adherent/nonNonadherent Adherent adherent as % Preperiod (n = 126) (n = 80) of nonadherent Any diabetes prescription

7.15

12.93

81 (P <.05)

Any brand-name diabetes prescription Any generic diabetes prescription Any mail-order diabetes prescription

2.89

5.41

87 (P <.05)

2.81

6.00

113 (P <.05)

1.17

2.59

121 (P <.05)

Any diabetes-testing supply

1.44

1.55

Year 1

Nonadherent Adherent (n = 106) (n = 102)

Any diabetes prescription

9.47

18.26

93 (P <.05)

Any brand-name diabetes prescription Any generic diabetes prescription Any mail-order diabetes prescription

3.61

8.03

122 (P <.05)

other years (75% in the preperiod, 43% in year 1, and 67% in year 2). The number of office visits was 30% lower for adherent patients in the preperiod compared with nonadherent patients but 6.3% and 3.5% higher in year 1 and 2, respectively (Figure 3). Laboratory/diagnostic visits showed similar trends: lower by 9.1% for adherent patients in the preperiod compared with nonadherent patients but higher by 2.5% and 17.1% in years 1 and 2, respectively (Figure 4). No statistical tests were done on these measures due to small sample and low event rate. In a comparison of medical expenditures for diabetes-related services in all 3 years (results not shown), there was a 70% difference for adherent patients compared with nonadherent patients in the preperiod, a 75% difference in year 1, and no difference in year 2.

Discussion Following the work of Chernew et al,10 we expanded the examination of a prescription1.61 3.29 104 (P <.05) centered VBBD for a more comprehensive set of outcomes than previously included. Our Any diabetes-testing supply 2.16 2.05 â&#x2C6;&#x2019;5 results show that prescription utilization for Nonadherent Adherent diabetes medications increased in years 1 and 2, Year 2 (n = 106) (n = 93) although the rates of increase were lower in year Any diabetes prescription 8.68 19.65 126 (P <.05) 2 compared with year 1. The 9.5% increase in diabetes medications in year 1 was higher than Any brand-name diabetes 3.80 8.44 122 (P <.05) prescription the national average of 6.2% for 2006, and the 5.5% increase in year 2 was higher than the Any generic diabetes 3.13 9.07 190 (P <.05) prescription national average of 2.2% for diabetes prescriptions.17,18 The increase in brand-name medicaAny mail-order diabetes 1.58 3.32 110 (P <.05) prescription tions was greater in both years compared with generics. It is possible that members had some Any diabetes-testing supply 1.71 2.25 32 (P <.05) moral hazard behavior with the use of brandPMPY indicates per member, per year. name medications after copays were reduced as member out-of-pocket costs for brand-name 121% higher in the preperiod, 104% higher in year 1, diabetes medications decreased by 22% and 17% in and 110% higher in year 2 compared with nonadherent years 1 and 2, respectively. patients. Diabetes-testing supply use for adherent However, there were some decreases in the use of patients was higher by 8% in the preperiod, lower by diabetes-testing supplies, particularly in year 2 (11%) 5% in year 1, and higher by 32% in year 2 compared compared with the preperiod. We believe we did not with the nonadherent patients. capture all use of diabetes-testing supplies through the Figure 1 shows that the mean number of emergency paid pharmacy claims because it is likely that members department visits was much lower for adherent patients were purchasing glucometers and testing supplies on compared with nonadherent patients in all 3 years and their own before the reduction in copays and continued disparity was greater in each year (50% in the preperito use the same testing supplies. While more than 90% od, 55% in year 1, and 83% in year 2). Hospitalizations of members purchased prescription medications, fewer for adherent patients (Figure 2) were fewer in all 3 than 50% purchased any diabetes-testing supplies in all years, but fewest in the preperiod compared with the 3 observation periods.

3.70

8.23

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0.20 0.15 0.10

0.11 0.06 0.03

0.05 0

0.05

0.04

Preperiod Year 1 Year 2 Observation period

PMPY indicates per member, per year.

0.07 0.06 0.05 0.04 0.03 0.02 0.01 0

Nonadherent Adherent

NO. 1

0.07

3 0.06 0.04

0.04

0.02 0.01

PMPY indicates per member, per year.

2.5 2

Nonadherent 2.72 Adherent 2.55

2.49 2.58

2.22 1.55

1.5 1 0.5 0

Preperiod Year 1 Year 2 Observation period

Medication adherence increased 7.7% in year 1 and dropped between 0.2% and 3% in year 2 compared with the preperiod. In years 1 and 2, mean levels of adherence ranged from 65% to 73% (less than the 80% cutoff for an individual to be classified as adherent). But there was an increase in the number of adherent patients in both years compared with the preperiod for patients taking any or oral diabetes medications (13% to 14%). However, even with these increases, the number of adherent patients remained below 55% of the population in all time periods. In particular, only 20% of insulin users were adherent in all time periods. Medical utilization for diabetes services showed some decrease in use, notably for emergency department visits and hospitalizations in year 2 compared with the preperiod, but the trends showed increases in total medical costs for both years (16% in year 1 and 14% in year 2). There were some decreases in medical utilization caused by complications from diabetes, but the low prevalence in a sample of 225 members makes these results difficult to interpret. As expected, pharmacy expenditures for all diabetes prescriptions increased considerably: 47% and 53% in years 1 and 2, respectively. Increases in expenditures for brand-name medications were more than 100% in both years. Because pharmacy and medical expenditures increased, a return on investment was not achieved during the study period. The impact of a prescription-centered VBBD program on adherent versus nonadherent patients supports the impact of improving medication adherence on health outcomes. Adherent patients were less likely to have emergency department visits than nonadherent patients, a discrepancy that widened following the reduction in copays (50% fewer in the preperiod, 55% fewer in year 1, and 83% fewer in year 2). Adherent patients were also more likely to have an increase in the number of office visits and laboratory/diagnostic visits

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Figure 3 Office Visits: Adherent vs Nonadherent Patients

Mean visits PMPY, N

0.23

Nonadherent Adherent

Mean visits PMPY, N

0.25

Figure 2 Hospitalizations: Adherent vs Nonadherent Patients

Preperiod Year 1 Year 2 Observation period

PMPY indicates per member, per year.

after the reduction in Figure 4 Laboratory/Diagnostic Visits: Adherent vs Nonadherent Patients copays compared with nonadherent patients. Nonadherent 4.18 4.5 3.96 4.06 Adherent There are several 4 3.47 3.5 lessons learned from 2.86 2.67 3 this endeavor. First, 2.5 the prescription-cen2 1.5 tered VBBD may im1 prove medication be0.5 haviors. The VBBD 0 Preperiod Year 1 Year 2 we measured was a Observation period â&#x20AC;&#x153;no-frillsâ&#x20AC;? approach to PMPY indicates per member, per year. changing medication adherence. Over a 3-year period, the only change to diabetes management was the copay reduction. With only a change in financial incentives, there were noticeable increases in medication adherence, use of diabetes medications, and the number of adherent patients. It has been well established that medication adherence is influenced by several factors, only one of which is reducing financial barriers for medications. Therefore, additional attempts may be needed to reinforce these behaviors through other means, such as education about adherence to medications, methods to remind patients about taking their medication, or other efforts to help patients better manage their disease (excluding the existing disease management program that was available throughout the 3-year period). Further reinforcement of adherence through additional value-based efforts could enhance the increases in medication adherence. Second, employers need to be encouraged to think in different ways about a return on investment for a prescription-centered VBBD. Employers may expect to offset the increased pharmacy costs they incur due to lower copays with savings on medical costs. However, our results show that such saving may not be realized even 2 years after the implementation of a VBBD. Our findMean visits PMPY, N

Figure 1 Emergency Department Visits: Adherent vs Nonadherent Patients

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ings show that patients who were adherent had fewer emergency department visits, continued to increase their adherence, and had more office visits and laboratory/diagnostic services after a copay reduction was introduced. Therefore, employers need to be encouraged to think of a return on investment in alternative terms and expect to notice long-term improvements in disease management by their members. Employers also should find ways to encourage members to improve their adherence with medications for chronic conditions. By getting more members to achieve adherence levels of 80% or greater, employers may realize savings in medical costs over time.

Employers need to be encouraged to think of a return on investment in alternative terms and expect to notice long-term improvements in disease management by their members. Limitations Our study had several limitations. First, different forms of reduced prescription copay VBBD models exist and could include: (1) eliminating all copays for disease-specific medications, (2) reducing the copay levels at all tiers or reducing the differential between the tiers for disease-specific medications, (3) reducing copays for disease-specific brand-name medications, and (4) reducing copays for certain chronic condition medications. The employer group participating in this study chose to eliminate copays for brand-name medications and testing supplies for diabetes. Their rationale for doing so was to (1) create an even “playing field” so that their members could have access to all diabetes medications at a singular and uniform copay, and (2) to maintain some level of cost-sharing and thereby responsibility for purchasing their diabetes medications albeit at a lower copay. However, the very nature of the prescription-based reduction of copays for only brand-name medications could result in the unintended consequence of overutilization of brand-name diabetes medications, which could negatively impact any cost-savings in medical utilization. Second, the $4 prescription program by Wal-Mart was initiated in September 200618,19 and may have affected the adherence levels we observed in this population as it included many generic oral diabetes medications. We did not have data on whether members in our sample chose to purchase diabetes medications from Wal-

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Mart directly for $4 rather than through their health plan, thereby resulting in lower observed adherence levels in the health plan data we utilized for this study. As the popularity of Wal-Mart’s $4 prescription program continues to grow, the impact of this source of prescription medications needs to be considered in making any assessments of a prescription-centered VBBD. Third, we did not have a control group. This would have allowed us to tease apart the effects of the copay reduction from any underlying trends in prescription utilization. We tried to identify a comparison group from the health plan’s other employer groups with a similar 3tier pharmacy benefit, type of industry, age, gender, and risk score distribution. However, our efforts did not yield an appropriate comparison group. Although we used national benchmarks to compare the overall change in diabetes medications, a more accurate comparison would involve a control group or benchmark data from a matched group of patients with diabetes across health plans. We are currently in the process of creating such a benchmark using an external dataset. Fourth, our small sample size due to the inclusion criteria limits the interpretation of some of our findings, specifically the utilization of emergency department visits and hospitalizations, which are not common medical events (ie, most members do not incur such events). Changes in emergency department visits and hospitalizations should be interpreted with caution because the mean number of annual visits per member was small (<0.1) in all years. In addition, insulin adherence may have been overestimated using the PDC, because the amount of insulin a patient consumes is based on the dosage and directions for use, none of which are available in pharmacy claims data. Fifth, we were not able to compare changes in prescription use for diabetes by tier status in the pharmacy claims. The identifiers for tier status (tiers 1-3) were not available in the claims and cross references using the formulary, and brand/generic indicator was not conclusive. Thus we were unable to examine whether members purchased more expensive brand-name medications that were placed in the highest or third tier before the copay reduction was introduced, which could imply the possibility of moral hazard behavior after the program was implemented. Similarly, because 30% of our sample had diagnosis codes for both type 1 and type 2 diabetes, the resulting sample sizes after all the inclusion criteria were met did not permit a comparison of these 2 forms of diabetes. Sixth, the ultimate impact of a prescription-centered VBBD for diabetes is on clinical outcomes. Although we

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Copay Reduction Program

were not able to collect data on clinical markers such as HbA1C levels, examining these outcomes for improvements in the mean levels of HbA1C markers and the number of patients whose HbA1C levels improved after the copay reductions for medications could provide greater evidence of the positive impact of a VBBD. Our approach took an overall assessment of each measure within a time period. Another approach examines quarterly changes in adherence over the observed time period. Because of our limited sample size we chose to examine the PMPY levels of each outcome in each observation period.10 Finally, we are not certain that we captured data on all testing supplies. Fewer than 50% of the patients in our sample purchased diabetes-testing supplies in the preperiod, and after the copay reduction there were decreases in the purchase of glucometers and testing supplies. It is possible that members were purchasing testing supplies from alternative sources.

Conclusions A prescription-centered VBBD can have an impact on medication adherence which is influenced by many factors, and reducing financial barriers through VBBD should be coupled with other behavior modification. Because adherent patients have lower healthcare costs, employers should think about a return on investment as a long-term goal that can result in savings when more employees become adherent with their medications. â&#x2013; Disclosure Statement Dr Nair is a consultant to Centocor, Inc. Dr Saseen is a consultant to Daichii Sankyo, Inc. Ms Park is an employee of GlaxoSmithKline.

References 1. Hunt S, Maerki S, Rosenberg W. Assessing quality-based benefit design. April 2006. www.chcf.org/documents/insurance/QualityBased BenefitDesignFullReport.pdf. Accessed November 25, 2008. 2. National Business Coalition on Health. Enhancing the evidence links in eValue8 value based benefit design content description. November

2007.www.evalue8.org/eValue8/about/evidencebriefing_vbbd.pdf. Accessed November 25, 2008. 3. Fendrick AM, Chernew ME. Value-based insurance design: aligning incentives to bridge the divide between quality improvement and cost containment. Am J Manag Care. 2006;12(Spec No):SP5-SP10. 4. CCH HR Management. Employers shifting towards value-based benefit design, survey shows. May 19, 2008. http://hr.cch.com/news/ hrm/051908a.asp. Accessed November 5, 2008. 5. Health Industries Research Companies. Employer & Coalition Services: value-based benefits designs. Fall 2007. http://hirc.com/files/ public/HIRC_ValueBasedBenefits.pdf. Accessed November 25, 2008. 6. Chernew M, Fendrick AM. Value and increased cost sharing in the American health care system. Health Serv Res. 2008;43:451-457. 7. Tamblyn R, Laprise R, Hanley JA, et al. Adverse events associated with prescription drug cost-sharing among poor and elderly persons. JAMA. 2001;285:421-429. 8. Cranor CW, Bunting BA, Christensen DB. The Asheville Project: long-term clinical and economic outcomes of a community pharmacy diabetes care program. J Am Pharm Assoc (Wash). 2003;43:173-184. 9. Mahoney JJ. Reducing patient drug acquisition costs can lower diabetes health claims. Am J Manag Care. 2005;11(5 suppl):S170-S176. 10. Chernew ME, Shah MR, Wegh A, et al. Impact of decreasing copayments on medication adherence within a disease management environment. Health Aff (Millwood). 2008;27:103-112. 11. Denny CC, Emanuel EJ, Pearson SD. Why well-insured patients should demand value-based insurance benefits. JAMA. 2007;297:2515-2518. 12. Conway C. MBGH annual employer benefit survey reveals growing shift to value-based benefit design. May 1, 2008. www.reuters.com/ article/pressRelease/idUS127367+01-May-2008+PRN20080501. Accessed November 5, 2008. 13. Research Data Assistance Center (ResDAC) at the University of Minnesota, School of Public Health, Division of Health Services Research & Policy. Chronic condition data warehouse. October 2008. www.resdac.umn.edu/CCW/data_available.asp. Accessed December 6, 2008. 14. Ho PM, Rumsfeld JS, Masoudi FA, et al. Effect of medication nonadherence on hospitalizations and mortality among patients with diabetes mellitus. Arch Intern Med. 2006;166:1836-1841. 15. Robst J, Levy JM, Ingber MJ. Diagnosis-based risk adjustment for Medicare prescription drug plan payments. Health Care Financ Rev. 2007;28:15-30. 16. Liang KY, Zeger SL. Longitudinal data analysis using generalized linear models. Biometrika. 1986;73:13-22. 17. Express Scripts. 2006 Drug Trend Report. April 2007. www. expressscripts.com/industryresearch/industryreports/drugtrendreport/ 2006/dtrFinal.pdf. Accessed November 5, 2008. 18. Express Scripts. 2007 Drug Trend Report. April 2008. www. expressscripts.com/industryresearch/industryreports/drugtrendreport/ 2007/dtrFinal.pdf. Accessed November 5, 2008. 19. Morrison, K. Wal-Mart expands low-price drug program. May 7, 2008. Business. The Morning News. www.nwaonline.net/articles/2008/ 05/05/business/050608bizwmdrugs.txt. Accessed November 5, 2008.

Stakeholder Perspective Improved Clinical Outcomes the True Value of Copay Reductions for Diabetic Employees, Despite Increased Overall Costs EMPLOYERS: This is a case report of an employer groupâ&#x20AC;&#x2122;s almost 3-year study to institute a copay reduction program for their diabetic employees and their dependents. The article also reviews the implications of value-based benefit design for health plans and employers.

In this study, copays were reduced from a 3-tiered plan to a single-level copay for all diabeties medications and diabetes-testing supplies. Two outcomes were measured. The pharmacy outcome measured adherence versus nonadherence. The medical utilization outcome measured diabetes-related emerContinued next page

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gency department (ED) visits, hospitalizations, outpatient visits, and diagnostic visits in adherent and nonadherent members. Members could obtain any diabetic prescription medication at a $10 copay; therefore, for insured members the higher-cost brand-name drugs were free of any marginally increased copay amount. Results show that members utilized the “free” benefit and obtained the more expensive drugs. What did the employer group get for this added expense? Claims expenditure data appear to be the only measurement evaluated in this study, showing that the expenses were higher for pharmacy costs and diabetes supplies. Overall medical utilization expenses also increased, while medical utilization of diabetes-specific ED visits and diabetes-specific hospitalizations decreased from year 1 to year 2. Patients selected higher-priced brand-name diabetes medications and supplies, remained on the medications at a higher rate, and had fewer visits to the ED as the study progressed. During the study peri-

od, the employer group did not achieve cost-savings from this copay design, based on pharmacy and medical utilization expenditures. MEDICAL/PHARMACY DIRECTORS: One lesson for medical directors and others responsible for pharmacy benefit design in the treatment of diabetic members is that copay reduction alone will likely not generate cost-savings. However, another lesson is that to determine whether quality improvements occur in the management of diabetic members, more than just claims data must be analyzed: In a diabetic population, measuring clinical outcomes—such as the rates or progression of renal disease, retinopathy, and peripheral neuropathies—may reveal the true value associated with these types of benefit-design changes. Geoffrey P. Cole, MD, MBA Chief Medical Officer Health Plan Select Athens, Georgia

Unmanaged Moment

“Between you and me, I’m fed up being a guinea pig!”

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GENERIC DRUG TRENDS

Recent Slowdown in National Health Expenditures Attributed to Growing Use of Generics By Dalia Buffery, MA, ABD

team of experts from the Centers for Medicare & Medicaid Services (CMS) released new data in the early days of the new year, detailing the most recent national health spending data for 2007, based on Medicare and Medicaid data, the Census Bureau’s data, private health insurance filings with state commissioners, provider surveys, and many other sources.1 These new data from the National Health Expenditure Accounts show that the rate of increase in healthcare spending in the United States grew in 2007 at the lowest rate since 1998.1 Although the total decline in growth of the national health expenditures (NHE) in 2007 is rather small compared with the growth in 2006, a mere 0.6%— reflecting an increase of 6.1% in 2007 compared with 6.7% in 2006—the trend reversal can portend significant changes for some industry stakeholders, particularly those in the pharmaceutical industry. The main reason for the spending growth slowdown, the CMS authors report, is the ever-increasing use of generic drugs in the past few years. According to IMS Health, the share of generic drug use among all prescription drugs dispensed in the United States reached a new height in 2007—at 67.3%.2 The previous rates of generic drug use were 63% in 2006 and 60% in 2005,2,3 signaling a clear trend of constant growth in demand for this type of medications. However, the decline in spending in 2007 on pharmaceutical drugs overall is not duplicated in other sectors of the healthcare system; most of the national spending categories on healthcare did (as expected) increase in 2007, including out-of-pocket consumer spending (by 5.3% vs 3.3% in 2006), hospital spending (by 7.3% vs 6.9% in 2006), nursing home costs (by 4.8% vs 4.0% in 2006), and home healthcare services (by 11.3%). Of note, the private health insurance cost increase remained the same as in 2006 (at 6%, a much better rate than the 10.2% increase in 2002), as did physician and clinical services (by 6.5%, as in 2006).1 Two other factors cited by the authors as contribut-

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ing to the 2007 slowing in NHE were the decreased growth in prescription drug prices overall and the growing concerns of consumers about drug safety.1 Prescription drug prices rose by 1.4% overall in 2007, according to these new NHE data, compared with a 3.6% growth in 2006.1 And even this reduced growth in drug costs can be largely attributed to the increased use in generic drugs, which are said to cost, on average, 30% to 80% less than their branded counterparts, according to the Generic Pharmaceutical Association,4 a fact that is cited by the authors of the CMS report as one of the explanations for the overall reduction in drug expenditures.

Since it is widely accepted that prescription drug costs amount to only about 10% of all healthcare spending, the question arises whether this new trend of slowing spending on national healthcare can be maintained in the years to come, even with a continued increase of generic drug use. Nevertheless, since it is widely accepted that prescription drug costs amount to only about 10% of all healthcare spending, the question arises whether this new trend of slowing spending on national healthcare can be maintained in the years to come, even with a continued increase of generic drug use, especially in light of the anticipated changes to the healthcare system that may be implemented by the new administration (which, even if not sweeping changes, may initially lead to increased costs). Such sentiment was, indeed, expressed by Richard S. Foster, FSA, chief actuary of CMS, in his comments about the newly released findings. “I wouldn’t expect the good news to continue,” said Dr Foster.5

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GENERIC DRUG TRENDS

In addition to the increase in generic drug use, the authors of the report suggest that the loss of patent exclusivity of many “blockbuster” branded drugs in 2006 and 2007 “had a large impact on the 2007 prescription drug trend.”1 Blockbuster prescription drugs losing patent exclusivity in 2006 and 2007, according to the authors, were1: • In 2006—Flonase, Pravachol, Zocor, and Zoloft • In 2007—Norvasc, Ambien, Lotrel, Coreg, and Toprol-XL. Finally, this report of NHE reductions in 2007 may indeed signal an emerging, if temporary, trend of cost reductions in healthcare spending as a result of drug cost reductions overall, as was also suggested by a report from the Pharmacy Benefit Management Institute (PBMI).4 A survey done by PBMI in 2008 revealed reductions in the average rate of increase of drug expenditures to employers in 2008. The growth rate of

drug expenditures to employers in 2008 was 4.86%— the lowest cost increase to employers since 1995, according to PBMI.4 ■

References 1. Harman M, Martin A, McDonnell P, et al; the National Health Expenditures Accounts Team. National health spending in 2007: slower drug spending contributes to lowest rate of overall growth since 1998. Health Aff (Millwood). 2009;28:246-261. 2. IMS Health. IMS Health reports U.S. prescription sales grew 3.8 percent in 2007, to $286.5 billion. March 12, 2008. www.imshealth.com/ portal/site/imshealth/menuitem.a46c6d4df3db4b3d88f611019418c22a/? vgnextoid=280c1d3be7a29110VgnVCM10000071812ca2RCRD&vgne xtchannel=41a67900b55a5110VgnVCM10000071812ca2RCRD&vgne xtfmt=default. Accessed January 3, 2009. 3. Medco Health Solutions. 2007 Drug Trend Report. Franklin Lakes, NJ; 2007. 4. Felthouse DH. Focus on lowest net cost drug reduces costs for patients, plan sponsors. Am Health Drug Benefits. 2008;1(9):10-11. 5. Associated Press. Generic drug helped to slow health-care spending in 2007. January 5, 2009. www.observer-reporter.com/OR/Print/01-06f0259-BC-HealthSpending-HFR-01-05-0731. Accessed January 5, 2009.

Unmanaged Moment

AMERICAN HEALTH & DRUG BENEFITS

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Pharmacy Essentials.

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AHA MEETING HIGHLIGHTS

Cost-Sharing Strategies Decrease Adherence to Statin Therapy By Alice Goodman

dherence to statin therapy is known to be poor, estimated to be about 50% at 12 months after initiation, even among patients with good insurance benefits, said Sebastian Schneeweiss, MD, Associate Professor of Medicine and Epidemiology at Harvard Medical School in Boston, MA, during the American Heart Association 2008 Scientific Sessions. Dr Schneeweiss presented results of a study that evaluated the consequences of copayment and coinsurance policies on the initiation of statin therapy after acute myocardial infarction (MI) and adherence to statin therapy in older individuals (age *65) residing in British Columbia (BC). In a population-based naturalistic study of older adults insured by the Canadian healthcare system, adherence to statin therapy was reduced by abrupt changes in health plan coverage, such as copay and coinsurance. At 15 months, adherence rates were approximately 5% lower for those with cost-sharing benefits compared with patients who were fully insured. Initiation of coinsurance almost doubled the risk of non-adherence to statin therapy. “Although interventions such as copays and coinsurance may produce net savings for the health plan, in the long run they can lead to unanticipated harmful outcomes that increase costs,” said Dr Schneeweiss, noting that a 100% coinsurance benefit under the Canadian system is similar to the so-called doughnut hole of Medicare Part D in the United States. “Many, but not all, commercial drug benefit plans under Part D have chosen to close the doughnut hole,” he added. The study population was drawn from the BC-funded drug insurance plan and included 3 cohorts of elderly patients: • Group 1 (n = 12,500) was the baseline cohort, with full prescription drug coverage within 6 months before January 2001 • Group 2 (n = 13,186), a cohort that started statin therapy within 6 months before January 2002, when

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January 2009

a $25 copay policy was initiated • Group 3 (n = 15,830), a cohort initiating statins within 6 months before May 2003, when a policy of 25% cost-sharing of drugs was put into effect. Follow-up for each cohort began on policy initiation date and extended for 9 months after policy changes. A group of Pennsylvania (PA)-based Medicare recipients who were hospitalized for acute MI and had full drug coverage (no copayments) throughout the study served as a time-trend control group. The number of new statin users grew 4 to 8 times faster compared with the population growth of BC residents aged *65 years. Over time, an increased number of older patients and patients with cardiac risk factors were using statins. Adherence—defined as more than 80% of proportion of days covered—was calculated for each patient each month. Median patient cost-sharing for a 90-day statin supply was $21.50 (Canadian) under the copay policy and $41.80 (Canadian) under the coinsurance policy. At 6 months after initiating statin therapy, adherence rates for cohorts 1, 2, and 3 were 73.2%, 74.5%, and 72%, respectively. At 15 months, adherence rates fell to 55.8%, 50.5%, and 50.8%, respectively. When looking at a subgroup of post-MI patients in this study, no copay effect was evident with regard to statin therapy initiation. The PA-based control group had lower levels of statin use than the BC cohort, which could be partly explained by the patients’ poor health and low-income status. Lower income was associated with an increased likelihood of stopping statin therapy independent of insurance status. Taking statins for secondary prevention after acute MI or revascularization decreased the odds of stopping statin use by 37%. Independent of insurance status, a recent history of MI, revascularization, or multiple comorbidities made patients less likely to discontinue statin therapy. ■

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Are your plan members with type 2 diabetes reaching goal? The recommendation for early treatment • Many patients are not reaching their ADA A1C target goal of <7%, and many are stopping their medications.1,2 • Recent data show a drop in the use of oral antidiabetic medications.3 • In 2008, data published showed that 44% of patients with diabetes were not at goal based on A1C values.1

Early and aggressive diabetes management has the potential to help get patients to A1C goals as quickly as possible AACE initial pharmacologic treatment recommendation*4

A1C Levels

6%–7%

Initiate monotherapy

7%–8%

Initiate combination therapy

8%–10%

Initiate/intensify combination therapy

>10%

Initiate/intensify insulin therapy

*For patients naïve to pharmacological therapy.

Early combination approach5 Diet + exercise OAD monotherapy OAD combinations

HbA1c (%)

OADs up-titration OAD + basal insulin OAD + multiple p dailyy insulin injections

9 8 7

HbA1c=7% HbA1c=6.5%

• The Global Partnership for Effective Diabetes Management†‡ recommends a shift from the reactive “stepwise” management to a proactive approach including early introduction of combination therapy as needed, addressing underlying pathophysiology, and including treatment of insulin resistance.5

Duration of diabetes Adapted from Goldstein.

• Patients who initially started on ﬁxed-dose combinations stayed on therapy at least 50 days longer than those who started on monotherapy.3 †The Global Partnership for Effective Diabetes Management was established with the aim of uncovering the barriers to good glycemic control and identifying ways to help people overcome them. ‡The Global Partnership for Effective Diabetes Management is industry supported. References: 1. Hoerger TJ, Segel JE, Gregg EW, Saaddine JB. Is glycemic control improving in U.S. adults? Diabetes Care. 2008;31:81-86. 2. Rodgers K. Ensuring compliance in patients with diabetes. In: Diabetes: Disease Management Guide. 4th ed. Montvale, NJ: Thomson PDR; 2004:501-505. 3. Data on ﬁle, Takeda Pharmaceuticals North America, Inc. 4. AACE Diabetes Mellitus Clinical Practice Guidelines Task Force. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the management of diabetes mellitus. Endocr Pract. 2007;13(suppl 1):3-68. 5. Goldstein BJ, Gomis R, Lee H-K, Leiter LA, on behalf of the Global Partnership for Effective Diabetes Management. Type 2 diabetes–treat early, treat intensively. Int J Clin Pract. 2007;61(suppl 157):16-21. ©2008 Takeda Pharmaceuticals North America, Inc.

XPIO-01287

11/08

Printed in U.S.A.

INFORMATION FOR AUTHORS

American Health & Drug Benefits THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN

Manuscripts submitted to American Health & Drug Benefits (AHDB) must be original and must not have been published previously, either in print or in electronic form. Manuscripts cannot be submitted elsewhere while under consideration by AHDB. To be considered for publication, manuscripts must adhere to the format described in this document. All manuscripts are subject to peer review, and acceptance is based on that review. If accepted, authors will be notified of any recommended revisions, and a revised manuscript should be resubmitted in its entirety, with all changes made. Routine editorial changes will be made to conform to house style, following the AMA Manual of Style, 10th ed. (New York, NY: Oxford University Press; 2007). The edited manuscript is sent to the author for a final review and approval. Time from submission to publication is generally 3 to 5 months. COPYRIGHT/DISCLOSURE Authors are required to sign a Copyright Transfer Form, assigning all copyrights to Engage Healthcare Communications, LLC, publisher of AHDB, as well as a Financial Disclosure Form. Authors are required to disclose any financial interests—direct or indirect—and any affiliations or involvement (competitive or amiable) with organizations that have a financial interest in the subject matter or materials discussed in the manuscript. PERMISSIONS Authors must secure a written permission to reuse or adapt any table or figure from a previously published (online or in print) article or from any other source. Provide the letter of permission when submitting the manuscript, or indicate that permission will be provided, and cite the original source with the graphic element in the manuscript. MANUSCRIPT FORMAT • Title page: Include a proper title for the article and list the names, titles, and affiliations of all authors. Also list the name, address, telephone number, and e-mail address of the corresponding author • Abstract: Provide a 150-250 word abstract that describes the main objectives of the article and why this article is important or what it adds to the literature • Conclusion: The conclusion should add comments that offer the rationale for the article and what the article adds to the literature • Double space the entire manuscript and number pages consecutively • Tables and figures must be cited in the text, but the actual graphics must then be placed at the end of the article, after

AMERICAN HEALTH & DRUG BENEFITS

January 2009

the references. Type all tables and all figure heads and captions in Word • References: Use up to 25-30 current, post-1990 references, cited consecutively in the text (as superscripts) and listed at the end of the manuscript. Avoid automatic numbering or footnote/endnote features (see references section) • Length: 2500-3000 words, plus tables and figures • Figures/images must be saved as individual files, at high resolution (300 dpi), as jpg, tif, or eps. Attach an individual file for each image. A copy may be included in the article but cannot substitute an electronic image file for figures. Images not saved appropriately will delay the peer-review process significantly. For help with images, please contact editorial@ahdbonline.com. AUTHORS Provide all authors’ highest academic degree and all professional affiliations. Also provide the name, address, telephone number, e-mail, and fax of the corresponding author. If possible, please provide a headshot of the lead author. REFERENCES Cite references consecutively in the text (as superscripts), then place each complete reference at the end of the article under heading “References.” Use proper citation format according to the AMA Manual of Style. See examples below. Use the most up-to-date, post-1990 references, citing primary sources only. Try to limit the number of references to about 30. Do not use automatic numbering or footnote/endnote features. Reference examples: 1. Peters JL, Sutton AJ, Jones DR, et al. Comparison of two methods to detect publication bias in meta-analysis. JAMA. 2006;295:676-680. 2. McGrath JJ, Murray RM. Risk factors for schizophrenia: from conception to birth. In: Hirsch SR, Weinberger DR, eds. Schizophrenia. Oxford, England: Blackwell Press; 2003. 3. Waters R, Pettypiece S. Drug sales in the US grow at slower pace as generic use surges. Bloomberg news, March 12, 2008. http://www.bloomberg.com/apps/news?pid=newsarchive&sid=a LfUw7_sYMRY. Accessed March 13, 2008. HOW TO SUBMIT MANUSCRIPTS Save the manuscript as a Word file and attach individual files for each image or figure. Save images or charts individually as an image file (jpeg, tif, eps). Digital graphics must be saved at a high resolution of at least 300 dpi. Submit the manuscript to editorial@ahdbonline.com. For assistance with the submission, call 732-992-1892. REPRINTS Reprints may be ordered at a nominal fee by contacting editorial@AHDBonline.com.

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CLINICAL

Partial Compliance with Antipsychotics Increases Mental Health Hospitalizations in Schizophrenic Patients: Analysis of a National Managed Care Database Chris M. Kozma, PhD; Peter J. Weiden, MD

Objective: To investigate the relationship between partial compliance with antipsychotic medication and mental health hospitalization in managed care patients with schizophrenia. Study Design: We performed a retrospective evaluation of 1499 outpatients with *1 antipsychotic claims and a diagnosis of schizophrenia in a managed care database (PHARMetrics). Methods: Patients were followed for 12 months after their initial oral antipsychotic prescribing event. Compliance was estimated by gaps in medication therapy, medication consistency and persistence, and medication possession ratio. Categorical and logistic regression analyses modeled effects of compliance, age, and gender on hospitalization risk. Results: The managed care cohort had an overall hospitalization risk of 5.9% during followPeter J. Weiden up. Increased hospitalization risk was associated with lower partial compliance, as measured by 3 of the 4 definitions. Patients with a maximum gap of >30 days were 4.7 times more likely to be hospitalized than those with a maximum gap of 0 to 10 days (P <.001). Low medication consistency of <70% and a medication possession ratio of <70% were significantly associated with increased risk of hospitalization (P <.001). Logistic regression analyses indicated that hospitalization odds decreased 16.9% (P <.001) and 18.8% (P <.001) for every 10% increase in medication possession ratio and medication consistency, respectively. Conclusion: Small decreases in compliance with antipsychotics are associated with increased hospitalization risk among patients with schizophrenia in a managed care population. [AHDB. 2009;2(1):31-38].

edication noncompliance is considered to be the single most important factor leading to relapse among patients with schizophrenia.1 One meta-analysis of maintenance antipsychotic treatment found that noncompliance causes about 40% of relapses.2 The advent of newer, second-generation oral antipsychotics has had a greater impact on efficacy than on adherence. For example, patients maintained on second-generation antipsychotics are about one third less likely to relapse compared with those receiving first-generation medications,3 but the overall gains in preventing nonadherence by moving from first-gen-

eration to second-generation medications have been much more modest.4 Schizophrenia is a very debilitating and expensive disease, resulting in $62.7 billion in direct and indirect costs in 2002 in the United States, of which $32.4 billion was indirect costs, including unemployment, reduced workplace productivity, family caregiving, and suicide. Direct healthcare costs totaled $22.8 billion ($8.0 billion in long-term care, $7.0 billion in outpatient costs, $2.8 billion inpatient, and $5.0 billion in drug therapy). In 2002, direct healthcare costs in terms of per member per year equaled $79 per US resident.5

Dr Kozma is Independent Research Consultant and Adjunct Professor, College of Pharmacy, University of South Carolina, Columbia, SC; Dr Weiden is Professor of Psychiatry and Director of Psychotic Disorders Program, Department of Psychiatry, University of Illinois at Chicago, IL.

Copay and Compliance Studies in other therapeutic areas have demonstrated that increases in prescription drug copayments decrease compliance rates. For newly initiated renin angiotensin system blockers, every $1 increase in

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CLINICAL

KEY POINTS ▲ Medication noncompliance is considered the single most

important factor leading to relapse among patients with schizophrenia. ▲ Studies in other therapeutic areas have demonstrated that

increases in prescription drug copayments decrease compliance rates. ▲ Results of this retrospective study support the association

between reduced compliance with antipsychotic medications and increased risk of mental health hospitalization. ▲ Risk of hospitalization for schizophrenia decreases by almost

20% for every 10% increase in medication compliance. ▲ Patients with therapy gaps of 30 or more days per prescrip-

tion have almost a 5 times greater risk of being hospitalized compared with patients whose therapy gaps are 0 to 10 days.

copayments per 30-day supply resulted in a 1.9% increased gap between refills, and a 2.8% increase in the odds of being nonpersistent (discontinued treatment).6 In a study of antihypertensive therapies, patients with a $20 copay had 76% of the compliance of those with a $5 copay; and those with a $20 to $165 copay had 48% of the compliance of those with a $5 copay.7 With oral hypoglycemic therapies, patients with a $10 increase in copay had an 18.5% reduction in utilization from baseline.8 An increase in copayment from $10 to $20 for statin therapy resulted in a 6% to 10% reduction in the number of fully compliant patients.9 When copayments were doubled across all therapeutic categories in one health plan, reductions in utilization ranged from 45% for nonsteroidal antiinflammatory drugs to 25% for diabetes medications.10 Conversely, a decrease in copayment resulted in a 7% to 14% increase in compliance in 4 of the 5 chronic medication categories studied.11 The relationship between compliance and copayment in schizophrenia has not been reported.

Other Factors Influencing Compliance In real-world practice, medication-taking behavior is complex and influenced by factors other than copayment. In a published review of 39 studies, the patientlevel factors most often associated with nonadherence in patients with schizophrenia included poor insight into the disease, negative attitude toward the medication, previous nonadherence, substance abuse, short illness duration, poor discharge planning, and poor therapeutic alliance.12

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Representation of compliance as an “all-or-none” behavior, as implied by noncompliance versus compliance, does not accurately describe patient behaviors. In fact, several studies have found that “partial compliance” (taking some, but not all, prescribed medication) more accurately describes the pattern for most patients with schizophrenia.13,14 Partial compliance can take several forms, including taking an amount consistently less than that recommended, displaying irregular (“on” and “off”) dosing behavior, and having discrete gaps in antipsychotic therapy (eg, patients unwilling or unable to refill prescriptions). Therefore, a new research emphasis has been placed on assessing the pattern and extent of noncompliant behaviors, and the degree of relapse risk associated with various levels of partial compliance.15,16 Administrative pharmacy claims data have become an increasingly important tool in compliance pattern evaluations,17,18 predicated on the general principle that the upper bound of patient compliance is limited by the availability of sufficient medication. Prescription claims have been used to estimate compliance in such chronic disease states as hypertension,19 congestive heart failure,20 and glaucoma.21 In combination with medical records, pharmacy claims data can also be used to demonstrate relationships between compliance behavior and outcomes (eg, hospitalization risk and increased healthcare costs) and are useful in examining patient response to disease management programs designed to enhance compliance behavior.22 We utilized 4 measures of partial compliance: medication possession ratio (MPR), medication consistency, gaps in medication therapy, and medication persistence.13,23,24 MPR, the most frequently used assessment in compliance evaluation, is a composite measure that incorporates assessment of both “skipping” and “quitting.”13,23 Consistency and medication gaps estimate compliance with reference to “skipped” doses. Persistence identifies discontinuation (quitting) behavior or a gap at the end of the observation period. A detailed description of each measure with an example calculation is provided in Table 1. Utilizing all these 4 definitions, a recent study by Weiden and colleagues examined the relationship between partial compliance with antipsychotic treatment (MPR <0.7) and mental health hospitalization risk among 4325 outpatients diagnosed with schizophrenia in a California Medicaid database.24 The investigators found that lower compliance (across all 4 definitions) was associated with increased odds of hospitalization. Another study showed a similar relationship

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Table 1 Compliance Measures, Assessed Behaviors, Calculation Details, and Example Calculations Measure

Behavior assessed

Example calculation*

Calculation details

MPR

Skipping Number of ambulatory days that any medication from the doses, quitting category of interest (eg, antipsychotics) is available (based medication on dispensing dates and days’ supply) divided by the number of ambulatory days in the study period. This combines noncompliance during therapy and noncompliance after therapy is discontinued into 1 measurement (range: 0-1, or 0%-100% if multiplied by 100)

50% MPR = 30 + 30 + 30 days/180 days

Consistency

Skipping doses Sum of the days’ supply dispensed between the first and last prescription (not counting days’ supply on last prescription) divided by number of days between fill dates of first and last prescription. Repeated for each drug entity (eg, risperidone, olanzapine, haloperidol) in the category of interest (eg, antipsychotics) and a weighted average (based on days’ supply) is taken across all drugs in the category, eliminating the effect of nonpersistent behaviors (range: 0-1, or 0%-100% if multiplied by 100)

50% consistency during therapy = (30 days + 30 days)/120 days

Medication gap Skipping doses Number of ambulatory days where no medication from the 3 gaps, 30 days each category of interest (eg, antipsychotics) is available based on Average gap: 30 days dispensing dates and days’ supply; represented as the number Maximum gap: 30 days of gaps, average gap or by maximum gap (reported in days) Persistence

Quitting medication

Number of days from dispensing date of first prescription to end of days’ supply of last prescription divided by total days in study period. This eliminates the effect of compliance behavior while drug was available (range: 0-1, or 0%-100% if multiplied by 100)

83% persistence = 150 days from start to end of therapy/180 days 17% reduction from 100% due to 30-day gap at end of observation period

A patient treated with monotherapy who receives 3 prescriptions, each for a 30-day supply, 60 days apart over a 180-day observation period. MPR indicates medication possession ratio. *

between partial or nonadherence to antipsychotic medication and rates of psychiatric hospitalizations in a Medicaid database of patients diagnosed with schizophrenia.25 Partial compliance has also been shown to be a risk factor for hospitalization in the Veterans Administration, with patients having lower compliance (MPR <0.8) almost 2.5 times more likely to be admitted than patients with higher compliance (MPR 0.8-1.1).23 Previous research has not determined if the relationship between compliance and hospitalization exists in patients with schizophrenia in a managed care plan. The purpose of our analysis was to investigate if the relationship between partial compliance and increased hospital risk exists in a national managed care population.

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Methods At the time of our data extraction, the PHARMetrics data set contained claims data from more than 57 managed care organizations and 33 million patients, representing a cross section of the United States. This mental health subset was extracted from the larger PHARMetrics managed care database encompassing data from January 1, 2000, through February 28, 2002. Internal Review Board assessment was unnecessary because all personal identifiers were removed and at no time did investigators have knowledge of patients’ identities. Patients meeting all the following criteria were included: • A diagnosis of schizophrenia or schizoaffective disor-

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Table 2 Descriptive Statistics for the Study Population Variable (N = 1499) Age, mean (SD) Gender Women Men Most frequent geographic area on claims by region East Midwest West South Unknown Most frequent payer type on claims Commercial Medicaid Medicare risk Self-insured Unknown Compliance Measures MPR, mean (SD) MPR categories *70% (compliant) <70% (noncompliant) Maximum gap in days, mean (SD) Maximum gap categories in days 0-10 11-30 >30

Consistency, mean (SD) Consistency categories* *70% (compliant) <70% (noncompliant) Persistence, mean (SD) Persistence categories *90% (compliant) <90% (noncompliant)

N (%) 45.1 (12.4) 800 (53.4) 699 (46.6) 246 (16.4) 1028 (68.6) 21 (1.4) 157 (10.5) 47 (3.1) 693 (46.2) 157 (10.5) 259 (17.3) 58 (3.9) 332 (22.1) 76.1 (24.7) 1047 (69.8) 452 (30.2) 50.8 (72.5) 508 (33.9) 395 (26.4) 596 (39.8) 83.3 (20.6) 1077 (77.0) 322 (23.0) 92.6 (19.3) 1325 (88.4) 174 (11.6)

*The number used for consistency calculation is 1399. MPR indicates medication possession ratio.

der (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] codes of 295.XX, 296.0X, 296.1X, 296.4X, or 296.9X) at any point during the period of available data • At least 1 oral antipsychotic claim in 1999 • At least 2 dispensing events for any antipsychotic medication during the specified enrollment period (January 1, 2000-December 31, 2001)

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• Continuous enrollment in the same plan for at least 13 months after the index date (defined as the date of the patient’s first antipsychotic prescription during the enrollment period). As in the Weiden study,24 patients were excluded if they resided in a long-term care setting, received decanoate forms of antipsychotics, had a ratio of days dispensed to days’ supply of ≥10 (an indication of potential problems with the days’ supply field), had any missing or zero values in the quantity dispensed or days’ supply field for any prescription event, had a bipolar diagnosis (ICD-9-CM codes of 296.0, 296.1, 296.4-296.8), or were more than 18 years of age. This type of exclusion ensures that medication gaps accurately depict partial compliance in patients with schizophrenia.24 The primary dependent measure was a dichotomous variable indicating the presence of at least 1 “mental health–related” hospitalization in the postindex year. Each unique hospitalization event was identified using an algorithm supplied by PHARMetrics. ICD-9-CM codes were selected for diagnoses for which antipsychotic use might prevent hospitalization.24 Compliance results were analyzed as both categorical and continuous measures. Using chi-square analysis, compliance measures were categorized according to predefined ranges to assess the relationship between categories and risk of hospitalization. Maximum gap categories were defined as 0, 1–10, 11–30, or >30 days; medication consistency and MPR categories, ≥70% compliance as good compliance and <70% compliance as partial compliance; medication persistence categories, ≥90% compliant and <90% as partial compliance or discontinued therapy. The literature suggests that a cutoff at 70% for MPR compliance measurements is reasonable. These levels were selected to maintain consistency in reporting the findings between this managed care population and the Medicaid population.24 Continuous measures were used for the logistic regression analyses to model relationships between various compliance measures and the presence of a mental health hospitalization during the 12-month follow-up. Independent models were used to analyze maximum gap, consistency and persistence, persistence alone, and MPR. Age and gender were also included in the logistic regression models as independent factors. Interactions were retained in the model if they added significantly to the explanatory power; variables were eliminated if they were insignificant and had a negative impact on model fit.

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Figure 1 Hospitalization Rate as Measured by Maximum Gap (Days) in Medication Therapy Percentage of patients with indicated maximum gap that experienced at least 1 mental health hospitalization within 12 months of the index date

0.1

Hospitalization rate, %

Results A total of 1499 patients met study inclusion and exclusion criteria, of which 699 (46.6%) were men and 800 (53.4%) were women (Table 2). The mean patient age (years ± SD) was 45.1 ± 12.4, ranging from 18 to 95 (median 46). Some 89 patients (5.9%) had at least 1 mental health hospitalization during the 12 months after the index date. The mean number ± SD of mental health hospitalizations per patient was 0.08 ± 0.35; the maximum number of mental health hospitalizations was 4. The mean number of hospitalized days per patient was 0.68 ± 3.94 (range 0-87). The mean number ± SD of dispensing events (prescription claims) in this population was 12.9 ± 9.3, and there was an average ± SD of 1.34 ± 0.63 different antipsychotic drug entities dispensed per patient. A total of 1399 patients had at least 3 dispensing events for a single drug, permitting assessment of medication consistency. On average, the study population seemed compliant, with mean values ± SD of 0.833 ± 0.206 for consistency, 0.926 ± 0.193 for persistence, and 0.761 ± 0.247 for MPR. The average theoretical maximum gap in therapy ± SD was 50.8 ± 72.5 days (median 19 days). Regarding medication gap analysis, the percentage of patients with at least 1 mental health hospitalization rose with each increasing increment of maximum gap (Figure 1). A significantly higher proportion of patients with a maximum gap >30 days (10.1%) experienced a mental health hospitalization than did those with maximum medication gaps of 1 to 10 days (2.3%; P <.001 vs >30 days) and 11 to 30 days (4.6%; P = .0016 vs >30 days). Comparisons to patients with a maximum gap of 0 days are noteworthy despite the relatively small number of patients (n = 33). No patients with 0 days of maximum gap were hospitalized. A 0- to 10-day gap category (combining the 0 and 110–day groups) was used as the reference group in the logistic regression since there were no hospitalizations for patients in the 0 days of maximum gap category (ie, the logistic regression will not converge). Compared with patients in the 0- to 10-day group, the odds of hospitalization were 2.099 times greater (P = .0569) and 4.659 times greater (P <.001) for the 11- to 30-day and >30-day groups, respectively (Table 3). Maximum gap length was also evaluated as a continuous measure using logistic regression analysis. In this model, each increase of 5 days in maximum potential gap per prescription at any time during the 1-year study was associated with a 2.1% increase (P = .004) in the odds of hospitalization. In addition, a 10-year increase in age was associated with reductions in the

10.1

0.1 0.1

5.9

0.1 4.6 0.0 2.3 0.0 0.0 0.0 0 A (n = 33)

1-10 B (n = 475)

11-30 C (n = 395)

>30 D (n = 596)

Total (N = 1499)

Gaps in medication therapy, days Chi-square analysis results D > C P = .0016 D > B P <.001

D > A P = .0629 C > B P = .0667

C > A P = .3825 B > A P = 1.000

Table 3 Odds of Hospitalization: Results of Logistic Models for Gaps in Medication Therapy, Consistency, Persistence, and Possession Ratio Odds of Hospitalization Estimate 95% CI Medication possession ratio

0.831

0.771-0.896

<.001

11-30 days

2.099

0.992-4.646

.0569

>30 days

4.659

2.510-9.477

<.001

Maximum gap (continuous measure)

1.021

1.009-1.032

.004

Medication consistency

0.812

0.735-0.899

<.001

Medication persistence

0.932

0.855-1.028

.1334

Maximum gap (0-10 days as reference):

CI indicates confidence interval.

risk of hospitalization in all maximum gap models described above (25.0%-26.7%; largest P ≤.018). Partial compliance, assessed using consistency and MPR, was significantly associated with increased risk of hospitalization (Figure 2). Patients who were ≥70% compliant, as measured by the MPR, were significantly less likely to have been hospitalized than those who

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Figure 2 Hospitalization Rate as Measured by MPR, Consistency, and Persistence Percentage of patients in indicated categories that experienced at least 1 mental health hospitalization within 12 months after the index date (chi-square analysis results)

P <.001

P = .1096

Hospitalization rate, %

10.4 9.6

8.2 8 5.5

6 4

4.0

2 0 *70

<70

*70

<70

*90

<90

(n = 452) (n = 1047) (n = 332) (n = 1077) (n = 174) (n = 1325)

MPR

Consistency

Persistence

MPR indicates medication possession ratio.

were <70% compliant (4% vs 10.4%; P <.001), as were those with consistency ≥70% versus <70% (4.0% vs 9.6%; P <.001). Using the more common 80% criterion for MPR and consistency, similar results were found. Patients who were ≥80% compliant, as measured by the MPR, were significantly less likely to have been hospitalized than those who were <80% compliant (3% vs 10.4%; P <.001), as were those with consistency ≥80% versus <80% (3.8% vs 8.5%; P <.001). The difference in hospitalization risk among patients who were <90% compliant by the persistence measure was not statistically significant when compared with patients who were ≥90% compliant (8.2% vs 5.5%; P = .1096). Logistic regression analyses supported the categorical analysis findings. The odds of hospitalization were significantly affected by both compliance and age when using either the MPR or the consistency models. A 10% increase in compliance was associated with reductions in the odds of hospitalization of 16.9% for MPR (P <.001) and 18.8% for consistency (P <.001). A 10year increase in age was associated with reductions in the risk of hospitalization, by 31.1% in the consistency model (P = .003), by 28.4% in the persistence model (P = .004), and by 26.1% in the MPR model (P = .012). Similar to the categorical analysis findings, medication persistence did not reach statistical significance as a predictor of hospitalization (P = .1334). Patient gender was not significant in the logistic regression models.

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Discussion The results of this retrospective study of pharmacy claims data from a large, national managed care database support the relationship, among patients with schizophrenia, between partial compliance with antipsychotic medication regimens and increased risk of mental health hospitalization. The relationship was statistically significant across 3 of the 4 definitions of compliance measured: maximum gap, medication consistency, and MPR. The results from categorical and logistic regression analyses were also similar across 3 of the 4 definitions. Although there is ample literature documenting noncompliance and increased relapse risk, many previous studies had only one measure for assessing noncompliance. Few studies have analyzed the impact of a comprehensive range of compliance behaviors. The conceptual framework and the compliance variables employed in our study are similar to those used in a recent study of patients with schizophrenia in a Medicaid population.23 The Medicaid study, based on a larger patient population (4325 vs 1499), produced results remarkably similar to those in the present study with regard to the relationship between compliance and hospitalization and the statistical significance of the findings. Both the Medicaid study and the current analysis were based on patient populations that had low discontinuation rates: 97.0% and 84.6% of the respective populations achieved persistence for >90% of the 1-year study period. Even within these relatively compliant, yet different patient populations, there was a significant and consistent relationship between multiple measures of partial compliance and increased hospitalization risk. The maximum gap findings, which defined 4 different categories of compliance as independent variables, are particularly compelling in this regard: the odds of hospitalization rose with each increment of partial compliance. Each 5-day increase in the maximum potential gap in therapy was associated with a 2.1% increase in the odds of hospitalization (eg, from 5.9% to 6.02% for a 5-day gap, or a 50-day gap increases the patients’ baseline risk level by 21%). If their baseline risk is 5.9%, the risk of hospitalization is 7.1% (5.9 ✕ 1.21) after a maximum potential 50-day gap in therapy. The average maximum gap in this population was 50.8 days between 2 prescriptions. This managed care study and the Weiden Medicaid study had the same directional relationship between persistence and hospitalization risk; however, the relationship was not statistically significant in the managed care population. The difference can be partially

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attributed to the different study population sizes. A relationship was expected because persistence is the measurement of the maximum gap that exists (if any) at the end of the study period. The most significant difference between the 2 study populations is the overall rate of psychiatric hospitalization; 5.9% in the managed care study versus 15.1% in the Medicaid study.17 It is difficult to identify a single factor that explains the 2.5-fold difference. It is possible that Medicaid patients may represent a more severe illness spectrum than do those in the PHARMetrics database. Although hospitalization rates differed in the 2 studies, both analyses indicated a significant relationship between partial compliance and risk of mental health hospitalization. Copayments were likely to be higher in the managed care (commercial) population versus the Medicaid population, and their hospitalization rates were lower. This study was subject to all of the limitations of a nonexperimental study. The presence of an association does not necessarily indicate causation. It is possible, and perhaps likely, that patients with poor compliance may also have other poor health habits that might be related to hospitalization; however, given the theoretical link between compliance and relapse in schizophrenia, the results are logical from a clinical standpoint. A double-blind randomized trial in which patients are randomly assigned to a noncompliant or subtherapeutic regimen with gaps in therapy is not likely to be seen as ethical, so nonexperimental designs are necessary. Other limitations in our study that may restrict the generalizability of these findings include the retrospective nature of the analysis and the use of inclusion/ exclusion criteria that resulted in a population with slightly higher levels of compliance than those in the general population (ie, patients who had <2 dispensing events/claims [ultra-low compliance, tolerability, or lack of efficacy] during the study period were excluded). Our data analysis was restricted to variables consistently represented in the PHARMetrics database and to plans that included “days’ supply” and “quantity dispensed” as part of pharmacy records. These data were necessary to calculate the partial compliance measures. Patient samples are not included in the claims database. Future research using medical records could be conducted to assess the association between compliance and more intermediate outcomes of relapse that occur before hospitalization. This would provide a more sensitive understanding of the negative patient outcomes prehospitalization and their relationship to compli-

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ance. Furthermore, a study conducted with intermediate negative outcomes from medical records could explore the potential modifiers of hospitalization risk that are not reflected in a claims database, including baseline disease severity, duration of schizophrenia, socioeconomic status, and the availability and use of nonpharmacologic (psychosocial) therapies. Increased attention to improving compliance across the entire range of partial compliance behavior and removing barriers to compliance (by using behavioral interventions, removing or lowering economic barriers such as copayments, or using new compliance-friendly drug delivery systems) may improve outcomes and lower costs in schizophrenia treatment. Future research is needed to determine if removal of economic barriers (copayments) directly results in a reduction in relapse costs through an improvement in compliance.

Conclusion The findings of this study, based on a managed care population of patients with schizophrenia, indicate that partial compliance with oral antipsychotic treatment is associated with a significantly increased risk of hospitalization. These results are consistent with a previous analysis of compliance measures in a Medicaid population of patients with schizophrenia. This present study highlights the central role of medication compliance in long-term treatment of schizophrenia. ■ Acknowledgment This study was supported by Ortho-McNeil Janssen Medical Affairs. Disclosure Statement Dr Kozman is a consultant for Ortho-McNeil Janssen. Dr Weiden receives grant support from AstraZeneca, Bristol-Myers Squibb/ Otsuka America Pharmaceutical, and Ortho-McNeil Janssen, and is a consultant for and on the Speaker’s Bureau for AstraZeneca, Bristol-Myers Squibb/Otsuka America Pharmaceutical, OrthoMcNeil Janssen, Organon, Pfizer, Shire, Vanda, and Wyeth.

References 1. Ayuso-Gutierrez JL, del Rio Vega JM. Factors influencing relapse in the long-term course of schizophrenia. Schizophr Res. 1997;28:199-206. 2. Weiden PJ, Olfson M. Cost of relapse in schizophrenia. Schizophr Bull. 1995;21:419-429. 3. Csernansky JG, Mahmoud R, Brenner R; Risperidone-USA-79 Study Group. A comparison of risperidone and haloperidol for the prevention of relapse in patients with schizophrenia. N Engl J Med. 2002;346:16-22. 4. Velligan DI, Lam F, Ereshefsky L, et al. Psychopharmacology: perspectives on medication adherence and atypical antipsychotic medications. Psychiatr Serv. 2003;54:665-667. 5. Wu EQ, Birnbaum HG, Shi L, et al. The economic burden of schizophrenia in the United States in 2002. J Clin Psychiatry. 2005;66:1122-1129. 6. Zhang D, Carlson AM, Gleason PP, et al. Relationship of the magnitude of member cost-share and medication persistence with newly initiated

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renin angiotensin system blockers. J Manag Care Pharm. 2007;13: 664-676. 7. Taira DA, Wong KS, Frech-Tamas F, et al. Copayment level and compliance with antihypertensive medication: analysis and policy implications for managed care. Am J Manag Care. 2006;12:678-683. 8. Roblin DW, Platt R, Goodman MJ, et al. Effect of increased cost-sharing on oral hypoglycemic use in five managed care organizations: how much is too much? Med Care. 2005;43:951-959. 9. Goldman DP, Joyce GF, Karaca-Mandic P. Varying pharmacy benefits with clinical status: the case of cholesterol-lowering therapy. Am J Manag Care. 2006;12:21-28. 10. Goldman DP, Joyce GF, Escarce JJ, et al. Pharmacy benefits and the use of drugs by the chronically ill. JAMA. 2004;29:2344-2350. 11. Chernew ME, Shah MR, Wegh A, et al. Impact of decreasing copayments on medication adherence within a disease management environment. Health Aff (Millwood). 2008;27:103-112. 12. Lacro JP, Dunn LB, Dolder CR, et al. Prevalence of and risk factors for medication nonadherence in patients with schizophrenia: a comprehensive review of recent literature. J Clin Psychiatry. 2002;63:892-909. 13. Docherty JP, Grogg AL, Kozman C, et al. Antipsychotic maintenance in schizophrenia: partial compliance and clinical outcome. Poster presented at: the American College of Neuropsychopharmacology 41st Annual Meeting; December 8-12, 2002; San Juan, Puerto Rico. 14. McCombs JS, Nichol MB, Stimmel GL, et al. Use patterns for antipsychotic medications in Medicaid patients with schizophrenia. J Clin Psychiatry. 1999;60(suppl 19):5-11; discussion 12-13. 15. Keith SJ, Kane JM. Partial compliance and patient consequences in schizophrenia: our patients can do better. J Clin Psychiatry. 2003;64: 1308-1315.

16. Marder SR. Overview of partial compliance. J Clin Psychiatry. 2003;64(suppl 16):3-9. 17. Steiner JF, Koepsell TD, Fihn SD, et al. A general method of compliance assessment using centralized pharmacy records: description and validation. Med Care. 1988;26:814-823. 18. Steiner JF, Prochazka AV. The assessment of refill compliance using pharmacy records: methods, validity, and applications. J Clin Epidemiol. 1997;50:105-116. 19. Maronde RF, Chan LS, Larsen FJ, et al. Underutilization of antihypertensive drugs and associated hospitalization. Med Care. 1989;27:11591166. 20. Monane M, Bohn RL, Gurwitz JH, et al. Noncompliance with congestive heart failure therapy in the elderly. Arch Intern Med. 1994;154:433-437. 21. Gurwitz JH, Glynn RJ, Monane M, et al. Treatment for glaucoma: adherence by the elderly. Am J Public Health. 1993;83:711-716. 22. Skaer TL, Sclar DA, Markowski DJ, et al. Effect of value-added utilities on prescription refill compliance and Medicaid health care expenditures—a study of patients with non-insulin-dependent diabetes mellitus. J Clin Pharm Ther. 1993;18:295-299. 23. Valenstein M, Copeland LA, Blow FC, et al. Pharmacy data identify poorly adherent patients with schizophrenia at increased risk for admission. Med Care. 2002;40:630-639. 24. Weiden PJ, Kozma C, Grogg A, et al. Partial compliance and risk of rehospitalization among California Medicaid patients with schizophrenia. Psychiatr Serv. 2004;55:886-891. 25. Gilmer TP, Dolder CR, Lacro JP, et al. Adherence to treatment with antipsychotic medication and health care costs among Medicaid beneficiaries with schizophrenia. Am J Psychiatry. 2004;161:692-699.

Stakeholder Perspective Encouraging Compliance Key for Positive Outcomes in Schizophrenia/Chronic Diseases PATIENTS: Although schizophrenia is a particularly onerous disease, all chronic diseases have many issues that are exacerbated by noncompliance. Patients would be better able to function in society when maintained on proper medication therapy. Medication compliance is not easy for the patient with schizophrenia and often requires an involved family/community support system to remain engaged and ensure favorable outcomes. All patients need to be active participants in their therapy, understanding disease progression and the consequences of poor management. Of particular interest in this study is that Medicaid schizophrenia patients had a much greater relapse and hospitalization rate than other patients, suggesting that although out-of-pocket cost can be a determining factor of noncompliance, other issues likely have notable impact on medication compliance. Realistically, although particularly dramatic in schizophrenia, noncompliance will have negative results for all patients requiring maintenance therapies. PHYSICIANS: Physicians must help manage patients’ expectations and educate them about the

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importance of medication compliance. They need to direct patients to social support services and know what programs can be accessed to relieve financial burdens of medication compliance. Physicians could also have patients’ refill records provided on a regular basis or during follow-up visits to confirm compliance. PAYERS: Payers need to drive value-based care by finding opportunities to encourage compliance. This, in return, will provide benefits by decreasing the need for additional service and care driven by adverse events associated with noncompliance. Payers must look at all available tools to keep patients compliant, focusing on their physician and pharmacy providers to identify at-risk patients and provide follow-up care. Using educational programs, disease management programs, and counselors as needed to provide patients with pathways to selfadvocacy is imperative to ensure compliance Paul Anthony Polansky, BSPharm, MBA Executive Vice President and Chief Pharmacy Officer Sanovia Corporation, Philadelphia, PA

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Alzheimer’s Disease: A Healthcare Burden of Epidemic Proportion T.S. Dharmarajan, MD, FACP, AGSF; Srinivas G. Gunturu, MD Alzheimer’s disease is the most common cause of dementia and increases in prevalence exponentially with age, with trends in the United States likely to worsen in ensuing decades. The pathology in Alzheimer’s disease is characterized by an increase in extracellular amyloid plaques and intraneural neurofibrillary tangles, with neuronal destruction in several areas of the brain, and biochemically by a deficiency in acetylcholine; clinical manifestations include progressive loss of memory, change in personality, and behavioral disturbances. Pharmacotherapy includes the T.S. Dharmarajan Srinivas G. Gunturu use of cholinesterase inhibitors and memantine; addressing the many behavioral manifestations of the disease, especially in advanced stages, imposes tremendous burden to caregivers and healthcare resources. [AHDB. 2009;2(1):39-47.]

lzheimer’s disease (AD), the most common cause of dementia, increases in prevalence exponentially with age, and the trend of growing incidence of the disease is likely to continue in the United States. Alzheimer’s dementia is a common, acquired disorder that is manifested as slowly progressive memory loss with at least 1 cognitive dysfunction (ie, aphasia, apraxia, agnosia, or executive dysfunction) and resulting in impaired occupational and social performance. The deterioration in cognition from earlier levels must occur in the absence of delirium or other causes of dementia (eg, Parkinson’s disease or vascular dementia).1,2 The National Institute of Neurologic and Communicative Disorders and Stroke-Alzheimer’s Disease and Related Disorders Association classifies AD as3,4: • Definite—clinical diagnosis and histology confirmed • Probable—clinical syndrome, no histology • Possible—atypical presentation, no alternative diagnosis or histologic proof. It is important to distinguish AD, which refers to the pathologic changes in the brain, from Alzheimer’s dementia, which refers to the clinical manifestations. AD is more common than Alzheimer’s with dementia; not everyone with AD, even AD that is proved at

Dr Dharmarajan is Vice-Chairman, Department of Medicine, Clinical Director, Division of Geriatrics, Montefiore Medical Center, North Division, Bronx, and Professor of Medicine and Associate Dean, New York Medical College, Valhalla, NY; Dr Gunturu is a resident, Department of Medicine, Montefiore Medical Center, North Division, Bronx, NY.

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autopsy, necessarily manifests the clinical features of dementia. There are currently more than 5 million Americans with AD, and the prevalence increases with age. The prevalence of AD is 4% among people younger than 65 years, which increases to more than 13% in the older than 65-year age-group, and up to 50% in the older than 85-year age-group.5 But these US trends are not universal. In Japan, vascular dementia is more common than Alzheimer’s dementia.6 The US Alzheimer’s Association predicts a surge in the incidence of AD in the baby boom era (Figure 1). AD is the fifth leading cause of death in people older than 65 years in the United States.7

Economic Burden of AD With annual costs exceeding $100 billion, dementia in AD is the third most costly illness in the United States, following heart disease and cancer.8 The annual cost of caring for AD varies from $42,049 for institutionalized patients to $12,572 for patients living in the community.9 However, the tremendous mental and physical burden costs on the caregiver are hard to delineate. Delay in disease progression through early diagnosis and early initiation of therapy may cut costs. Direct costs are incurred for long-term care in nursing homes or by physicians; indirect costs include lost productivity of caregivers.10 Because a major AD epidemic is being forecast, health plans and the healthcare system must be prepared to fund the care of the many potential patients.

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KEY POINTS ▲ Alzheimer’s disease, the most common cause of dementia, is

a major healthcare burden, with a prediction for worsening trends in the United States. ▲ Key features are insidious onset, memory loss, and cognitive

decline, coupled with personality changes. ▲ Nonpharmacologic measures in management are as impor-

tant as pharmacotherapy to address wandering, agitation, feeding difficulties, falls, incontinence, and cognition. ▲ Cholinesterase inhibitors and N-methyl-D-aspartic acid

receptor antagonists are the mainstay of pharmacotherapy, but no medication today can reverse or cure the disease. ▲ The healthcare infrastructure needs to address the needs of

patients with Alzheimer’s disease and associated caregiver burden.

Figure 1 Projected Annual Incidence of Alzheimer’s Disease in the United States 1,200,000

New cases per year

1,000,000

800,000

600,000

400,000

200,000

0 2000

2010

2030

2050

Year Source: Alzheimer’s Association. Alzheimer’s disease facts and figures. 2008. www.alz.org/national/documents/report_alzfactsfigures2008.pdf.

Initiating early interventions in community-living patients with AD often is associated with lower overall costs compared with costs for institutional placement.10 Table 1 outlines the economic impact of AD and dementia on the healthcare system.11

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Neuropathology The core of AD pathology involves formation of amyloid neuritic plaques and neurofibrillary tangles (NFTs). Beta-amyloid (Aß) 42 is derived from proteolysis of amyloid precursor protein, which undergoes polymerization to form abnormal, insoluble, sticky amyloid plaques, resulting in inflammation and loss of neurons in areas of the brain involving memory and cognition (Figure 2). Hyperphosphorylation of tau protein leads to formation of insoluble intraneuronal NFTs and to neuronal destruction. Senile plaques and NFTs are markers of AD. In patients with AD, senile plaques are seen throughout the neocortex, whereas NFTs are seen in the amygdala, hippocampus, thalamus, association areas, and the cortical region. Although amyloid plaques and NFTs occur with normal aging, it is the distribution, density, and neuronal loss in the association areas and the cerebral cortex that characterize Alzheimer’s dementia. Because these plaques and tangles are insoluble, future therapy should focus on prevention strategies. Risk Factors Of the different risk factors that have been linked to AD and dementia, aging is the most important factor. Data are inconsistent for most of the other risk factors, which include genetic factors, white race, female sex, low education level, poor physical status, a history of head trauma, depression or postoperative delirium, family history of dementia, elevated C-reactive protein, and lower household income. Predisposition to dementia in general is linked to low thyroid-stimulating hormone, hypertension, folic acid or vitamin B12 deficiency, elevated homocysteine levels, hyperlipidemia, smoking, diabetes mellitus and metabolic syndrome, and cerebrovascular disease. Although no single risk factor is known to cause Alzheimer’s dementia, it is tempting to speculate an interplay between aging and genetics, modified by environmental factors. The link between AD and genes is evident in early- and late-onset AD, but no single genetic etiology is known to cause AD. The neuropathology of AD mimics Down syndrome; patients with Down syndrome who live to age 40 manifest neuropathology identical to Alzheimer’s dementia. In early-onset familial AD, genes PS1, APP, and PS2 are linked to chromosomes 1, 14, and 21; late-onset AD is linked to the APOE gene and to chromosome 19. The €4 allele of the APOE gene is implicated in increased risk of late-onset AD, whereas €2 allele appears protective, and €3 allele is neutral.

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Clinical Features of Dementia in AD The onset of dementia in AD is insidious, with a progressive decline in functioning level. Possibly the earliest stage is mild cognitive impairment (MCI), which is evident without impairment in social or occupational functioning. Cognitive impairment without dementia is more prevalent than dementia; the Aging, Demographics and Memory Study found that 22% of adults older than 71 years in the United States had cognitive impairment without dementia; 8% died and 11.7% advanced to dementia annually.12 The conversion rate is 1% to 2% annually.13 MCI is common and is considered a precursor to dementia, but not necessarily Alzheimer’s dementia. A diagnosis at this early stage helps delay onset of dementia and nursing home placement. The 3-stage classification categorizes Alzheimer’s dementia into mild, moderate, and severe stages.14 A diagnosis is often missed by the first physician consulted, and “normal aging” is a common misdiagnosis.10 In mild dementia, patients have memory loss for recent events and are unable to learn new facts; welleducated patients may mask their difficulties. Subtle personality changes are evident. Behavioral and motor changes are not evident, and patients are independent for activities of daily living (ADLs). In moderate dementia, worsening of recent, remote, and recall memory is more readily apparent, along with significant cognitive impairment and personality changes. Behavioral changes include agitation, aggressive behavior, anxiety and depression, with partial dependence for ADLs. With severe or advanced Alzheimer’s dementia, memory, language, and cognition are markedly impaired, requiring complete caregiver dependence. The patient is incontinent, unable to feed or swallow, resulting in poor nutrition, and speech deteriorates to a few words and can include echolalia and palilalia. Patients are lost in familiar environments; wandering, falls, and accidents are common. At this stage, nursing home placement and means for nutrition are at stake. Cognitive Assessment The Mini-Mental State Examination (MMSE) is a common screening instrument used to evaluate cognition, and is administered in less than 10 minutes. A score higher than 24 does not rule out dementia nor does a score below 24 confirm dementia; age and educational status influence the score. MMSE scores deteriorate at a rate of about 4 points annually in Alzheimer’s dementia.

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Table 1 Economic Impact of Alzheimer’s Disease, 2000 Economic costs • Dementia increased the cost of care 3-fold compared with care for patients without dementia (about $13,000 vs $4500 per person) • Patients with dementia stayed in the hospital 3.4 times longer than cognitively intact patients • Hospital stays for dementia cost 3.2 times more compared with patients without dementia • When additional comorbidity occurred (coronary heart disease, heart failure, diabetes, chronic obstructive lung disease), costs for patients with dementia doubled or more compared with patients without dementia • Medicare home care costs were 3.8 times higher than patients without dementia • More physician visits were required for patients with dementia than for other Medicare beneficiaries • Costs are high for care of Alzheimer’s dementia patients in all settings: at home, in daycare, in an assisted-living facility, and in a nursing home Health plan policy recommendations from the Alzheimer’s Association • Include affordable prescription drug benefits • Include medication management, education of family or caregiver, multidisciplinary care conferences, and help access community resources • Provide benefits to include home visits by nursing or other professionals • Targeted coordinated care to benefit those with dementia Adapated with permission from Alzheimer’s disease and chronic health conditions: the real challenge for 21st century Medicare. © Alzheimer’s Association. www.alz.org/national/documents/report_chroniccare.pdf.

The Clock Drawing Test (CDT) is easily administered. The Mini-Cog test is a composite of the CDT combined with a “3-item recall”; its strengths are brevity and ease of administration. The Mini-Cog test takes no more than 5 minutes and appears more valid in better-educated individuals. The Functional Assessment Staging and Global Deterioration Scale help evaluate functional deterioration and dependency for assistance.

Evaluation Most important in the evaluation of dementia in AD is the initial focused history (and physical examination), with the history obtained separately from the patient and from a family member or caregiver who truly knows the patient. A diagnosis of Alzheimer’s dementia can be made

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by the primary physician and is considered a diagnosis of inclusion rather than of exclusion.

Drug-Induced Memory Loss Several medications can lead to memory impairment; a detailed review of over-the-counter drugs and supplements is indicated, especially products with anticholinergic activity that are known to worsen cognition. Decline in cognition results from the drugs blocking muscarinic receptors; the resulting worsening of working memory, speed of processing, and praxis predict overall performance and cognitive status, as well as its impairment.15 A recent study of 107 medications revealed moderate-to-severe anticholinergic activity with many frequently used medications (oxybutinin, tolterodine, diphenhydramine, amitriptyline, thioridazine, among

others) warranting caution with their use in dementia.15 These drug-induced anticholinergic effects can cause cognitive deficits that resemble dementia and have the potential to worsen memory in those with MCI.

Diagnosis A patient with dementia should be offered neuroimaging at least once, to exclude treatable causes; a computed tomography scan or magnetic resonance imaging will demonstrate common structural alterations in the brain. No specific pattern in imaging is diagnostic of Alzheimer’s dementia. Brain atrophy in neuroimaging is common in older adults; although seen in AD, atrophy by itself is not diagnostic of cognitive impairment. Lately, there is increasing awareness of the role of positron emission tomography (PET) imaging in early diagnosis of Alzheimer’s dementia through mea-

Figure 2 Neuropathophysiology of Alzheimer’s Disease APP

Alpha-secretase

Gamma-secretase

Beta-secretase

Future role for secretase inhibitors or PPAR-γ agonists Alpha APP (soluble fragments)

Insoluble, toxic beta-amyloid

Beta-amyloid aggregation and senile plaques

Mechanisms: inflammation, oxidation, ischemia

Tau hyperphosphorylation and neurofibrillary tangles

Neuronal destruction AChE Role for memantine (NMDA receptor antagonist)

Role for AChE inhibitors Acetylcholine deficit

Cognitive impairment Behavioral alterations Features of Alzheimer’s dementia

APP indicates amyloid precursor protein; PPAR-γ, peroxisome proliferator-activated receptor-gamma; AChE, acetylcholinesterase; NMDA, N-methyl-D-aspartate.

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surement of decreased localized glucose metabolism correlating with loss of cognition. PET scans have the potential to help make the diagnosis before advanced clinical manifestations develop, with reasonable sensitivity (84%-93%) and specificity (93%) even in the stage of MCI.16 The scan also helps distinguish Alzheimer’s dementia from other dementias.10 Although no single laboratory test is diagnostic of AD or dementia, routine and some individualized tests can be used to delineate any treatable cause. Genetic testing for AD is not routinely offered at this time.17 Finally, the differential diagnosis of Alzheimer’s dementia includes other causes of dementia, including vascular dementia, Lewy body dementia, frontotemporal dementia, dementia of Parkinson’s disease, normal pressure hydrocephalus, and reversible causes, such as hypothyroidism and B12 deficiency, among others. Delirium, a short-term disorder that causes alteration in level of mentation and difficulties in sustaining attention, as well as depression, can mimic or complicate dementia; these are reversible and their treatments differ from that of Alzheimer’s dementia.

Management Early diagnosis of Alzheimer’s dementia helps plan the future, and initiation of therapy with cholinesterase inhibitors (ChEIs) to maximize benefit in preserving functional status. Besides cognition, many aspects of AD demand attention.18 Behavioral manifestations of dementia are foremost in AD, demanding caregiver attention and difficulties in management of wide-ranging moods; in one study, apathy, agitation, aggressive behavior, and depression were most common, whereas hallucinations and delusions, anxiety, and wandering were less common.19 Sudden alterations in behavior warrant a search for causes that precipitate delirium, such as infection, pain, electrolyte imbalance, or medication-related adverse effects. Approaches to treatment include empathy, tact, ensuring safe environments, and pharmacotherapy. Therapeutic touch (namely, a meditative, compassionate hand touch to help or heal) can help minimize agitation.20 Visual and hearing impairments are common with aging and contribute to even greater handicaps in Alzheimer’s dementia. Because they may be a cause of behavioral changes, glasses and hearing aids should be available at all times. Several simple measures can be instituted to provide a safe environment in the home, hospital, or institution. Measures for environment safety minimize falls.

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These include appropriate carpeting (avoid scatter rugs); avoidance of slippery floors (in bathrooms) and clutter; use of cordless phones, handrails, and proper lighting; and so on. Difficult decisions may lead to frustration and agitation.21 When patients are agitated, arguments are pointless. Restraints are discouraged, and should be used short-term, weighing the benefit against the burden. Cognitive training may benefit daily functional activities. In aimless wanderers, precipitating factors need to be looked for and rectified. Sleep disturbances are handled through regular sleep schedules, evening exercises, avoidance of bright light and noise, and limiting fluids in the late hours to decrease bathroom visits at night. Regular ongoing physical activity correlates with cognitive improvement.22 Worsening confusion at night or evenings (“sundowning”) is addressed by reducing sensory stimuli, use of night lights, and familiar contacts and environment. As the disease progresses, dietary restrictions are minimized, with quality of life (QOL) gaining greater importance. In terminal stages, a common consideration is the insertion of a percutaneous endoscopic gastrostomy (PEG) tube for enteral feeding, a decision fraught with ethical dilemmas.23 Studies have not confirmed that PEGs prolong life, improve QOL or nutritional status, or lower the likelihood for pressure ulcers and aspiration pneumonia. Nearly half of terminal AD patients who receive PEG tubes die within a year.23 Advance directives are ideally implemented early when the patient still has some capacity to make decisions. A durable power of attorney for healthcare (healthcare proxy) can make decisions on behalf of the patient who loses capacity in advanced disease. Hospitals and institutions are required to document whether patients have advance directives and if they do not, offer an opportunity to execute one. In general, we address advance directives inadequately; in our hospital, we have demonstrated that efforts by health providers result in vastly improved responses from patients.24

Pharmacotherapy Goals of pharmacotherapy (Table 2) in AD are to preserve cognition and function to the extent that is possible, slow progression of the disease, and address behavioral disturbances.25 Cholinesterase Inhibitors Several ChEIs (acetylcholinesterase, butyrylcholinesterase) are the mainstay of treatment based on the principle of enhancing neurotransmitter function and

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acetylcholine availability at the neurons. No agent prevents neuronal death. Tacrine (Cognex), the first ChEI developed, is no longer used because of its adverse effects; 3 additional ChEIs are generally similar in effectiveness. Clinicians should choose a pharmacologic agent based on tolerability, adverse effects, cost, and ease of use; the evidence to compare the effectiveness is weak based on review of studies presented in recent guidelines.26,27 They differ in pharmacokinetics and side effects. Significant anecdotal and unproved use of combinations also exist.28 Peak efficacy is attained in 3 months.25 In mild-to-moderate forms of AD, a single ChEI is typically used. In moderate-to-severe stages, a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, memantine (Namenda) may be indicated (with or without a ChEI) to enhance cognition, func-

tion, and behavior-related measures. Memantine is an antiglutamatergic agent; glutamate is a neurotransmitter essential for learning and memory through facilitation of NMDA receptors.27 For those with dysphagia, liquid formulations are available. Another option is transdermal rivastigmine (Exelon), associated with better gastrointestinal tolerance and potentially improved adherence to regimen.29 Withdrawal of a drug may lead to rapid loss of efficacy and clinical deterioration, whereas appropriate use can delay nursing home placement, a stated priority for caregivers, and help manage adverse behaviors.28

Antipsychotics When behavioral disturbances become worse and nonpharmacologic approaches fail, medications may be tried for that purpose. General principles of psychotrop-

Table 2 Pharmacology of Alzheimer’s Disease Mechanism of action

Drug

Dose

Indication, additional requirements

Food interactions Metabolism Food decreases absorption

Tacrine

AChE* and BuChE* inhibitor

10-40 mg q6h

Follow liver function tests, no longer used

Donepezil

AChE inhibitor

5-10 mg/d

1.5-6 mg bid

Half-life Elimination Adverse effects

CYP*1A2

2-4 h

Mild-to-moderate None dementia

CYP*2D6

70-80 h Hepatic

Mild-to-moderate Delays dementia, also available as transdermal patch

Cholinesterase- 1.5-2 h mediated hydrolysis

Galantamine AChE 4-12 mg inhibitor bid and nicotine modulatory receptor effect

Mild-to-moderate Decreases dementia

CYP2D6, CYP3A4

5-7 h

Memantine

Moderate-tosevere dementia

Nonhepatic

60-80 h Renal (active tubular secretion)

Rivastigmine AChE and BuChE inhibitor

NMDA receptor antagonist

5-20 mg/d

None

Hepatic

Approx. cost per month, $

Withdrawal (up to 310-360 55%), maximum side effects, abnormal liver function, nausea, vomiting, diarrhea Withdrawal (0%57%), nausea, vomiting, diarrhea

170-190

Renal

Withdrawal (12%29%), nausea, vomiting, diarrhea, confusion, insomnia

184-193

Renal and hepatic

Withdrawal (8%-54%), nausea, vomiting, diarrhea, anorexia

180-380

Withdrawal (95%-12%), nausea, diarrhea, dizziness, agitation

130-160

AChE indicates acetylcholinesterase; BuChE, butyrylcholinesterase; NMDA, N-methyl-D-aspartate; CYP, cytochrome P 450. *Average cost in the United States (not standardized). Sources: Geldmacher DS. Alzheimer’s disease: current pharmacotherapy in the context of patient and family needs. J Am Geriatr Soc. 2003;51:S289-S295; Qaseem A, Snow V, Cross JT Jr, et al. Current pharmacologic treatment of dementia: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med. 2008;148:370-378; Standridge JB. Current status and future promise of pharmacotherapeutic strategies for Alzheimer’s disease. J Am Med Direct Assn. 2005;6:194-199; Xiong G, Doraiswamy PM. Combination drug therapy for Alzheimer’s disease: what is evidence-based, and what is not? Geriatrics. 2005;60:22-26.

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ic therapy that apply to the elderly include a “start low, go slow” approach, understanding the pharmacokinetic changes with aging, and monitoring for side effects. Drug therapy should be considered short-term (3-6 months), with intent to terminate therapy after resolution of symptoms, as adverse events evolve with time.28 Antipsychotics include the traditional haloperidol (Haldol) and risperidone (Risperdol) and the atypical antipsychotics olanzapine (Zyprexa) or quetiapine (Seroquel). The antidepressants paroxetine (Paxil), sertraline (Zoloft), and citalopram (Celexa); valproic acid (Depakote); and others are used for agitation or difficult behavior.2,28 Keeping the dose low minimizes adverse effects, such as movement disorders. Some atypical drugs have been linked to the development of glucose intolerance and vascular complications with long-term use.

Caregiver Burden The majority of patients (70%) with AD—with or without dementia—live in the community and are dependent on caregivers, typically a woman (wife or daughter); hence the need to understand the existence of “caregiver burden” requiring support. Caregivers need education and counseling to understand the course of AD and the means to deal with the family member who has the disease. A pilot study demonstrated that home care agencies can assess specific caregiver needs and help improve caregiver mastery to decrease strain.30 Caregivers of demented individuals tend to devote precious time for caregiving, often at the expense of their own occupational or leisure activities, and suffer from physical, mental, and emotional stress.31 Caregivers often suffer from depression, musculoskeletal disorders, and hypertension. Institutionalization of patients with AD associated with dementia results from 1 or more variables that are patient-related (aggressive behavior, incontinence, feeding difficulties, terminal dementia) or caregiverrelated (poor health, financial impact, poor support, depression, impaired QOL). Medicare Coverage for Care in AD The majority of patients with AD and dementia are likely to be older than 65 years of age and eligible for Medicare, which includes coverage for: • Hospital stay at variable rates (which is influenced by illness severity, management strategies, and duration of stay) • Skilled nursing care only after a hospital stay of 3 days

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or more (and demonstrating a need for skilled care) • Home healthcare and “reasonable and necessary” physician visits. The 2003 Medicare Modernization, Improvement, and Prescription Drug Act (Part D) introduced voluntary prescription drug coverage applicable to Medicare beneficiaries. The Centers for Medicare & Medicaid Services requires health plans to cover essentially all protected drug classes used in AD (eg, antipsychotics and antidepressants), as well as two thirds of the drugs used in AD in nonprotected classes.

Although ChEIs are covered by Medicare to the tune of 67% to 100%, prior authorization is required 12% to 25% of the time. Similar formulary coverage is available for antipsychotics. Although ChEIs are covered by Medicare to the tune of 67% to 100% (depending on a given drug within the class), prior authorization is required 12% to 25% of the time.32 Similar formulary coverage is available for antipsychotics. Nursing homes and pharmacies identify a set of preferred drugs in each class, with some choices available.32 Medicare provides coverage for PET scans, based on documentation of recent dementia and cognitive decline of at least 6-month duration, and when the patient meets diagnostic criteria for AD and frontotemporal dementia, as ascertained by the provider. Finally, it is apparent that patients with Alzheimer’s dementia manifest more comorbidity than matched controls, and therefore cost more to care for. Annual costs are 34% higher for patients with Alzheimer’s dementia compared with those without dementia; outpatient pharmacy is a major cost factor.33

Future Perspectives Earlier diagnosis of AD may help alter its course. Detection of tau protein and Aß42 measurements in cerebrospinal fluid have the potential to discriminate early Alzheimer’s dementia from other causes of memory loss.34 The role for PET scans and genetic testing in the diagnosis may change in the future. Exploring the region-specific decline in cerebral glucose metabolism in AD may be a novel approach in the future. Data on the role for testosterone, estrogen, vitamins E and C,35 and beta-carotene are inconsistent with

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regard to benefits in Alzheimer’s dementia. And the evidence that gingko biloba has a role in preventing or delaying cognitive decline is similarly not convincing.36 Tarenflurbil (Flurizan), a selective Aß42-lowering agent, is an investigational agent with a new mechanism of action and is currently in clinical trials. It promises benefits for ADLs and global functioning in mild AD.37 In preliminary studies, nonsteroidal anti-inflammatory drugs were believed to lower Aß production by modulation of gamma-secretase activity or through anti-inflammatory actions. However, they are yet to deliver these expected benefits in randomized controlled trials. Similarly, a potential was suggested for beta- and gamma-secretase inhibitors to decrease formation of insoluble Aß or alternatively the upregulation of alpha-secretase to increase soluble amyloid formation; these are promising concepts, but are yet far from reality. Testosterone supplementation in those with low testosterone levels failed to improve either cognition or function for patients with AD,38 but a recent study indicated that serum bioavailable (not total) testosterone had lower risk for MCI.39 Peroxisome proliferator-activated receptor-gamma agonists, such as rosiglitazone (Avandia), may be novel therapeutic agents for improved memory and cognition.40 Immunotherapy (eg, vaccination) to target Aß protein and tau protein has been tried, but active immunization was fraught with development of aseptic meningoencephalitis in humans. Passive immunization trials are now under way.41 Statins show promise in slowing cognitive decline. The mechanisms postulated include cholesterol lowering, lessening vascular damage, and anti-inflammatory and antioxidant effects. Epidemiologic data suggest lower incidence of Alzheimer’s dementia for those using statins. Anecdotal reports suggest that the Mediterranean diet42 and fruits and vegetable juices43 delay the progression of AD. Finally, maintaining appropriate folate levels may prove useful, and acetyl-L-carnitine may also be beneficial.

Conclusion AD with dementia is characterized by gradual memory loss and cognitive impairment, followed by personality changes and behavioral problems. Although several risk factors are implicated, a precise etiology is not delineated. AD may be the result of interplay between aging, genes, and environment. The result is a severe burden to caregivers and to society, placing a heavy toll

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on healthcare resources. And as the prediction is for AD to become more prevalent, we need to plan wisely to allocate appropriate resources to meet the demands of the disease, while continuing to channel research funds to delay onset, slow progress, or reverse the disease.

References 1. Kidd PM. Alzheimer’s disease, amnestic mild cognitive impairment, and age-associated memory impairment: current understanding and progress toward integrative prevention. Altern Med Rev. 2008;13:85-115. 2. Kawas CH. Early Alzheimer’s disease. N Engl J Med. 2003;349:1056-1063. 3. Cummings JL. Alzheimer’s disease. N Engl J Med. 2004;351:56-67. 4. McKhann G, Drachman D, Folstein M, et al. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology. 1984;34:939-944. 5. Alzheimer’s Association. Alzheimer’s disease facts and figures. 2008. www.alz.org/national/documents/report_alzfactsfigures2008.pdf. Accessed August 19, 2008. 6. Hendrie HC. Epidemiology of dementia and Alzheimer’s disease. Am J Geriatr Psychiatry. 1998;6(2 suppl 1):S3-S18. 7. Alzheimer’s Association. Alzheimer’s Association Report Alzheimer’s Disease Facts and Figures. 2007. www.alz.org/national/documents/PR_ FFfactsheet.pdf. Accessed August 19, 2008. 8. Geldmacher DS. Cost-effective recognition and diagnosis of dementia. Semin Neurol. 2002;22:63-70. 9. Rice DP, Fox PJ, Max W, et al. The economic burden of Alzheimer’s disease care. Health Aff (Millwood). 1993;12:164-176. 10. Leifer BP. Early diagnosis of Alzheimer’s disease: clinical and economic benefits. J Am Geriatr Soc. 2003;51(5 suppl dementia):S281-S283. 11. Alzheimer’s Disease and Chronic Health Conditions: the Real Challenge for 21st Century Medicare. Alzheimer’s Association. www.alz. org/national/documents/report_chroniccare.pdf. Accessed August 11, 2008. 12. Plassman BL, Langa KM, Fisher GG, et al. Prevalence of cognitive impairment without dementia in the United States. Ann Intern Med. 2008;148:427-434. 13. Petersen RC, Doody R, Kurz A, et al. Current concepts in mild cognitive impairment. Arch Neurol. 2001;58:1985-1992. 14. Cummings JL. Understanding and Treating Alzheimer’s Disease: A Primer. Teaneck, NJ: Elsai Inc, and Pfizer, Inc; 1997:4-37. 15. Chew ML, Mulsant BH, Pollock BG, et al. Anticholinergic activity of 107 medications commonly used by older adults. J Am Geriatr Soc. 2008;56:1333-1341. 16. Herholz K. PET studies in dementia. Ann Nucl Med. 2003;17:79-89. 17. Bird TD. Genetic factors in Alzheimer’s disease. N Engl J Med. 2005; 52:862-864. 18. Dharmarajan TS, Pais WP. Managing Alzheimer’s dementia. Resid Staff Physician. 2004;50:9-16. 19. Lyketsos CG, Steinberg M, Tschanz JT, et al. Mental and behavioral disturbances in Alzheimer dementia: findings for the Cache County Study on Memory and Aging. Am J Psychiatry. 2000;157:708-714. 20. Woods DL, Dimond M. The effect of therapeutic touch on agitated behavior and cortisol in persons with Alzheimer’s disease. Biol Res Nurs. 2002;4:104-114. 21. Cora VL. Helping family caregivers of older adults with dementia: providing education and support during these difficult times. Elder Care. 2006;6:1-4. 22. Rolland Y, Abellan van Kan G, Vellas B. Physical activity and Alzheimer’s disease: from prevention to therapeutic perspectives. J Am Med Direct Assoc. 2008;9:390-405. 23. Dharmarajan TS, Unnikrishnan D, Pitchumoni CS. Percutaneous endoscopic gastrostomy and outcome in dementia. Am J Gastroenterol. 2001;96:2556-2563. 24. Imtiaz M, Bojanapally P, Dharmarajan TS, et al. Improving the process of advance directives in healthcare: role for demographics and other

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characteristics. Presentation at the American College of Physicians Internal Medicine Annual Meeting; May 15-17, 2008; Washington, DC. 25. Geldmacher DS. Alzheimer’s disease: current pharmacotherapy in the context of patient and family needs. J Am Geriatr Soc. 2003;51(5 suppl dementia):S289-S295. 26. Qaseem A, Snow V, Cross JT Jr, et al. Current pharmacologic treatment of dementia: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med. 2008;148:370-378. 27. Standridge JB. Current status and future promise of pharmacotherapeutic strategies for Alzheimer’s disease. J Am Med Direct Assn. 2005;6:194-199. 28. Xiong G, Doraiswamy PM. Combination drug therapy for Alzheimer’s disease: what is evidence-based, and what is not? Geriatrics. 2005;60:22-26. 29. Guay DR. Rivastigmine transdermal patch: role in the management of Alzheimer’s disease. Consultant Pharmacist. 2008;23:598-609. 30. Mittelman MS, Roth DL, Clay OJ, Haley WE. Preserving health of caregivers: impact of spouse caregiver intervention. Am J Geriatr Psychiatry. 2007;15:780-789. 31. Ory MG, Hoffman RR 3rd, Yee JL, et al. Prevalence and impact of caregiving: a detailed comparison between dementia and nondementia caregivers. Gerontologist. 1999;9:177-185. 32. Stevenson DG, Huskamp HA, Keating NL, Newhouse JP. Medicare Part D and nursing home residents. J Am Geriatr Soc. 2007;55:11151125. 33. Kuo TC, Zhao Y, Weir S, et al. Implications of comorbidity on costs for patients with Alzheimer disease. Med Care. 2008;46:839-846.

34. Hampel H, Mitchell A, Blennow K, et al. Core biological marker candidates of Alzheimer’s disease: perspectives for diagnosis, prediction of outcome and reflection of biological activity. J Neural Transm. 2004; 111:247-272. 35. Boothby LA, Doering PL. Vitamin C and vitamin E for Alzheimer’s disease. Ann Pharmacother. 2005;39:2073-2080. 36. DeKosky ST, Furberg CD. Turning over a new leaf: ginkgo biloba in prevention of dementia? Neurology. 2008;70:1730-1731. 37. Wilcock GK, Black SE, Hendrix SB, et al. Efficacy and safety of tarenflurbil in mild to moderate Alzheimer’s disease: a randomized phase II trial. Lancet Neurol. 2008;7:483-493. 38. Emmelot-Vonk MH, Verhaar HJ, Nakhai Pour HR, et al. Effect of testosterone supplementation on functional mobility, cognition, and other parameters in older men: a randomized controlled trial. JAMA. 2008;299:39-52. 39. Chu LW, Tam S, Lee PW, et al. Bioavailable testosterone is associated with a reduced risk of amnestic mild cognitive impairment in older men. Clin Endocrinol (Oxf). 2008;68:589-598. 40. Landreth G, Jiang Q, Mandrekar S, Heneka M. PPAR-gamma agonists as therapeutics for the treatment of Alzheimer’s disease. Neurotherapeutics. 2008;5:481-489. 41. Hawkes CA, McLaurin J. Immunotherapy as treatment for Alzheimer’s disease. Expert Rev Neurother. 2007;7:1535-1548. 42. Scarmeas N, Luchsinger JA, Mayeux R, Stern Y. Mediterranean diet and Alzheimer disease mortality. Neurology. 2007;69:1084-1093. 43. Dai Q, Borenstein AR, Wu Y, et al. Fruits and vegetable juices and Alzheimer’s disease: the Kame project. Am J Med. 2006;119:751-759.

Stakeholder Perspective The Challenge of Value-Based Benefit Design in Alzheimer’s Disease PAYERS: A coordinated approach spanning the healthcare and disease progression continuum presents a challenge to payers when designing value-based benefits for the treatment of Alzheimer’s disease (AD). The main goals of AD therapy are delaying the progression of the disease and mitigating the sequelae and complications of advanced disease. Dementia is the most common manifestation of and most economically burdensome in AD, yet it is not necessarily manifested in all cases with the disease. When dementia does manifest in AD, it is predominantly in the later years of a patient’s life. Although the economic burden, both direct and indirect, is up at the top of the national healthcare expenditures, the largest share of this burden is borne by Medicare plans, because of the typically older age-group that is affected by AD. Some evidence suggests that early intervention may delay or slow the manifestations of the disease, but it is difficult to predict which patients may benefit most from intervention, and which patients may never progress to dementia. In addition, among patients who do progress to AD, it is difficult to determine if the intervention slowed that process, and to what extent.

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Finally, payers must decide if they are willing to pay for interventions without any assurances of positive outcomes, especially when their obligation may soon be transferred to a Medicare provider. Until clearly defined screening mechanisms for prediction of outcomes or consensus guidelines are introduced, payers will continue to struggle with the development of a value-based benefit offering for members with AD. PATIENTS: The process of losing control of the functional aspects of one’s life and personal independence is probably one of the most anxiety-producing events a patient and his or her loved ones can experience. Although all those affected would seek to thwart or at least slow that process, no clear direction from either the medical literature or the payer stakeholders exists to help with such a plan. In fact, the lack of direction may cause the patient in the early stages of AD and his or her family to bear a significant portion of the financial burden for a management plan suggested by the treating physician. Jeffrey Januska, PharmD Director of Pharmacy CenCal Health Goleta, California

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Prescription Copay Reduction Program for Diabetic Employees Kavita V. Nair, PhD; Kerri Miller, PharmD, BCPS; Joseph Saseen, PharmD, FCCP, BCPS; Pamela Wolfe, MS; Richard Read Allen, MS; Jinhee Park, CPhil, MA, MS

Value-based benefit design (VBBD) is a relatively new strategy that incorporates innovative approaches to employees’ benefits as a way to encourage them to adopt health-promoting behaviors and increase compliance, as well as to potentially reduce overall costs. This new study adds to the growing literature on VBBD, showing mixed results in terms of benefits to patients and employers. A total of 12,443 employees and dependents were covered under this program. But the study focused on a small group of patients with diabetes. The program placed all diabetes drugs and testing supplies at tier 1, so the cost for all members for these drugs/testing supplies was a $10 retail copay or a $20 mail-order copay. The investigators looked at 225

employees with diabetes in 1 employer group to see the impact of implementing copay reductions on diabetic patients’ medication compliance, overall healthcare costs, and healthcare utilizations. At the end of this 2year study, the number of adherent patients increased for all oral diabetes medications compared with the 9month baseline period before study initiation. Mean medication adherence increased by 7.74% in year 1, but this rate dropped by 2.31% in year 2. In addition, diabetes-specific office visits and laboratory/diagnostic visits were reduced during the study. However, this positive impact on patient adherence and clinical outcomes resulted in an increase in pharmacy expenditures for diabetes medications.

Partial Compliance with Antipsychotics Increases Mental Health Hospitalizations in Schizophrenic Patients Chris M. Kozma, PhD; Peter J. Weiden, MD

Medication noncompliance is known to result in relapse in patients with schizophrenia, a condition with potentially dire consequences if not properly treated. In this new, retrospective study, Drs Kozma and Weiden investigated pharmacy claims data to assess the impact of low or partial compliance with antipsychotic medications on hospitalization of patients with schizophrenia. The results support the association between reduced compliance with antipsychotic medications and increased risk of hospitalization: the risk of schizophrenia-related hospital-

ization decreased by almost 20% for every 10% increase in medication compliance, reinforcing the significant role of compliance for this patient population. Patients with therapy gaps of 30 or more days per prescription had almost a 5 times greater risk of being hospitalized compared with patients whose therapy gaps were 0 to 10 days per prescription. The authors conclude that even small decreases in compliance with antipsychotics are associated with increased hospitalization risk for patients with schizophrenia in a managed care population.

Alzheimer’s Disease: A Healthcare Burden of Epidemic Proportion T.S. Dharmarajan, MD, FACP, AGSF; Srinivas G. Gunturu, MD

Alzheimer’s disease (AD), the most common cause of dementia, increases in prevalence exponentially with age, and the trend of growing incidence of the disease is likely to continue in the United States. A variety of drugs are currently available to manage the symptoms of AD, but no therapy has been shown to prevent the disease. With annual costs exceeding $100 billion, dementia in AD is one of the most costly illnesses in the United States. The annual cost of caring for AD varies from $42,049 for institutionalized patients to $12,572 for patients living in the community. The tremendous

AMERICAN HEALTH & DRUG BENEFITS

January 2009

mental and physical burden costs on the caregiver are hard to delineate. Direct costs are incurred for long-term care in nursing homes or by physicians; indirect costs include lost productivity of caregivers. With the aging of the US population and the increase in AD cases, an AD epidemic is being forecast, suggesting that health plans and the healthcare system as a whole should be prepared to deal with this extra cost. Initiating early interventions in community-living patients with AD often is associated with lower overall costs compared with costs for institutional placement.

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NO. 1

Brief Summary of Prescribing Information USE IN PREGNANCY When used in pregnancy during the second and third trimesters, drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus. When pregnancy is detected, MICARDIS® tablets should be discontinued as soon as possible. See WARNINGS: Fetal/Neonatal Morbidity and Mortality INDICATIONS MICARDIS is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents. CONTRAINDICATIONS MICARDIS (telmisartan) is contraindicated in patients who are hypersensitive to any component of this product. WARNINGS Fetal/Neonatal Morbidity and Mortality Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature in patients who were taking angiotensin converting enzyme inhibitors. When pregnancy is detected, MICARDIS (telmisartan) tablets should be discontinued as soon as possible. The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug. These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to an angiotensin II receptor antagonist only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should have the patient discontinue the use of MICARDIS tablets as soon as possible. Rarely (probably less often than once in every thousand pregnancies), no alternative to an angiotensin II receptor antagonist will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intra-amniotic environment. If oligohydramnios is observed, MICARDIS tablets should be discontinued unless they are considered life-saving for the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Infants with histories of in utero exposure to an angiotensin II receptor antagonist should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. There is no clinical experience with the use of MICARDIS tablets in pregnant women. No teratogenic effects were observed when telmisartan was administered to pregnant rats at oral doses of up to 50 mg/kg/day and to pregnant rabbits at oral doses up to 45 mg/kg/day. In rabbits, embryolethality associated with maternal toxicity (reduced body weight gain and food consumption) was observed at 45 mg/kg/day [about 12 times the maximum recommended human dose (MRHD) of 80 mg on a mg/m2 basis]. In rats, maternally toxic (reduction in body weight gain and food consumption) telmisartan doses of 15 mg/kg/day (about 1.9 times the MRHD on a mg/m2 basis), administered during late gestation and lactation, were observed to produce adverse effects in neonates, including reduced viability, low birth weight, delayed maturation, and decreased weight gain. Telmisartan has been shown to be present in rat fetuses during late gestation and in rat milk. The no observed effect doses for developmental toxicity in rats and rabbits, 5 and 15 mg/kg/day, respectively, are about 0.64 and 3.7 times, on a mg/m2 basis, the maximum recommended human dose of telmisartan (80 mg/day). Hypotension in Volume-Depleted Patients In patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients (e.g., those being treated with high doses of diuretics), symptomatic hypotension may occur after initiation of therapy with MICARDIS® tablets. This condition should be corrected prior to administration of MICARDIS tablets, or treatment should start under close medical supervision with a reduced dose. If hypotension does occur, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized. PRECAUTIONS General. Impaired Hepatic Function: As the majority of telmisartan is eliminated by biliary excretion, patients with biliary obstructive disorders or hepatic insufficiency can be expected to have reduced clearance. MICARDIS (telmisartan) tablets should be used with caution in these patients. Impaired Renal Function: As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensinaldosterone system (e.g., patients with severe congestive heart failure), treatment with angiotensinconverting enzyme inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. Similar results may be anticipated in patients treated with MICARDIS tablets. In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen were observed. There has been no long term use of MICARDIS tablets in patients with unilateral or bilateral renal artery stenosis but an effect similar to that seen with ACE inhibitors should be anticipated. Information for Patients. Pregnancy: Female patients of childbearing age should be told about the consequences of second- and third-trimester exposure to drugs that act on the renin-angiotensin system, and they should also be told that these consequences do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. These patients should be asked to report pregnancies to their physicians as soon as possible. Drug Interactions. Digoxin: When telmisartan was coadministered with digoxin, median increases in digoxin peak plasma concentration (49%) and in trough concentration (20%) were observed. It is, therefore, recommended that digoxin levels be monitored when initiating, adjusting, and discontinuing telmisartan to avoid possible overor under-digitalization. Warfarin: Telmisartan administered for 10 days slightly decreased the mean warfarin trough plasma concentration; this decrease did not result in a change in International Normalized Ratio (INR). Other Drugs: Coadministration of telmisartan did not result in a clinically significant interaction with acetaminophen, amlodipine, glibenclamide, simvastatin, hydrochlorothiazide or ibuprofen. Telmisartan is not metabolized by the cytochrome P450 system and had no effects in vitro on cytochrome P450 enzymes, except for some inhibition of CYP2C19. Telmisartan is not expected to interact with drugs that inhibit cytochrome P450 enzymes; it is also not expected to interact with drugs metabolized by cytochrome P450 enzymes, except for possible inhibition of the metabolism of drugs metabolized by CYP2C19. Carcinogenesis, Mutagenesis, Impairment of Fertility There was no evidence of carcinogenicity when telmisartan was administered in the diet to mice and rats for up to 2 years. The highest doses administered to mice (1000 mg/kg/day) and rats (100 mg/kg/day) are, on a mg/m2 basis, about 59 and 13 times, respectively, the maximum recommended human dose (MRHD) of telmisartan. These same doses have been shown to provide average systemic exposures to telmisartan >100 times and >25 times, respectively, the systemic exposure in humans receiving the MRHD (80 mg/day). Genotoxicity assays did not reveal any telmisartanrelated effects at either the gene or chromosome level. These assays included bacterial mutagenicity tests with Salmonella and E. coli (Ames), a gene mutation test with Chinese hamster V79 cells, a cytogenetic test with human lymphocytes, and a mouse micronucleus test. No drug-related effects on the reproductive performance of male and female rats were noted at 100 mg/kg/day (the highest dose administered), about 13 times, on a mg/m2 basis, the MRHD of telmisartan. This dose in the rat resulted in an average systemic exposure (telmisartan AUC as determined on day 6 of pregnancy) at least 50 times the average systemic exposure in humans at the MRHD (80 mg/day). Pregnancy Pregnancy Categories C (first trimester) and D (second and third trimesters). See WARNINGS, Fetal/Neonatal Morbidity and Mortality. Nursing Mothers It is not known whether telmisartan is excreted in human milk, but telmisartan was shown to be present in the milk of lactating rats. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Of the total number of patients receiving MICARDIS in clinical studies, 551 (18.6%) were 65 to 74 years of age and 130 (4.4%) were 75 years or older. No overall differences in effectiveness and safety were observed in these patients compared to younger patients and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. ADVERSE REACTIONS MICARDIS (telmisartan) has been evaluated for safety in more than 3700 patients, including 1900 treated for

over six months and more than 1300 for over one year. Adverse experiences have generally been mild and transient in nature and have only infrequently required discontinuation of therapy. In placebo-controlled trials involving 1041 patients treated with various doses of telmisartan (20-160mg) monotherapy for up to 12 weeks, an overall incidence of adverse events similar to that of placebo was observed. Adverse events occurring at an incidence of 1% or more in patients treated with telmisartan and at a greater rate than in patients treated with placebo, irrespective of their causal association, are presented as follows: The most common adverse events occurring with MICARDIS Tablets monotherapy at a rate of ≥1% and greater than placebo, respectively, were: upper respiratory tract infection (URTI) (7%, 6%), back pain (3%, 1%), sinusitis (3%, 2%), diarrhea (3%, 2%), and pharyngitis (1%, 0%). In addition to the adverse events, the following events occurred at a rate of 1% but were at least as frequent in the placebo group: influenza-like symptoms, dyspepsia, myalgia, urinary tract infection, abdominal pain, headache, dizziness, pain, fatigue, coughing, hypertension, chest pain, nausea and peripheral edema. Discontinuation of therapy due to adverse events was required in 2.8% of 1455 patients treated with MICARDIS tablets and 6.1% of 380 placebo patients in placebo-controlled clinical trials. The incidence of adverse events was not dose-related and did not correlate with gender, age, or race of patients. The incidence of cough occurring with telmisartan in six placebo-controlled trials was identical to that noted for placebo-treated patients (1.6%). In addition to those listed above, adverse events that occurred in more than 0.3% of 3500 patients treated with MICARDIS monotherapy in controlled or open trials are listed below. It cannot be determined whether these events were causally related to MICARDIS tablets: Autonomic Nervous System: impotence, increased sweating, flushing; Body as a Whole: allergy, fever, leg pain, malaise; Cardiovascular: palpitation, dependent edema, angina pectoris, tachycardia, leg edema, abnormal ECG; CNS: insomnia, somnolence, migraine, vertigo, paresthesia, involuntary muscle contractions, hypoaesthesia; Gastrointestinal: flatulence, constipation, gastritis, vomiting, dry mouth, hemorrhoids, gastroenteritis, enteritis, gastroesophageal reflux, toothache, non-specific gastrointestinal disorders; Metabolic: gout, hypercholesterolemia, diabetes mellitus; Musculoskeletal: arthritis, arthralgia, leg cramps; Psychiatric: anxiety, depression, nervousness; Resistance Mechanism: infection, fungal infection, abscess, otitis media; Respiratory: asthma, bronchitis, rhinitis, dyspnea, epistaxis; Skin: dermatitis, rash, eczema, pruritus; Urinary: micturition frequency, cystitis; Vascular: cerebrovascular disorder; and Special Senses: abnormal vision, conjunctivitis, tinnitus, earache. During initial clinical studies, a single case of angioedema was reported (among a total of 3781 patients treated with telmisartan). Clinical Laboratory Findings In placebo-controlled clinical trials, clinically relevant changes in standard laboratory test parameters were rarely associated with administration of MICARDIS tablets. Hemoglobin: A greater than 2 g/dL decrease in hemoglobin was observed in 0.8% telmisartan patients compared with 0.3% placebo patients. No patients discontinued therapy due to anemia. Creatinine: A 0.5 mg/dL rise or greater in creatinine was observed in 0.4% telmisartan patients compared with 0.3% placebo patients. One telmisartan-treated patient discontinued therapy due to increases in creatinine and blood urea nitrogen. Liver Enzymes: Occasional elevations of liver chemistries occurred in patients treated with telmisartan; all marked elevations occurred at a higher frequency with placebo. No telmisartan-treated patients discontinued therapy due to abnormal hepatic function. Post-Marketing Experience The following adverse reactions have been identified during post-approval use of MICARDIS tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to MICARDIS tablets. The most frequently spontaneously reported events include: headache, dizziness, asthenia, coughing, nausea, fatigue, weakness, edema, face edema, lower limb edema, angioneurotic edema, urticaria, hypersensitivity, sweating increased, erythema, chest pain, atrial fibrillation, congestive heart failure, myocardial infarction, blood pressure increased, hypertension aggravated, hypotension (including postural hypotension), hyperkalemia, syncope, dyspepsia, diarrhea, pain, urinary tract infection, erectile dysfunction, back pain, abdominal pain, muscle cramps (including leg cramps), myalgia, bradycardia, eosinophilia, thrombocytopenia, uric acid increased, abnormal hepatic function/liver disorder, renal impairment including acute renal failure, anemia, and increased CPK. Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers, including MICARDIS. OVERDOSAGE Limited data are available with regard to overdosage in humans. The most likely manifestation of overdosage with MICARDIS (telmisartan) tablets would be hypotension, dizziness and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, supportive treatment should be instituted. Telmisartan is not removed by hemodialysis. DOSAGE AND ADMINISTRATION Dosage must be individualized.The usual starting dose of MICARDIS (telmisartan) tablets is 40 mg once a day. Blood pressure response is dose related over the range of 20-80 mg. Special Populations: Patients with depletion of intravascular volume should have the condition corrected or MICARDIS tablets should be initiated under close medical supervision (see WARNINGS, Hypotension in Volume-Depleted Patients). Patients with biliary obstructive disorders or hepatic insufficiency should have treatment started under close medical supervision (see PRECAUTIONS, General, Impaired Hepatic Function, and Impaired Renal Function). Most of the antihypertensive effect is apparent within two weeks and maximal reduction is generally attained after four weeks. When additional blood pressure reduction beyond that achieved with 80 mg MICARDIS is required, a diuretic may be added. No initial dosing adjustment is necessary for elderly patients or patients with mild-to-moderate renal impairment, including those on hemodialysis. Patients on dialysis may develop orthostatic hypotension; their blood pressure should be closely monitored. MICARDIS tablets may be administered with other antihypertensive agents. MICARDIS tablets may be administered with or without food. Rx only MC-BS (03/07)

Printed in U.S.A.

(10/07)

MC48827

Get patients with difﬁcult-to-control hypertension to goal1

MICARDIS. More than POWER…

BP PROTECTION in the early morning2

USE IN PREGNANCY When used in pregnancy during the second and third trimesters, drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus. When pregnancy is detected, MICARDIS Tablets should be discontinued as soon as possible (see WARNINGS, Fetal/Neonatal Morbidity and Mortality). MICARDIS is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents. MICARDIS is contraindicated in patients who are hypersensitive to any component of this product. The most common adverse events occurring with MICARDIS Tablets monotherapy at a rate of ≥1% and greater than placebo, respectively, were: upper respiratory tract infection (URTI) (7%, 6%), back pain (3%, 1%), sinusitis (3%, 2%), diarrhea (3%, 2%), and pharyngitis (1%, 0%). Please see Brief Summary of Product Information on adjacent page.

References: 1. Weber MA,White WB,Giles TD,et al.An effectiveness study comparing algorithm-based antihypertensive therapy with previous treatments using conventional and ambulatory blood pressure measurements. J Clin Hypertens. 2006;8:241-250. 2. White WB,Giles T,Bakris GL,et al.Measuring the efficacy of antihypertensive therapy by ambulatory blood pressure monitoring in the primary care setting. Am Heart J. 2006;151:176-184.

Printed in U.S.A.

(10/07)

MC48828