AHDB November 2014 Vol 7 No 8

THE PEER-REVIEWED FORUM FOR REAL-WORLD EVIDENCE IN BENEFIT DESIGN ™ NOVEMBER 2014

VOLUME 7, NUMBER 8

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

Cardiometabolic Health Theme Issue EDITORIAL

Read All About It David B. Nash, MD, MBA INTRODUCTION

Cardiometabolic Health in 2014: Clinical and Economic Implications ™

Dalia Buffery, MA, ABD BUSINESS

Impact of the New ACC/AHA Guidelines on the Treatment of High Blood Cholesterol in a Managed Care Setting Josephine N. Tran, PharmD, MS; Toros Caglar, PhD; Karen M. Stockl, PharmD; Heidi C. Lew, PharmD; Brian K. Solow, MD; Paul S. Chan, MD, MSc Stakeholder Perspective: Real-World Consequences of the 2013 ACC/AHA Cholesterol Guidelines for the Prevention of Cardiovascular Disease

By Joseph D. Jackson, PhD CLINICAL

Utilization of Parenteral Anticoagulants and Warfarin: Impact on the Risk of Venous Thromboembolism Recurrence in the Outpatient Setting Jennifer Cai, MS, MPH; Ronald Preblick, PharmD, MPH; Qiaoyi Zhang, MD, PhD; Winghan Jacqueline Kwong, PharmD, PhD Stakeholder Perspective: Better Compliance with Clinical Guidelines for Venous Thromboembolism Can Improve Patient Outcomes, Reduce Costs

By James T. Kenney, RPh, MBA

New and Emerging Drugs and Targets for Type 2 Diabetes: Reviewing the Evidence Brien Rex Miller, DO; Hanh Nguyen, DO; Charles Jia-Haur Hu, DO; Chihyi Lin, DO; Quang T. Nguyen, DO, FACP, FACE, FTOS Stakeholder Perspective: Addressing Adherence a Key Challenge in the Management of Patients with Type 2 Diabetes

By Jeffrey A. Bourret, PharmD, MS, RPh, BCPS, FASHP

© 2014 Engage Healthcare Communications, LLC

www.AHDBonline.com

With schizophrenia,

choosing an antipsychotic individualized to patients’ needs

can be complex.1

Not actual patients.

1. Lehman AF, Lieberman JA, Dixon LB, et al. Practice Guideline for the Treatment of Patients With Schizophrenia. 2nd ed. Arlington, VA: American Psychiatric Association; 2004.

2. Kane JM, Sanchez R, Perry PP, et al. Aripiprazole intramuscular depot as maintenance treatment in patients with schizophrenia: a 52-week, multicenter, randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2012;73(5):617-624. 3. Abilify Maintena [package insert]. Rockville, MD: Otsuka Pharmaceutical Company; February 2013.

INDICATION and IMPORTANT SAFETY INFORMATION for Abilify Maintena® (aripiprazole) for extended-release injectable suspension INDICATION Abilify Maintena is an atypical antipsychotic indicated for the treatment of schizophrenia.

Efficacy was demonstrated in a placebo-controlled, randomized-withdrawal maintenance trial in patients with schizophrenia and additional support for efficacy was derived from oral aripiprazole trials.

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IMPORTANT SAFETY INFORMATION Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk (1.6 to 1.7 times) of death compared to placebo (4.5% vs 2.6%, respectively). Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Abilify Maintena is not approved for the treatment of patients with dementiarelated psychosis.

Contraindication: Known hypersensitivity reaction to aripiprazole. Reactions have ranged from pruritus/urticaria to anaphylaxis.

Cerebrovascular Adverse Events, Including Stroke: Increased incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, have been reported in clinical trials of elderly patients with dementia-related psychosis treated with oral aripiprazole.

Accessing long-acting injectables

shouldn’t be.

Position Abilify Maintena® (aripiprazole) at parity with all long-acting injectables on your formulary. Offer the efficacy* and safety of oral aripiprazole for schizophrenia in a once-monthly formulation.2,3,†

* Abilify Maintena significantly delayed the time to impending relapse vs placebo (P<0.0001) in a phase III, 52-week, double-blind, randomized-withdrawal clinical trial; Abilify Maintena (n=269) vs placebo (n=134).3 † Efficacy was demonstrated in a placebo-controlled, randomized-withdrawal maintenance trial in patients with schizophrenia and additional support for efficacy was derived from oral aripiprazole trials. In conjunction with first dose, take 14 consecutive days of concurrent oral aripiprazole (10 mg to 20 mg) or current oral antipsychotic.

IMPORTANT SAFETY INFORMATION (continued) Neuroleptic Malignant Syndrome (NMS): A potentially fatal symptom complex sometimes referred to as NMS may occur with administration of antipsychotic drugs, including Abilify Maintena. Rare cases of NMS occurred during aripiprazole treatment. Signs and symptoms of NMS include hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (e.g., irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available.

Tardive Dyskinesia (TD): The risk of developing TD (a syndrome of abnormal, involuntary movements) and the potential for it to become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic increase. The syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. Prescribing should be consistent with the need to minimize TD. There is no known treatment for established TD, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn.

Continued on next page.

Please see IMPORTANT SAFETY INFORMATION continued, and BRIEF SUMMARY of FULL PRESCRIBING INFORMATION, including Boxed WARNING, on the following pages.

IMPORTANT SAFETY INFORMATION for Abilify Maintena® (aripiprazole) for extended-release injectable suspension (continued) Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that include: Hyperglycemia/Diabetes Mellitus: Hyperglycemia, in some cases extreme and associated with ketoacidosis, coma, or death, has been reported in patients treated with atypical antipsychotics including aripiprazole. Patients with diabetes should be regularly monitored for worsening of glucose control; those with risk factors for diabetes should undergo baseline and periodic fasting blood glucose testing. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia should also undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.

Dyslipidemia: Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics. There were no significant differences between aripiprazole- and placebo-treated patients in the proportion with changes from normal to clinically significant levels for fasting/nonfasting total cholesterol, fasting triglycerides, fasting low-density lipoproteins (LDLs), and fasting/nonfasting high-density lipoproteins (HDLs).

Weight Gain: Weight gain has been observed. Clinical monitoring of weight is recommended.

Orthostatic Hypotension: Aripiprazole may cause orthostatic hypotension. Abilify Maintena should be used with caution in patients with known cardiovascular disease, cerebrovascular disease, or conditions which would predispose them to hypotension.

Leukopenia, Neutropenia, and Agranulocytosis: Leukopenia, neutropenia, and agranulocytosis have been reported. Patients with a history of clinically significant low white blood cell (WBC) count or drug-induced leukopenia/neutropenia should have their complete blood count monitored frequently during the first few months of therapy while receiving Abilify Maintena. In such patients, consider discontinuation of Abilify Maintena at the first sign of a clinically significant decline in WBC count in the absence of other causative factors.

Seizures/Convulsions: Abilify Maintena should be used with caution in patients with a history of seizures or with conditions that lower the seizure threshold.

Potential for Cognitive and Motor Impairment: Abilify Maintena may impair judgment, thinking, or motor skills. Instruct patients to avoid operating hazardous machinery including automobiles until they are certain Abilify Maintena does not affect them adversely.

Body Temperature Regulation: Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic agents. Advise patients regarding appropriate care in avoiding overheating and dehydration. Appropriate care is advised for patients who may exercise strenuously, may be exposed to extreme heat, receive concomitant medication with anticholinergic activity, or are subject to dehydration.

Dysphagia: Esophageal dysmotility and aspiration have been associated with Abilify Maintena; use caution in patients at risk for aspiration pneumonia.

Alcohol: Advise patients to avoid alcohol while taking Abilify Maintena.

Concomitant Medication: Dosage adjustments are recommended in patients who are CYP2D6 poor metabolizers and in patients taking concomitant CYP3A4 inhibitors or CYP2D6 inhibitors for greater than 14 days. If the CYP3A4 inhibitor or CYP2D6 inhibitor is withdrawn, the Abilify Maintena dosage may need to be increased. Avoid the concomitant use of CYP3A4 inducers with Abilify Maintena for greater than 14 days because the blood levels of aripiprazole are decreased and may be below the effective levels. Dosage adjustments are not recommended for patients with concomitant use of CYP3A4 inhibitors, CYP2D6 inhibitors or CYP3A4 inducers for less than 14 days.

Most commonly observed adverse reaction: The safety profile of Abilify Maintena is expected to be similar to that of oral aripiprazole.

In patients who tolerated and responded to oral aripiprazole and single-blind Abilify Maintena and were then randomized to receive Abilify Maintena or placebo injections, the incidence of adverse reactions was similar between the two treatment groups. The adverse reaction ≥ 5% incidence and at least twice the rate of placebo for oral aripiprazole vs placebo, respectively, was: Akathisia (8% vs 4%) in adult patients with schizophrenia.

Injection Site Reactions: In the open-label, stabilization phase of a study with Abilify Maintena in patients with schizophrenia, the percent of patients reporting any injection site-related adverse reaction was 6.3% for Abilify Maintena-treated patients.

Dystonia is a class effect of antipsychotic drugs. Symptoms of dystonia may occur in susceptible individuals during the first days of treatment and at low doses.

Pregnancy/Nursing: Based on animal data, may cause fetal harm. Abilify Maintena should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Aripiprazole is excreted in human breast milk. A decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

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Please see BRIEF SUMMARY of FULL PRESCRIBING INFORMATION, including Boxed WARNING, on adjacent pages.

©2014 Otsuka America Pharmaceutical, Inc., Rockville, MD March 2014 09US14EBY0024

ABILIFY MAINTENA™ (aripiprazole) for extended-release injectable suspension, for • Hyperglycemia/Diabetes Mellitus: Hyperglycemia, in some cases extreme and associated with diabetic ketoacidosis, hyperosmolar coma, or death, has been reported in patients treated intramuscular use BRIEF SUMMARY OF PRESCRIBING INFORMATION (For complete details, please see Full with atypical antipsychotics. There have been reports of hyperglycemia in patients treated with aripiprazole. Assessment of the relationship between atypical antipsychotic use and glucose Prescribing Information and Medication Guide.) abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED population. Given these confounders, the relationship between atypical antipsychotic use and PSYCHOSIS hyperglycemia-related adverse reactions is not completely understood. However, epidemiological See full prescribing information for complete boxed warning. studies suggest an increased risk of hyperglycemia-related adverse reactions in patients treated • Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at with atypical antipsychotics. Because aripiprazole was not marketed at the time these studies an increased risk of death were performed, it is not known if aripiprazole is associated with this increased risk. Precise risk estimates for hyperglycemia-related adverse reactions in patients treated with atypical • ABILIFY MAINTENA is not approved for the treatment of patients with dementia-related antipsychotics are not available. Patients with an established diagnosis of diabetes mellitus who psychosis are started on atypical antipsychotics should be monitored regularly for worsening of glucose INDICATIONS AND USAGE: ABILIFY MAINTENA (aripiprazole) is indicated for the treatment control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes), of schizophrenia. Efficacy was demonstrated in a placebo-controlled, randomized-withdrawal who are starting treatment with atypical antipsychotics should undergo fasting blood glucose maintenance trial in patients with schizophrenia and additional support for efficacy was derived from testing at the beginning of treatment and periodically during treatment. Any patient treated with oral aripiprazole trials. atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, CONTRAINDICATIONS: ABILIFY MAINTENA is contraindicated in patients with a known polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during hypersensitivity to aripiprazole. Hypersensitivity reactions ranging from pruritus/urticaria to treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some anaphylaxis have been reported in patients receiving aripiprazole. cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, WARNINGS AND PRECAUTIONS: Increased Mortality in Elderly Patients with Dementia- some patients required continuation of anti-diabetic treatment despite discontinuation of the Related Psychosis: Elderly patients with dementia-related psychosis treated with antipsychotic atypical antipsychotic drug. drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration In an analysis of 13 placebo-controlled monotherapy trials in adults, primarily with of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in schizophrenia or bipolar disorder, the mean change in fasting glucose in aripiprazoledrug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over treated patients (+4.4 mg/dL; median exposure 25 days; N=1057) was not significantly the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about different than in placebo-treated patients (+2.5 mg/dL; median exposure 22 days; N=799).

4.5%, compared to a rate of about 2.6% in the placebo group.

Table 1 shows the proportion of aripiprazole-treated patients with normal and borderline Although the causes of death were varied, most of the deaths appeared to be either cardiovascular fasting glucose at baseline (median exposure 25 days) that had high fasting glucose (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies measurements compared to placebo-treated patients (median exposure 22 days). suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational Table 1: Changes in Fasting Glucose From Placebo-controlled Monotherapy Trials in Adult Patients studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of Category Change (at least once) Treatment n/N % the patients is not clear. ABILIFY MAINTENA is not approved for the treatment of patients with from Baseline Arm dementia-related psychosis.

Aripiprazole 31/822 3.8 Normal to High Cerebrovascular Adverse Reactions, Including Stroke in Elderly Patients with Dementia- Fasting (<100 mg/dL to ≥126 mg/dL) Placebo 22/605 3.6 Related Psychosis: In placebo-controlled clinical studies (two flexible dose and one fixed dose Glucose Aripiprazole 31/176 17.6 Borderline to High study) of dementia-related psychosis, there was an increased incidence of cerebrovascular (≥100 mg/dL and <126 mg/dL to ≥126 mg/dL) Placebo 13/142 9.2 adverse reactions (e.g., stroke, transient ischemic attack), including fatalities, in oral aripiprazoletreated patients (mean age: 84 years; range: 78-88 years). In the fixed-dose study, there was a At 24 weeks, the mean change in fasting glucose in aripiprazole-treated patients was not statistically significant dose response relationship for cerebrovascular adverse reactions in patients significantly different than in placebo-treated patients [+2.2 mg/dL (n=42) and +9.6 mg/dL treated with oral aripiprazole. ABILIFY MAINTENA is not approved for the treatment of patients with (n=28), respectively]. dementia-related psychosis.

• Dyslipidemia: Undesirable alterations in lipids have been observed in patients treated with Neuroleptic Malignant Syndrome: A potentially fatal symptom complex sometimes referred to atypical antipsychotics. as Neuroleptic Malignant Syndrome (NMS) may occur with administration of antipsychotic drugs, There were no significant differences between aripiprazole- and placebo-treated patients in the including ABILIFY MAINTENA. Rare cases of NMS occurred during aripiprazole treatment in the proportion with changes from normal to clinically significant levels for fasting/nonfasting total worldwide clinical database. cholesterol, fasting triglycerides, fasting LDLs, and fasting/nonfasting HDLs. Analyses of patients Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and with at least 12 or 24 weeks of exposure were limited by small numbers of patients. evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and Table 2 shows the proportion of adult patients, primarily from pooled schizophrenia and bipolar cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria disorder monotherapy placebo-controlled trials, with changes in total cholesterol (pooled from (rhabdomyolysis), and acute renal failure.

17 trials; median exposure 21 to 25 days), fasting triglycerides (pooled from eight trials; median The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it exposure 42 days), fasting LDL cholesterol (pooled from eight trials; median exposure 39 to 45 is important to exclude cases where the clinical presentation includes both serious medical illness days, except for placebo-treated patients with baseline normal fasting LDL measurements, who (e.g., pneumonia, systemic infection) and untreated or inadequately treated extrapyramidal signs had median treatment exposure of 24 days) and HDL cholesterol (pooled from nine trials; median and symptoms (EPS). Other important considerations in the differential diagnosis include central exposure 40 to 42 days). anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.

The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and Table 2: Changes in Blood Lipid Parameters From Placebo-controlled Monotherapy Trials in Adults other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical Treatment Arm n/N % monitoring; and 3) treatment of any concomitant serious medical problems for which specific Total Cholesterol Aripiprazole 34/1357 2.5 treatments are available. There is no general agreement about specific pharmacological treatment Normal to High (<200 mg/dL to ≥240 mg/dL) Placebo 27/973 2.8 regimens for uncomplicated NMS. Aripiprazole 40/539 7.4 Fasting Triglycerides If a patient requires antipsychotic drug treatment after recovery from NMS, the potential Normal to High (<150 mg/dL to ≥200 mg/dL) Placebo 30/431 7.0 reintroduction of drug therapy should be carefully considered. The patient should be carefully Aripiprazole 2/332 0.6 Fasting LDL Cholesterol monitored, since recurrences of NMS have been reported.

Normal to High (<100 mg/dL to ≥160 mg/dL) Placebo 2/268 0.7 Tardive Dyskinesia: A syndrome of potentially irreversible, involuntary, dyskinetic movements, Aripiprazole 121/1066 11.4 may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome HDL Cholesterol Placebo 99/794 12.5 appears to be highest among the elderly, especially elderly women, it is impossible to rely upon Normal to Low (≥40 mg/dL to <40 mg/dL) prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely In monotherapy trials in adults, the proportion of patients at 12 weeks and 24 weeks with changes to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause from Normal to High in total cholesterol (fasting/nonfasting), fasting triglycerides, and fasting tardive dyskinesia is unknown.

LDL cholesterol were similar between aripiprazole- and placebo-treated patients: at 12 weeks, The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are Total Cholesterol (fasting/nonfasting), 1/71 (1.4%) vs. 3/74 (4.1%); Fasting Triglycerides, 8/62 believed to increase as the duration of treatment and the total cumulative dose of antipsychotic (12.9%) vs. 5/37 (13.5%); Fasting LDL Cholesterol, 0/34 (0%) vs. 1/25 (4.0%), respectively; and at drugs administered to the patient increase. However, the syndrome can develop, although much 24 weeks, Total Cholesterol (fasting/ nonfasting), 1/42 (2.4%) vs. 3/37 (8.1%); Fasting Triglycerides, less commonly, after relatively brief treatment periods at low doses.

5/34 (14.7%) vs. 5/20 (25%); Fasting LDL Cholesterol, 0/22 (0%) vs. 1/18 (5.6%), respectively.

There is no known treatment for established tardive dyskinesia, although the syndrome may remit, • Weight Gain: Weight gain has been observed with atypical antipsychotic use. Clinical monitoring partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, of weight is recommended. In an analysis of 13 placebo-controlled monotherapy trials, primarily however, may suppress (or partially suppress) the signs and symptoms of the syndrome and, from pooled schizophrenia and bipolar disorder, with a median exposure of 21 to 25 days, the thereby, may possibly mask the underlying process. The effect of symptomatic suppression on the mean change in body weight in aripiprazole-treated patients was +0.3 kg (N=1673) compared to long-term course of the syndrome is unknown.

–0.1 kg (N=1100) in placebo-controlled patients. At 24 weeks, the mean change from baseline Given these considerations, ABILIFY MAINTENA should be prescribed in a manner that is most in body weight in aripiprazole-treated patients was –1.5 kg (n=73) compared to –0.2 kg (n=46) in likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should placebo-treated patients. generally be reserved for patients who suffer from a chronic illness that 1) is known to respond Table 3 shows the percentage of adult patients with weight gain ≥7% of body weight in the to antipsychotic drugs and 2) for whom alternative, equally effective, but potentially less harmful 13 pooled placebo-controlled monotherapy trials. treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response Table 3: Percentage of Patients From Placebo-controlled Trials in Adult Patients with Weight Gain ≥7% of Body Weight should be sought. The need for continued treatment should be reassessed periodically.

If signs and symptoms of tardive dyskinesia appear in a patient treated with ABILIFY MAINTENA Indication Treatment Arm N n (%) drug discontinuation should be considered. However, some patients may require treatment with ABILIFY MAINTENA despite the presence of the syndrome.

Aripiprazole 852 69 (8.1) Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes Schizophreniaa Placebo 379 12 (3.2) that include hyperglycemia/diabetes mellitus, dyslipidemia, and weight gain. While all drugs in Weight gain ≥7% Aripiprazole 719 16 (2.2) the class have been shown to produce some metabolic changes, each drug has its own specific of body weight Bipolar Maniab Placebo 598 16 (2.7) risk profile. Although the following metabolic data were collected in patients treated with oral a formulations of aripiprazole, the findings pertain to patients receiving ABILIFY MAINTENA as well.

4-6 weeks’ duration. b3 weeks’ duration.

Orthostatic Hypotension: Aripiprazole may cause orthostatic hypotension, perhaps due to its α1 -adrenergic receptor antagonism. Orthostasis occurred in 4/576 (0.7%) patients treated with ABILIFY MAINTENA during the stabilization phase, including abnormal orthostatic blood pressure (1/576, 0.2%), postural dizziness (1/576, 0.2%), presyncope (1/576, 0.2%) and orthostatic hypotension (1/576, 0.2%).

In the stabilization phase, the incidence of significant orthostatic change in blood pressure (defined as a decrease in systolic blood pressure ≥20 mmHg accompanied by an increase in heart rate ≥25 when comparing standing to supine values) was 0.2% (1/575).

Leukopenia, Neutropenia, and Agranulocytosis: Class Effect: In clinical trials and post-marketing experience, leukopenia and neutropenia have been reported temporally related to antipsychotic agents, including oral aripiprazole. Agranulocytosis has also been reported.

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia. In patients with a history of a clinically significant low WBC or drug-induced leukopenia/neutropenia perform a complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of ABILIFY MAINTENA at the first sign of a clinically significant decline in WBC in the absence of other causative factors.

Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue ABILIFY MAINTENA in patients with severe neutropenia (absolute neutrophil count <1000/mm 3) and follow their WBC counts until recovery.

Seizures: As with other antipsychotic drugs, use ABILIFY MAINTENA cautiously in patients with a history of seizures or with conditions that lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.

Potential for Cognitive and Motor Impairment: ABILIFY MAINTENA, like other antipsychotics, may impair judgment, thinking, or motor skills. Instruct patients to avoid operating hazardous machinery, including automobiles, until they are reasonably certain that therapy with ABILIFY MAINTENA does not affect them adversely.

Body Temperature Regulation: Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing ABILIFY MAINTENA for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, (e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration).

Dysphagia: Esophageal dysmotility and aspiration have been associated with antipsychotic drug use, including ABILIFY MAINTENA. ABILIFY MAINTENA and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.

ADVERSE REACTIONS: The following adverse reactions are discussed in more detail in other sections of the labeling in the Full Prescribing Information: • Increased Mortality in Elderly Patients with Dementia-Related Psychosis [see Boxed Warning and Warnings and Precautions (5.1)] • Cerebrovascular Adverse Reactions, Including Stroke in Elderly Patients with Dementia-Related Psychosis [see Boxed Warning and Warnings and Precautions (5.2)] • Neuroleptic Malignant Syndrome [see Warnings and Precautions (5.3)] • Tardive Dyskinesia [see Warnings and Precautions (5.4)] • Metabolic Changes [see Warnings and Precautions (5.5)] • Orthostatic Hypotension [see Warnings and Precautions (5.6)] • Leukopenia, Neutropenia, and Agranulocytosis [see Warnings and Precautions (5.7)] • Seizures [see Warnings and Precautions (5.8)] • Potential for Cognitive and Motor Impairment [see Warnings and Precautions (5.9)] • Body Temperature Regulation [see Warnings and Precautions (5.10)] • Dysphagia [see Warnings and Precautions (5.11)] Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Safety Database of ABILIFY MAINTENA and Oral Aripiprazole: Aripiprazole has been evaluated for safety in 16,114 adult patients who participated in multiple-dose, clinical trials in schizophrenia and other indications, and who had approximately 8,578 patient-years of exposure to oral aripiprazole. A total of 3,901 patients were treated with oral aripiprazole for at least 180 days, 2,259 patients were treated with oral aripiprazole for at least 360 days, and 933 patients continuing aripiprazole treatment for at least 720 days.

ABILIFY MAINTENA 300-400 mg every 4 weeks has been evaluated for safety in 1,287 adult patients in clinical trials in schizophrenia, with approximately 1,281 patient-years of exposure to ABILIFY MAINTENA. A total of 832 patients were treated with ABILIFY MAINTENA for at least 180 days (at least 7 consecutive injections) and 630 patients treated with ABILIFY MAINTENA had at least 1 year of exposure (at least 13 consecutive injections).

The conditions and duration of treatment with ABILIFY MAINTENA included double-blind and open-label studies. The safety profile of ABILIFY MAINTENA is expected to be similar to that of oral aripiprazole. Therefore, most of the safety data presented below are derived from trials with the oral formulation. In patients who tolerated and responded to treatment with oral aripiprazole and single-blind ABILIFY MAINTENA and were then randomized to receive ABILIFY MAINTENA or placebo injections under double-blind conditions, the incidence of adverse reactions was similar between the two treatment groups.

Adverse Reactions of ABILIFY MAINTENA and Oral Aripiprazole: Adverse Reactions Associated with Discontinuation of Oral Aripiprazole: Based on a pool of five placebo-controlled trials (four 4-week and one 6-week) in which oral aripiprazole was administered to adults with schizophrenia in doses ranging from 2 mg/day to 30 mg/day, the incidence of discontinuation due to adverse reactions was 7% in oral aripiprazole-treated and 9% in placebo-treated patients. The types of adverse reactions that led to discontinuation were similar for the aripiprazole-treated and placebo-treated patients.

Commonly Observed Adverse Reactions of Oral Aripiprazole: Based on a pool of five placebocontrolled trials (four 4-week and one 6-week) in which oral aripiprazole was administered to adults with schizophrenia in doses ranging from 2 mg/day to 30 mg/day, the only commonly observed adverse reaction associated with the use of oral aripiprazole in patients with schizophrenia (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo) was akathisia (aripiprazole 8%; placebo 4%).

Less Common Adverse Reactions in Adults Treated with Oral Aripiprazole: Table 4 enumerates the pooled incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy (up to 6 weeks in schizophrenia and up to 3 weeks in bipolar mania), including only those reactions that occurred in 2% or more of patients treated with oral aripiprazole (doses ≥2 mg/ day) and for which the incidence in patients treated with aripiprazole was greater than the incidence in patients treated with placebo in the combined dataset.

Table 4: Adverse Reactions in Short-term, Placebo-controlled Trials in Adult Patients Treated with Oral Aripiprazole Percentage of Patients Reporting Reactiona System Organ Class Oral Aripiprazole (n=1843) Placebo (n=1166) Preferred Term Eye Disorders Blurred Vision 3 1 Gastrointestinal Disorders Nausea 15 11 Constipation 11 7 Vomiting 11 6 Dyspepsia 9 7 Dry Mouth 5 4 Toothache 4 3 Abdominal Discomfort 3 2 Stomach Discomfort 3 2 General Disorders and Administration Site Conditions Fatigue 6 4 Pain 3 2 Musculoskeletal and Connective Tissue Disorders Musculoskeletal Stiffness 4 3 Pain in Extremity 4 2 Myalgia 2 1 Muscle Spasms 2 1 Nervous System Disorders Headache 27 23 Dizziness 10 7 Akathisia 10 4 Sedation 7 4 Extrapyramidal Disorder 5 3 Tremor 5 3 Somnolence 5 3 Psychiatric Disorders Agitation 19 17 Insomnia 18 13 Anxiety 17 13 Restlessness 5 3 Respiratory, Thoracic, and Mediastinal Disorders Pharyngolaryngeal Pain 3 2 Cough 3 2 a Adverse reactions reported by at least 2% of patients treated with oral aripiprazole, except adverse reactions which had an incidence equal to or less than placebo.

An examination of population subgroups did not reveal any clear evidence of differential adverse reaction incidence on the basis of age, gender, or race.

Dose-Related Adverse Reactions of Oral Aripiprazole: Dose response relationships for the incidence of treatment-emergent adverse events were evaluated from four trials in adult patients with schizophrenia comparing various fixed oral doses of aripiprazole (2 mg/day, 5 mg/day, 10 mg/day, 15 mg/day, 20 mg/day, and 30 mg/day) to placebo. This analysis, stratified by study, indicated that the only adverse reaction to have a possible dose response relationship, and then most prominent only with 30 mg, was somnolence [including sedation]; (incidences were placebo, 7.1%; 10 mg, 8.5%; 15 mg, 8.7%; 20 mg, 7.5%; 30 mg, 12.6%).

Injection Site Reactions of ABILIFY MAINTENA: In the open-label, stabilization phase of a study with ABILIFY MAINTENA in patients with schizophrenia, the percent of patients reporting any injection site-related adverse reaction was 6.3% for ABILIFY MAINTENA-treated patients. The mean intensity of injection pain reported by subjects using a visual analog scale (0=no pain to 100=unbearably painful) was minimal and improved in subjects receiving ABILIFY MAINTENA from the first to the last injection in the open-label, stabilization phase (6.1 to 4.9).

Investigator evaluation of the injection site for pain, swelling, redness and induration following injections of ABILIFY MAINTENA in the open-label, stabilization phase were rated as absent for 74%-96% of subjects following the first injection and 77%-96% of subjects following the last injection.

Extrapyramidal Symptoms of Oral Aripiprazole: In short-term, placebo-controlled trials in schizophrenia, the incidence of reported EPS-related events, excluding events related to akathisia, for oral aripiprazole-treated patients was 13% vs. 12% for placebo; and the incidence of akathisiarelated events for aripiprazole-treated patients was 8% vs. 4% for placebo.

Objectively collected data from those trials was collected on the Simpson Angus Rating Scale (for EPS), the Barnes Akathisia Scale (for akathisia), and the Abnormal Involuntary Movement Scale (for dyskinesias). In the schizophrenia trials, the objectively collected data did not show a difference between aripiprazole and placebo, with the exception of the Barnes Akathisia Scale (aripiprazole, 0.08; placebo, –0.05).

Similarly, in a long-term (26-week), placebo-controlled trial of schizophrenia in adults, objectively collected data on the Simpson Angus Rating Scale (for EPS), the Barnes Akathisia Scale (for akathisia), and the Abnormal Involuntary Movement Scale (for dyskinesias) did not show a difference between aripiprazole and placebo.

Dystonia: Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.

Adverse Reactions in Long-Term, Double-Blind, Placebo-Controlled Trials of Oral Aripiprazole: The adverse reactions reported in a 26-week, double-blind trial comparing oral aripiprazole and placebo in patients with schizophrenia were generally consistent with those reported in the short-term, placebo-controlled trials, except for a higher incidence of tremor [8% (12/153) for oral aripiprazole vs. 2% (3/153) for placebo]. In this study, the majority of the cases of tremor were of mild intensity (8/12 mild and 4/12 moderate), occurred early in therapy (9/12 ≤49 days), and were of limited duration (7/12 ≤10 days). Tremor infrequently led to discontinuation (<1%) of oral aripiprazole.

In addition, in a long-term, active-controlled study, the incidence of tremor was 5% (40/859) for oral aripiprazole.

Other Adverse Reactions Observed During the Premarketing Evaluation of Oral Aripiprazole: Following is a list of MedDRA terms that reflect adverse reactions reported by patients treated with oral aripiprazole at multiple doses ≥2 mg/day during any phase of a trial within the database of 13,543 adult patients. All events assessed as possible adverse drug reactions have been included with the exception of more commonly occurring events. In addition, medically/clinically meaningful adverse reactions, particularly those that are likely to be useful to the prescriber or that have pharmacologic plausibility, have been included. Events already listed in other parts of Adverse Reactions (6), or those considered in Warnings and Precautions (5) or Overdosage (10) have been excluded. Although the reactions reported occurred during treatment with aripiprazole, they were not necessarily caused by it.

Events are further categorized by MedDRA system organ class and listed in order of decreasing frequency according to the following definitions: those occurring in at least 1/100 patients (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing); those occurring in 1/100 to 1/1000 patients; and those occurring in fewer than 1/1000 patients.

Blood and Lymphatic System Disorders: ≥1/1000 patients and <1/100 patients - thrombocytopenia; Cardiac Disorders: ≥1/1000 patients and <1/100 patients - palpitations, cardiopulmonary failure, myocardial infarction, cardio-respiratory arrest, atrioventricular block, extrasystoles, angina pectoris, myocardial ischemia; <1/1000 patients - atrial flutter, supraventricular tachycardia, ventricular tachycardia; Eye Disorders: ≥1/1000 patients and <1/100 patients - photophobia, diplopia, eyelid edema, photopsia; Gastrointestinal Disorders: ≥1/1000 patients and <1/100 patients - gastroesophageal reflux disease, swollen tongue, esophagitis; <1/1000 patients - pancreatitis; General Disorders and Administration Site Conditions: ≥1/100 patients - asthenia, peripheral edema, chest pain; ≥1/1000 patients and <1/100 patients - face edema, angioedema; <1/1000 patients - hypothermia; Hepatobiliary Disorders: <1/1000 patients - hepatitis, jaundice; Immune System Disorders: ≥1/1000 patients and <1/100 patients - hypersensitivity; Injury, Poisoning, and Procedural Complications: ≥1/100 patients - fall; <1/1000 patients - heat stroke; Investigations: ≥1/1000 patients and <1/100 patients - blood prolactin increased, blood urea increased, blood creatinine increased, blood bilirubin increased; <1/1000 patients - blood lactate dehydrogenase increased, glycosylated hemoglobin increased; Metabolism and Nutrition Disorders: ≥1/1000 patients and <1/100 patients - anorexia, hyponatremia, hypoglycemia, polydipsia; <1/1000 patients - diabetic ketoacidosis; Musculoskeletal and Connective Tissue Disorders: ≥1/1000 patients and <1/100 patients - muscle rigidity, muscular weakness, muscle tightness, mobility decreased; <1/1000 patients - rhabdomyolysis; Nervous System Disorders: ≥1/100 patients - coordination abnormal; ≥1/1000 patients and <1/100 patients - speech disorder, hypokinesia, hypotonia, myoclonus, akinesia, bradykinesia; <1/1000 patients - choreoathetosis; Psychiatric Disorders: ≥1/100 patients - suicidal ideation; ≥1/1000 patients and <1/100 patients - loss of libido, suicide attempt, hostility, libido increased, anger, anorgasmia, delirium, intentional self injury, completed suicide, tic, homicidal ideation; <1/1000 patients - catatonia, sleepwalking; Renal and Urinary Disorders: ≥1/1000 patients and <1/100 patients - urinary retention, polyuria, nocturia; Reproductive System and Breast Disorders: ≥1/1000 patients and <1/100 patients - menstruation irregular, erectile dysfunction, amenorrhea, breast pain; <1/1000 patients gynecomastia, priapism; Respiratory, Thoracic, and Mediastinal Disorders: ≥1/100 patients - nasal congestion, dyspnea; Skin and Subcutaneous Tissue Disorders: ≥1/100 patients - rash (including erythematous, exfoliative, generalized, macular, maculopapular, papular rash; acneiform, allergic, contact, exfoliative, seborrheic dermatitis, neurodermatitis, and drug eruption), hyperhydrosis; ≥1/1000 patients and <1/100 patients - pruritus, photosensitivity reaction, alopecia, urticaria.

Postmarketing Experience: The following adverse reactions have been identified during post-approval use of oral aripiprazole. 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: rare occurrences of allergic reaction (anaphylactic reaction, angioedema, laryngospasm, pruritus/urticaria, or oropharyngeal spasm).

DRUG INTERACTIONS: Carbamazepine or Other CYP3A4 Inducers: Concomitant use of ABILIFY MAINTENA with carbamazepine or other CYP3A4 inducers decreases the concentrations of aripiprazole. Avoid use of ABILIFY MAINTENA in combination with carbamazepine and other inducers of CYP3A4 for greater than 14 days [see Indications and Usage, Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

Ketoconazole or Other Strong CYP3A4 Inhibitors: Concomitant use of ABILIFY MAINTENA with ketoconazole or other CYP3A4 inhibitors for more than 14 days increases the concentrations of aripiprazole and reduction of the ABILIFY MAINTENA dose is recommended [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)]. Due to prolonged-release characteristics of ABILIFY MAINTENA, short-term co-administration of ketoconazole or other inhibitors of CYP3A4 with ABILIFY MAINTENA does not require a dose adjustment.

Quinidine or Other Strong CYP2D6 Inhibitors: Concomitant use of ABILIFY MAINTENA with quinidine or other CYP2D6 inhibitors increases the concentrations of aripiprazole after longerterm use (i.e., over 14 days) and reduction of the ABILIFY MAINTENA dose is recommended [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)]. Due to prolonged-release characteristics of ABILIFY MAINTENA, short-term co-administration of quinidine or other CYP2D6 inhibitors with ABILIFY MAINTENA does not require a dose adjustment.

CNS Depressants: Given the CNS depressant effects of aripiprazole, use caution when ABILIFY MAINTENA is taken in combination with other centrally-acting drugs or alcohol.

Anti-Hypertensive Agents: Due to its α1 -adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.

USE IN SPECIFIC POPULATIONS: Pregnancy: Pregnancy Category C: Risk Summary: Adequate and well controlled studies with aripiprazole have not been conducted in pregnant women. Neonates exposed to antipsychotic drugs (including ABILIFY MAINTENA) during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery.

In animal studies, aripiprazole demonstrated developmental toxicity, including possible teratogenic effects in rats and rabbits at doses 1-10 times the oral maximum recommended human dose [MRHD] of 30 mg/day based on a mg/m2 body surface area. ABILIFY MAINTENA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Clinical Considerations: Fetal/Neonatal Adverse Reactions: Monitor neonates exhibiting extrapyramidal or withdrawal symptoms. Some neonates recover within hours or days without specific treatment; others may require prolonged hospitalization.

Animal Data: Pregnant rats were treated with oral doses of 3 mg/kg/day, 10 mg/kg/day, and 30 mg/kg/day (1 times, 3 times, and 10 times the oral maximum recommended human dose [MRHD] of 30 mg/day on a mg/m2 body surface area) of aripiprazole during the period of organogenesis. Gestation was slightly prolonged at 30 mg/kg. Treatment caused a slight delay in fetal development, as evidenced by decreased fetal weight (30 mg/kg), undescended testes (30 mg/kg), and delayed skeletal ossification (10 mg/kg and 30 mg/kg). There were no adverse effects on embryofetal or pup survival. Delivered offspring had decreased body weights (10 mg/kg and 30 mg/kg), and increased incidences of hepatodiaphragmatic nodules and diaphragmatic hernia at 30 mg/kg (the other dose groups were not examined for these findings). A low incidence of diaphragmatic hernia was also seen in the fetuses exposed to 30 mg/kg. Postnatally, delayed vaginal opening was seen at 10 mg/kg and

30 mg/kg and impaired reproductive performance (decreased fertility rate, corpora lutea, implants, live fetuses, and increased post-implantation loss, likely mediated through effects on female offspring) was seen at 30 mg/kg. Some maternal toxicity was seen at 30 mg/kg; however, there was no evidence to suggest that these developmental effects were secondary to maternal toxicity.

In pregnant rats receiving aripiprazole injection intravenously (3 mg/kg/day, 9 mg/kg/day, and 27 mg/kg/day) during the period of organogenesis, decreased fetal weight and delayed skeletal ossification were seen at the highest dose, which also caused some maternal toxicity.

Pregnant rabbits were treated with oral doses of 10 mg/kg/day, 30 mg/kg/day, and 100 mg/kg/day (2 times, 3 times, and 11 times human exposure at the oral MRHD of 30 mg/day based on AUC and 6 times, 19 times, and 65 times the oral MRHD of 30 mg/day based on mg/m2 body surface area) of aripiprazole during the period of organogenesis. Decreased maternal food consumption and increased abortions were seen at 100 mg/kg. Treatment caused increased fetal mortality (100 mg/kg), decreased fetal weight (30 mg/ kg and 100 mg/kg), increased incidence of a skeletal abnormality (fused sternebrae at 30 mg/kg and 100 mg/kg), and minor skeletal variations (100 mg/kg).

In pregnant rabbits receiving aripiprazole injection intravenously (3 mg/kg/day, 10 mg/kg/day, and 30 mg/kg/day) during the period of organogenesis, the highest dose, which caused pronounced maternal toxicity, resulted in decreased fetal weight, increased fetal abnormalities (primarily skeletal), and decreased fetal skeletal ossification. The fetal no-effect dose was 10 mg/kg, which produced 5 times the human exposure at the oral MRHD based on AUC and is 6 times the oral MRHD of 30 mg/day based on mg/m2 body surface area.

In a study in which rats were treated with oral doses of 3 mg/kg/day, 10 mg/kg/day, and 30 mg/kg/day (1 times, 3 times, and 10 times the oral MRHD of 30 mg/day on a mg/m 2 body surface area) of aripiprazole perinatally and postnatally (from day 17 of gestation through day 21 postpartum), slight maternal toxicity and slightly prolonged gestation were seen at 30 mg/kg. An increase in stillbirths and decreases in pup weight (persisting into adulthood) and survival were seen at this dose.

In rats receiving aripiprazole injection intravenously (3 mg/kg/day, 8 mg/kg/day, and 20 mg/kg/day) from day 6 of gestation through day 20 postpartum, an increase in stillbirths was seen at 8 mg/kg and 20 mg/kg, and decreases in early postnatal pup weights and survival were seen at 20 mg/kg.

These doses produced some maternal toxicity. There were no effects on postnatal behavioral and reproductive development.

Nursing Mothers: Aripiprazole is excreted in human breast milk. A decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use: Safety and effectiveness of ABILIFY MAINTENA in patients <18 years of age have not been evaluated.

Geriatric Use: Safety and effectiveness of ABILIFY MAINTENA in patients >60 years of age have not been evaluated. In oral single-dose pharmacokinetic studies (with aripiprazole given in a single oral dose of 15 mg), aripiprazole clearance was 20% lower in elderly (≥65 years) subjects compared to younger adult subjects (18 to 64 years). There was no detectable age effect, however, in the population pharmacokinetic analysis of oral aripiprazole in schizophrenia patients. Also, the pharmacokinetics of oral aripiprazole after multiple doses in elderly patients appeared similar to that observed in young, healthy subjects. No dosage adjustment of ABILIFY MAINTENA is recommended for elderly patients [see also Boxed Warning and Warnings and Precautions (5.1)].

CYP2D6 Poor Metabolizers: Approximately 8% of Caucasians and 3–8% of Black/African Americans cannot metabolize CYP2D6 substrates and are classified as poor metabolizers (PM).

Dosage adjustment is recommended in CYP2D6 poor metabolizers due to high aripiprazole concentrations [see Dosage and Administration (2.3), Clinical Pharmacology (12.3)].

OVERDOSAGE: Human Experience: The largest known case of acute ingestion with a known outcome involved 1260 mg of oral aripiprazole (42 times the maximum recommended daily dose) in a patient who fully recovered.

Common adverse reactions (reported in at least 5% of all overdose cases) reported with oral aripiprazole overdosage (alone or in combination with other substances) include vomiting, somnolence, and tremor. Other clinically important signs and symptoms observed in one or more patients with aripiprazole overdoses (alone or with other substances) include acidosis, aggression, aspartate aminotransferase increased, atrial fibrillation, bradycardia, coma, confusional state, convulsion, blood creatine phosphokinase increased, depressed level of consciousness, hypertension, hypokalemia, hypotension, lethargy, loss of consciousness, QRS complex prolonged, QT prolonged, pneumonia aspiration, respiratory arrest, status epilepticus, and tachycardia.

Management of Overdosage: In case of overdosage, call the Poison Control Center immediately at 1-800-222-1222.

PATIENT COUNSELING INFORMATION: Physicians are advised to discuss the FDA-approved patient labeling (Medication Guide) with patients for whom they prescribe ABILIFY MAINTENA. Distributed and marketed by Otsuka America Pharmaceutical, Inc., Rockville, MD 20850 Marketed by Lundbeck, Deerfield, IL 60015 USA ABILIFY MAINTENA is a trademark of Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan © 2013 Otsuka Pharmaceutical Co., Ltd. 09US12L-1001B February 2013

EDITORIAL BOARD EDITOR-IN-CHIEF

David B. Nash, MD, MBA Founding Dean, The Dr Raymond C. and Doris N. Grandon Professor, Jefferson School of Population Health Thomas Jefferson University, Philadelphia, PA DEPUTY EDITORS

Joseph D. Jackson, PhD Program Director, Applied Health Economics and Outcomes Research, Jefferson School of Population Health, Thomas Jefferson University Laura T. Pizzi, PharmD, MPH, RPh Professor, Dept. of Pharmacy Practice, Jefferson School of Pharmacy, Thomas Jefferson University AGING AND WELLNESS

Eric G. Tangalos, MD, FACP, AGSF, CMD Professor of Medicine Mayo Clinic, Rochester, MN CANCER RESEARCH

Al B. Benson, III, MD, FACP, FASCO Professor of Medicine, Associate Director for Clinical Investigations Robert H. Lurie Comprehensive Cancer Center Northwestern University, IL Samuel M. Silver, MD, PhD, FASCO Professor of Internal Medicine, Hematology/Oncology Assistant Dean for Research, Associate Director Faculty Group Practice, University of Michigan Medical School EMPLOYERS

Gregory Shaeffer, MBA, RPh, FASHP Vice President, Consulting Pharmacy Healthcare Solutions AmerisourceBurgen, Harrisburg, PA Arthur F. Shinn, PharmD, FASCP President, Managed Pharmacy Consultants, LLC, Lake Worth, FL F. Randy Vogenberg, RPh, PhD Principal, Institute for Integrated Healthcare Greenville, SC ENDOCRINOLOGY

James V. Felicetta, MD Chairman, Dept. of Medicine Carl T. Hayden Veterans Affairs Medical Center, Phoenix, AZ Quang Nguyen, DO, FACP, FACE Medical Director, Las Vegas Endocrinology Adjunct Associate Professor Endocrinology Touro University Nevada EPIDEMIOLOGY RESEARCH

Joshua N. Liberman, PhD Executive Director, Research, Development & Dissemination, Sutter Health, Concord, CA GOVERNMENT

Kevin B. “Kip” Piper, MA, FACHE President, Health Results Group, LLC Washington, DC HEALTH INFORMATION TECHNOLOGY

Kelly Huang, PhD Operating Partner, Spindletop Capital Austin, TX HEALTH OUTCOMES RESEARCH

Russell Basser, MBBS, MD, FRACP Senior Vice President Global Clinical Research and Development CSL Behring, King of Prussia, PA Diana Brixner, RPh, PhD Professor & Chair, Dept. of Pharmacotherapy Executive Director, Outcomes Research Center Director of Outcomes, Personalized Health Care Program, University of Utah, Salt Lake City

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Joseph E. Couto, PharmD, MBA Clinical Program Manager Cigna Corporation, Bloomfield, CT Steven Miff, PhD Senior Vice President VHA, Inc., Irving, TX Kavita V. Nair, PhD Professor and Director, Graduate Program Track in Pharmaceutical Outcomes Research Skaggs School of Pharmacy and Pharmaceutical Sciences University of Colorado, Aurora Gary M. Owens, MD President, Gary Owens Associates Ocean View, DE Andrew M. Peterson, PharmD, PhD Dean, Mayes School of Healthcare Business and Policy, Associate Professor, University of the Sciences, Philadelphia Sarah A. Priddy, PhD Director, Competitive Health Analytics Humana, Louisville, KY Timothy S. Regan, BPharm, RPh, CPh Executive Director, Strategic Accounts Xcenda, Palm Harbor, FL Vincent J. Willey, PharmD Associate Professor, School of Pharmacy University of the Sciences, Philadelphia David W. Wright, MPH President, Institute for Interactive Patient Care Bethesda, MD HEALTH & VALUE PROMOTION

Craig Deligdish, MD Hematologist/Oncologist Oncology Resource Networks, Orlando, FL Thomas G. McCarter, MD, FACP Chief Clinical Officer Executive Health Resources, PA Byron C. Scott, MD, MBA Medical Director National Clinical Medical Leader Truven Health Analytics, Chicago, IL Albert Tzeel, MD, MHSA, FACPE Regional Medical Director Medicare Operations, North Florida Humana, Jacksonville MANAGED MARKETS

Jeffrey A. Bourret, PharmD, MS, BCPS, FASHP Senior Director, North America Medical Affairs Medical Lead, Specialty Payer & Channel Customer Strategy, Pfizer Inc Richard B. Weininger, MD Chairman, CareCore National, LLC Bluffton, SC PATIENT ADVOCACY

Mike Pucci Sr VP, Commercial Operations and Business Development, PhytoChem Pharmaceuticals Lake Gaston, NC

Jeff Jianfei Guo, BPharm, MS, PhD Professor of Pharmacoeconomics & Pharmacoepidemiology, College of Pharmacy Univ. of Cincinnati Medical Center, OH PHARMACY BENEFIT DESIGN

Joel V. Brill, MD, AGAF, CHCQM Chief Medical Officer, Predictive Health, Phoenix, AZ Teresa DeLuca, MD, MBA Assistant Clinical Professor, Psychiatry, Mount Sinai School of Medicine, New York, NY Leslie S. Fish, PharmD Vice President of Clinical Programs Fallon Community Health Plan, MA John Hornberger, MD, MS Cedar Associates, LLC CHP/PCOR Adjunct Associate, Menlo Park, CA Michael S. Jacobs, RPh MSJ Associates, Sandy Springs, GA Matthew Mitchell, PharmD, MBA, FAMCP Director, Pharmacy Services SelectHealth, Murray, UT Paul Anthony Polansky, BSPharm, MBA PAPRx, LLC Gulph Mills, PA Christina A. Stasiuk, DO, FACOI Senior Medical Director Cigna, Philadelphia, PA POLICY & PUBLIC HEALTH

Joseph R. Antos, PhD Wilson H. Taylor Scholar in Health Care Retirement Policy, American Enterprise Institute Washington, DC Robert W. Dubois, MD, PhD Chief Science Officer National Pharmaceutical Council, Washington, DC Jack E. Fincham, PhD, RPh Professor of Pharmacy, School of Pharmacy Presbyterian College, Clinton, SC Walid F. Gellad, MD, MPH Assistant Professor of Medicine, University of Pittsburgh, Staff Physician, Pittsburgh VA Medical Center, Adjunct Scientist, RAND Health Paul Pomerantz, MBA CEO, American Society of Anesthesiologists Park Ridge, IL J. Warren Salmon, PhD Professor of Health Policy & Administration School of Public Health University of Illinois at Chicago Raymond L. Singer, MD, MMM, CPE, FACS Chief, Division of Cardiothoracic Surgery Vice Chair, Department of Surgery for Quality & Patient Safety and Outreach Lehigh Valley Health Network, PA RESEARCH & DEVELOPMENT

PAYER-PROVIDER FINANCES

Bruce Pyenson, FSA, MAAA Principal & Consulting Actuary Milliman, Inc, New York, NY

Christopher (Chris) P. Molineaux President, Pennsylvania BIO Malvern, PA Michael F. Murphy, MD, PhD Chief Medical Officer and Scientific Officer Worldwide Clinical Trials King of Prussia, PA

PERSONALIZED MEDICINE

SPECIALTY PHARMACY

Amalia M. Issa, PhD, MPH Director, Program in Personalized Medicine & Targeted Therapeutics, University of the Sciences, Philadelphia PHARMACOECONOMICS

Josh Feldstein President & CEO, CAVA, The Center for Applied Value Analysis, Inc, Norwalk, CT

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Atheer A. Kaddis, PharmD Senior Vice President Sales and Business Development Diplomat Specialty Pharmacy, Flint, MI James T. Kenney, Jr, RPh, MBA Pharmacy Operations Manager, Harvard Pilgrim Health Care, Wellesley, MA Michael Kleinrock Director, Research Development IMS Institute for Healthcare Informatics

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Cardiometabolic Health Theme Issue EDITORIAL

425 Read All About It

David B. Nash, MD, MBA INTRODUCTION

427 Cardiometabolic Health in 2014: Clinical and Economic Implications

Dalia Buffery, MA, ABD BUSINESS

430 Impact of the New ACC/AHA Guidelines on the Treatment of High Blood Cholesterol in a Managed Care Setting Josephine N. Tran, PharmD, MS; Toros Caglar, PhD; Karen M. Stockl, PharmD; Heidi C. Lew, PharmD; Brian K. Solow, MD; Paul S. Chan, MD, MSc 442 Stakeholder Perspective: Real-World Consequences of the 2013 ACC/AHA Cholesterol Guidelines for the Prevention of Cardiovascular Disease

By Joseph D. Jackson, PhD

Continued on page 422

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CLINICAL

444 Utilization of Parenteral Anticoagulants and Warfarin: Impact on the Risk of Venous Thromboembolism Recurrence in the Outpatient Setting Jennifer Cai, MS, MPH; Ronald Preblick, PharmD, MPH; Qiaoyi Zhang, MD, PhD; Winghan Jacqueline Kwong, PharmD, PhD 450 Stakeholder Perspective: Better Compliance with Clinical Guidelines for Venous Thromboembolism Can Improve Patient Outcomes, Reduce Costs

By James T. Kenney, RPh, MBA 452 New and Emerging Drugs and Targets for Type 2 Diabetes: Reviewing the Evidence Brien Rex Miller, DO; Hanh Nguyen, DO; Charles Jia-Haur Hu, DO; Chihyi Lin, DO; Quang T. Nguyen, DO, FACP, FACE, FTOS 462 Stakeholder Perspective: Addressing Adherence a Key Challenge in the Management of Patients with Type 2 Diabetes

By Jeffrey A. Bourret, PharmD, MS, RPh, BCPS, FASHP

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What is the value of one year on velCaDe (bortezomib)? ®

for patients with previously untreated multiple myeloma, 1 year of treatment with velCaDe in combination with MP* delivered a >1-year sustained median overall survival (os) advantage.1† At 60.1-month median follow-up: VELCADE (bortezomib)+MP provided a median OS of 56.4 months vs 43.1 months with MP alone (HR=0.695 [95% CI, 0.57-0.85]; p<0.05) At 3-year median follow-up: VELCADE+MP provided an OS advantage over MP that was not regained with subsequent therapies Of the 69% of MP patients who received subsequent therapies, 50% received VELCADE or a VELCADE-containing regimen1 Results were achieved using VELCADE twice weekly followed by a weekly dosing for a median of 50 weeks (54 weeks planned)1

the additional value of choice of administration.

Subcutaneous VELCADE demonstrated efficacy consistent with IV for the primary endpoints2‡: At 12 weeks, subcutaneous VELCADE: 43% achieved overall response rate (ORR) and 7% complete response (CR) vs IV: 42% ORR and 8% CR § II

The median age of patients in the VISTA† trial was 71 years (range: 48-91).

At 24 weeks, subcutaneous VELCADE ± dexamethasone: 53% achieved ORR and 11% CR vs IV: 51% ORR and 12% CR§ II More than 80% of previously untreated patients starting on VELCADE receive subcutaneous administration 3¶

Indication and Important Safety Information for VELCADE® (bortezomib) INDICATION VELCADE (bortezomib) is indicated for the treatment of patients with multiple myeloma.

CONTRAINDICATIONS VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration. Fatal events have occurred with intrathecal administration of VELCADE. WARNINGS, PRECAUTIONS, AND DRUG INTERACTIONS ▼ Peripheral neuropathy: Manage with dose modification or discontinuation. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment. ▼ hypotension: Use caution when treating patients taking antihypertensives, with a history of syncope, or with dehydration. ▼ Cardiac toxicity: Worsening of and development of cardiac failure have occurred. Closely monitor patients with existing heart disease or risk factors for heart disease. ▼ Pulmonary toxicity: Acute respiratory syndromes have occurred. Monitor closely for new or worsening symptoms.

▼ Posterior reversible encephalopathy syndrome: Consider MRI imaging for onset of visual or neurological symptoms; discontinue VELCADE if suspected. ▼ Gastrointestinal toxicity: Nausea, diarrhea, constipation, and vomiting may require use of antiemetic and antidiarrheal medications or fluid replacement. ▼ thrombocytopenia or neutropenia: Monitor complete blood counts regularly throughout treatment. ▼ tumor lysis syndrome: Closely monitor patients with high tumor burden. ▼ hepatic toxicity: Monitor hepatic enzymes during treatment. ▼ embryo-fetal risk: Women should avoid becoming pregnant while being treated with VELCADE. Advise pregnant women of potential embryo-fetal harm. ▼ Closely monitor patients receiving VELCADE in combination with strong CyP3a4 inhibitors. Avoid concomitant use of strong CyP3a4 inducers.

ADVERSE REACTIONS Most commonly reported adverse reactions (incidence ≥20%) in clinical studies include nausea, diarrhea, thrombocytopenia, neutropenia, peripheral neuropathy, fatigue, neuralgia, anemia, leukopenia, constipation, vomiting, lymphopenia, rash, pyrexia, and anorexia.

Please see Brief Summary for VELCADE adjacent to this advertisement.

For Reimbursement Assistance, call 1-866-VELCADE (835-2233), Option 2, or visit VELCADE-HCP.com.

*Melphalan+prednisone. † VISTA TRIAL: a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE administered intravenously in combination with MP vs MP in previously untreated multiple myeloma. The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and overall survival. At a prespecified interim analysis (median follow-up 16.3 months), VELCADE+MP resulted in significantly superior results for TTP (median 20.7 months with VELCADE+MP vs 15.0 months with MP [p=0.000002]), PFS, overall survival, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition. Updated analysis was performed. ‡ SuBCuTAnEouS VS IV was a randomized (2:1), open-label, non-inferiority phase 3 trial (N=222) in patients with relapsed multiple myeloma designed to establish whether subcutaneous VELCADE (bortezomib) was non-inferior to intravenous administration.2 Non-inferiority was defined as retaining 60% of the intravenous treatment effect, measured by ORR, at the end of 4 cycles.2 The primary endpoint was ORR at 4 cycles. The secondary endpoints were response rate at 8 cycles, median TTP and PFS (months), 1-year OS, and safety. § Responses were based on criteria established by the European Group for Blood and Marrow Transplantation.2 II 82 patients (55%) in the subcutaneous VELCADE group and 39 patients (53%) in the IV group received dexamethasone. ¶ Out of 275 estimated unique patients receiving VELCADE as of May 2013.3 References: 1. Mateos MV, Richardson PG, Schlag R, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol. 2010;28(13):2259-2266. 2. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study.

Lancet Oncol. 2011;12(5):431-440. 3. Data on file 59, Millennium Pharmaceuticals, Inc.

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Brief Summary

VELC3X0043_A_Velcade_BS_7x10_r3.indd 1

Embryo-fetal: Pregnancy Category D. Women of reproductive potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses.

ADVERSE EVENT DATA: Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose administered intravenously twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously-treated multiple myeloma (N=1008) and previously-treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma.

In the integrated analysis, the most commonly reported (≥10%) adverse reactions were nausea (49%), diarrhea NOS (46%), fatigue (41%), peripheral neuropathies NEC (38%), thrombocytopenia (32%), vomiting NOS (28%), constipation (25%), pyrexia (21%), anorexia (20%), anemia NOS (18%), headache NOS (15%), neutropenia (15%), rash NOS (13%), paresthesia (13%), dizziness (excl vertigo 11%), and weakness (11%). Eleven percent (11%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (4%) and neutropenia (2%). A total of 26% of patients experienced a serious adverse reaction during the studies. The most commonly reported serious adverse reactions included diarrhea, vomiting, and pyrexia (3% each), nausea, dehydration, and thrombocytopenia (2% each), and pneumonia, dyspnea, peripheral neuropathies NEC, and herpes zoster (1% each).

In the phase 3 VELCADE+melphalan and prednisone study in previously untreated multiple myeloma, the safety profile of VELCADE administered intravenously in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse reactions in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (48% vs 42%), neutropenia (47% vs 42%), peripheral neuropathy (46% vs 1%), nausea (39% vs 21%), diarrhea (35% vs 6%), neuralgia (34% vs <1%), anemia (32% vs 46%), leukopenia (32% vs 28%), vomiting (26% vs 12%), fatigue (25% vs 14%), lymphopenia (23% vs 15%), constipation (23% vs 4%), anorexia (19% vs 6%), asthenia (16% vs 7%), pyrexia (16% vs 6%), paresthesia (12% vs 1%), herpes zoster (11% vs 3%), rash (11% vs 2%), abdominal pain upper (10% vs 6%), and insomnia (10% vs 6%).

In the phase 3 VELCADE subcutaneous vs intravenous study in relapsed multiple myeloma, safety data were similar between the two treatment groups. The most commonly reported adverse reactions in this study were peripheral neuropathy NEC (37% vs 50%), thrombocytopenia (30% vs 34%), neutropenia (23% vs 27%), neuralgia (23% vs 23%), anemia (19% vs 23%), diarrhea (19% vs 28%), leukopenia (18% vs 20%), nausea (16% vs 14%), pyrexia (12% vs 8%), vomiting (9% vs 11%), asthenia (7% vs 16%), and fatigue (7% vs 15%). The incidence of serious adverse reactions was similar for the subcutaneous treatment group (20%) and the intravenous treatment group (19%). The most commonly reported SARs were pneumonia and pyrexia (2% each) in the subcutaneous treatment group and pneumonia, diarrhea, and peripheral sensory neuropathy (3% each) in the intravenous treatment group.

DRUG INTERACTIONS: Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients. Monitor patients for signs of bortezomib toxicity and consider a bortezomib dose reduction if bortezomib must be given in combination with strong CYP3A4 inhibitors (eg, ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%. Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur. Efficacy may be reduced when VELCADE is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s wort (Hypericum perforatum) may decrease bortezomib exposure unpredictably and should be avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant.

USE IN SPECIFIC POPULATIONS: Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use: The safety and effectiveness of VELCADE in children has not been established.

Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out.

Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, VELCADE should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer’s prescribing information.

Patients with Hepatic Impairment: The exposure of bortezomib is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients.

Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication.

Please see full Prescribing Information for VELCADE at VELCADEHCP.com.

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

Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright © 2013, Millennium Pharmaceuticals, Inc. V-12-0306a All rights reserved. Printed in USA V-14-0258

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INDICATIONS: VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. VELCADE for Injection is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy.

CONTRAINDICATIONS: VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration. Fatal events have occurred with intrathecal administration of VELCADE. WARNINGS AND PRECAUTIONS: Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory; however, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain, or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. In the Phase 3 relapsed multiple myeloma trial comparing VELCADE subcutaneous vs intravenous, the incidence of Grade ≥2 peripheral neuropathy events was 24% for subcutaneous and 39% for intravenous. Grade ≥3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 15% in the intravenous treatment group.

Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy.

Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may require a decrease in the dose and/or a less dose-intense schedule. In the VELCADE vs dexamethasone phase 3 relapsed multiple myeloma study, improvement in or resolution of peripheral neuropathy was reported in 48% of patients with ≥Grade 2 peripheral neuropathy following dose adjustment or interruption. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.

Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 8%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics.

Cardiac Toxicity: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have occurred during VELCADE therapy, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing, heart disease should be closely monitored. In the relapsed multiple myeloma study of VELCADE vs dexamethasone, the incidence of any treatment-related cardiac disorder was 8% and 5% in the VELCADE and dexamethasone groups, respectively.

The incidence of adverse reactions suggestive of heart failure (acute pulmonary edema, pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock) was ≤1% for each individual reaction in the VELCADE group. In the dexamethasone group, the incidence was ≤1% for cardiac failure and congestive cardiac failure; there were no reported reactions of acute pulmonary edema, pulmonary edema, or cardiogenic shock. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.

Pulmonary Toxicity: Acute Respiratory Distress Syndrome (ARDS) and acute diffuse infiltrative pulmonary disease of unknown etiology, such as pneumonitis, interstitial pneumonia, and lung infiltration have occurred in patients receiving VELCADE. Some of these events have been fatal.

In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease.

In the event of new or worsening cardiopulmonary symptoms, consider interrupting VELCADE until a prompt, comprehensive, diagnostic evaluation is conducted.

Posterior Reversible Encephalopathy Syndrome (PRES): Posterior Reversible Encephalopathy Syndrome (PRES; formerly termed Reversible Posterior Leukoencephalopathy Syndrome (RPLS)) has occurred in patients receiving VELCADE. PRES is a rare, reversible, neurological disorder, which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing PRES, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing PRES is not known.

Gastrointestinal Toxicity: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting, sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur.

Fluid and electrolyte replacement should be administered to prevent dehydration. Interrupt VELCADE for severe symptoms.

Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern, with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice-weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline.

The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study of VELCADE vs dexamethasone, the incidence of bleeding (≥Grade 3) was 2% on the VELCADE arm and <1% on the dexamethasone arm. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. Gastrointestinal and intracerebral hemorrhage has been reported in association with VELCADE. Transfusions may be considered.

Tumor Lysis Syndrome: Tumor lysis syndrome has been reported with VELCADE therapy.

Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment.

Monitor patients closely and take appropriate precautions.

Hepatic Toxicity: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic reactions include hepatitis, increases in liver enzymes, and hyperbilirubinemia. Interrupt VELCADE therapy to assess reversibility. There is limited re-challenge information in these patients.

EDITORIAL

Read All About It David B. Nash, MD, MBA Editor-in-Chief, American Health & Drug Benefits; Founding Dean, ­Jefferson School of Population Health, Philadelphia, PA

I

am frustrated. Despite more than 2 decades of personal involvement in the public reporting of healthcare outcomes and the widespread dissemination of these reports, there remains very little uptake by consumers of the information reported. Research contends that “most consumers do not believe quality varies from hospital to hospital, clinic to clinic, or physician to physician. Only 35% of adults think there are big differences in the quality of care among their local hospitals.”1 What has led to this state of affairs, and what can we do about it?

While I was still a Robert Wood Johnson Clinical Scholar at the University of Pennsylvania in the mid1980s, I had the opportunity to participate in what would become one of the first peer-reviewed journals focused on the outcomes of open heart surgery, the Journal of the American Medical Association. In a 1991 article in the journal, my colleagues and I reported on the differences in outcomes across 5 academic medical centers in Philadelphia, PA, for patients undergoing coronary artery bypass grafting (CABG) surgery.2 We discovered dramatic and significant differences in mortality across the 5 hospitals, while correcting for the severity of illness in multiple ways. In other words, patients undergoing CABG surgery at one hospital had nearly double or triple the mortality rate of those undergoing the same procedure at a different hospital that is literally down the street.2 Accompanying our article was an article from our colleagues at Dartmouth-Hitchcock Medical Center.3 Both articles, and an editorial by Donald M. Berwick, MD, MPP, President and Chief Executive Officer of the Institute for Healthcare Improvement,4 are often cited as the beginning of the consumerism movement in healthcare.

After the publication of those articles and contemporaneous with my move to Jefferson School of Population Health in 1990, I continued to work closely with the Pennsylvania Health Care Cost Containment Council (PHC4), one of the leading state-sponsored, tax-supported outcomes dissemination organizations in the nation. I still chair the technical advisory group of health services researchers and policy leaders who advise the PHC4 leaders.

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I have also had the privilege of publishing more than a dozen peer-reviewed articles in major national journals focusing on state report cards and have led an effort that clearly demonstrates why the stakeholders that really use report cards to improve quality are the hospitals themselves rather than consumers, employers, or managed care plans.5 My articles were followed by 2 of the most widely read textbooks on quality and safety, with multiple chapters focused on public reporting.6,7 I remain perplexed as to why consumers do not use report cards. One reason may be that report cards are “too complicated” for the average consumer. Sure, it might be difficult to explain severity-adjusted morbidity and mortality, which are the cornerstones of most report cards. It is also understandable that the public may be befuddled by medical nomenclature and its related technical jargon. Another argument contends that consumers simply do not have the time to confer online en route to a hospital for a medical emergency. Some colleagues have suggested that consumers are simply not motivated to utilize a report card until they have a clinical problem, and by then they may be too preoccupied, too ill, or simply unaware as to how to find a report card.

More reasonable researchers contend that we simply are not giving consumers information they find valuable.

Hibbard and colleagues, for example, have published the results of a study focused on managed care–related report cards that clearly demonstrate that most report cards describe the outcomes of procedures in ways that do not provide consumers with discriminatory power to enable them, for example, to select one provider over another.8 As a result, there is a growing body of literature that questions whether report cards ever improve quality.

Back to my frustration. In a post–Affordable Care Act world of transparency and accountability, how can we reconcile 20 years of underutilization of report cards, especially in an environment that is focused on the need for better information and increasing patient engagement in their own care? I am wrestling with this issue mightily.

Fortunately, recent work appears promising. In 2011, a national summit on public reporting was sponsored by the Agency for Healthcare Research and Quality ­

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(AHRQ), which brought together more than 125 individuals—believers and skeptics alike. The results of this summit were recently published in a supplement, in which attendees provided a “guided vision” for public reporting for consumers and made 10 critically important recommendations for the future.9 According to Hussey and colleagues, “by 2025—or ideally much sooner—consumers will access and appropriately use health care provider performance information in selecting providers. Specifically, consumers in every community in the United States will have ready access to comparable, accurate, meaningful, and actionable performance information on primary care physicians, specialists, hospitals, and ultimately the full spectrum of providers to enhance the quality of their decision making.”1 Wow! This is a beautiful guiding vision that is certainly worth endorsing.

I believe that financial incentives that drive patients to high-value providers (those with a low error rate, who practice using the best available evidence and who, therefore, obtain good outcomes at a low cost) will be the cornerstone of any future public accountability system.

How might we achieve this vision? The AHRQ investigators laid out a series of recommendations that include strengthening the demand for public policymakers, report sponsors, and consumer organizations to raise awareness about variation in healthcare quality.9 In other words, continue the work that our school has pioneered in disseminating the sorry state of affairs in our country, in which medical errors remain the third leading cause of death.10 The second AHRQ recommendation calls for identifying, developing, and testing a new generation of meaningful and scientifically sound measures that meet the consumers’ needs.9 This clearly is going to take a lot of additional research and will need to engage organizations such as the Joint Commission, the Leapfrog Group, the National Quality Forum, and many others.

Among the 8 remaining recommendations, let me highlight 3. Recommendation 4 calls for federal engagement with consumers to develop and test measures that are accessible, understandable, and usable.9 I hope that we will, as a nation, fund research that will lead to measures that make sense. Recommendation 7 calls for public and private consensus on the standards and data elements used in performance measures.9 We have been

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struggling with this lack of consensus in the policy community for nearly 30 years. How to achieve such consensus is not described in any additional detail.

Finally, recommendation 10 states, “public and private payers, through public policy and purchasing actions, should act in coordinated ways to financially support public reporting and collection of the underlying data.”9 I believe this tenth recommendation explicitly calls for the employer community to engage with providers to create a report card that makes sense. I certainly support this final recommendation and hope that there are opportunities for the different stakeholders to come together and implement this vision.

In conclusion, most of our readers would not dream of making a dinner reservation at a new restaurant without carefully reading its recent reviews on Yelp. Similarly, most of our peer group (in a social sense) would not purchase a large electronic item without checking Consumer Reports. Then why is it that the vast majority of even highly educated individuals do not access report cards, even cards that are readily available and based on good research, when it comes time to make a decision on healthcare purchasing?

I am hopeful that the recent publication by the AHRQ Task Force will garner a good deal of public attention. I believe that financial incentives that drive patients to high-value providers (those with a low error rate, who practice using the best available evidence and who, therefore, obtain good outcomes at a low cost) will be the cornerstone of any future public accountability system.

If you, too, are frustrated about this issue, please let me know. Better yet, tell me about a report card that you think makes sense. I am interested in your views, and you can reach me via e-mail at david.nash@jefferson.edu. n

References

1. Hussey PS, Luft HS, McNamara P. Public reporting of provider performance at a crossroads in the United States: summary of current barriers and recommendations on how to move forward. Med Care Res Rev. 2014;71(5 suppl):5S-16S. 2. Williams SV, Nash DB, Goldfarb N. Differences in mortality from coronary artery bypass graft surgery at five teaching hospitals. JAMA. 1991;266:810-815.

3. O’Connor GT, Plume SK, Olmstead EM, et al; for the Northern New England Cardiovascular Disease Study Group. A regional prospective study of in-hospital mortality associated with coronary artery bypass grafting. JAMA. 1991;266:803-809.

4. Berwick DM. The double edge of knowledge. JAMA. 1991;266:841-842.

5. Bentley JM, Nash DB. How Pennsylvania hospitals have responded to publicly released reports on coronary artery bypass graft surgery. Jt Comm J Qual Improv.

1998;24:40-49.

6. Nash DB, Clarke JL, Skoufalos A, Horowitz M, eds. Health Care Quality: The Clinician’s Primer. Tampa, FL: American College of Physician Executives; 2012.

7. Joshi MS, Ransom ER, Nash DB, Ransom SB, eds. The Healthcare Quality Book: Vision, Strategy, and Tools. 3rd ed. Chicago, IL: Health Administration Press; 2014.

8. Hibbard JH, Greene J, Daniel D. What is quality anyway? Performance reports that clearly communicate to consumers the meaning of quality of care. Med Care Res Rev. 2010;67:275-293.

9. Damberg CL, McNamara P, eds. Supplemental issue: informing the next generation of public reporting for consumers. Med Care Res Rev. 2014;71(5 suppl):3S-107S. 10. James JT. A new, evidence-based estimate of patient harms associated with hospital care. J Patient Saf. 2013;9:122-128.

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INTRODUCTION

Cardiometabolic Health in 2014: Clinical and Economic Implications Dalia Buffery, MA, ABD Editorial Director, American Health & Drug Benefits

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he high clinical and economic burdens associated with cardiometabolic conditions, including cardiovascular disease, diabetes, and obesity, in the United States present ongoing challenges for patients, providers, payers, drug manufacturers, and the entire healthcare system. Heart disease continues to lead the morbidity and mortality trends in the United States,1 with diabetes lagging not far behind, especially when factoring in individuals with prediabetes.2 Also, the number of obese Americans, especially among the younger population, continues to rise,3 despite efforts by healthcare professionals and the federal government to increase awareness of the risks associated with excess weight.

The numbers associated with cardiometabolic conditions in the United States are staggering. In 2011, 76.4 million patients in the United States had hypertension, 16.3 million had chronic heart disease, 7 million had stroke, and 5.7 million had heart failure—all directly increasing the mortality risk from heart disease.1 In 2007, approximately 25.8 million US patients had diabetes, and many millions more had prediabetes.2 Of note, according to new reported published in October 2014, the rate of diabetes doubled between 1990 and 2008 but plateaued between 2008 and 2012, although it increased in some subpopulations.4 Perhaps most alarming, in 2012, 34.9% of US adults and 17% of US youth were obese,3 and it is projected that approximately 21% of the US population will have type 2 diabetes by 2050.5 These numbers should give pause to anyone involved in the attempt to stem these conditions or manage patients with 1 or more of these conditions.

Despite the wealth of treatment options for heart disease and diabetes, heart disease remains the leading cause of disease-related mortality in the United States,6 and less than 50% of patients with diabetes reach the American Diabetes Association’s glycemic goal of hemoglobin A1c <7%.7 Advances in the search for biomarkers and in personalized medicine may help to better understand the biologically and genetically based risk factors for cardiometabolic complications. A barrier in the treatment of obesity is overcoming the issue of lifestyle behavior as the main cause of this condition and accepting it as a medical condition with a unique pathophysiology.8

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The economic outlook for cardiometabolic conditions is as dire as the clinical picture. In 2007, the estimated total cost associated with diabetes in the United States was $174 billion.2 In 2008, the estimated total cost for obesity was $147 billion. And in 2010, the US healthcare system spent $272.5 billion in direct costs on the treatment of patients with cardiovascular disease.

Yet, these numbers pale in comparison to the current projections of $818.1 billion that the United States will likely spend by 2030 for the treatment of cardiovascular disease,9 or the $957 billion projected to be spent on obesity by 2030.10 These figures may be enough of an incentive to encourage the pharmaceutical industry and the federal government to devote increasing resources and efforts on innovative therapies for the promotion of cardiometabolic health in the United States and potentially worldwide.

This issue of American Health & Drug Benefits includes important contributions to the medical literature in cardiometabolic health, highlighting the need for new strategies to address the ever-growing clinical and economic conundrums associated with cardiovascular disease, diabetes, and obesity in the United States, and the need to improve compliance with clinical guidelines.

Tran and colleagues analyze the implications of the 2013 guidelines issued by the American College of Cardiology and the American Heart Association (ACC/AHA) for the treatment of high blood cholesterol, which present a paradigm change in the approach to the prevention of heart disease.11 Using real-­world claims data, the authors project that the new ACC/AHA recommendations will have a significant impact on the use of cholesterol-lowering medications: nearly 25% more patients in the United States are expected to be starting statin therapy in the next 3 years. Furthermore, they calculated that this 25% increase in statin use would be accompanied by a 68% reduction in nonstatin prescriptions for patients with elevated cholesterol. In his Stakeholder Perspective, Jackson suggests that because the majority of statins today are available as generics, “the projected increased utilization of statins that Tran and colleagues highlight may actually save money for health insurance plans and other payers.” 12

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Cai and colleagues investigated the level of adherence to anticoagulation guidelines in the real world using claims data from a large national database.13 The current clinical guidelines recommend the early initiation of warfarin with parenteral anticoagulation therapy for the treatment of patients with acute venous thromboembolism (VTE) and for the prevention of VTE recurrence, which is especially high in the early months of an acute event. Although acute VTE is associated with a high mortality risk and long-term complications, Cai and colleagues found that many patients are not managed according to the current treatment guidelines. In their study, only 25% of the 4403 patients with acute VTE received warfarin on the same day as initiating parenteral anticoagulant therapy, and more than 50% of patients received warfarin 3 days after initiating parenteral anticoagulant therapy.13 This research points to a gap in patient care that could result in unnecessary morbidity and mortality in this high-risk patient population.

Finally, Miller and colleagues review the efforts in drug development to address the diabetes challenge.14 They review the evidence for new drug classes for the treatment of patients with type 2 diabetes, including drugs that were recently approved by the US Food and Drug Administration (FDA) or drugs that are currently in development.14 The authors focus on the new class of sodium glucose cotransporter-2 inhibitors and the new glucagon-like peptide-1 agents, as well as a few other recently approved drugs.

Although 14 classes of drugs are currently available for the treatment of type 2 diabetes mellitus, Miller and colleagues show that in 2011, almost 15% of patients with type 2 diabetes were not taking a medication for their disease.14 This lack of patient adherence, says Bourret in his accompanying Stakeholder Perspective, remains a major barrier to proper glycemic control.15 It is also likely the reason that the majority of the new oral drug classes recently approved by the FDA or that are in development include once-daily agents, which potentially could improve adherence. In addition, the new injections entering the market, according to Miller and colleagues, are now offered in a pen format, again with the goal of improving adherence.14 Perhaps most important, according to Miller and colleagues, the new agents entering the market or being developed for the treatment of patients with diabetes are either weight-friendly or can induce weight loss, an important aspect in diabetes management. The new drugs are also associated with a lower risk for hypoglycemia; considering the mean total cost of $17,564 per hypogly-

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cemic episode requiring hospitalization, this can be a meaningful improvement to the healthcare system as a whole, Miller and colleagues note.14 With the rise in life expectancy and the aging of the US population, as well as the growing number of obese patients, the unsustainable clinical and economic predicament of cardiometabolic conditions can be expected to persist, requiring new solutions. The sample of articles assembled in this issue provides insight into some of the challenges facing all healthcare stakeholders—providers, payers, researchers, drug developers, and policymakers—and the need for heightened innovation in the search for new and improved solutions.

Applying the implications from health economics research and personalized medicine into patient care may open new opportunities to improve the clinical and economic outcomes in cardiometabolic health.

We invite all readers to submit comments, critiques, and letters related to the topics discussed in this issue at www.AHDBonline.com. n

References

1. Roger VL, Go AS, Lloyd-Jones DM, et al, for the American Heart Association.

Heart disease and stroke statistics—2011 update. Circulation. 2011;123:e18-e209.

2. Centers for Disease Control and Prevention. 2011 National diabetes fact sheet. www.cdc.gov/diabetes/pubs/estimates11.htm#11. Accessed October 30, 2014.

3. Ogden CL, Caroll MD, Kit BK, Flegal KM. Prevalence of childhood and adult obesity in the United States, 2011-2012. JAMA. 2014;311:806-814.

4. Geiss LS, Wang J, Cheng YJ, et al. Prevalence and incidence trends for diagnosed diabetes among adults aged 20 to 79 years, United States, 1980-2012. JAMA. 2014;312:1218-1226.

5. Boyle JP, Thompson TJ, Gregg EW, et al. Projection of the year 2050 burden of diabetes in the US adult population: dynamic modeling of incidence, mortality, and prediabetes prevalence. Popul Health Metr. 2010;8:29.

6. Kochanek K, Xu J, Murphy SL, et al. Deaths: preliminary data for 2009. Natl Vital Stat Rep. 2011;59:1-51.

7. Fitch K, Iwasaki K, Pyenson B. Improved management can help reduce the economic burden of type 2 diabetes: a 20-year actuarial projection. Milliman Client ­Report. April 28, 2010. http://publications.milliman.com/publications/health-­ published/pdfs/improved-management-can-help.pdf. Accessed October 30, 2014.

8. American Medical Association. AMA adopts new policies on second day of voting at annual meeting. Press release; June 18, 2013. www.ama-assn.org/ama/pub/news/ news/2013/2013-06-18-new-ama-policies-annual-meeting.page. Accessed October 30, 2014.

9. Heidenreich PA, Trogdon JG, Khavjou OA, et al, for the American Heart Association. Forecasting the future of cardiovascular disease in the United States. Circulation. 2011;123:933-944.

10. American Heart Association. Statistical fact sheet: overweight and obesity. 2013 Update. www.heart.org/idc/groups/heart-public/@wcm/@sop/@smd/documents/ downloadable/ucm_319588.pdf. Accessed October 30, 2014.

11. Tran JN, Caglar T, Stockl KM, Lew HC, et al. Impact of the new ACC/AHA guidelines on the treatment of high blood cholesterol in a managed care setting. Am Health Drug Benefits. 2014;7:426-439.

12. Jackson JD. Real-world consequences of the 2013 ACC/AHA cholesterol guidelines for the prevention of cardiovascular disease (stakeholder perspective). Am Health Drug Benefits. 2014;7:438-439.

13. Cai J, Preblick R, Zhang Q, at al. Utilization of parenteral anticoagulants and warfarin: impact on the risk of venous thromboembolism recurrence in the outpatient setting. Am Health Drug Benefits. 2014;7:441-448.

14. Miller BR, Nguyen H, Hu CJ-H, et al. New and emerging drugs and targets for type 2 diabetes: reviewing the evidence. Am Health Drug Benefits. 2014;7:451-462.

15. Bourret JA. Addressing adherence a key challenge in the management of patients with type 2 diabetes (stakeholder perspective). Am Health Drug Benefits.

2014;7:461-462.

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If only it were this easy to spot SLE* organ damage

33% to 50% of SLE patients experience permanent organ damage within the first 5 years of diagnosis.1,2

To learn more about SLE, visit

www.TalkSLE.com

SLE can affect nearly every major organ, including the skin, kidneys, joints, lungs, and heart.3 Even when minimal symptoms are present, organ damage can still occur. 2 *systemic lupus erythematosus

REFERENCES: 1. Chambers SA, Allen E, Rahman A, Isenberg D. Damage and mortality in a group of British patients with systemic lupus erythematosus followed up for over 10 years. Rheumatology (Oxford). 2009;48(6):673-675. 2. Urowitz MB, Gladman DD, Ibañez D, et al. Evolution of disease burden over five years in a multicenter inception systemic lupus erythematosus cohort. Arthritis Care Res (Hoboken). 2012;64(1):132-137. 3. Lopez R, Davidson JE, Beeby MD, Egger PJ, Isenberg DA. Lupus disease activity and the risk of subsequent organ damage and mortality in a large lupus cohort.

Rheumatology (Oxford). 2012;51(3):491-498. ©2014 GSK group of companies.

All rights reserved. Printed in USA. BN2671R0 April 2014

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ORIGINAL RESEARCH

Impact of the New ACC/AHA Guidelines on the Treatment of High Blood Cholesterol in a Managed Care Setting Josephine N. Tran, PharmD, MS; Toros Caglar, PhD; Karen M. Stockl, PharmD; Heidi C. Lew, PharmD; Brian K. Solow, MD; Paul S. Chan, MD, MSc Stakeholder Perspective, page 442

Am Health Drug Benefits.

2014;7(8):430-443 www.AHDBonline.com Received August 14, 2014 Accepted in final form October 6, 2014

Disclosures are at end of text

BACKGROUND: In November 2013, the American College of Cardiology (ACC) and the American Heart Association (AHA) together issued new guidelines for the treatment of patients with high cholesterol, providing a new paradigm for the management of cholesterol in the primary and secondary prevention of coronary artery disease.

OBJECTIVE: To examine the impact of the 2013 ACC/AHA cholesterol treatment guidelines on pharmacy utilization of cholesterol-lowering drugs in a real-world managed care setting.

METHODS: Pharmacy claims from OptumRx, a national pharmacy benefit management provider, for the period between January 1, 2013, and December 31, 2013 (baseline period), were used to identify candidates for cholesterol-lowering therapy and to estimate the number of potential patients who will be starting or intensifying statin therapy based on the updated cholesterol treatment guidelines. Potential candidates for cholesterol-lowering treatments included patients with diabetes or hypertension aged 40 to 75 years who were not already receiving a cholesterol-lowering medication, as well as patients receiving cholesterol-­ lowering therapies during the baseline period. The baseline cholesterol-lowering medication market share was used to project changes in pharmacy utilization over the next 3 years.

RESULTS: Based on the 2013 ACC/AHA cholesterol treatment guidelines, there will be a 25% increase in the proportion of the overall population that is treated with statins over the next 3 years, increasing from 3,909,407 (27.7%) patients to 4,892,668 (34.7%) patients. The largest proportion of the increase in statin utilization is projected to be for primary prevention in patients aged 40 to 75 years who were not receiving any cholesterol-lowering treatment at baseline. These projected changes will increase the overall number of statin prescriptions by 25% and will decrease the number of nonstatin cholesterol-lowering medication prescriptions by 68% during the next 3 years.

CONCLUSION: The new 2013 ACC/AHA cholesterol treatment guidelines are projected to have a significant impact on the utilization of cholesterol-lowering drugs by increasing the overall proportion of the population receiving statin therapy and by decreasing the utilization of nonstatin cholesterol-­ lowering medications.

I

n November 2013, the American College of Cardiology (ACC) and the American Heart Association (AHA) released together new clinical guidelines for the treatment of patients with high blood cholesterol.1 The 2013 guidelines provide a new paradigm for cholesterol management in the primary and secondary prevenDr Tran is Senior Research Consultant, Clinical Programs and Outcomes Research, OptumRx, Irvine, CA; Dr Caglar is Senior Research Consultant, Clinical Programs and Outcomes Research, OptumRx; Dr Stockl is Senior Director, Clinical Programs and Outcomes Research, OptumRx; Dr Lew is Vice President, Clinical Programs, OptumRx; Dr Solow is Chief Medical Officer, Clinical, OptumRx; Dr Chan is Associate Professor, Division of Cardiology, University of Missouri-Kansas City.

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tion of coronary artery disease (CAD); these recommendations are based on clinical evidence from randomized controlled trials of cholesterol-lowering therapies rather than on expert consensus as in previous guidelines.2,3 Before the 2013 guidelines, the Adult Treatment Panel (ATP) III report of the National Cholesterol Education Program was the main clinical guideline for the primary and secondary prevention of CAD.4 The ATP III recommends statin therapy in patients with established cardiovascular (CV) disease or diabetes whose low-density lipoprotein cholesterol (LDL-C) levels are ≥100 mg/dL, or in patients with a combination of elevated LDL-C levels and a 10-year risk for CAD based on the Framingham risk calculator.4 The primary focus of the ATP III guideline was on a treatto-target strategy, in which lipid-modifying medications were titrated to achieve specific LDL-C levels.

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Based on clinical trials that have shown that LDL-C– lowering therapy reduces the risk for CAD, the ATP III guideline used LDL-C as the target of cholesterol-­ lowering therapy.4 This recommendation diverges from current clinical evidence, because there are no major randomized clinical trials that have tested the benefits of treating patients to LDL-C targets.

The 2013 ACC/AHA clinical guidelines no longer recommend the treat-to-target strategy for the management of cholesterol levels in patients with CAD, and instead recommend the use of fixed-dose, high-intensity and fixed-dose, moderate-intensity statin therapies to treat high-risk populations. These high-risk groups include patients with clinical atherosclerotic CV disease (ASCVD), patients with primary LDL-C elevations of ≥190 mg/dL, patients with diabetes who are aged 40 to 75 years, or patients aged 40 to 75 years without diabetes or ASCVD but with LDL-C levels between 70 mg/dL and 189 mg/dL whose estimated 10-year ASCVD risk is ≥7.5% based on a new risk calculator.1 Overall, with a focus on treating high-risk groups with cholesterol-lowering therapies that have been shown in randomized clinical trials to reduce the risk for ASCVD, the 2013 ACC/AHA guidelines recommend the use of statins for ASCVD risk reduction. The guidelines no longer recommend the use of nonstatin cholesterol-­ lowering therapies for ASCVD risk reduction, and they expand statin therapy for the primary prevention of ASCVD in patients with lower LDL-C levels who are at an increased risk for ASCVD. Recently, Pencina and colleagues projected that the 2013 guidelines would increase the number of US adults who would be eligible for statin therapy, with the greatest increase expected to be in adults aged 60 to 75 years.5 However, the potential impact of the 2013 cholesterol treatment guidelines on the pharmacy utilization of stat­ in and non­stat­in cholesterol-lowering medications in a managed care or­ganization remains unknown. In this present study, therefore, we sought to estimate the impact of the 2013 guidelines­on the pharmacy utilization of cholesterol-lowering medications in various risk groups in a managed care setting.

Methods Study Population OptumRx is a large pharmacy benefit management company serving more than 30 million people nationwide through a network of more than 66,000 community pharmacies and mail service facilities. Approximately 60% of the OptumRx population consists of commercial patients, 30% are Medicare beneficiaries, and approximately 10% are Medicaid patients. In this study, we used pharmacy claims from OptumRx for the baseline period

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KEY POINTS In late 2013, the American College of Cardiology and the American Heart Association released new guidelines for the treatment of high blood cholesterol, presenting a paradigm change in primary and secondary prevention of heart disease. ➤ In this new analysis, pharmacy claims data were used to calculate the potential impact of the new guidelines on the use of different classes of cholesterol-lowering medications. ➤ Based on the 2013 recommendations, this analysis projects that nearly 25% more patients will potentially be starting statin therapy during the next 3 years. ➤ Most patients are expected to start or switch to a high-dose statin, with the greatest percentage change to be seen in commercial and Medicaid patient populations. ➤ A 25% increase in overall statin prescriptions ­ and a 68% decrease in nonstatin cholesterollowering drug prescriptions are predicted under the new guidelines. ➤ Overall, the guidelines are projected to have a significant impact on cholesterol-lowering drugs by increasing statin use and decreasing the use of nonstatin cholesterol-lowering medications. ➤

between January 1, 2013, and December 31, 2013 to determine the number of potential patients who may be starting or switching to statin therapy based on the 2013 cholesterol treatment guidelines. The potential patients in this study included all continuously eligible patients with either pharmacy claims for any cholesterol medication (regardless of age), and patients aged 40 to 75 years who were not receiving any cholesterol treatment medications but who had pharmacy claims for medications for diabetes or hypertension.

We assumed that this first group of patients, who were already receiving cholesterol-lowering treatment, represents either secondary prevention in patients with established CAD or secondary prevention in patients with hypercholesterolemia, according to the 2013 cholesterol treatment guidelines. The latter setting represents patients with established diabetes or patients being treated for primary prevention of ASCVD. Cholesterol values were not available to assess the risk for patients receiving treatment for the primary prevention of ASCVD. Thus, hypertension medications were used as a proxy to estimate the 10-year CV risk, because this information could be obtained via pharmacy claims, and systolic blood pressure is a major component of the risk calculator.

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Diabetes medications that were used based on pharmacy claims and, therefore, did not distinguish between type 1 and type 2 diabetes. These diabetes medications included biguanides, sulfonylureas, thiazolidinediones, and dipeptidyl peptidase-4 inhibitors.

Medications for the treatment of hypertension included beta-­­ blockers, calcium channel blockers, direct renin inhibitors, a­ ngiotensin II receptor blockers, and angiotensin-­converting enzyme inhibitors.

Cholesterol-Lowering Therapy For all patients eligible for cholesterol-lowering therapy in the study cohort, we identified whether they had any pharmacy claims for treatment during the study period. Claims information was obtained for several classes of cholesterol-lowering therapies, including statins, bile acid–binding resins, cholesterol absorption inhibitors, fibrates, niacin, and omega-3 fatty acids.

For patients receiving statin therapy, the average daily dose for each statin over the time period was used to determine the statin intensity that each patient was taking, and patients were categorized based on their treatment intensity (ie, low, moderate, high), using the definitions in the 2013 ACC/AHA cholesterol treatment guidelines (Table 1).1

Table 1 Statin Intensity Classifications High-intensity statin therapy Moderate-intensity Low-intensity (daily dose statin therapy statin therapy lowers LDL-C (daily dose lowers (daily dose on average by LDL-C on average lowers LDL-C approximately by approximately on average ≥50%) 30% to <50%) by <30%) Atorvastatin 40-80 mg Rosuvastatin 20-40 mg

Atorvastatin 10-20 mg Rosuvastatin 5-10 mg Simvastatin 20-40 mg Pravastatin 40-80 mg Lovastatin 40 mg Fluvastatin XL ­ 80 mg Fluvastatin 40 mg twice daily Pitavastatin 2-4 mg

Simvastatin 10 mg Pravastatin 10-20 mg Lovastatin 20 mg Fluvastatin 20-40 mg Pitavastatin 1 mg

LDL-C indicates low-density lipoprotein cholesterol.

Reprinted with permission from Stone NJ, et al. J Am Coll Cardiol. 2014;63(25 pt B):2889-2934.

Figure 1 Flow Diagram to Determine Who Will Be Starting or Switching Statin Therapies Start high-intensity statin

Not currently using cholesterol-­ lowering medications

Start moderate-intensity statin Start low-intensity statin Do not start statin therapy High-intensity ­statin users

Members eligible for statin therapy

Moderate-intensity statin users Statin users

Switch to high-­ intensity statin Stay the same Switch to high-­ i­ ntensity statin

Cholesterol-lowering medication users

Nonstatin cholesterol-lowering medication users

Low-intensity ­statin users

Switch to moderate-­ intensity statin

Start high­intensity statin

Stay the same

Start moderate­intensity statin Stay the same

Note: See Table 1 for statin dosing intensity information.

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Estimating the Impact of the New Cholesterol Guidelines on Treatment A projection model was constructed using Microsoft Excel 2010 to estimate the changing proportion of patients receiving statins and nonstatin cholesterol-lowering treatments, and to estimate the number of patients receiving statin therapy during the baseline period who would have received an intensified statin dosing (Figure 1).

Table 2 provides a summary of the model inputs and the assumptions used in the model. We assumed that all patients receiving statin therapy at baseline who were already using this for primary or secondary prevention (eg, patients with previous myocardial infarction or coronary revascularization) would continue to receive therapy. For patients aged 40 to 75 years who were not receiving cholesterol-lowering medications, we assumed that all patients with diabetes would initiate a statin treatment, based on the 2013 guidelines.

We also assumed, based on expert opinion, that 60% of patients with hypertension would meet the primary prevention criteria for a ≥7.5% 10-year risk for CV events and would be initiated on statin therapy. Systolic blood pressure is a big part of the risk calculator; however, because we are using medications for hypertension as

a proxy, some patients receiving these medications may have their hypertension controlled with treatment.

Our model also estimates that 33% of patients who were receiving only nonstatin cholesterol-lowering medications at baseline would switch to a statin treatment based on the 2013 guidelines. Although nonstatin ­cholesterol-lowering medications are no longer recommended for ASCVD risk reduction, some patients receiving these nonstatin cholesterol-lowering medications were presumed to be intolerant of statin therapy.6-8 Finally, for patients receiving a statin and a concomitant nonstatin cholesterol-lowering medication, we projected that 100% of patients would have their nonstatin cholesterol-lowering medications discontinued, because these are no longer recommended for ASCVD risk reduction. Studies have shown declining persistence to therapy, or the duration of time from initiation to discontinuation of therapy, over time for new therapies9-11; therefore, our model projects that approximately 66% of patients, whom we assumed would start receiving statin therapy, would continue to use treatment at the end of the 3-year projection period.

To estimate the number of patients receiving a statin at baseline who would have intensification of statin

Table 2 Summary of Model Inputs and Assumptions Model inputs • Pharmacy claims from a national PBM provider between November 1, 2012, and October 31,

2013, were used to project the number of potential patients who will be starting or switching statin therapies •P otential statin users include: – Continuously eligible patients with diabetes or hypertension aged 40-75 years who are not ­receiving any cholesterol medications – Continuously eligible patients receiving lower-intensity statins or other nonstatin cholesterol-­ lowering therapies aseline cholesterol drugs market share was used to project pharmacy utilization for potential •B patients who will be starting or switching therapies •E xpert opinion was used when information was not available in the medical literature

Assumptions

• Patients receiving a statin at baseline will not be taken off statin therapy •P atients receiving a statin and a nonstatin cholesterol-lowering medication will have the nonstatin agent removed •P atients who were not receiving any cholesterol-lowering medications, were aged 40-75 years, and have diabetes or hypertension will start statin therapy; approximately 60% of members receiving ­hypertension medication and all members receiving diabetes medications will start receiving a statina • Approximately 33% of patients receiving nonstatin cholesterol-lowering medications will be ­switching to statin therapya • Approximately 50% of patients receiving low-intensity statin therapies will switch to a moderate-­ intensity or high-intensity statin therapya • Approximately 25% of patients receiving a moderate-intensity statin will switch to a high-­ intensity statina • Patients are assumed to use the same current market share for various statin medications • Approximately 66% of patients newly starting statin therapy are projected to continue therapy over timeb

Estimates based on expert specialist opinion.

Estimate based on ranges between 40% and 73% found in the literature.9-11 PBM indicates pharmacy benefit management. a

b

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dosing—because the 2013 cholesterol guidelines recommend moderate- to high-dose statin therapy for all 4 treatment groups—we calculated the proportion of patients at baseline who were receiving statins at low-, moderate-, and high-intensity potencies, as outlined in Table 1. Based on expert opinion, we assumed that 50% of patients receiving a low-­intensity statin would be switched to a moderate- or high-intensity statin, and 25% of patients receiving a moderate-­intensity statin would be switched to a high-intensity statin based on the 2013 guideline recommendations for specific groups.

We based these assumptions on the fact that not all patients can tolerate higher-intensity statin treatment6-8; these latter patients would continue to receive their baseline s­ tatin strength.

In addition, we assessed the impact of the 2013 guidelines on medication treatment patterns among commercial, Medicare, and Medicaid health plans. We assumed that the cholesterol medication market share for commercial, Medicare, and Medicaid plans remained the same over the 3-year period of our projections—that is, the percentage of each cholesterol medication use relative to each other would be the same over time for each plan. The cholesterol medication market share was used to determine which statin medications the patients are projected to be using. For example, the patients who are expected to start high-intensity statins would be divided among the high-intensity statins based on the proportions of the various high-dose statins.

Assumptions and expert opinions were used in the model where the information in the medical literature

Table 3 Baseline Cholesterol-Lowering Medication Utilization Patients in a Patients in a Patients in a commercial plan, Medicaid plan, Medicare plan, Total population, Patients receiving cholesterol-­lowering N (%) N (%) N (%) N (%) medications (N = 4,402,866) (N = 2,173,914) (N = 7,537,720) (N = 14,114,500) Statin users, by dosing intensitya

Statin and nonstatin cholesterol-lowering medication usersb Nonstatin cholesterol-­lowering medication users

All cholesterol-­ lowering medication usersc

Low-intensity ­statin

54,503 (13.20)

18,684 (21.90)

497,458 (14.60)

570,645 (14.60)

Moderate-intensity statin

287,968 (69.80)

59,556 (69.70)

2,377,955 (69.70)

2,725,480 (69.70)

High-intensity statin

70,329 (17.00)

7196 (8.40)

535,758 (15.70)

613,283 (15.70)

Total

412,800 (9.380)

85,436 (3.93)

3,411,171 (45.25)

3,909,407 (27.70)

Total

45,327 (1.030)

10,159 (0.47)

364,656 (4.84)

420,142 (2.98)

Bile acid– binding resins

10,285 (12.39)

1629 (9.06)

92,151 (15.89)

104,065 (15.29)

Cholesterol ab­sorp­ tion inhibitors

13,800 (16.62)

1573 (8.74)

141,624 (24.43)

156,997 (23.06)

Fibrates

42,835 (51.59)

12,430 (69.09)

279,033 (48.13)

334,298 (49.10)

Niacin

10,300 (12.41)

2120 (11.78)

64,621 (11.15)

77,041 (11.32)

Omega-3 fatty acids

15,204 (18.31)

1899 (10.56)

62,893 (10.85)

79,996 (11.75)

Total

83,024 (1.89)

17,990 (0.83)

579,786 (7.69)

680,800 (4.82)

Total

450,497 (10.23)

93,267 (4.29)

3,626,301 (48.11)

4,170,065 (29.54)

Patients aged 40-75 years not receiving cholesterol-lowering medications With diabetes With hypertension claims but no diabetes Overall total

48,796 (3.00)

15,211 (5.10)

213,098 (8.70)

277,105 (6.40)

230,743 (14.40)

41,289 (13.90)

761,533 (31.20)

1,033,565 (23.80)

1,605,973 (36.48)

297,051 (13.66)

2,442,821 (32.41)

4,345,845 (30.79)

See Table 1 for statin dosing intensity definitions.

These patients are receiving a statin and a nonstatin cholesterol-lowering medication, and these counts are not mutually exclusive of the patients counted under the statin and the nonstatin cholesterol-lowering medication user groups. c Unique members who are receiving any cholesterol-lowering medications. a

b

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was limited or where exact measures were not known at the time. A univariate sensitivity analysis was conducted to examine the uncertainties in the model. The measures we examined included (1) the percentage of patients receiving a statin and a concomitant nonstatin cholesterol-­lowering medication who were projected to have the nonstatin cholesterol-lowering medications discontinued, (2) the percentage of patients who were not taking a cholesterol medication but who would be starting a statin therapy, and (3) the percentage of patients who would be intensifying their statin therapy.

Results Table 3 shows the baseline cholesterol utilization patterns in the commercial, Medicaid, and Medicare

populations. During the baseline period, we identified 14,114,500 continuously eligible patients in the national pharmacy benefit organization. Of these, 4,170,065 (29.5%) patients were already receiving a cholesterol-­ lowering medication, whereas 4,345,845 (30.8%) patients aged 40 to 75 years were not receiving any cholesterol-­ lowering medications.

Of the patients not receiving cholesterol-lowering medications at baseline, 277,105 patients had pharmacy claims for diabetes mellitus and 1,033,565 patients had pharmacy claims for hypertension medications. A total of 3,909,407 (27.7%) patients were receiving statin therapy for cholesterol management at baseline, with the majority of them in the Medicare population (45.25%), followed by the commercial (9.38%) and Medicaid (3.93%) populations.

Table 4 Projected Cholesterol-Lowering Medications Utilization Patients in a Patients in a Patients in a commercial plan, Medicaid plan, Medicare plan, Total population, Patients receiving cholesterol-­lowering N (%) N (%) N (%) N (%) medications (N = 4,402,866) (N = 2,173,914) (N = 7,537,720) (N = 14,114,500) Statin users, by dosing intensitya

Statin and nonstatin cholesterol-lowering medication usersb Nonstatin cholesterol-lowering medication users

All cholesterol-­ lowering medication usersc

Low-intensity statin

27,252 (4.4)

9342 (7.3)

248,729 (6.0)

285,323 (5.8)

Moderate-intensity statin

392,928 (64.2)

90,642 (70.8)

2,566,826 (61.8)

3,050,396 (62.3)

High-intensity statin

192,302 (31.4)

28,021 (21.9)

1,336,627 (32.2)

1,556,950 (31.8)

Total

612,482 (13.91)

128,005 (5.89)

4,152,182 (55.09)

4,892,668 (34.66)

Total

0 (0)

0 (0)

Bile acid–­­ binding resins

5667 (22.4)

1000 (19.1)

48,163 (33.4)

54,831 (31.4)

Cholesterol ­absorp­tion ­inhibitors

4801 (19.0)

378 (7.2)

41,549 (28.8)

46,728 (26.8)

0 (0)

0 (0)

Fibrates

13,270 (52.5)

4204 (80.1)

77,550 (53.8)

95,024 (54.4)

Niacin

3901 (15.4)

790 (15.1)

21,231 (14.7)

25,922 (14.8)

Omega-3 fatty acids

7018 (27.8)

535 (10.2)

16,180 (11.2)

23,733 (13.6)

Total

25,257 (0.57)

5247 (0.24)

144,137 (1.91)

174,641 (1.24)

Total

637,739 (14.48)

4,296,319 (57.00)

5,067,309 (35.90)

133,252 (6.13)

Patients aged 40-75 years not receiving cholesterol-lowering medications With diabetes claims With hypertension claims, but no ­diabetes medication claim Overall total

0 (0) 92,297 (6.51) 1,418,731 (32.22)

0 (0)

0 (0)

16,516 (6.42) 257,067 (11.83)

0 (0)

304,613 (17.18)

413,426 (11.99)

1,772,803 (23.52)

3,448,601 (24.43)

See Table 1 for statin dosing intensity definitions.

These patients are receiving a statin and a nonstatin cholesterol-lowering medication, and these counts are not mutually exclusive of the patients counted under the statin and the nonstatin cholesterol-lowering medication user groups. c Unique members who are receiving any cholesterol-lowering medications. a

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A total of 23,180,535 statin prescriptions were processed across the populations over the 1-year study period. The majority of statin users were receiving moderate-intensity statins (69.7%), followed by high-­intensity statins (15.7%), and low-intensity statins (14.6%). A total of 4.8% of the overall population was receiving a nonstatin cholesterol-lowering medication for the management of cholesterol, with 61.7% of these patients concomitantly receiving a statin. The remaining 38.3% of patients were receiving nonstatin cholesterol-­lowering medications only and would qualify for statin therapy.

Among patients receiving a nonstatin cholesterol-lowering medication, 13.8% of patients were taking bile acid– binding resins, 20.9% were using cholesterol absorption inhibitors, 44.4% were using fibrates, 10.2% were taking niacin, and 10.6% used omega-3 fatty acids.

Applying our projections, of the 14,114,500 patients identified, an estimated 4,892,668 (34.66%) patients will receive statin therapy for cholesterol management under the 2013 guidelines, with the majority of statin users being in the Medicare population (55.09%), followed by the commercial (13.91%) and Medicaid (5.89%) populations (Table 4).

The largest increase in statin utilization over the next 3 years is estimated to be in the group of patients between the ages of 40 and 75 years who are not receiv-

ing any cholesterol medications and who are now starting statin therapy (Figure 2). This group accounts for approximately 897,244 (6.4%) patients of the total population, with the largest impact seen in the Medicare population (8.9%), followed by the commercial (4.2%) and Medicaid (1.8%) populations (Figure 2).

The remaining 86,017 (0.3%) patients starting a statin medication were previously only receiving a nonstatin cholesterol-lowering medication.

Our analysis also revealed a significant impact on the number of patients who would be switching their type of cholesterol-lowering therapy (Figure 2). It is projected that 285,323 patients who are receiving a low-intensity statin will be intensified to a moderate-intensity or high-­intensity statin, whereas 681,370 patients receiving a moderate-­ intensity statin will switch to a high-intensity statin. For patients receiving a nonstatin cholesterol-­lowering medication, with the assumption that 33% of patients will switch to a statin therapy, an estimated 86,017 are projected to start a moderate- or high-­ intensity statin. In addition, 420,142 patients who were receiving concomitant therapy with a statin and a nonstatin cholesterol-lowering medication are projected t­o have the nonstatin cholesterol-­ lowering medication ­discontinued (Table 4).

The projected impact of the new guidelines is an overall 25% increase in the number of patients who

Figure 2 Projected Percentage of the Population Starting Statin Therapy or Switching to Higher-Intensity Statin Therapy

Percent of population

8.9% 6.4%

Commercial

Medicare

Medicaid

Total population

7.9% 4.8%

4.3%

3.3% 1.8% 0.3% 0.1%

Patients receiving nonstatin cholesterollowering medications

Patients who qualify for but are not receiving any cholesterol-­lowering medications

Population by health plan type

0.9% 0.6%

0.6% 0.4%

2.0%

1.6%

Patients receiving a low-intensity statin

0.7%

Patients receiving a moderate-­­ intensity statin

Patients who qualify for but are not Patients receiving any receiving nonstatin Patients Patients receiving ­ cholesterol-lowering cholesterol-lowering receiving a lowa moderate-­ medications, medications, intensity statin, intensity statin, N (%) N (%) N (%)a N (%)a

Commercial (N = 4,402,866)

187,242 (4.3)

12,440 (0.3)

27,252 (0.6)

71,992 (1.6)

Medicaid (N = 2,173,914)

39,984 (1.8)

2584 (0.1)

9342 (0.4)

14,889 (0.7)

Medicare (N = 7,537,720)

670,018 (8.9)

70,993 (0.9)

248,729 (3.3)

594,489 (7.9)

Total population (N = 14,114,500)

897,244 (6.4)

86,017 (0.6)

285,323 (2.0)

681,370 (4.8)

See Table 1 for statin dosing intensity information.

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will be treated with a statin, with nearly 1 million more patients receiving a statin therapy under the new guidelines (Figure 3). Although more patients are starting statins in the Medicare population than in other groups, the commercial insurance and Medicaid populations have the greatest percentage change as a result of the lower initial number of patients receiving statin therapy at baseline. This increase in the number of patients receiving a statin is projected to result in a 25% overall increase in statin prescriptions (42%, 40%, and 23% in the commercial, Medicaid, and Medicare populations, respectively) and a 68% decrease in other nonstatin cholesterol-lowering medications (64%, 66%, and 69% in the commercial, Medicaid, and Medicare populations, respectively).

The largest change in the statin drugs market share will be seen in the high-intensity medications, with the majority of patients starting or switching to this high-­intensity class (Figure 4).

The sensitivity analysis showed that certain assumptions in the model will have a larger impact on utilization than other assumptions (Figure 5). The projected numbers of statin users and statin prescriptions are the most sensitive to the percentage of patients who are not receiving cholesterol-lowering medications, those who have hypertension, and patients who would start receiv-

ing statin therapy. Varying the percentage of patients with hypertension who would start receiving a statin therapy by ±25% (35%-85%) would result in a 5% change in the number of statin users and a 4% change in the number of statin prescriptions.

The projected number of patients receiving nonstat­ in cholesterol-lowering medications is the most sensitive to changes in the percentage of patients receiving concomitant statin and nonstatin cholesterol-­lowering medications who would be discontinuing the nonstat­ in cholesterol-lowering medication, as well as the number of patients receiving a nonstatin cholesterol-­ lowering medication who would be switching to a stat­ in therapy. Varying the percentage of patients receiving nonstatin cholesterol-­lowering medications who would be switching to a statin therapy by ±25% ­(8%-58%) would result in a 37% change in the number of patients receiving a non­ statin cholesterol-­ lowering medication.

Lowering the percentage of patients receiving both a statin and a nonstatin cholesterol-lowering medication who would be discontinuing the nonstatin cholesterol-­ lowering therapy by 50% would lead to a 120% change in the number of patients receiving a nonstatin cholesterol-­ lowering medication. We also found that varying the statin persistence rate based on literature did

Figure 3 Change in Cholesterol-Lowering Medication Utilization from Baseline

Percent change from baseline

48% 50%

42% 40% 22% 25%

Commercial

Medicare

Medicaid

Total population

23% 25% Patients receiving nonstatin medications

Patients receiving statin therapy

Statin prescriptions

–70% –71% –75% –74%

Population by health plan type Commercial (N = 4,402,866)

Nonstatin prescriptions

–64% –66% –69% –68%

Change in Change in number Change in nonstatin number ­of of patients receiving cholesterol-lowering patients Change in statin nonstatin cholesterolmedication receiving statin, prescriptions, lowering medications, prescriptions, N (%) N (%) N (%) N (%) 199,682 (48.4)

1,011,725 (42.1)

–57,767 (–69.6)

–275,823 (–63.6)

Medicaid (N = 2,173,914)

42,569 (49.8)

248,209 (40.4)

–12,743 (–70.8)

–83,614 (–66.0)

Medicare (N = 7,537,720)

741,011 (21.7)

4,647,888 (23.0)

–435,649 (–75.1)

–2,304,136 (–69.1)

Total population (N = 14,114,500)

983,261 (25.2)

5,907,823 (25.5)

–506,159 (–74.3)

–2,663,574 (–68.4)

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not have a major impact on the use of cholesterol-­ lowering medications, and lowering persistence rates decreased statin prescriptions by 5%.

Discussion In this analysis, we evaluated the potential impact of the new cholesterol treatment guidelines on the utilization of cholesterol-lowering medications in a real-world managed care setting and examined its potential impact in certain payer populations. Specifically, we applied real-­world data and expert opinion from the practicing community in an attempt to determine the impact of the new guidelines. Our analysis suggests that the 2013 ACC/AHA guidelines will increase the overall number of patients who are treated with statins in the overall managed care population from 27.7% to 34.7% over the next 3-year period, with the greatest increase resulting from the new ASCVD primary prevention risk group defined by the 2013 guidelines. Patients who are not re-

ceiving any cholesterol-lowering medications and who are between the ages of 40 and 75 years comprise 30.8% of this managed care population. Of these patients, 30.2% receive treatment for diabetes or hypertension and could potentially be prescribed a statin.

Extrapolating data from the National Health and Nutrition Examination Survey to a population of 115.4 million US adults, Pencina and colleagues estimated that 56 million (48.6%) American adults would now be eligible for statin therapy.5 They also projected that there would be 11.1% more statin users than previously would have been eligible under the ATP III guidelines.5 Our estimates yielded a lower number of patients who would be eligible for a statin therapy in this managed care population; however, the projected change in statin utilization is expected to increase by approximately 25% over the next 3 years.

Similar to the study by Pencina and colleagues, our projections show that the greatest impact of the new

Figure 4 Expected Shift in Statin Dose-Intensity Utilization

Percent change

289%

173%

149%

154%

36% High

Commercial

Medicare

Medicaid

Total

52% 8%

12%

Moderate Statin dose intensity

Population by health plan type Commercial (N = 4,402,866)

Medicaid (N = 2,173,914)

Medicare (N = 7,537,720)

Total population (N = 14,114,500)

Low

Statin dose intensitya

–50%

Current patients, N

–50%

–50%

–50%

Projected patients, N

Percent change, % 173.4

High

70,329

192,302

Moderate

287,968

392,928

36.4

Low

54,503

27,252

–50.0

High

7196

28,021

289.4

Moderate

59,556

90,642

52.2

Low

18,684

9342

–50.0

High

535,758

1,336,627

149.5

Moderate

2,377,955

2,566,826

7.9

Low

497,458

248,729

–50.0

High

613,283

1,556,950

153.9

Moderate

2,725,479

3,050,396

11.9

Low

570,645

285,323

–50.0

See Table 1 for statin dosing intensity information.

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33

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1%

4%

Base case, %

0%

0%

0%

Percent change of statin persistence rates

Percentage of patients receiving low-intensity statin therapy who will switch to a moderate-intensity or high-intensity statin

Percent change of low-­ intensity statin users

–2%

–1%

1%

1%

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Percent change of moderate-­ Percentage of patients receiving moderate-intensity statin intensity statin users therapies who will switch to a high-intensity statin

Percentage of patients receiving a nonstatin cholesterol-­ lowering medication who will switch to a statin therapy

Percent change in nonstatin cholesterol-­ ­lowering medication users

–4%

Percentage of patients aged 40-75 years who are not receiving a cholesterol-lowering medication but are receiving an antidiabetes medication who will start taking a statin

–6%

Percent change in patients with diabetes starting statin therapy

6%

Percentage of patients aged 40-75 years who are not receiving a cholesterol medication but are receiving an antihypertensive medication and will start taking a statin

Description

2%

–4%

–1%

–1%

Percent change in patients with hypertension starting statin therapy

0%

5%

–4%

Patients receiving a statin and a nonstatin cholesterol-­ lowering medication, with the percentage of patients who will discontinue their nonstatin cholesterol-lowering medication removed

–6%

0%

0%

1%

–5%

5b. Statin Prescriptions

Percent change in patients with statin and nonstatin cholesterol-lowering ­medications

Label

Percent change in patients with statin and nonstatin cholesterol-lowering medications –2%

–1%

Percent change in patients with diabetes starting statin therapy

Percent change in patients with hypertension starting statin therapy –5%

–1%

0%

Percent change in low-­­ intensity statin users

Percent change in nonstatin cholesterol-lowering medication users

0%

0%

5a. Statin Medication Users

Percent change in moderate-­ intensity statin users

Percent change in statin persistence rates

Low

Figure 5 Sensitivity Analysis Varying Different Model Assumptions

4%

4%

6%

0%

0%

0%

37%

120%

40

0

25

8

75

35

50

Low, %

73

50

75

58

100

85

100

High, %

–60% –40% –20% 0% 20% 40% 60% 80% 100% 120% 140%

–37%

0%

0%

0%

5c. Nonstatin Cholesterol-Lowering Medication Users

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guidelines is with patients between the ages of 40 and 75 years who were not receiving therapy at baseline and who will be starting statin therapy for the primary prevention of ASCVD. Although we did not specifically evaluate the patients’ ages, we found that the Medicare population, which generally covers patients aged ≥65 years, is estimated to have the largest change in cholesterol utilization.

Unlike the study by Pencina and colleagues, our analysis did not focus solely on statin therapy but also examined the impact to all cholesterol-lowering medications. We assumed that patients receiving a statin and a concomitant nonstatin cholesterol-lowering medication would stop the latter medication. This is based on the assumption that these nonstatin cholesterol-lowering medications were added to augment the statin therapy to get the patient to an LDL-C target. Because the treat-to-target approach is no longer a recommended strategy, it was assumed that these nonstatin cholesterol-lowering medications would be removed. This may underestimate the number of patients who may be taking these non­statin cholesterol-lowering medications for other cholesterol-­lowering benefits, such as for lowering elevated triglyceride levels.

In our sensitivity analysis, we varied the percentage of patients, currently using statin and nonstatin cholesterol-­ lowering medications, who would be stopping their nonstatin cholesterol-lowering agent between 50% and 100%.

By decreasing the percentage of patients who would be discontinuing their nonstatin cholesterol-lowering therapy to 50%, we calculated a 120% increase in the number of patients using a nonstatin cholesterol-lowering medication. In addition, we assumed that 33% of patients receiving a nonstatin cholesterol-lowering medication are projected to start a statin therapy, because it is likely that some of these patients were potentially not receiving a statin previously because of intolerance.

The prevalence of true statin intolerance in the medical literature has been shown to be 5% to 10%, with a higher percentage of patients (10%-20%) having statin-­associated muscle problems.6-8 By varying the percentage of patients receiving a nonstatin cholesterol-lowering medication who would be projected to switch to a statin therapy between 8% and 58%, we observed a large impact on the utilization of nonstatin cholesterol-lowering medications.

In addition, the 2013 guidelines do not recommend treatment with low-intensity statins; however, based on expert opinion, we assumed that 50% of the patients using low-intensity statins may not be able to tolerate a higher-intensity statin therapy. Varying this estimate in our sensitivity analysis by 25% did not greatly affect other utilization rates. Based on the 2013 guidelines, certain patients (eg, diabetic patients aged <40 years with LDL-C levels between 70 mg/dL and 189 mg/dL)

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who were previously receiving statin medications may now be taken off therapy, because they are no longer defined as an ASCVD high-risk group. However, we did not assume that such patients would discontinue therapy during the initial phase that the 2013 guidelines are being implemented. A possible reason for this is because of the reluctance of providers and patients to stop a statin therapy as a result of the long-perceived benefits of statin therapy in this population. As a result, we may be overestimating the number of patients who would continue to receive a statin therapy during the next 3 years.

In this study we also assumed that among patients who are not receiving cholesterol-lowering therapy, those with diabetes or hypertension have a higher risk for ASCVD. Based on the 2013 guidelines, all diabetic patients between the ages of 40 and 75 years should be receiving a statin therapy. By contrast, based on expert opinion, we assumed that approximately 60% of patients in this group who are receiving antihypertensive medications should also start receiving a statin. Some of the patients receiving an antihypertensive medication are assumed to have their hypertension controlled with therapy, or be at a lower risk for ASCVD and, therefore, do not have to use statin therapy. Our sensitivity analysis showed that a 25% change in the percentage of patients receiving antihypertensive medications that would be starting to use statin therapy (between 35% and 85%) will change the projected number of statin users by 5%.

In another part of our analysis we applied adherence to therapy and market share to determine which medications will be used after the 2013 ACC/AHA guidelines.

Karter and colleagues examined adherence and persistence in a cohort of new medication users (ie, antidiabetes agents, antihypertensives, lipid-lowering medications) during a 2-year period, and found that 4.7% of patients were primary nonadherent to their medication regimen (ie, no dispensing), 17.6% were early nonpersistent (ie, only 1 prescription fill), and 4.4% discontinued therapy without either provider consultation or switching therapies.10 This amounts to approximately 26.7% of patients who discontinued therapy or who did not start therapy during a 2-year period.

Overall, 39% of patients in the study by Karter and colleagues were persistent with their therapy at 2 years, with the remainder of discontinuations resulting from changes in therapy initiated by the provider.10 Based on this, we assumed that approximately 66% of patients in the model would be persistent with therapy at 3 years, which we examined in our sensitivity analysis. Varying the persistence estimates between 40% and 73%, we found that lowering the persistence rate to 40% decreased statin prescriptions by 5%. It is unknown what

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the rate of acceptance or provider adherence to the 2013 guidelines would be, and thus, we assumed that these projections would take place during a 3-year period.

Limitations Our study has several limitations. First, because of the nature of the claims data, we were not able to apply LDL-C levels or the new risk calculator to determine the specific CV event risk for each patient. Pharmacy claims data were examined, so proxy medications were used to identify patients with diabetes or hypertension.

In addition, the 2013 guidelines do not apply to patients with stage II to IV heart failure and hemodialysis, who could not be easily identified in our pharmacy claims database and were not accounted for in the projections. To evaluate the impact of the 2013 guidelines in a real-world setting, we used expert specialist opinion where there was limited medical information or uncertainty in the clinical application of the guidelines. Because these estimates were used directly in the projection, we varied them in a sensitivity analysis to determine their impact.

Another limitation is that there are several unknown impacts of the guidelines, including provider uptake of the guidelines and patient adherence to the guidelines.

Thus, assumptions were made to estimate the impact of the guidelines’ uptake. Because of the timing of the guidelines’ release, there were controversies regarding the risk calculator that may affect acceptance of the guideline; these were not taken into consideration in our projections.

One other limitation in this model is that we did not take into consideration the age of patients who may be starting or switching to moderate- or high-intensity statins. The 2013 guidelines recommend the use of moderate-­intensity statins for patients aged ≥75 years.

Because the Medicare population is the largest utilizer of statin therapy in our population, we might have overestimated the number of patients who could potentially be receiving high-intensity statins in this population, by not accounting for the proportion of these members who may actually be using moderate-intensity statin therapy.

Furthermore, the cholesterol drugs market share in this managed care population was used to determine how statins would be utilized, which may change with any changes in statin utilization or with formulary changes in the future.

Conclusions The 2013 ACC/AHA guidelines for the management of cholesterol are projected to increase the number of statin users by 25% in a managed care population with more than 25 million members. The largest

increase in statin use will be in the population of patients aged 40 to 75 years who are not currently receiving any cholesterol-lowering therapy. Because the 2013 guidelines focus on the use of higher-intensity statins in these high-risk groups, we expect to see an increase in the use of these agents as more patients start therapy or switch from lower-intensity statins. In addition, the 2013 ACC/AHA guidelines are also projected to have a large impact on the use of nonstat­ in cholesterol-lowering medications as patients are gradually being switched to statin therapy as recommended by the new guidelines. Of the entire managed care population, the Medicare population, which includes mainly older patients, is expected to see the greatest impact of the new guidelines in cholesterol-­ lowering drug utilization. ■ Acknowledgments Dr Tran, Dr Caglar, Dr Stockl, Dr Lew, Dr Solow, and Dr Chan were responsible for the writing of this manuscript. Dr Tran and Dr Caglar validated the data. Dr Tran is the guarantor of the quality and validity of this article.

Dr Chan provided clinical consultation for this article.

Author Disclosure Statement Dr Tran, Dr Caglar, Dr Stockl, Dr Lew, and Dr Solow are employees of OptumRx; Dr Chan is a consultant to and is on the advisory board of OptumRx. OptumRx did not receive any external funding for this study.

References

1. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63(25 pt B):2889-2934.

Erratum in: J Am Coll Cardiol. 2014;63(25 pt B):3024-3025.

2. Downs J, Good C. New cholesterol guidelines: has Godot finally arrived? Ann Intern Med. 2014;160:354-355.

3. Krumholz HM. The new cholesterol and blood pressure guidelines: perspective on the path forward. JAMA. 2014;311:1403-1405.

4. National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III).

Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002;106:3143-3421.

5. Pencina MJ, Navar-Boggan AM, D’Agostino RB Sr, et al. Application of new cholesterol guidelines to a population-based sample. N Engl J Med. 2014;370:1422-1431.

6. Grundy SM. Statin discontinuation and intolerance: the challenge of lifelong therapy. Ann Intern Med. 2013;158:562-563.

7. Zhang H, Plutzky J, Skentzos S, et al. Discontinuation of statins in routine care settings: a cohort study. Ann Intern Med. 2013;158:526-534.

8. Kashani A, Phillips CO, Foody JM, et al. Risks associated with statin therapy: a systematic overview of randomized clinical trials. Circulation. 2006;114:2788-2797.

9. Shenolikar RA, Balkrishnan R. Oral antidiabetes medication adherence and health care utilization among Medicaid-enrolled type 2 diabetic patients beginning monotherapy. Diabetes Care. 2008;31:e5.

10. Karter AJ, Parker MM, Moffet HH, et al. New prescription medication gaps: a comprehensive measure of adherence to new prescriptions. Health Serv Res. ­ 2009;44(5 pt 1):1640-1661.

11. Raebel MA, Ellis JL, Carroll NM, et al. Characteristics of patients with primary non-adherence to medications for hypertension, diabetes, and lipid disorders. J Gen Intern Med. 2012;27:57-64.

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STAKEHOLDER PERSPECTIVE

Real-World Consequences of the 2013 ACC/AHA Cholesterol Guidelines for the Prevention of Cardiovascular Disease

By Joseph D. Jackson, PhD Program Director, Applied Health Economics and Outcomes Research, Jefferson School of Population Health, Thomas Jefferson University, Philadelphia, PA

RESEARCHERS/PROVIDERS: From the approval of the first statin, lovastatin (Mevacor), in 1987 in the United States, there have been naysayers, despite the overwhelming scientific (and clinical) evidence in support of the cholesterol hypothesis, namely, the persistent use of prescribed statins to reduce heart disease events.1,2 In 1989, Thomas Moore wrote a commentary discussing “The Cholesterol Myth” in the Atlantic Monthly,3 and as recently as 2013, Abramson and Redberg4 and Kolata,5 writing in the New York Times, panned the 2013 American College of Cardiology/American Heart Association (ACC/AHA) guidelines (published in 2014) for the management of high blood cholesterol with statins to reduce the risk for cardiovascular disease.2 In more than a dozen randomized controlled trials (RCTs), statins have been conclusively proved to significantly reduce all-cause mortality, cardiac death, stroke, coronary revascularization, and major coronary events in at-risk populations for the primary and secondary prevention of heart disease.6 One of the key concerns of the naysayers is the incidence of side effects, particularly muscle pain (myopathy), in the populations of patients using statins, especially in the primary prevention setting. Critics cite the rates of side effects with statins to be as high as 18% to 20% based largely on observational evidence.

By contrast, Dr Rory Collins, Head of the Cholesterol Treatment Trialists’ (CTT) Collaboration, cites the rate of 5% as statin-related side effects, based on dozens of RCTs in the CTT and on a Cochrane review.7 The side effects seen with statins can usually be managed by a change in the statin dose or by switching the statin.

Therefore, the 2013 ACC/AHA guideline authors, and most physicians who practice evidence-based medicine, believe that more individuals who are at risk for cardiovascular disease because of elevated blood cholesterol should be treated with a statin.2 PAYERS: Are statins worth the cost? An important aspect of drug cost and value is the question of who will be receiving the treatment in the real world. In this issue of American Health & Drug Benefits, Tran and

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colleagues provide a guided tour of what the 2013 ACC/AHA guidelines mean for managed care organizations in the real world.8 Epidemiologically, the new guidelines were projected to add 13 million new patients for treatment with cholesterol-lowering drugs, and most of the population would come from adults aged 60 to 75 years.9 An important provision in the new guidelines is the recommendation for a risk assessment to guide cholesterol-lowering treatment rather than treatment based on a laboratory measure of cholesterol levels, which has not been supported by event-level evidence from RCTs. This change to risk-based prescribing is consistent with the evidence of benefit versus risk and with best medical practice.

Pharmacologic treatment in addition to diet and exercise (which are increasingly emerging as important) are the best ways to manage cardiovascular disease.

Risk assessment is an important aspect of optimal medical practice and of assessing the economic value of treatment.10,11 The 2013 ACC/AHA guidelines specify a risk rate of ≥7.5% over 10 years as a criterion for treatment with a statin.2 In 2003, using evidence of event-level data from RCTs, Caro and colleagues found that the price of branded statins would be cost-effective at a threshold of $50,000 per a life-year gained, with a 10-year risk of 7.5%.11 Furthermore, based on the price of generic statins, which is applicable to most statins today, cost-­ effectiveness threshold levels would actually yield a cost-savings—that is, more money would be spent on managing the cardiovascular events (ie, heart attack, stroke, death, percutaneous coronary intervention, and surgery) than the cost spent on all at-risk patients who would be using a generic statin. Thus, the projected increased utilization of statins that Tran and colleagues highlight may actually save money for health insurance plans and other payers.

PATIENTS: The 2013 ACC/AHA cholesterol guidelines are good news for patients with high cholesterol who are at risk for cardiovascular events. We know

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STAKEHOLDER PERSPECTIVE Continued that of the approximately 100 million Americans aged 40 to 75 years, 31 million would meet the ACC/AHA risk definition to qualify for treatment with a statin. We also know that 60% of these 31 million patients will have a cardiovascular event in their lifetime.12 The ACC/AHA guidelines also indicate that physicians should discuss risk status with their patients.2 This means that in addition to prescribing a statin, with an alert to watch for side effects (especially muscle pain), providers should talk to their patients about diet and exercise levels, according to best medical practice.

Furthermore, Tran and colleagues note that there has been a decrease in the use of nonstatin treatments in this patient population.8 This is an important observation, because patients should not use unproved treatments. The best current example of this is niacin for the treatment of heart disease, which is intended to increase high-density lipoprotein (HDL) levels.

The HPS2-THRIVE (Heart Protection Study 2– Treatment of HDL to Reduce the Incidence of Vascular Events) and the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/ High Triglycerides: Impact on Global Health Outcomes) studies, as well as studies with cholesterylester transfer protein inhibitors (eg, torcetrapib and anacetrapib), have demonstrated no reduction in cardiovascular events for drugs that raise HDL levels, such as niacin: the side effects of niacin are well known, and the drug is difficult for patients to tolerate.13,14 Tran and colleagues have provided a real-world

analysis of probable treatment scenarios under the new 2013 ACC/AHA cholesterol treatment guidelines.

This should help us to appreciate the benefits, risks, and costs that are likely to be the consequences of these new recommendations. ■ 1. Vagelos PR, Galambos L. Medicine, Science, and Merck. Cambridge, UK: Cambridge University Press; 2004:155-156.

2. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63(25 pt B):2889-2934.

Erratum in: J Am Coll Cardiol. 2014;63(25 pt B):3024-3025.

3. Moore TJ. The cholesterol myth. The Atlantic Monthly. September 1989:37-59.

4. Abramson JD, Redberg RF. Don’t give more patients statins. New York Times.

November 13, 2013. www.nytimes.com/2013/11/14/opinion/dont-give-more-pa tients-statins.html?_r=0. Accessed November 5, 2014.

5. Kolata G. Bumps in the road to new cholesterol guidelines. New York Times.

November 25, 2013. www.nytimes.com/2013/11/26/health/heart-and-stroke-studyhit-by-a-wave-of-criticism.html?pagewanted=all. Accessed November 5, 2014.

6. Shah RV, Goldfine AB. Statins and risk of new-onset diabetes mellitus. Circulation.

2012;126:e282-e284.

7. Wood S. Statin papers stand: expert panel endorses the BMJ’s stance on retraction request. Medscape. August 1, 2014. www.medscape.com/viewarticle/829298.

Accessed November 5, 2014.

8. Tran JN, Caglar T, Stockl KM, Lew HC, et al. Impact of the new ACC/AHA guidelines on the treatment of high blood cholesterol in a managed care setting.

Am Health Drug Benefits. 2014;7:426-439.

9. Pencina MJ, Navar-Boggan AM, D’Agostino RB, et al. Application of new cholesterol guidelines to a population-based sample. N Engl J Med. 2014;370:1422-1431.

10. L’Italien GL, Ford I, Jackson JD, et al. The cardiovascular event reduction tool (CERT)—A simplified cardiac risk prediction model developed from the West of Scotland Coronary Prevention Study (WOSCOPS). Am J Cardiol. 2000;85:720-724.

11. Caro JJ, Huybrechts KF, Jackson JD, et al. Allocating funds for cardiovascular disease prevention in light of the NCEP ATP III guidelines. Am J Manag Care.

2003;9:477-489.

12. Smith SC Jr, Wood S. Who’s at risk? A defense of the CV risk calculator.

Medscape. November 20, 2013. www.medscape.com/viewarticle/814711. Accessed November 5, 2014.

13. Mandrola JM. Five lessons from the niacin failure. Medscape. July 21, 2014. www.medscape.com/viewarticle/828580. Accessed November 5, 2014.

14. Stetka B, Aronow W. Niacin with statins? No dice. Medscape. September 19, 2014. www.medscape.com/viewarticle/829961. Accessed November 5, 2014.

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ORIGINAL RESEARCH

Utilization of Parenteral Anticoagulants and Warfarin: Impact on the Risk of Venous

Thromboembolism Recurrence in the Outpatient Setting Jennifer Cai, MS, MPH; Ronald Preblick, PharmD, MPH; Qiaoyi Zhang, MD, PhD; Winghan Jacqueline Kwong, PharmD, PhD

BACKGROUND: Clinical guidelines recommend parenteral anticoagulation therapy with an early initiation

Stakeholder Perspective, of warfarin therapy for the treatment of patients with acute venous thromboembolism (VTE) and the prepage 450

Am Health Drug Benefits.

2014;7(8):444-451 www.AHDBonline.com Received September 15, 2014 Accepted in final form October 7, 2014

Disclosures are at end of text

vention of recurrence.

OBJECTIVES: To evaluate the outpatient utilization of parenteral anticoagulant therapy and warfarin among patients with VTE, and to examine the effects of parenteral anticoagulant use and the time to warfarin initiation from VTE diagnosis on the risk for VTE recurrence.

METHODS: The Truven Health MarketScan Commercial Claims Database was used to identify patients aged 18 to 64 years who had an outpatient claim for deep-vein thrombosis or pulmonary embolism between January 2010 and December 2011 (ie, index date) and had no VTE diagnosis or treatment during the 12 months before the index date, had no hospital or emergency department VTE claim within 7 days after the index outpatient VTE claim, and had received warfarin <30 days after the index date. A recurrent VTE event was defined as a VTE-related emergency department visit or hospitalization within 8 to 365 days after the index date. A Cox proportional hazards model was used to estimate the adjusted hazard ratio (HR) associated with VTE recurrence risk related to parenteral anticoagulant use and warfarin initiation timing.

RESULTS: A total of 5820 patients were included in the study (mean age, 50.5 years); of these, 45% were female. A total of 75.7% (4403) of the patients receiving warfarin also received a parenteral anticoagulant, and the median time from VTE diagnosis to warfarin initiation was 5 days for parenteral anticoagulant users compared with 11 days for nonusers. Parenteral anticoagulant use was associated with a 49% recurrent VTE risk reduction (HR, 0.51; 95% confidence interval [CI], 0.43-0.60; P <.001). Each day of delayed warfarin initiation from the diagnosis of acute VTE was associated with a 1% increase in the risk for VTE recurrence (HR, 1.01; 95% CI, 1.01-1.02; P = .003).

CONCLUSIONS: Overall, 1 in 4 patients with VTE who had received warfarin in the outpatient setting did not receive parenteral anticoagulation therapy. Among those who received warfarin, its initiation was not always timely, despite its positive effects on reducing VTE recurrence. These findings highlight the potential quality-of-care concerns associated with the failure to use or the delayed implementation of guideline-recommended VTE treatment, and the need to improve compliance with clinical guidelines in the treatment of patients with VTE.

V

enous thromboembolism (VTE) encompasses deep-vein thrombosis (DVT) and pulmonary embolism (PE). VTE is a chronic disease that is associated with a high risk for recurrence, especially Ms Cai is Associate Director, Health Economics & Outcomes Research; Dr Preblick is Director, Health Economics & Outcomes Research; Dr Zhang is Senior Director, Health Economics & Outcomes Research; Dr Kwong is Senior Director, Health Economics & Outcomes Research; all at Daiichi Sankyo, Inc, Parsippany, NJ.

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during the initial months of therapy.1-7 The risk for VTE recurrence is higher for patients with “unprovoked” VTE (ie, VTE occurring in the absence of malignancy or any of the factors of “provoked” VTE) than for patients with provoked VTE (ie, VTE occurring within 3 months of hospitalization, major surgery, pregnancy, trauma, or fracture).8 The rates of VTE recurrence in patients with unprovoked VTE have been estimated at 10% after 1 year and 30% after 5 years of the first VTE event compared with patients with VTE provoked by surgery, in whom the recurrence rates are estimated to be 1% after 1 year and 3% after 5 years.8

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VTE recurrence is recognized as an important risk factor for mortality and long-term complications, such as postthrombotic syndrome after DVT and pulmonary hypertension after PE. Recurrent VTE events also pose a significant economic burden to the healthcare system.

In a recent retrospective analysis of claims data, patients with VTE recurrence were found to have 2.2-fold to 3-fold higher healthcare costs in the 1 year after their first VTE event, which was primarily driven by an increase in inpatient services utilization.7 The American College of Chest Physicians (ACCP) recommends initial parenteral anticoagulant therapy as an option for the initial treatment of acute DVT or PE.8 The ACCP guidelines recommend the early initiation of warfarin therapy rather than delayed initiation (eg, on the same day as parenteral therapy is started), and the continuation of parenteral anticoagulation therapy for a minimum of 5 days until the international normalized ratio (INR) is ≥2.0 for at least 24 hours. The ACCP also recommends continuation of anticoagulation therapy for 3 months in patients with acute DVT and PE to allow for the complete treatment of the acute episode of VTE and to prevent recurrent episodes of VTE.8 The outpatient treatment of uncomplicated VTE has become more common since the availability of subcutaneous low-molecular-weight heparin (LMWH) therapy as an alternative to intravenous unfractionated heparin for the treatment of VTE.8-10 Although the administration of heparin therapy and INR monitoring are much easier in the inpatient setting, there are challenges associated with the outpatient treatment of VTE. The outpatient use of LMWH requires the coordination of care, laboratory monitoring, and patient education and participation in treatment.11 It remains unclear how well parenteral anticoagulation therapy utilization in the outpatient clinical practice is consistent with the treatment guidelines for VTE. In addition, although previous randomized clinical trials suggest that the early initiation of warfarin therapy with a shorter course of heparin therapy for approximately 5 days is as effective as the delayed initiation of warfarin with a 10-day course of heparin, and that this approach has the benefit of reducing the risk for heparin-induced thrombocytopenia,8 it remains unclear how well this recommendation has been adopted in real-world clinical settings.

The objectives of this study were to assess the utilization of parenteral anticoagulation therapy and the timing of the initiation of warfarin for the treatment of VTE in the outpatient setting, and to examine the effects of parenteral anticoagulation therapy and the timing of warfarin initiation relative to a diagnosis of VTE on the risk of VTE recurrence.

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KEY POINTS Recurrent venous thromboembolism (VTE) is a risk factor for mortality and long-term, serious complications; the risk for recurrence is especially high in the early months of an acute VTE event. ➤ Recurrent VTE poses a significant economic burden to the healthcare system. ➤ Current clinical guidelines recommend the early addition of warfarin to parenteral anticoagulation to reduce the risk for VTE recurrence. ➤ In this study of 4403 patients with acute VTE who received parenteral anticoagulants in the outpatient setting, only 25% of patients received warfarin on the same day of initiating parenteral anticoagulant therapy; 52% received warfarin 3 days after initiating parenteral anticoagulant therapy. ➤ Overall, parenteral anticoagulation plus warfarin reduced the risk for recurrent VTE by 49% over ­1 year. ➤ In this study, each day that the initiation of warfarin was delayed from the VTE diagnosis translated to a 1% increase in VTE recurrence risk. ➤

Methods Patient Population A retrospective cohort study was conducted utilizing the Truven Health MarketScan Commercial Administrative Claims Database, which contains the integrated enrollment history and medical and pharmacy claims data for more than 137 million patients with commercial health insurance that is provided through their employers in the United States. The study sample consisted of patients aged 18 to 64 years who had an outpatient claim associated with a diagnosis of VTE between January 1, 2010, and December 31, 2011, as identified by International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes 451.x, 452, and 453.x (excluding 451.82 and 453.8) for either DVT, or diagnosis code 415.1x (excluding 415.12) for PE. The date corresponding to the first outpatient claim with a qualifying ICD-9 diagnosis code for acute VTE was defined as that patient’s index date. Patients with a diagnosis of atrial fibrillation, atrial flutter, coagulation disorder, VTE, or a warfarin prescription within 12 months before the index date (baseline period) were excluded. Patients aged ≥65 years were excluded from this analysis, because the claims data may not be complete in the database for Medicare-eligible patients.

To ensure that the index acute VTE events were treated solely in an outpatient setting, the patients who

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had a claim for a VTE-related emergency department visit or hospitalization within 7 days from the index outpatient claim were excluded from this analysis. Eligible patients were required to have a pharmacy claim for warfarin within 30 days after the index date for VTE outpatient diagnosis, and to be continuously eligible for health plan benefit coverage for at least 12 months before (baseline) and 12 months after (follow-up) the index date. Warfarin was the only oral anticoagulant indicated by the US Food and Drug Administration for the treatment of VTE during the study time frame. All study patients were followed for 12 months after the index outpatient claim for VTE. Patients were classified as having an index DVT event or a PE with or without DVT event. To capture all the parenteral anticoagulant use subsequent to the index VTE event, the pharmacy claims and the outpatient administration claims (with J codes J1645, J1650,

Demographics and Clinical Characteristics of Patients Table 1 Treated with Warfarin for VTE among Parenteral Anticoagulant Users and Nonusers Characteristics Total patients in the cohort, N (%) Mean age, yrs (SD) Female, N (%) PE as index VTE event, N (%)

Parenteral Parenteral anticoagulant anticoagulant users nonusers 4403 (75.7)

1417 (24.3)

50 (10)

52.2 (9.7)a

a

1951 (44.3)

665 (46.9)

420 (9.5)

247 (17.4)a

a

Time to warfarin initiation from index VTE claim Mean (SD), days Median, days

9.8 (9)a

13.1 (8.5)a

5

11

Time to warfarin initiation relative to parenteral anticoagulation ­therapy initiation Before starting parenteral agent, N (%)

61 (1.39)

—

Same day as initiating parenteral agent, N (%)

1094 (24.85)

—

Within 3 days of starting parenteral agent, N (%)

960 (21.8)

—

>3 days after starting parenteral agent, N (%)

2288 (51.96)

—

Baseline Elixhauser Comorbidity Index score, mean (SD)

1.4 (1.6)a

2.1 (2.1)a

Patients with cancer, N (%)

379 (8.6)

134 (9.5)

Significant difference, P <.01.

PE indicates pulmonary embolism; SD, standard deviation; VTE, venous thromboembolism.

a

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J1652, J1655, or J1644) for unfractionated heparin, LMWH (ie, dalteparin, enoxaparin, tinzaparin), and fondaparinux (ie, factor Xa inhibitor) within 7 days of the index date were taken into account. The time to the initiation of warfarin was calculated from the index outpatient claim date to the first warfarin pharmacy claim date for each patient.

Recurrent VTE was defined as a VTE-related emergency department visit or hospitalization claim occurring between 8 and 365 days subsequent to the date of the index outpatient claim for VTE. Outpatient claims for VTE that occurred between 8 and 365 days of the index VTE diagnosis and emergency department and hospitalization VTE claims that occurred within <8 days of the index VTE diagnosis were not considered a recurrent VTE event, because they could be caused by the continuous care of the index VTE. Using emergency department visit and hospitalization claims that are associated with a VTE diagnosis to identify VTE recurrence is consistent with the method used in another published claims analysis.7 The patient demographics and clinical information, including patient age, sex, type of health insurance, and baseline comorbidity information, was extracted. A summary score derived from the Elixhauser Comorbidity Index (ECI) was used to assess the patient overall baseline comorbidity burden.12 This baseline comorbidity score was calculated using ICD-9 codes that are associated with specific comorbid conditions during the 12month baseline period.12,13

Statistical Analysis The parenteral anticoagulation agents that were used in the outpatient setting and the time to warfarin initiation from initiation of parenteral therapy were summarized. Characteristics, such as age, sex, type of index VTE, time to warfarin initiation, baseline ECI score, and cancer diagnosis in patients who were parenteral anticoagulant therapy users or nonusers were analyzed.

Descriptive statistics were used to calculate all study variables. The mean, median, and standard deviation were calculated for each continuous variable, and statistical comparisons between parenteral anticoagulant users and nonusers were performed using t-tests. Frequency statistics were calculated for categorical variables, and comparisons were made using chi-square tests.

A Cox proportional hazards model was used to assess the association of parenteral anticoagulant use and the time from VTE diagnosis to warfarin initiation with the risk for VTE recurrence, while adjusting for age, sex, health insurance type, index VTE type, and baseline comorbidity index (ie, ECI) score. The cumulative probability of a patient being free of VTE recurrence over

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time with the use of parenteral anticoagulant use (illustrated as users and nonusers) was plotted using the ­Kaplan-Meier method.

Results The study cohort consisted of a total of 5820 patients who received treatment for their index acute VTE events in the outpatient setting and who received a prescription for warfarin within 30 days of their index outpatient VTE-related claim. Overall, the mean patients’ age was 50.5 years, and 45% of the patients were female.

Most patients (88.5%) had an index acute DVT event.

Of the total study cohort, 4403 (75.7%) patients received a parenteral anticoagulant within 7 days of the qualifying index VTE-related outpatient claim. The demographics and clinical characteristics of parenteral anticoagulant users and nonusers in the study are presented in Table 1. Enoxaparin was the most frequently used parenteral anticoagulant, followed by fondaparinux, dalteparin, and unfractionated heparin (Figure 1).

Only 25% of patients received warfarin on the same day as their parenteral anticoagulant therapy was initiated, and 52% received warfarin more than 3 days after the initiation of parenteral anticoagulant therapy. Among patients who received warfarin after the initiation of parenteral anticoagulation, the median time to the initiation of warfarin from the initiation of parenteral anticoagulation was 9 days. Parenteral anticoagulant users were younger than nonusers (mean age, 50 vs 52.2 years, respectively; P <.001). The median time to parenteral anticoagulant initiation from the index VTE outpatient claim was 1 day for an index DVT claim and 2 days for an index PE claim.

The time from an index VTE outpatient claim to the initiation of warfarin was longer among parenteral anticoagulant nonusers than users (median, 11 vs 5 days, respectively; P <.01). The median times to the initiation of warfarin therapy from the index VTE outpatient claim were 8 days and 6 days from the index diagnoses of DVT and PE, respectively. Parenteral anticoagulant users had a lower ECI score than nonusers (mean score, 1.4 vs 2.1, respectively; P <.001).

In our study cohort, 626 (10.8%) patients had recurrent VTE events within 1 year after the index acute VTE event. The 1-year VTE recurrence rate for parenteral anticoagulant users was lower than that for nonusers (8.7% vs 17.3%, respectively; P <.001). Kaplan-Meier curves of time to VTE recurrence among parenteral anticoagulant users and nonusers are included in Figure 2. Cox proportional hazards model results are reported in Table 2.

Parenteral anticoagulant therapy was associated with a 49% risk reduction of VTE recurrence (adjusted hazard ratio [HR], 0.51; 95% confidence interval [CI], 0.43-

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istribution of Parenteral Anticoagulant Figure 1 D Therapies Used by the Study Cohort

6.1%

0.2% 3.2% 4.7%

Dalteparin Enoxaparin Fondaparinux Unfractionated heparin Tinzaparin

85.9%

0.60; P <.001). Each additional 1-day delay of warfarin use was associated with a 1% increase of VTE recurrence risk (HR, 1.01; 95% CI, 1.01-1.02; P = .003). Increasing patient age was associated with a lower risk for VTE recurrence (HR, 0.989; 95% CI, 0.981-0.997; P = .007).

Higher baseline comorbidity burden as assessed by the ECI score was significantly associated with an increased risk for VTE recurrence (HR, 1.12; 95% CI, 1.07-1.17; ­P <.001).

Discussion Our results show that parenteral anticoagulant therapy in conjunction with warfarin therapy is effective in reducing the risk for VTE recurrence, conferring a 49% reduction over 1 year compared with patients who received warfarin but not a parenteral anticoagulant. This finding is consistent with results from a previous clinical trial that showed an unacceptably high incidence of symptomatic extension or VTE recurrence among patients taking a vitamin K antagonist but not receiving heparin compared with patients receiving heparin plus a vitamin K antagonist (20% vs 6.7%, respectively).14 However, contrary to current treatment guidelines that recommend the use of parenteral anticoagulant therapy in conjunction with vitamin K antagonist therapy for the treatment of VTE,8 based on real-­ world a­ dministrative claims, we found that only 76% of patients with VTE who were managed in the outpatient setting and received warfarin also received parenteral anticoagulant therapy. We also found that

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Cumulative probability of no VTE recurrence

Figure 2 K aplan-Meier Curve of VTE Recurrence among Parenteral Anticoagulant Users and Nonusers 1.00 0.80 0.60 0.40

Nonusers

Users

0.20 0.00

0

30

60

90

120

150 180 210 240 Time to VTE recurrence, days

270

300

330

360

VTE indicates venous thromboembolism.

Table 2 Adjusted Risk for VTE Recurrence Based on a Cox Proportional Hazards Regression Model Risk factor

Adjusted hazard ratio

P value

Parenteral anticoagulant use

0.51 (95% CI, 0.43-0.60)

<.01

Days from VTE diagnosis to warfarin initiation

1.01 (95% CI, 1.01-1.02)

<.01

Outpatient PE index event (ref, DVT)

0.95 (95% CI, 0.74-1.21)

.66

Elixhauser Comorbidity Index

1.12 (95% CI, 1.07-1.17)

<.01

Male sex (ref, female)

0.98 (95% CI, 0.84-1.15)

.83

0.989 (95% CI, 0.981-0.997)

.01

Age

The health insurance types were adjusted in the regression analysis; the results are not shown.

CI indicates confidence interval; DVT, deep-vein thrombosis; PE, pulmonary embolism; VTE, venous thrombo­ embolism.

a

more than 50% of patients with VTE did not receive warfarin until more than 3 days after the initiation of parenteral therapy, despite the treatment guidelines that recommend the initiation of vitamin K antagonist therapy as early as the same day as the initiation of parenteral anticoagulation.8 Our results also show that the delayed initiation of warfarin relative to the

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time of a VTE diagnosis significantly increases the risk for VTE recurrence.

The 1-year VTE recurrence rate of 10.8% observed in the present study is generally consistent with published estimates of up to a 15% rate.1-7 Heit and colleagues estimated the 1-year DVT recurrence rate to be 5.6% to 12.9% among a cohort of 1719 patients in Minnesota with an index VTE event between 1966 and 1990.5 Cushman and colleagues estimated an annual VTE recurrence rate of 7.7% (95% CI, 4.5%-10.9%) among 21,680 patients aged â&#x2030;Ľ45 years from 2 combined study cohorts (the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study) across 6 communities during the 2 years subsequent to an index VTE event.2 Hansson and colleagues found a cumulative incidence of 7% of recurrent VTE at 1 year among patients in Sweden.4 Our study population is unique in that it was geographically diverse across the United States compared with other studies of VTE recurrence that were geographically limited.2,5 Underlying differences in patient risk factors, the age limitation of the study sample, and different methods used for identifying recurrent VTE cases may have contributed to differences in recurrence rates across the studies.

The current study is among only a few studies that assess the relationship of anticoagulation treatment with VTE recurrence using real-world clinical practice data. In an analysis of abstracted medical records of 1166 patients with VTE in Minnesota during 14 years to assess the predictors of VTE recurrence, Heit and

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colleagues found that time from symptom onset to heparin use was not significantly associated with the risk for recurrence.15 Although increasing the proportion of time of using warfarin therapy with an INR ≥2.0 significantly reduced the risk for recurrence, the durations of parenteral anticoagulant therapy and warfarin overlap were not associated with recurrence.15 Our study extended beyond these findings to evaluate the impact of the early initiation of warfarin on treatment outcomes. Our results demonstrate that parenteral anticoagulant therapy and the early initiation of warfarin play independent roles in the reduction of VTE recurrence risk. These results corroborate the results from other clinical studies16 and support the benefit of early warfarin initiation. Because of limited availability of laboratory data, we were unable to assess INR control in our study.

Finally, we found that the risk for VTE recurrence decreased with increasing patient age; the adjusted risk of recurrence decreased by 1.1% for every additional year of a patient’s age. Although increasing patient age has been identified in a few studies as a risk factor for VTE recurrence,1,5 some studies have found conflicting results or no effect between age and recurrent VTE.4,17,18

Limitations Several limitations should be noted when interpreting our study’s findings. First, our study was limited to patients whose index VTE events were in an outpatient setting, and may not be generalizable to patients with acute VTE who were hospitalized. Our patient population, therefore, presumably represents less severe patients for whom outpatient VTE treatment was deemed appropriate by their physicians. By not including VTE-related outpatient visits when neither emergency department visits nor hospitalizations were claimed, the recurrent VTE event rate could have been underestimated.

Second, because our study utilized administrative medical and pharmacy claims, some important clinical information (eg, INR) was not captured in the database.

Using ICD-9 codes to identify the patients with VTE may be subject to some misclassifications in our study.

Other research found that relying solely on claims data could likely underestimate the actual clinical care provided19; this may also apply to our study. Because not all patients are suitable for home-based treatment with LMWH, parenteral anticoagulant therapy might have been administered in a healthcare provider’s office and might not have been recorded in outpatient prescription claims. We attempted to overcome this potential bias by using J codes in addition to prescription claims to identi-

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fy the use of parenteral anticoagulants. However, our identification method was not conducive to identifying any prescribed parenteral anticoagulation therapies that were not filled by the patients at a pharmacy, nor was it conducive to assessing patient adherence to parenteral anticoagulation therapy.

Finally, the current US guidelines recommend initial parenteral anticoagulant therapy with warfarin or anticoagulation with rivaroxaban as treatment for acute DVT or PE that is not associated with active cancer. The recent introduction of novel oral anticoagulants without the requirement for INR monitoring will allow more flexibility in the treatment of acute VTE and the prevention of recurrent VTE. However, data on rivaroxaban were not available in the database when we conducted this study.

Our results demonstrate that parenteral anticoagulant therapy and the early initiation of warfarin play independent roles in the reduction of VTE recurrence risk.

Future studies to assess the utilization of novel oral anticoagulation therapy for the treatment of VTE are warranted.

Conclusions This study showed that 1 in 4 patients with VTE receiving warfarin in an outpatient setting did not have evidence of parenteral anticoagulant use. Among patients who received parenteral anticoagulation therapy, the initiation of warfarin was not always timely. Our study further demonstrated that parenteral anticoagulation therapy coadministered with warfarin was associated with a 49% reduction of VTE recurrence risk versus warfarin alone, and delayed warfarin initiation was also associated with an increase for VTE recurrence risk.

These data suggest that there are potential discrepancies between the evidence-based US guideline recommendations and clinical practice patterns and warrant further investigation. Future research using alternative data sources to assess the potential barriers to the adoption of clinical guidelines will be important to improve the quality of VTE treatment and clinical outcomes in the outpatient setting. ■ Acknowledgment The authors wish to acknowledge the editorial assistance provided by Jenifer Wogen (of MedMentis Consulting, LLC) for this manuscript.

Continued

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Funding Source This research was funded by Daiichi Sankyo, Parsippany, NJ. Author Disclosure Statement Ms Cai, Dr Preblick, Dr Zhang, and Dr Kwong are employees of Daiichi Sankyo Inc.

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2. Cushman M, Tsai AW, White RH, et al. Deep vein thrombosis and pulmonary embolism in two cohorts: the longitudinal investigation of thromboembolism etiology. Am J Med. 2004;117:19-25.

3. White RH. The epidemiology of venous thromboembolism. Circulation.

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5. Heit JA, Mohr DN, Silverstein MD, et al. Predictors of recurrence after deep vein thrombosis and pulmonary embolism: a population-based cohort study. Arch Intern Med. 2000;160:761-768.

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cians. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 suppl):e419S-e494S. Erratum in: Chest. 2012;142:1698-1704.

9. McRae SJ, Ginsberg JS. Initial treatment of venous thromboembolism. Circulation.

2004;110(9 suppl 1):I-3–I-9. Errata in: Circulation. 2004;110(24 suppl 1):IV-33; Circulation. 2005;111:378.

10. Aujesky D, Roy P-M, Verschuren F, et al. Outpatient versus inpatient treatment for patients with acute pulmonary embolism: an international, open-label, randomised, non-inferiority trial. Lancet. 2011;378:41-48.

11. Yeager BF, Matheny SC. Low-molecular-weight heparin in outpatient treatment of DVT. Am Fam Physician. 1999;59:945-952.

12. Elixhauser A, Steiner C, Harris DR, Coffey RM. Comorbidity measures for use with administrative data. Med Care. 1998;36:8-27.

13. Baser O, Palmer L, Stephenson J. The estimation power of alternative comorbidity indices. Value Health. 2008;11:946-955.

14. Brandjes DP, Heijboer H, Büller HR, et al. Acenocoumarol and heparin compared with acenocoumarol alone in the initial treatment of proximal-vein thrombosis. N Engl J Med. 1992;327:1485-1489.

15. Heit JA, Lahr BD, Petterson TM, et al. Heparin and warfarin anticoagulation intensity as predictors of recurrence after deep vein thrombosis or pulmonary embolism: a population-based cohort study. Blood. 2011;118:4992-4999.

16. Smith SB, Geske JB, Maguire JM, et al. Early anticoagulation is associated with reduced mortality for acute pulmonary embolism. Chest. 2010;137:1382-1390.

17. Douketis JD, Foster GA, Crowther MA, et al. Clinical risk factors and timing of recurrent venous thromboembolism during the initial 3 months of anticoagulant therapy. Arch Intern Med. 2000;160:3431-3436.

18. Murin S, Romano PS, White RH. Comparison of outcomes after hospitalization for deep venous thrombosis or pulmonary embolism. Thromb Haemost.

2002;88:407-414.

19. DeVoe JE, Gold R, McIntire P, et al. Electronic health records vs Medicaid claims: completeness of diabetes preventive care data in community health centers.

Ann Fam Med. 2011;9:351-358.

STAKEHOLDER PERSPECTIVE

Better Compliance with Clinical Guidelines for Venous Thromboembolism Can Improve Patient Outcomes, Reduce Costs

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

PAYERS: Health plans manage large numbers of patients with complex diseases and strive to achieve the best clinical outcomes while balancing the need to control costs. Guidelines provide an excellent way to reduce practice variation and help to deliver more predictable outcomes for patients. Because of the number and extent of the guidelines and the organizations that develop and promulgate them, many health plans allow physicians to identify and follow guidelines based on their experience, expertise, and general preferences.

The article by Cai and colleagues highlights the need for better compliance with clinical guidelines and the potential to improve outcomes and to reduce costs with their appropriate application by physicians for the treatment of patients who are at risk for venous thromboembolism (VTE).1 The guidelines from the American College of Chest Physicians (ACCP) recommend the use of warfarin and parenteral anticoag-

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ulants for the treatment and prevention of VTE and identify, using outcomes-based published data, the risk for VTE recurrence in provoked and unprovoked patient groups.2 These ACCP evidence-based guidelines support the general philosophy of health plans of focusing on patient outcomes for the delivery of consistent value to patients and to purchasers of healthcare services.

The cost of oral warfarin and of the parenteral agents that are currently available as generic options is relatively low for standard courses of therapy. The true financial risk that concerns health plans is the cost of treatment for subsequent episodes of VTE that could have been prevented with effective anticoagulation through improved physician compliance with guidelines and greater adherence to therapy by patients.

As Cai and colleagues discuss in their article,1 one study identified a 2- to 3-fold increase in healthcare costs

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Utilization of Parenteral Anticoagulants and Warfarin

STAKEHOLDER PERSPECTIVE Continued during the first year after an acute VTE event.3 This opportunity to prevent subsequent VTE-related clinical events that utilize high-cost resources is an area of routine focus by a health plan’s medical management.

PROVIDERS: One opportunity to encourage physicians to consider and comply with the ACCP-recommended anticoagulation guidelines is the implementation of bundled payment contracts for surgical procedures, including for hip and knee replacement surgeries. The bundle would comprise all aspects of care before and after surgery, including physician-administered medications that are needed for the complete treatment of the individual patient. A key aspect of the bundled payment process is to work with providers to help them reduce the risk for complications resulting from surgery and to improve the management of patients and to decrease the cost of potential complications or to eliminate them entirely.

Data mining can be used to evaluate patients throughout their surgical and recovery periods by identifying the patterns of care that lead to positive and negative outcomes. Information gleaned from the analysis provided by Cai and colleagues can help to highlight potential areas of risk for VTE and opportunities for improvements in current clinical practice that will help to reduce that risk, will save money for the provid-

er group, and ultimately for the health plan or the self-insured employer.1 HEALTHCARE SYSTEM: The data presented by Cai and colleagues effectively highlight the value of appropriate use of anticoagulant therapy using current national guidelines and the need for improvement in the care delivery and management of patients receiving anticoagulant agents. We often hear drug manufacturers promoting earlier treatment or earlier intervention in patients to achieve positive clinical outcomes and to avoid long-term complications. This analysis highlights the validity of early intervention.

It is clear that earlier initiation of treatment with warfarin and parenteral anticoagulants has the potential to save the healthcare system significant dollars while improving outcomes for individual patients.4 ■ 1. Cai J, Preblick R, Zhang Q, et al. Utilization of parenteral anticoagulants and warfarin: impact on the risk of venous thromboembolism recurrence in the outpatient setting. Am Health Drug Benefits. 2014;7:442-449.

2. Kearon C, Akl EA, Comerota AJ, et al; for the American College of Chest Physicians. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 suppl):e419S-e496S. Erratum in: Chest. 2012;142:1698-1704.

3. Lin J, Preblick R, Lingohr-Smith M, Kwong WJ. Incremental health care resource utilization and economic burden of venous thromboembolism recurrence from a U.S. payer perspective. J Manag Care Pharm. 2014;20:174-186.

4. Smith SB, Geske JB, Maguire JM, et al. Early anticoagulation is associated with reduced mortality for acute pulmonary embolism. Chest. 2010;137:1382-1390.

Call for Papers American Health & Drug Benefits offers an open forum for all healthcare participants to exchange ideas and present their data, innovations, and initiatives to facilitate patient-centered healthcare and benefit design models that meet the needs of all stakeholders—Distributors, Employers, Manufacturers, Patients, Payers, Policymakers, Providers, Purchasers, and Researchers. Topics and type of articles of high interest include: • Adherence Concerns • Benefit Design • Case Studies • Comorbidities and Cost Issues • Comparative Effectiveness Research • Decision-Making Tools • Ethics in Medicine • Health Economics Outcomes

• Pharmacogenomics • Policy Issues • Prevention Initiatives • Real-World Evidence • Reimbursement Strategies • Social Media in Healthcare • Survey Results • Value-Based Healthcare

• Health Information Exchange • Health Plan Initiatives • Innovations in Healthcare • Literature Reviews • Managed Care • Medicare/Medicaid • Patient Outcomes/Advocacy • Pharmacoeconomics

SUBMIT articles to editorial@engagehc.com or at www.AHDBonline.com Articles must follow the Manuscript Instructions for Authors, available online Vol 7, No 8

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REVIEW ARTICLE

New and Emerging Drugs and Targets for Type 2 Diabetes: Reviewing the Evidence Brien Rex Miller, DO; Hanh Nguyen, DO; Charles Jia-Haur Hu, DO; Chihyi Lin, DO; Quang T. Nguyen, DO, FACP, FACE, FTOS Stakeholder Perspective, page 462

Am Health Drug Benefits.

2014;7(8):452-463 www.AHDBonline.com Received September 29, 2014 Accepted in final form October 28, 2014

Disclosures are at end of text

BACKGROUND: Diabetes is a deadly and costly disease. The number of adults in the United States with newly diagnosed diabetes has nearly tripled from 1980 to 2011. At the current pace, 1 in 3 US adults will have diabetes in their lifetime. Currently, 14 classes of drugs are available to treat type 2 diabetes mellitus, but only 36% of patients with type 2 diabetes achieve glycemic control with the currently available therapies. Therefore, new treatment options are desperately needed.

DISCUSSION: Despite the availability of many pharmacotherapies, in 2011 an estimated 3.1 million (14.9%) patients with type 2 diabetes still reported not taking medications to treat their diabetes. Patient compliance is a major obstacle facing practicing clinicians on a daily basis. New treatment options are desperately needed, but efficacy and tolerability are no longer the only criteria contributing to the success of a drug. Ease of administration, convenient dosing frequency, being weight control friendly, and having a low risk for hypoglycemia are important factors for the survival of a new drug in the US healthcare system. The present review is focused on important new drugs and drug classes in the pipeline, as well as on recently approved drugs, including sodium glucose cotransporter-2 inhibitors, glucagon-like peptide-1 agents, and new insulin therapies, as well as on the technologic improvements in the delivery and dosing frequency of some of the currently available drugs.

CONCLUSIONS: In the United States, diabetes can be expected to continue to wreak significant human and financial tolls. The associated complications will continue to climb if they are not controlled and stopped. New therapies for diabetes are clearly needed that will better address these unmet needs. The common threads among the emerging therapies are their convenience of administration and dosing frequency, which are important to the improvement of patient adherence.

T

ype 2 diabetes mellitus is an ongoing medical problem that clinicians deal with on a daily basis.

The necessity of treating diabetes adequately is essential because of the many comorbidities and complications associated with uncontrolled diabetes. These comorbidities are very costly to the healthcare system and to the patient. In 2012, 28.9 million adult patients in the United States were diagnosed or undiagnosed with diabetes; of these, 15.5 million were men and 11.2 million were aged â&#x2030;Ľ65 years.1 The number of newly diagnosed patients with diabetes in 2012 was approximately 1.7 million, the majority of whom were aged 45 to 64 Dr Miller is Resident, Department of Internal Medicine, Valley Hospital Medical Center, Las Vegas, NV; Dr H. Nguyen is Resident, Department of Internal Medicine, Valley Hospital Medical Center, Las Vegas, NV; Dr Hu is Resident, Department of Internal Medicine, Valley Hospital Medical Center, Las Vegas, NV; Dr Lin is Resident, Department of Internal Medicine, Valley Hospital Medical Center, Las Vegas, NV; Dr Q.T. Nguyen is Medical Director, Las Vegas Endocrinology, Clinical Associate Professor, Clinical Education, AZCOM, Adjunct Associate Professor of Endocrinology, Touro University Nevada.

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years.1 The prevalence of diabetes is still increasing. The number of US adults (aged 18-79 years) with newly diagnosed diabetes has nearly tripled in the past few decades, from 493,000 in 1980 to more than 1.5 million in 2011.2 At the current pace, approximately 1 in 3 US adults will have diabetes in their lifetime.1 The numerous comorbidities associated with diabetes include, but are not limited to, kidney failure, obesity, coronary artery disease, peripheral vascular disease, hypertension, stroke, and amputations.1 In the years 2003-2006, cardiovascular (CV) disease mortality rates were approximately 1.7 times higher among adults aged â&#x2030;Ľ18 years with diagnosed diabetes than among adults without diagnosed diabetes.1 In 2010, after adjusting for population age differences, hospitalization rates for heart attack and stroke were 1.8 times and 1.5 times higher, respectively, among adults aged â&#x2030;Ľ20 years with diagnosed diabetes than among adults without diagnosed diabetes.1 The estimated total cost for type 2 diabetes mellitus was $245 billion in 2012, of which $176 billion was in direct medical expenditures.1 With these trends, the cost and debilitating effects of this disease are only going to escalate, unless better glycemic control is achieved.

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New and Emerging Drugs and Targets for Type 2 Diabetes

The older medications for diabetes, especially insulin and sulfonylureas, are associated with the common side effects of weight gain and hypoglycemia, which can be costly to the healthcare system. A retrospective study evaluated the incidence and cost of hypoglycemic events in patients with type 2 diabetes during 4 years.3 The analysis showed that the mean cost per 1 inpatient admission was $17,564, including $1387 for an emergency department visit and $394 for an outpatient visit. The total direct medical cost of hypoglycemia during the 4-year study was $52,223,675, which accounted for approximately 1% of all the inpatient costs, 2.7% of emergency department costs, and 0.3% of outpatient costs.3 The annual medical cost of obesity is currently estimated to be approximately $147 billion.4 Using drugs for the treatment of diabetes that can aid in weight loss rather than increase weight gain is cost-effective and can aid in patient adherence. In one study, researchers estimated that 1% of weight loss in 1 year could decrease a patient’s total healthcare cost by approximately $213 per patient who is using antidiabetic medications.5 Another study ascertained that patients with type 2 diabetes mellitus who lost weight with a treatment regimen are more likely to adhere to their regimen than patients who gain weight with their medication.6 Increased adherence to oral antihyperglycemic agents has been shown to be associated with reduced healthcare utilization as well as cost.7 As many as 14 classes of drugs are currently available for the treatment of type 2 diabetes mellitus.8 Despite the availability of pharmacotherapies, an estimated 3.1 million (14.9%) US adults with type 2 diabetes were still not taking a medication for diabetes in 2011.9 According to the 1999-2000 National Health and Nutrition Examination Survey, only approximately 36% of patients with type 2 diabetes achieve glycemic control—defined as a hemoglobin (Hb)A1c level of <7%—with the currently available therapies.10 New medications with different mechanisms of action or with novel approaches to therapy are needed to improve patient outcomes and to reduce the clinical burden of this condition.

The current article reviews some of the newly approved therapies by the US Food and Drug Administration (FDA), as well as those that are currently being tested as new options for the treatment of type 2 diabetes mellitus. Most drugs in this review have voucher and coupon programs provided by the manufacturer to offset the cost of the medications (Table).

The risks and benefits of each drug discussed in this article should be weighed appropriately when a drug regimen is chosen for a particular patient with diabetes. In addition, because many of these drugs have only recently become available in the United States, long-term evidence from real-world utilization is lacking. Furthermore,

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KEY POINTS The number of US adults with newly diagnosed diabetes has nearly tripled from 1980 to 2011 and continues to rise. ➤ Despite the many drugs available for treating type 2 diabetes, only 36% of patients in the United States achieve glycemic control; patient adherence is a major obstacle. ➤ Efficacy and tolerability are no longer the only criteria for the success of a new drug; ease of administration, convenient dosing frequency, being weight control friendly, and having a low hypoglycemic risk are important factors for new antidiabetes drugs. ➤ New oral drug classes have recently been approved by the FDA and more are in development, most of which are once-daily agents. ➤ All new injections for diabetes are now in a pen format to improve patient adherence. ➤ Significantly, the new agents being introduced to the market are either weight-friendly or can induce weight loss, and have lower risks for hypoglycemia. ➤ At a mean total cost of $17,564 per hypoglycemic episode requiring hospitalization, this can be a meaningful improvement to the healthcare system as a whole. ➤

the FDA has requested postmarketing studies for some of these new agents, to investigate the potential risks for patients with diabetes to ensure that these new classes of drugs are safe for long-term use in this patient population.

Sodium Glucose Cotransporter-2 Inhibitors The most recent class to be approved by the FDA for the treatment of type 2 diabetes mellitus is sodium glucose cotransporter-2 (SGLT-2) inhibitors. SGLT-2 proteins are primarily found in the proximal convoluted tubule of the kidneys and are responsible for reabsorbing approximately 90% of the glucose that is filtered through the kidneys.11 By inhibiting SGLT-2, urinary glucose excretion is increased, thereby lowering the plasma glucose concentration. This drug class can be used as monotherapy or in combination with other antihyperglycemic agents as a result of its distinct mechanism of action.12 Canagliflozin The first SGLT-2 inhibitor to be approved by the FDA was canagliflozin (Invokana), which received FDA approval in March 2013. Canagliflozin is indicat-

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ed as an adjunct to diet and exercise for the improvement of glycemic control in adult patients with type 2 diabetes mellitus.13 Supplied as tablets for oral administration, the recommended starting dose of canagliflozin is 100 mg once daily, taken before the first meal of the day. In patients tolerating canagliflozin 100 mg once daily and who have an estimated glomerular filtration rate (eGFR) of ≥60 mL/min/1.73 m2 and require additional glycemic control, the dose can be increased to 300 mg once daily.

Clinical results. In a randomized, double-blind, placebo-controlled study over 26 weeks, 584 patients were randomized to canagliflozin 100 mg, canagliflozin 300 mg, or placebo, administered once daily.14 At week 26, there was a significant reduction of HbA1c from baseline with canagliflozin 100 mg and 300 mg compared with placebo (−0.77%, −1.03%, and +0.14%, respectively; P <.001).14 In addition, both doses of canagliflo­ zin significantly reduced fasting Table Emerging Therapies for the Treatment of Patients with Diabetes: Monthly Costs Drug class Monthly Monthly cost Date of FDA and name cost, $ with voucher, $ approval SGLT-2 inhibitors Canagliflozin (Invokana)

324.51-348.81

0 for commercial

March 2013

Dapagliflozin (Farxiga)

324.43-348.72

0 for cash and

January 2014

Empagliflozin (Jardiance)

313.19-325.93

0 for commercial

August 2014

Ipragliflozin (Suglat)

Not available in the US

Not available in the US

Approved in Japan only, January 2014

Tofogliflozin (CSG452)

Not available

Not available

Not yet approved

Exenatide pen (Bydureon)

454.31-473.80

25 for commercial insurance

March 2014

Albiglutide (Tanzeum)

338.62-352.58

10 for commercial insurance

April 2014

Dulaglutide (Trulicity)

Data not yet available

Data not yet available

September 2014

Not available

June 2014

insurance

commercial insurance insurance

GLP-1

Technosphere insulin Afrezza

Not available

FDA indicates US Food and Drug Administration; GLP-1, glucagonlike peptide-1; SGLT-2, sodium-glucose cotransporter-2.

Source: www.Goodrx.com, which compares local prescription drug costs.

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plasma glucose (FPG), 2-hour postprandial glucose, body weight, and systolic blood pressure.

There were few adverse events in the groups receiving canagliflozin, including genital mycotic infections, urinary tract infections, and osmotic diuresis, which can lead to orthostatic hypotension and syncope. The incidence of hypoglycemia was low across all groups. Overall, treatment with canagliflozin improved glycemic control and was generally well-tolerated in patients with type 2 diabetes who had inadequate glycemic control with diet and exercise.14 Canagliflozin was also assessed in a randomized, double-blind, active-controlled study of 755 patients inadequately controlled on the combination of metformin and a sulfonylurea.15 Patients received canagliflozin 300 mg in combination with metformin and a sulfonylurea or sitagliptin 100 mg in combination with metformin and a sulfonylurea. At week 52, canagliflozin 300 mg demonstrated superiority to sitagliptin 100 mg in reducing HbA1c (−1.03% vs −0.66%, respectively). Combination therapies including canagliflozin also demonstrated greater reductions in FPG, body weight, and systolic blood pressure than those with sitagliptin (P <.001).15 The overall adverse event rates were similarly low with canagliflozin and sitagliptin (76.7% vs 77.5%, respectively), but higher incidences of genital mycotic infections and osmotic diuresis were reported with canagliflozin, which led to 1 patient’s discontinuation of the drug.15 The trial’s findings demonstrate that canagliflozin is superior to sitagliptin in providing glycemic control and body-weight reduction in patients with type 2 diabetes who are already using metformin plus a sulfonylurea.15 Considering its site of action at the renal SGLT-2 transporters, canagliflozin is not expected to be effective in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m2), those with end-stage renal disease, or those who are undergoing dialysis, even though studies have not been conducted on these patient populations.

The efficacy and safety of canagliflozin were evaluated in a randomized, double-blind, placebo-controlled study that included 269 patients with moderate renal impairment (eGFR ≥30 to <50 mL/min/1.73 m2).16 These patients had less overall glycemic efficacy at 26 weeks and a higher incidence of adverse events related to reduced intravascular volume (ie, postural dizziness and orthostatic hypotension), renal-related adverse reactions, and decreases in eGFR compared with patients with mild renal impairment or with normal renal function (eGFR ≥60 mL/min/1.73 m2). Patients using canagliflozin 300 mg were also more likely to experience an elevation in potassium. Hence, the assessment of renal function is recommended before the initiation of canagliflozin, and periodically thereafter.16

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Finally, among the ongoing postmarketing studies required by the FDA for these agents is the phase 3 clinical trial Canagliflozin Cardiovascular Assessment Study (CANVAS) that is set to compare canagliflozin with placebo regarding CV events, including CV-related death, myocardial infarction, and stroke.17 A total of 4330 patients with type 2 diabetes whose diabetes was not well-controlled at the beginning of the study and who had a history of, or were at a high risk for, CV events were enrolled; they will be followed up for up to 9 years.

In January 2013, preliminary data from the CANVAS trial suggested that canagliflozin was not associated with an increased risk for CV events. Canagliflozin also caused a slight increase in low-density lipoprotein cholesterol, but the mechanism for this has yet to be elucidated.17

Dapagliflozin In January 2014, dapagliflozin (Farxiga) was the second SGLT-2 inhibitor to receive FDA approval to improve glycemic control, along with diet and exercise, in adult patients with type 2 diabetes.18 Similar to canagliflozin, dapagliflozin works in the renal tubules by inhibiting SGLT-2 transporters, resulting in the removal of excess glucose and its associated calories in the urine.

Dapagliflozin has been studied as a monotherapy and in combination with other therapies for type 2 diabetes, including metformin, pioglitazone, glimepiride, sitagliptin, and insulin.19,20 Clinical results. One major study assessing the safety and efficacy of dapagliflozin monotherapy was a 24week, parallel-group, double-blind, placebo-controlled phase 3 trial involving 558 patients with type 2 diabetes.19 Patients were divided into 2 groups based on their HbA1c levels: 485 patients were in the main cohort with an HbA1c of 7% to 10%, and 73 patients were in the group with an HbA1c of 10.1% to 12%. The patients with an HbA1c of 7% to 10% were randomly assigned to 1 of 7 arms to receive placebo or 2.5-mg, 5-mg, or 10-mg dap­agliflozin once daily in the morning (main cohort) or evening (exploratory cohort). The patients with an HbA1c of 10.1% to 12% (the highHbA1c exploratory cohort) were randomly assigned to receive placebo or 5-mg or 10-mg dapagliflozin once daily in the morning.

At week 24, the mean HbA1c changes from baseline in the main cohort were −0.23% with placebo and −0.58, −0.77, and −0.89% with 2.5-mg, 5-mg (P = .005), and 10-mg dapagliflozin, respectively (P <.001). Data from exploratory cohorts yielded similar and consistent results. No major episodes of hypoglycemia were reported with dapagliflozin, but urinary tract infections and genital infections were more common in the arms receiving dapagliflozin than with placebo.19

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In another randomized, double-blind, active-­ controlled, multicenter 52-week trial, dapagliflozin was compared with glipizide as an add-on therapy in diabetic patients who had inadequate glycemic control with metformin.20 Sulfonylureas are known to cause hypoglycemia and weight gain, and to have poor glycemic durability, although they are initially effective. The study aimed to assess whether dapagliflozin causes fewer of these adverse events.

A total of 814 patients with type 2 diabetes were divided into 2 groups to receive either dapagliflozin and metformin or glipizide and metformin.20 The mean HbA1c reduction in the dapagliflozin cohort (–0.52%) was statistically noninferior at week 52 compared with glipizide (–0.52%). In addition, dapagliflozin produced a significant weight loss of 3.2 kg compared with a weight gain of 1.2 kg with glipizide (P <.001). Furthermore, only 3.5% of patients receiving combination therapy with dapagliflozin and metformin had hypoglycemic episodes compared with 40.8% of patients in the glipizide group (P <.001). However, genital infections and lower urinary tract infections were more frequent with dapagliflozin than with glipizide, but patients with these infections responded to standard treatment and this rarely led to study discontinuation.20 Before its approval by the FDA, dapagliflozin was declined twice by the FDA, in July 2011 and January 2012, because of insufficient data on the drug’s safety profile.

The concern was of an increased number of bladder cancers diagnosed among dapagliflozin users in the initial trials.21 At the time of the July 2011 Endocrinology and Metabolic Drugs Advisory Committee meeting,9 total patients who were diagnosed with bladder cancer were receiving dapagliflozin (0.06 per 100 patient-years), and 1 patient with bladder cancer was in the control group (0.03 per 100 patient-years).22 The drug manufacturer argued that the increase in bladder cancers seen in patients taking dapagliflozin resulted from preexisting cancers. Nonetheless, at this time, the drug’s manufacturer and the FDA do not recommend dapagliflozin for patients with active bladder cancer.18,23 Similar to canagliflozin, dapagliflozin should not be used in patients with moderate or severe renal impairment, patients with end-stage renal disease, or patients on dialysis. Dapagliflozin can also cause dehydration, leading to hypotension, dizziness, fainting, and a decline in renal function.

The FDA is requiring 6 postmarketing studies to be conducted by the manufacturers of dapagliflozin, including further investigation on its CV risk, bladder cancer risk, effects on urinary flow and composition changes on bladder tumor promotion in rodents, efficacy and safety in pediatric patients, risk of liver damage,

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and pregnancy outcomes. These postmarketing studies will likely provide better insight into dapagliflozin’s benefit-risk profile.23

Empagliflozin In August 2014, empagliflozin (Jardiance) became the third SGLT-2 inhibitor to receive FDA approval for the treatment of type 2 diabetes as an adjunct to diet and exercise. Used as a tablet for oral administration, the recommended dose is 10 mg once daily in the morning, taken with or without food. In patients tolerating empagliflozin, the dose may be increased to 25 mg. The FDA approval of empagliflozin was based on a monotherapy study24 and in a combination study with metformin, sulfonylurea, pio­ glitazone, and insulin.25,26 Clinical results. The safety and efficacy of empagliflozin was shown to have linear pharmacokinetics with dose increases with respect to time.24 Empagliflozin was associated with an increase in urine glucose excretion compared with virtually no urine glucose excretion in the placebo group. It also significantly decreased blood glucose in the active drug group versus the placebo group. The amount of glucose in the urine increased from baseline to day 1 by 74 g, 90 g, and 81 g, with 10-mg, 25-mg, and 100-mg doses of empagliflozin, respectively. The adverse events observed with empagliflozin included excessive urination (10.3%), nasopharyngitis (9%), constipation (9%), and headache (7.7%). The increase in urinary glucose excretion remained elevated at similar levels during the 28-day trial period.24 The efficacy and safety of empagliflozin in patients with type 2 diabetes have been studied in conjunction with metformin in a 12-week, double-blind, placebocontrolled trial that compared the results with those of placebo and open-label sitagliptin 100 mg daily.25 Empagliflozin’s dosing was 1 mg, 5 mg, 10 mg, 25 mg, and 50 mg daily. The trial demonstrated a significant reduction of HbA1c with empagliflozin (–0.09 to –0.56%) compared with placebo (+0.15%). Furthermore, empagliflozin in conjunction with metformin had significant reductions of blood glucose levels (–2 to –28 mg/dL) compared with placebo (+5 mg/dL; P <.001), as well as significant benefits of body-weight reductions (–2.3 to –2.9 kg) compared with placebo (–1.2 kg; P <.01).

Empagliflozin had similar overall adverse event rates (29.6%-48.6%) compared with placebo (36.6%) and sitagliptin (35.2%). Empagliflozin had more urinary tract infections than placebo (4% vs 2.8%, respectively) and greater increase in urination (2.5% vs 1.4%, respectively). Genital infections were only reported with empagliflozin, at a rate of 4.0%.

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The once-daily dosing of empagliflozin was well-­ tolerated and was associated with significantly decreased levels in HbA1c, decreased fasting blood glucose, and decreased body weight in poorly controlled patients with type 2 diabetes who had been receiving metformin monotherapy.25 Empagliflozin was also investigated as an add-on to pioglitazone with or without metformin in patients with type 2 diabetes in a 24-week trial.26 A significant reduction of HbA1c was seen with empagliflozin 10 mg and 25 mg (–0.6% and –0.7%, respectively) compared with placebo (–0.1%; P <.001). In addition to reductions in fasting blood glucose levels in this trial, empagliflozin 10 mg and 25 mg was associated with significant weight loss (–1.62 kg and –1.47 kg, respectively) compared with increased weight (+0.34 kg; P <.001) with placebo. Significantly more patients with HbA1c levels of ≥7% had their HbA1c level reduced to <7 by the end of the trial with the 10-mg (23.8%) and 25-mg (30%) doses of empagliflozin than with placebo (7.7%; P <.001). Finally, similar proportions of patients reported adverse events with empagliflozin (67.3%-71.4%) and with placebo (72.7%). Confirmed hypoglycemia was reported by 1.2% to 2.4% of patients receiving empagliflozin and by 1.8% of patients receiving placebo.26 A special population trial was also conducted to determine the efficacy and tolerability of empagliflozin monotherapy in Japanese patients with type 2 diabetes mellitus.27 A total of 547 patients were randomized to empagliflozin 5 mg, 10 mg, 25 mg, 50 mg, or to placebo for 12 weeks. Significant reductions in HbA1c levels (approximately –0.7% to –0.95%), FPG, and body weight were reported in patients receiving empagliflozin compared with those receiving placebo. More patients with an HbA1c level of ≥7% at baseline reached an HbA1c level of <7% with empagliflozin (19%-33%) than with placebo (3%). Adverse events were reported by 33% to 38% of patients receiving empagliflozin and by 42% of patients receiving placebo.27 Empagliflozin has been studied with other therapies, such as for lipid control with simvastatin, in healthy volunteers.28 No serious adverse reactions or drug–drug interactions were observed when empagliflozin was combined with simvastatin. The pharmacokinetic results suggest that no dose adjustments for either drug are necessary when empagliflozin and simvastatin are coadministered.28

Ipragliflozin Ipragliflozin (Suglat) is an SGLT-2 inhibitor that gained regulatory approval in Japan in January 2014 for the treatment of patients with type 2 diabetes, but is not yet approved by the FDA. It is the first SGLT-2 inhibitor

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on the Japanese market, and is currently available only in Japan.29 Ipragliflozin is available in doses of 25-mg and 50-mg tablets, taken daily, and the dosing can be increased to 100 mg daily if lower doses are inefficient. Ipragliflozin has been studied in 6 phase 3 clinical trials in Japan and has demonstrated significant reductions in HbA1c, decreases in FPG, and decreases in total body weight without many adverse events. All the clinical trials were conducted in Japan, because the manufacturer decided to focus on the Asian market for ipragliflozin.29 Because ipragliflozin is still not available in the United States, and for lack of space, details of the trials are not included in this review.

Tofogliflozin Tofogliflozin (CSG452) is an investigational, potent, and highly selective SGLT-2 inhibitor that is currently in phase 3 clinical trials. It has the highest selectivity toward SGLT-2 compared with the other SGLT-2 inhibitors (canagliflozin, ipragliflozin, empagliflozin, luseogliflozin, and PF-04971729).30 The clinical data published on tofogliflozin are currently limited; however, early reports of tofogliflozin suggest that it is a true SGLT-2 inhibitor. The SGLTs have several functions in the body. The inhibition of SGLTs that are not involved in renal glucose absorption would lead to undesirable side effects. Therefore, the high selectivity of tofogliflo­ zin to SGLT-2s, if approved by the FDA, is expected to play an important role in terms of safety.30 Glucagon-Like Peptide-1 Drugs Incretins are hormones that are secreted by cells in the small intestine during an oral nutrient load. Glucagon-like peptide-1 (GLP-1) is an incretin that has potent antihyperglycemic effects. In the presence of hyperglycemia, GLP-1 causes the release of insulin from the pancreas, shuts down glucagon secretion, slows down gastric emptying, and acts on the hypothalamus to increase satiety.31 Currently, 4 GLP-1 agents are approved by the FDA—exenatide (which also has an extended-­ release version), albiglutide, dulaglutide, and liraglutide.

The first 3 of these GLP-1 drugs recently had significant marketing changes.

Exenatide Extended-Release Pen The new exenatide extended-release for injectable suspension pen (Bydureon) that was approved by the FDA for the treatment of type 2 diabetes on March 3, 2014, is a prefilled, single-use, once-weekly pen injector.32 The pen contains the same formulation and dose of exenatide as the original, single-dose tray that was approved by the FDA in 2012. It provides the same continuous supply of the drug as the original formulation, but

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the new pen is designed to be more user-friendly. Patients attach the needle, twist the base of the pen to mix the drug, then tap the pen firmly against the palm of their hand for 80 times or more, while rotating the pen until the solution is completely mixed.32 This new process is a significant improvement from the manual mixing of the drug in the 2012 version.

Each weekly dose in the pen is made up of microspheres that house exenatide and slowly dissolve over the span of a week. It requires no titration and can be administered at any time of the day, with or without meals. The exenatide extended-release pen improves glycemic control by reducing fasting and postprandial glucose concentrations in patients with type 2 diabetes.

The original single-dose tray version of Bydureon has been shown to provide powerful HbA1c reduction and weight loss.33 The exenatide extended-release pen aims to provide an easier method of delivery for patients.

Albiglutide Albiglutide (Tanzeum) subcutaneous injection is a long-acting GLP-1 receptor agonist approved by the FDA in April 2014 as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.34 The recommended dose is 30 mg once weekly given as a subcutaneous injection in the abdomen, thigh, or upper arm region. The dose may be increased to 50 mg once weekly if the glycemic response is inadequate.26 Albiglutide may be administered at any time of day, without regard to meals. As a once-weekly subcutaneous injection, it requires fewer injections than short-acting GLP-1 agonists.34 Clinical results. The clinical efficacy of albiglutide is demonstrated in a series of phase 3 trials named the HARMONY series.

HARMONY 2 demonstrated the efficacy of albiglutide as monotherapy in a 52-week, randomized, double-­ blind, placebo-controlled multicenter trial.35 Patients were randomized to 3 different groups, including (1) placebo, (2) albiglutide 30 mg weekly, and (3) albiglutide 30 mg weekly titrated to 50 mg weekly at week 12.

The mean patients’ age was 53 years, 55% of patients were men, the mean duration of diabetes was 4 years, and the mean baseline eGFR was 84 mL/min/1.73 m2. All 3 groups had approximately 100 patients, with a baseline HbA1c of approximately 8%.

Albiglutide achieved –0.7% and –0.9% reductions in HbA1c in the 30-mg and 50-mg groups, respectively, whereas patients receiving placebo had a 0.2% increase in HbA1c. A study extension to 3 years revealed a durable reduction in HbA1c.35 In the longest duration comparative study of albiglutide to date, HARMONY 3 compared the efficacy and

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safety of albiglutide versus sitagliptin, glimepiride, and placebo in patients whose glycemic levels were inadequately controlled with metformin.36 At week 104, the mean difference in HbA1c reduction when albiglutide was added to metformin was significantly superior to the comparator treatment: the reduction was –0.9% greater than in the placebo group (P <.001); –0.4% greater than in the sitagliptin group (P = .001); and 0.3% greater than in the glimepiride group (P = .003).36 Weight loss was also significantly greater (–2.4 kg) in the albiglutide group than in the glimepiride group (P <.001), but it was similar to the sitagliptin group (–0.4 kg) and the placebo group (–0.2 kg).37 Gastrointestinal adverse events during 2 years of observation across the placebo, sitagliptin, glimepiride, and albiglutide arms included nausea (11%, 7%, 6%, and 10%, respectively), vomiting (1%, 4%, 4%, and 6%, respectively), and diarrhea (11%, 9%, 9%, and 13%, respectively). There were no reports of severe hypoglycemia in the albiglutide arm.37 The HARMONY 4 study compared the use of albiglutide and insulin therapy in patients with diabetes. In a 52-week, randomized, open-label, noninferiority study, HARMONY 4 compared albiglutide with insulin glargine in patients receiving metformin with or without a sulfonylurea.38 Both groups achieved a similar reduction in HbA1c (–0.7% in the albiglutide group and –0.8% in the insulin glargine group), indicating the noninferiority of albiglutide to insulin glargine. In addition, patients receiving albiglutide lost weight (–1.1 kg), whereas those receiving insulin glargine gained weight (+1.6 kg), resulting in a treatment difference of 2.6 kg (P <.001) between the 2 groups.38 Similar results were seen when albiglutide was compared with prandial lispro insulin 3 times daily in patients using background glargine ≥20 U in a 26-week, randomized, noninferiority trial. The HbA1c levels were reduced by –0.82% in the group using albiglutide versus –0.66% in the group taking lispro insulin, meeting the noninferiority end point of the trial.39 Furthermore, patients receiving albiglutide lost weight (–0.73 kg), whereas those using insulin lispro experienced weight gain (+0.81 kg).39 Albiglutide has also been studied as an add-on therapy to other drugs, including pioglitazone. In HARMONY 1, patients whose glycemic control was inadequate with pioglitazone, with or without metformin, were ­administered either albiglutide 30 mg or placebo.40 At the 52-week primary end point, albiglutide combined with pioglitazone demonstrated a significant reduction ­in HbA1c levels from baseline compared with placebo (for a difference of –0.8% between the 2 treatments; ­P <.001). Of the patients receiving albiglutide, 44%

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achieved the HbA1c target of <7% compared with 15% of patients receiving placebo. Weight changes were not significantly different between the 2 groups. Adverse reactions of nausea and vomiting were comparable between the albiglutide and the placebo groups, but were higher with albiglutide than with placebo in diarrhea (11.3% vs 8.6%, respectively) and injection-site reactions (11.3% vs 7.9%, respectively).40 Finally, as a new member of the GLP-1 drug class, it is important to compare albiglutide with other drugs in this class. HARMONY 7 was a 32-week, randomized, open-label noninferiority phase 3 clinical trial comparing albiglutide with liraglutide in patients with uncontrolled type 2 diabetes.41 The results revealed a lower reduction of HbA1c levels with albiglutide than with liraglutide (–0.8% vs –1.0), which did not meet the noninferiority upper margin of 0.3% in this trial. In addition, patients in the albiglutide group had more injection-site reactions and fewer gastrointestinal events than patients in the liraglutide group.41

Dulaglutide The FDA approved dulaglutide (Trulicity) as a once-weekly subcutaneous injection to improve glycemic control, along with diet and exercise, in adults with type 2 diabetes on September 18, 2014.42 Dulaglutide is administered once weekly, any time of day, independent of meals, and should be injected subcutaneously in the abdomen, thigh, or upper arm. The recommended starting dose is 0.75 mg, which can be increased to a 1.5-mg dose for patients who need additional blood glucose control.42 ­ ­Dulaglutide has been studied in 6 clinical trials (AWARD 1-6) as a stand-alone therapy and in combination with other type 2 diabetes therapies, including metformin, ­sulfonylurea, thiazolidinedione, and prandial insulin.42.43 Significant reductions in HbA1c were seen in patients receiving dulaglutide.43 In AWARD-6, a head-to-head, phase 3, randomized, noninferiority trial of dulaglutide versus liraglutide in patients with uncontrolled type 2 diabetes receiving metformin, the least-squares mean reduction in HbA1c was –1.42% in the dulaglutide group and –1.36% in the liraglutide group.44 The mean treatment difference in HbA1c was –0.06% between the groups, which met the noninferiority criteria of the trial (margin, 0.4%).44 To our knowledge, this is the first time a once-weekly GLP-1 agent has achieved a noninferiority status versus a once-daily GLP-1 drug in a phase 3 clinical trial.

Dulaglutide has also been studied as a monotherapy versus metformin in patients with uncontrolled type 2 diabetes.45 At 26 weeks, changes from baseline in HbA1c levels were –0.78%, –0.71%, and –0.56% for dulaglutide 1.5 mg, dulaglutide 0.75 mg, and metformin, respective-

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ly. Nausea, diarrhea, and vomiting were the most common adverse events and occurred at similar rates in both the dulaglutide and metformin treatment groups. No severe hypoglycemia was reported.45

New Insulin Agents Afrezza Technosphere insulin human (Afrezza) is a recombinant regular human insulin inhalation powder approved by the FDA in June 2014 for the treatment of type 1 and type 2 diabetes mellitus. When the insulin is inhaled through the device, the powder is aerosolized and delivered to the lung. Afrezza should be administered at each mealtime and is touted as an alternative to injectable short-acting insulin.

Clinical results. The pharmacokinetics for the powder was studied in 11 healthy nonsmokers who were randomized to either a dose of single inhalation consisting of 25 U, 50 U, or 100 U of inhaled human insulin or to a fixed dose of 10 IU of regular human insulin. When comparing the 2 groups, it was noted that the inhaled insulin achieved peak concentration approximately 2 hours earlier than the regular human insulin. The pharmacokinetics measured by the area under the curve was found to be linear with the doses that were studied. No treatmentrelated adverse events were reported with the inhaled human insulin. It was concluded that this inhaled regular insulin had a more rapid absorption than the subcutaneous regular human insulin with linear pharmacokinetics.46 The regular human insulin inhaled powder has been studied in patients with type 1 and type 2 diabetes. Across a broad spectrum of diabetes severity, inhaled human insulin was noninferior to active comparators in 2 of 3 trials and was superior to placebo in HbA1c reduction, as was demonstrated in 24-week to 52-week clinical trials.47 A total of 334 patients receiving inhaled insulin with a basal insulin dose of glargine were compared with 343 patients receiving biaspart insulin given twice daily in patients with type 2 diabetes mellitus.48 The randomized, multicenter, noninferiority trial compared the treatments and their changes in HbA1c from baseline to the end of the 52-week trial. At the end of 52 weeks, the change in HbA1c with inhaled insulin plus insulin glargine was –0.68% and was similar and noninferior to that with biaspart insulin (–0.76%). The between-group difference was 0.07% (the noninferiority margin was 0.4%).

The inhaled insulin group demonstrated fewer adverse events of mild-to-moderate and severe hypoglycemic events and significantly less weight gain. The safety profiles of the drugs were similar, except the inhaled insulin demonstrated an increase in forced expiratory volume in 1 second (FEV1) and an increase in the occurrence of cough.48 Changes in FEV1 do not progress over time with use, and they reverse

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with the cessation of the medication.49 The FDA has approved the medication with a box warning that states that inhaled human insulin may cause acute bronchospasm and is not recommended for use by patients with asthma or chronic obstructive pulmonary disease.50 The most common adverse events, such as hypoglycemia, are similar to that of short-acting subcutaneous insulin. Other common side effects include throat pain or irritation (4.4%) and cough (25.6%).51

Miscellaneous Drugs with a Potential to Regulate Glucose Dysregulation Ranolazine Ranolazine is a novel antiangina drug used in the treatment of patients with chronic angina, and has also been shown to lower HbA1c and FPG levels in clinical trials. Ranolazine inhibits the cardiac late-phase sodium current during cardiac repolarization, thus improving sodium-calcium homeostasis and resulting in reduced myocardial ischemia. In patients with coronary artery disease and diabetes, ranolazine has been shown to decrease HbA1c levels in 2 clinical trials—the Combination Assessment of Ranolazine in Stable Angina (CARISA) trial52 and the Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndromes-Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36) trial.53 In the CARISA trial, ranolazine was associated with a statistically significant decline in HbA1c in a dose-­ dependent manner.52 After 12 weeks of treatment with ranolazine 750 mg or 1000 mg twice daily, the HbA1c level was reduced by 0.48% (P = .008) and 0.7% (P = .002) compared with placebo.52 This was further confirmed in the MERLIN-­TIMI 36 trial. The double-blind study included 6560 patients with non–ST-segment elevation myocardial infarction acute coronary syndrome and at least 1 indicator of moderate-to-high risk of a recurrent ischemic event who were randomized in a 1:1 ratio to ranolazine or to placebo.53 The results showed a significant reduction in HbA1c with ranolazine in addition to standard antidiabetic therapy. Ranolazine had a placebo-adjusted reduction in HbA1c of 0.28% in patients with an HbA1c of 6% to 8% and by 0.59% in patients with an HbA1c of 8% to 10%. In addition, ranolazine also had a placebo-corrected reduction in FPG of 25.7 mg/dL in patients with an initial FPG of ≥150 to 400 mg/dL and no change in FPG in patients with an initial FPG of <150 mg/dL.53 The exact mechanism of the reduction of HbA1c with ranolazine is not known, but experimental models have suggested that ranolazine increases glucose-stimulated ­insulin secretion in isolated pancreatic islet cells.54 In mice with streptozotocin-induced diabetes that were treated

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with ranolazine, the peak insulin levels were higher during the oral glucose tolerance test (P <.05), the islet morphology appeared healthier, there was higher beta-cell mass, and there were significantly less apoptotic cells in the pancreas.54

Perhaps the most exciting aspects of these novel developments in diabetes management are that the new agents are either weightfriendly or can induce weight loss, or they have lower risks for hypoglycemia.

Sevelamer Many patients with diabetes have concurrent nephropathy. In patients with chronic kidney disease, sevelamer is used in the management of hyperphosphatemia. In a single-center, randomized, crossover, open-label, intention-to-treat study, sevelamer was shown to lower HbA1c, total cholesterol, and triglycerides compared with calcium carbonate (P <.05).55 The mechanism behind sevelamer’s effect on HbA1c is unknown. Sevelamer is also a bile sequestrant in addition to being a phosphate binder. Thus, sevelamer’s effect on HbA1c is possibly related to its bile acid– binding ability.

Colesevelam is a bile sequestrant that is approved by the FDA for the management of diabetes and has been shown to lower HbA1c and FPG.56 Sevelamer enhances the delivery of bile acids to the distal colon via its bile sequestration capability, thereby promoting GLP-1 release and modulating HbA1c.57 Conclusions The problem of diabetes in the United States will continue to wreak heavy human and financial tolls.

The complications stemming from diabetes will continue to climb if they are not stemmed. The most common obstacle a physician faces in clinical practice is patient adherence. Aside from efficacy and safety, the common themes seen with these new and emerging drugs are the convenience of administration and the convenient dosing frequency.

All the oral drugs discussed in this review article are once-daily medications, with the exception of ranolazine.

All new injections for diabetes are coming out in a pen format to improve patient adherence. A new inhaled insulin was found to work more quickly than the injectable version of the drug, and it has shown to be as effective as other short-acting subcutaneous insulin agents.

Perhaps the most exciting aspects of these novel

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developments in diabetes management are that the new agents are either weight-friendly or can induce weight loss, or they have lower risks for hypoglycemia.

At a mean total cost of $17,564 per hypoglycemic episode requiring hospitalization,3 this is a meaningful improvement to the healthcare system as a whole.

Weight gain in patients with diabetes is counterproductive, because substances related to insulin resistance are upregulated in obese patients. Weight loss promotes HbA1c reduction, with a loss of 10% body weight potentially reducing HbA1c by 0.81%.58 This, in turn, improves insulin sensitivity potentiating other therapies.

Postmarketing data are continuing to be collected for these drugs to address safety concerns. No macrovascular outcomes data are currently available for the antidiabetes drugs that are mentioned in this review, although each drug will have to conduct a dedicated CV safety trial to meet the 2008 updated FDA guidance recommendations. The risks and benefits of each drug should be appropriately weighed when a diabetes regimen is chosen for a particular patient. ■ Author Disclosure Statement Dr Miller, Dr H. Nguyen, Dr Hu, and Dr Lin reported no conflicts of interest. Dr Q.T. Nguyen is on the Speaker’s Bureau for AstraZeneca.

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17. Neal B, Perkovic V, de Zeeuw D, et al; for the CANVAS Trial Collaborative Group. Rationale, design, and baseline characteristics of the Canagliflozin Cardiovascular Assessment Study (CANVAS)—a randomized placebo-controlled trial. Am Heart J. 2013;166:217-223.e11.

18. US Food and Drug Administration. FDA approves Farxiga to treat type 2 diabetes. Press release. January 8, 2014. www.fda.gov/NewsEvents/Newsroom/Press­ Announcements/ucm380829.htm. Accessed September 23, 2014.

19. Ferrannini E, Jimenez Ramos S, Salsali A, et al. Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care.

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22. US Food and Drug Administration. Background document. Dapagliflozin. NDA 202293. November 4, 2013. www.fda.gov/downloads/drugs/endocrinologicandmeta bolicdrugsadvisorycommittee/ucm378079.pdf. Accessed October 27, 2014.

23. Farxiga (dapagliflozin) tablets [prescribing information]. Princeton, NJ: BristolMyers Squibb; January 2014.

24. Heise T, Seewaldt-Becker E, Macha S, et al. Safety, tolerability, pharmacokinetics and pharmacodynamics following 4 weeks’ treatment with empagliflozin once daily in patients with type 2 diabetes. Diabetes Obes Metab. 2013;15:613-621.

25. Rosenstock J, Seman LJ, Jelaska A, et al. Efficacy and safety of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, as add-on to metformin in type 2 diabetes with mild hyperglycaemia. Diabetes Obes Metab. 2013;15:1154-1160.

26. Kovacs CS, Seshiah V, Swallow R, et al; for the EMPA-REG PIO trial investigators. Empagliflozin improves glycaemic and weight control as add-on therapy to pioglitazone or pioglitazone plus metformin in patients with type 2 diabetes: a 24week, randomized, placebo-controlled trial. Diabetes Obes Metab. 2014;16:147-158.

27. Kadowaki T, Haneda M, Inagaki N, et al; for the EMPA-REG DOSEJAPAN trial investigators. Empagliflozin monotherapy in Japanese patients with type 2 diabetes mellitus: a randomized, 12-week, double-blind, placebo-controlled, phase II trial. Adv Ther. 2014;31:621-638.

28. Macha S, Lang B, Pinnetti S, Broedl UC. Pharmacokinetics of empagliflozin, a sodium glucose cotransporter 2 inhibitor, and simvastatin following co-administration in healthy volunteers. Int J Clin Pharmacol Ther. 2014;52:973-980.

29. Astellas Pharma. Approval of Suglat tablets, a selective SGLT2 inhibitor for treatment of type 2 diabetes, in Japan. Press release. January 17, 2014. www.astellas. com/en/corporate/news/detail/approval-of-suglat-tablets-a-s.html. Accessed September 28, 2014.

30. Suzuki M, Honda K, Fukazawa M, et al. Tofogliflozin, a potent and highly specific sodium/glucose cotransporter 2 inhibitor, improves glycemic control in diabetic rats and mice. J Pharmacol Exp Ther. 2012;341:692-701.

31. Holst JJ. Treatment of type 2 diabetes mellitus with agonists of the GLP-1 receptor or DPP-IV inhibitors. Expert Opin Emerg Drugs. 2004;9:155-166.

32. Bydureon (exenatide) pen [prescribing information]. Wilmington, DE: Astra Zeneca Pharmaceuticals; October 2014.

33. Blevins T, Pullman J, Malloy J, et al. DURATION-5: exenatide once weekly resulted in greater improvements in glycemic control compared with exenatide twice daily in patients with type 2 diabetes. J Clin Endocrinol Metab. 2011;96:1301-1310.

34. Tanzeum (albiglutide) for injection [prescribing information]. Wilmington, DE: GlaxoSmithKline; June 2014.

35. Rendell M, Scott R, Ye J, et al. Harmony 2 year 3 results: albiglutide monotherapy in drug naïve patients with T2DM. Poster presented at the American Diabetes Association’s 74th Scientific Sessions; June 13-17, 2014; San Francisco, CA. 36. Ahrén B, Johnson SL, Stewart M, et al; for the HARMONY 3 Study Group.

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37. GlaxoSmithKline. GSK announces data from five phase III studies of albiglutide, an investigational once-weekly treatment for type 2 diabetes. Press release. June 24, 2013. http://us.gsk.com/en-us/media/press-releases/2013/gsk-announces-data-fromfive-phase-iii-studies-of-albiglutide-an-investigational-once-weekly-treatment-­fortype-2-diabetes/. Accessed September 24, 2014.

38. Weissman PN, Carr MC, Ye J, et al. HARMONY 4: randomised clinical trial comparing once-weekly albiglutide and insulin glargine in patients with type 2 diabetes inadequately controlled with metformin with or without sulfonylurea. Diabetologia. 2014;57:2475-2484.

39. Rosenstock J, Fonseca VA, Gross JL, et al; for the Harmony 6 Study Group.

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40. Reusch J, Stewart MW, Perkins CM, et al. Efficacy and safety of once-weekly glucagon-like peptide 1 receptor agonist albiglutide (HARMONY 1 trial): 52-week primary endpoint results from a randomized, double-blind, placebo-controlled trial in patients with type 2 diabetes mellitus not controlled on pioglitazone, with or without metformin. Diabetes Obes Metab. 2014;16:1257-1264.

41. Pratley RE, Nauck MA, Barnett AH, et al; for the HARMONY 7 study group.

Once-weekly albiglutide versus once-daily liraglutide in patients with type 2 diabetes inadequately controlled on oral drugs (HARMONY 7): a randomised, open-label, multicentre, non-inferiority phase 3 study. Lancet Diabetes Endocrinol. 2014;2:289297. Erratum in: Lancet Diabetes Endocrinol. 2014;2:e5.

42. Eli Lilly and Company. FDA approves Trulicity (dulaglutide), Lilly’s once-weekly therapy for adults with type 2 diabetes. Press release. September 18, 2014. https:// investor.lilly.com/releasedetail.cfm?releaseid=871658. Accessed September 28, 2014.

43. US Food and Drug Administration. FDA approves Trulicity to treat type 2 diabetes. Press release. September 18, 2014. www.fda.gov/NewsEvents/Newsroom/Press Announcements/ucm415180.htm. Accessed September 28, 2014.

44. Dungan KM, Povedano ST, Forst T, et al. Once-weekly dulaglutide versus once-daily liraglutide in metformin-treated patients with type 2 diabetes (AWARD6): a randomised, open-label, phase 3, non-inferiority trial. Lancet. 2014;384:13491357. Erratum in: Lancet. 2014;384:1348.

45. Umpierrez G, Tofé Povedano S, Pérez Manghi F, et al. Efficacy and safety of dulaglutide monotherapy versus metformin in type 2 diabetes in a randomized controlled trial (AWARD-3). Diabetes Care. 2014;37:2168-2176.

46. Rave K, Potocka E, Boss AH, et al. Pharmacokinetics and linear exposure of Afresa compared with the subcutaneous injection of regular human insulin. Diabetes Obes Metab. 2009;11:715-720. Erratum in: Diabetes Obes Metab. 2009;11:1175.

47. MannKind Corporation. Afrezza (insulin human [rDNA origin]) inhalation powder: an ultra-rapid acting insulin treatment to improve glycemic control in adult patients with diabetes mellitus. Briefing document. NDA 022472. April 1, 2014. www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM390865.pdf. Accessed September 29, 2014.

48. Rosenstock J, Lorber DL, Gnudi L, et al. Prandial inhaled insulin plus basal insulin glargine versus twice daily biaspart insulin for type 2 diabetes: a multicentre randomised trial. Lancet. 2010;375:2244-2253.

49. Santos Cavaiola T, Edelman S. Inhaled insulin: a breath of fresh air? A review of inhaled insulin. Clin Ther. 2014;36:1275-1289.

50. US Food and Drug Administration. FDA approves Afrezza to treat diabetes. Press release. June 27, 2014. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ ucm403122.htm. Accessed September 29, 2014.

51. Afrezza (insulin human) inhalation powder [prescribing information]. Danbury, CT: MannKind Corporation; June 2014 52. Timmis AD, Chaitman BR, Crager M. Effects of ranolazine on exercise tolerance and HbA1c in patients with chronic angina and diabetes. Eur Heart J. 2006;27:42-48.

53. Chisholm JW, Goldfine AB, Dhalla AK, et al. Effect of ranolazine on A1C and glucose levels in hyperglycemic patients with non-ST elevation acute coronary syndrome. Diabetes Care. 2010;33:1163-1168.

54. Ning Y, Zhen W, Fu Z, et al. Ranolazine increases β-cell survival and improves glucose homeostasis in low-dose streptozotocin-induced diabetes in mice. J Pharmacol Exp Ther. 2011;337:50-58.

55. Vlassara H, Uribarri J, Cai W, et al. Effects of sevelamer on HbA1c, inflammation, and advanced glycation end products in diabetic kidney disease. Clin J Am Soc Nephrol. 2012;7:934-942.

56. Bays HE, Goldberg RB, Truitt KE, Jones MR. Colesevelam hydrochloride therapy in patients with type 2 diabetes mellitus treated with metformin: glucose and lipid effects. Arch Intern Med. 2008;168:1975-1983.

57. Brønden A, Hansen M, Sonne DP, et al. Sevelamer in a diabetologist’s perspective: a phosphate-binding resin with glucose-lowering potential. Diabetes Obes Metab. 2014 Jul 9 [Epub ahead of print].

58. Shantha GP, Kumar AA, Kahan S, Cheskin LJ. Association between glycosylated hemoglobin and intentional weight loss in overweight and obese patients with type 2 diabetes mellitus: a retrospective cohort study. Diabetes Educ.

2012;38:417-426.

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CLINICAL

STAKEHOLDER PERSPECTIVE

Addressing Adherence a Key Challenge in the Management of Patients with Type 2 Diabetes

By Jeffrey A. Bourret, PharmD, MS, RPh, BCPS, FASHP Senior Director, North America Medical Affairs, Pfizer Inc, Collegeville, PA

PAYERS: The passage of the Accountable Care Act in 2010 is driving improved accountability for quality through the establishment of accountable care organizations (ACOs). ACOs provide incentives for healthcare providers to improve the quality of care delivered in physicians’ offices, hospitals, and long-term care settings. Concerns about the impact of diabetes on cost and quality of care are what drove the development and triple weighting of the Centers for Medicare & Medicaid Services 5-star quality rating measures for diabetes,1 which is a top priority for every health plan, ACO, hospital, and physician practice in the United States that serves patients with diabetes.

Even with multiple efforts to improve diet and exercise, pharmacologic treatments continue to be essential to improving the quality of care and minimizing the costs associated with the severe complications of type 2 diabetes in the short term and the long term. In the past, when oral agents failed in patients with diabetes, the only option was the initiation of injectable insulin. But the introduction of new medications that work through different mechanisms of action, alone or in combination, to control hyperglycemia has changed that approach. In their article, Miller and colleagues describe some of these new and emerging drugs and targets for treating type 2 diabetes.2 Clinically meaningful improvements in outcomes will not be achieved, however, until patient adherence is improved. Adherence is a major problem in patients with type 2 diabetes. As Miller and colleagues point out, a 2011 study reported that 3.1 million (14.9%) patients with type 2 diabetes did not take their medications.3 Poor adherence is multifactorial and is impacted by education, income, location, complex drug regimens, medication side effects, and patient support systems.

The adverse effects of antidiabetes drugs vary with each class and include gastrointestinal side effects; weight gain or loss; and the risk for hypoglycemia, which is one of the most common causes of costly hospitalizations associated with medication use in patients with diabetes. In their article, Miller and colleagues report that the average cost of a hospitalization episode for hypoglycemia is $17,564.2 Access to a broad choice of medications can aid in improving adherence through individualized treatment

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regimens; however, individualizing the treatment regimen for a patient with type 2 diabetes is complex. The choice of medicines must take into account many variables and patient characteristics, such as comorbidities, susceptibility to cardiac events, concomitant medications, the patient’s ability or willingness to self-inject, the patient’s preference for mode of administration, and the physician’s experience.

The number of medications available for the treatment of type 2 diabetes has substantially increased as a result of the pharmaceutical industry’s innovation and discovery of new medicines that offer improved efficacy that address tolerability and adverse effects of previously available agents, enabling physicians to individualize treatment in ways that they could not have in the past.

A paradigm shift has occurred in the treatment of hyperglycemia in patients with diabetes with the introduction of new medicines and an improved understanding of the heterogeneity of diabetes. The current clinical approach supports individualized treatment that takes into account a patient’s age, the medication cost, the medicine’s effect on weight gain or loss, the risk for hypoglycemia with individual drugs, and the drugs’ effectiveness in achieving the target blood glucose or hemoglobin A1c levels.4 The position statement of the American Diabetes Association and the European Association for the Study of Diabetes on the management of hyperglycemia in patients with type 2 diabetes emphasizes that their recommendations should be considered within the context of the needs, preferences, and drug tolerance of each patient; the individualization of treatment is the cornerstone of success.5 Payers should seek input from experienced endocrinologists in their pharmacy benefit design to balance cost and quality in a manner that allows physicians broad access to medications that are aligned with national treatment guidelines and include patient shared decision-making to determine the optimal treatment regimen.

PROVIDERS: Patient-centered care is defined as an approach to “providing care that is respectful of and responsive to individual patient preferences, needs, and values and ensuring that patient values guide all clinical deci-

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New and Emerging Drugs and Targets for Type 2 Diabetes

STAKEHOLDER PERSPECTIVE Continued sions.” 6 During the clinical encounter, the patient’s preferred level of involvement should be gauged and therapeutic choices explored, potentially with the utilization of decision aids.7 In a shared decision-making approach, clinicians and patients act as partners, mutually exchanging information and deliberating on options to reach a consensus on the therapeutic course of action.8 Strong evidence is available to support the effectiveness of this approach.9 Most important, engaging patients in their healthcare decisions may enhance adherence to therapy. It is critical for healthcare providers to discuss options with patients and to determine if patients will adhere to the treatments that are being prescribed for them. For example, if a patient prefers an oral medication to a self-injectable medicine and will refuse to fill a prescription or to use a self-injectable medication, this needs to be determined before the prescription is written and before the patient leaves the office.

Primary nonadherence is defined as patients who do not fill their first prescription. This has been a long-­ standing problem in medicine, and it is getting more attention as data become more readily available through the use of electronic medical records and electronic prescribing, which can determine if prescriptions written by physicians are actually filled.

Primary nonadherence can be reduced if a provider knows that a patient is unwilling to take a certain medication at the time of prescribing. If there are managed care restrictions on access to certain agents, the prior authorization follow-up should reflect this provider–patient discussion, as well as the patient’s unwillingness to take a preferred agent; this will assist the physician in gaining access to a nonpreferred agent to avoid the patient not

receiving treatment, which could lead to poor patient outcomes and downstream cost implications to payers.

PATIENTS: Ultimately, patients’ own lifestyles and preferences weigh into their personal decisions regarding what medications they will take. A core principle of evidence-based medicine is involving patients in decisions about their treatment, together with their physicians’ assessment of the best available evidence from the medical literature, their clinical experience, and the patients’ desires and behavioral inclinations.10 Patients have a responsibility to ask about available treatment options and to provide honest feedback to their healthcare providers regarding which treatment they are willing to adhere to. ■ 1. Academy of Managed Care Pharmacy; American Pharmacy Association. Medicare star ratings: stakeholder proceedings on community pharmacy and managed care partnerships in quality. J Am Pharm Assoc (2003). 2014;54:228-240.

2. Miller BR, Nguyen H, Hu CJ, et al. New and emerging drugs and targets for type 2 diabetes: reviewing the evidence. Am Health Drug Benefits. 2014;7:451-462.

3. Centers for Disease Control and Prevention. Number (in millions) of adults with diabetes by diabetes medication status, United States, 1997-2011. Updated December 7, 2012. www.cdc.gov/diabetes/statistics/meduse/fig1.htm. Accessed September 22, 2014.

4. Weerarathna TP. Individualizing treatment of type 2 diabetes. Sri Lanka J Diabetes Endocrinol Metab. 2014;4:56-58.

5. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012;35:1364-1379.

6. Committee on Quality of Health Care in America, Institute of Medicine. Crossing the Quality Chasm: A New Health System for the 21st Century. Washington, DC: National Academy Press; 2001.

7. Mullan RJ, Montori VM, Shah ND, et al. The diabetes mellitus medication choice decision aid: a randomized trial. Arch Intern Med. 2009;169:1560-1568.

8. Tsapas A, Matthews DR. N of 1 trials in diabetes: making individual therapeutic decisions. Diabetologia. 2008;51:921-925.

9. Shah ND, Mullan RJ, Breslin M, et al. Translating comparative effectiveness into practice: the case of diabetes medications. Med Care. 2010;48(6 suppl):S153-S158.

10. Guyatt GH, Haynes RB, Jaeschke RZ, et al; for the Evidence-Based Medicine Working Group. Users’ Guides to the Medical Literature: XXV. Evidence-based medicine: principles for applying the Users’ Guides to patient care. JAMA. 2000;284:1290-1296.

VISIT OUR ENHANCED USER-FRIENDLY WEBSITE American Health & Drug Benefits is an independent, peer-reviewed journal founded in 2008 Examines drug and other healthcare intervention value for payers, purchasers, providers, patients, manufacturers, regulators, distributors, and evaluators Provides up-to-date information on new drugs approved by the FDA

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