AHDB October 2014, Vol 7, No 7

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

VOLUME 7, NUMBER 7

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

EDITORIAL

Personalized Medicine: Are We There Yet? David B. Nash, MD, MBA PERSPECTIVE

Rewarding Innovation in Drug Development Emily Saadi and Greg White, MPP CLINICAL ™

Evaluation of Dabigatran for Appropriateness of Use and Bleeding Events in a Community Hospital Setting Anastasia L. Armbruster, PharmD, BCPS; Katie S. Buehler, PharmD, BCPS; Sun H. Min, PharmD; Margaret Riley, PharmD; Michael W. Daly, PharmD, MSCI, BCPS Stakeholder Perspective: Accurate Prescribing Key to Safe Use of Anticoagulants in Patients with Nonvalvular Atrial Fibrillation

By Raymond L. Singer, MD, MMM, CPE

Patient Preferences and Treatment Adherence Among Women Diagnosed with Metastatic Breast Cancer Marco daCosta DiBonaventura, PhD; Ronda Copher, PhD; Enrique Basurto, MSc; Claudio Faria, PharmD, MPH; Rose Lorenzo, BA Stakeholder Perspective: Predicting Behavior: It’s a Matter of Preference

By Albert Tzeel, MD, MHSA, FACPE

AMCP Nexus 2014 Highlights

© 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/m2 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 Philadelphia, PA Laura T. Pizzi, PharmD, MPH, RPh Professor, Dept. of Pharmacy Practice Jefferson School of Pharmacy, Thomas Jefferson University, Philadelphia, PA 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 Past Chair, NCCN Board of Directors 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

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 Joseph E. Couto, PharmD, MBA Clinical Program Manager Cigna Corporation, Bloomfield, CT

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Steven Miff, PhD Senior Vice President VHA, Inc., Irving, TX Terri S. Moore, PhD, RPh, MBA Senior Manager, Product Development URAC, Washington, DC 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 Paul Wilson Senior VP, Health Consumer Insights and Analytics, Blue Bell, PA 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 PAYER-PROVIDER FINANCES

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

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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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

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 SPECIALTY PHARMACY

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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EDITORIAL

371 Personalized Medicine: Are We There Yet?

David B. Nash, MD, MBA PERSPECTIVE

373 Rewarding Innovation in Drug Development

By Emily Saadi and Greg White, MPP CLINICAL

376 Evaluation of Dabigatran for Appropriateness of Use and Bleeding Events in a Community Hospital Setting Anastasia L. Armbruster, PharmD, BCPS; Katie S. Buehler, PharmD, BCPS; Sun H. Min, PharmD; Margaret Riley, PharmD; Michael W. Daly, PharmD, MSCI, BCPS 383 Stakeholder Perspective: Accurate Prescribing Key to Safe Use of Anticoagulants in Patients with Nonvalvular Atrial Fibrillation

By Raymond L. Singer, MD, MMM, CPE 386 Patient Preferences and Treatment Adherence Among Women Diagnosed with Metastatic Breast Cancer Marco daCosta DiBonaventura, PhD; Ronda Copher, PhD; Enrique Basurto, MSc; Claudio Faria, PharmD, MPH; Rose Lorenzo, BA 396 Stakeholder Perspective: Predicting Behavior: It’s a Matter of Preference

By Albert Tzeel, MD, MHSA, FACPE Continued on page 370

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DEPARTMENT

401 AMCP Nexus 2014 Highlights: Health Economics Outcomes and Payers’ Perspectives

• Narcolepsy Associated with Increased Healthcare Utilization, Costs, and Reduced Productivity

• Treatment Patterns and Total Healthcare Costs in Patients with Advanced Melanoma

• Clinical Pathways Can Improve the Use of Antipsychotic Medications in Patients with Schizophrenia

• Cost Implications of Therapies to Manage Obesity: A Budget Impact Analysis

• Real-World Healthcare Utilization and Medical Costs Lower with Dabigatran than with Warfarin in Patients with Nonvalvular Atrial Fibrillation

• Payers’ Perspectives on Accountable Care Organizations in Oncology

• Prognostic Test Cost-Effective in Patients with Early-Stage Lung Adenocarcinoma

• Workplace Onsite Pharmacy Improves Medication Adherence of Employees

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EDITORIAL

Personalized Medicine: Are We There Yet?

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

I

am privileged to still be seeing patients in our primary care practice within the Division of Internal Medicine at Sidney Kimmel Medical College (formerly Jefferson Medical College). Parenthetically, I am also the oldest physician in the group. Like many primary care physicians, I have recently seen an increase in the number of patients who bring results of proprietary genetic testing to the office. These results, often from companies such as 23andMe, a DNA analysis service, represent a sea change in at least one aspect of the doctor–patient relationship. In what some have called the “democratization” of information (see Eric Topol’s wonderful book, The Creative Destruction of Medicine),1 genetic typing is potentially the first step toward our realization of personalized medicine.

As of now, however, I do not believe we are quite there yet. In other words, I am unable to thoroughly interpret the results of testing from companies such as 23andMe, and the opportunities to modify a medication regimen, make solid evidentiary-based recommendations for changes in behavior, or for future clinical testing for patients are limited.

Let us first examine the public’s view of personalized medicine, and then review some examples of where we currently are, and where we may be in the future.

According to a March 2014 survey of public opinion conducted on behalf of the Personalized Medicine Coalition by KRC Research, a reputable public opinion research consultancy based in Washington, DC, a large majority (62%) of the 1024 American adults polled on the topic had not heard of personalized medicine, but they reacted positively when it was described to them.2 Among the surveyed adults who had heard the term (38%), only 2 in 10 believed they were very informed about personalized medicine. Furthermore, only 11% said that their doctor had discussed or had recommended any aspect of personalized medicine to them.2 First, let us define our terms. The investigators at KRC Research used the following description of personalized medicine when conducting the survey: “Personalized medicine is an emerging field that uses diagnostic tools to identify specific biologic markers, often genetic, to help determine which medical treatments and proce-

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dures will be best for each patient. By combining this information with an individual’s medical records and circumstances, personalized medicine allows doctors and patients to develop targeted prevention and treatment plans. The goal is to provide the right treatment in the right dose to the right patient at the right time.”2 The KRC Research investigators further noted that the majority of the survey participants were “excited about the potential benefits of personalized medicine, including choosing a treatment that is most likely to work for them and the potential to prevent illness.”2 A large majority of those surveyed “also recognize the value of these technologies and that they should be covered by insurance.”2 Finally, “the idea that personalized medicine can provide useful prevention and treatment information, help avoid or reduce side effects, avoid trial-anderror medicine, and give more control to prevent or treat illness are very compelling benefits.”2 One could quibble slightly with KRC Research’s definition of personalized medicine, but my hunch is that the results truly reflect the positions of the survey responders. Who could argue with treatment that avoids trial and error, is more focused on the individual, and that has long-term benefits when done correctly? So, yes, parts of these results are dependent on how we ask the question; however, although the public is not currently well informed, this situation will very likely change in the very near term.

Where are we now regarding the implementation of personalized medicine? Clearly, this is a complex issue. I have written about this complexity elsewhere,3 but it is fair to say that personalized medicine has not yet delivered on its “hype.” I certainly expected that by late 2014 we would be doing a buccal smear on our primary care patients, assessing their genotype quickly in the office, and making very specific, evidence-based recommendations for their future health and well-being. We have not yet realized this dream.

For example, findings from a recent meta-analysis by Stergiopoulos and Brown show that a “genotype-guided dosing strategy [for warfarin] did not result in a greater percentage of time that the INR [international normalized ratio] was within the therapeutic range, fewer pa-

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tients with an INR greater than 4, or a reduction in major bleeding or thromboembolic events compared with clinical dosing algorithms.”4 In other words, despite the availability of pharmacogenomic testing to determine who may benefit from therapy with warfarin and appropriate dosing, this meta-analysis of randomized clinical trials revealed no difference between our current standard of care and care complemented by genetic testing. In an editorial accompanying the meta-analysis, Kazi and Hlatky state that the “routine use of genetic testing to guide warfarin management cannot be recommended.”5 Warfarin is just one example. There are now a score of drugs that have been assessed in the literature based on genetic testing, and the take-home message is very mixed.

Kazi and Hlatky conclude that “evidence of improved clinical outcomes, not biological causability or hype, should drive the adoption of genetic tests into practice.”5 Although the example of warfarin is not compelling, evidence in psychiatric care (and other clinical areas,

I am confident that with new technology, we will overcome any current limitations, and my dream of practicing personalized medicine will be realized in my own practice lifetime. such as cancer care) may present a different story. In an article on pharmacogenomic testing, Winner states that “given that the current strengths of pharmacogenomics testing align directly with the common pharmacologic challenges in the elderly and the need for better outcomes with lower costs, the aging population may be the first large group of individuals to benefit from a paradigm shift in treatment with integrated pharmacogenomic testing.”6 Winner further suggests that within the burgeoning arena of geriatric psychiatry, pharmacogenomic testing will identify individual genetic differences as they relate to response to therapy, and that this can be used to personalize medication treatment for the large number of elderly patients with depression.

What about the future? In August, I had the opportunity to participate in a leadership panel program sponsored by Pennsylvania Bio (www.pabio.org), a large membership organization headquartered in suburban Philadelphia that represents more than 600 companies in the life sciences. At this leadership program entitled “From Personalized Medicine to Precision Prevention—

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What Will It Mean for You?,” the group of participating experts were very enthusiastic about the future of personalized medicine. Despite the regulatory and scientific challenges, these experts from across the state were very upbeat in their assessment of the future of personalized medicine. They also cited an increase in Wall Street’s interest in companies working in this arena.

With that in mind, I am personally intrigued by the work of companies such as Genelex Corporation and their YouScript system, a personalized prescribing system that uses genetic screening to reduce adverse drug events.7 For example, a description of YouScript’s services notes that “more than 75% of patients have detectable variations in their DNA that may increase their risk of unwanted side effects and adverse drug events.”8 YouScript brochures suggest that its testing is recommended for patients who take multiple medications, complain that their medications are not working or who are wary of standard dosing based on negative experiences, and are using complex drug treatment plans. This description applies to the vast majority of my own patients. So perhaps companies and services such as YouScript, 23andMe, and others are going to enjoy a very successful future.

We are certainly on the right road, but we’re not there yet. Although common therapeutic regimens involving drugs such as warfarin and tricyclic antidepressants are reporting variable outcomes within the personalized medicine arena, I am confident that with new technology, we will overcome any current limitations, and my dream of practicing personalized medicine will be realized in my own practice lifetime. Let us get past the hype and improve the science so we can make real advances in this field. For me, time is of the essence.

As always, I am interested in your views, and you can reach me at david.nash@jefferson.edu. n

References

1. Topol E. The Creative Destruction of Medicine: How the Digital Revolution Will Create Better Health Care. New York, NY: Basic Books; 2012.

2. Personalized Medicine Coalition, KRC Research. US public opinion about personalized medicine: survey shows public optimism about personalized medicine. March 5-16, 2014. www.personalizedmedicinecoalition.org/Userfiles/PMC-Corporate/file/ us_public_opinion_about_personalized_medicine.pdf. Accessed September 4, 2014.

3. Nash DB. The challenge of personalizing health care. Manag Care. 2013;22:49-53.

4. Stergiopoulos K, Brown DL. Genotype-guided vs clinical dosing of warfarin and its analogues: meta-analysis of randomized clinical trials. JAMA Intern Med. 2014;174: 1330-1338.

5. Kazi DS, Hlatky MA. Warfarin, genes, and the (health care) environment. JAMA Intern Med. 2014;174:1338-1339.

6. Winner J. Pharmacogenomic treatment support advances mental wellness. Todays Geriatr Med. 2014;7:20.

7. Genelex Corporation. YouScript. http://youscript.com. Accessed September 3, 2014.

8. Allscripts. https://store.allscripts.com/applications/id-13027/youscript. Accessed September 4, 2014.

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PERSPECTIVE

Rewarding Innovation in Drug Development

By Emily Saadi and Greg White, MPP Ms Saadi is a senior at Wardlaw-Hartridge School, Edison, NJ; Mr White is Senior Director, Global Market Access Policy, Johnson & Johnson, Washington, DC

T

he development of innovative medications is largely a private enterprise that relies chiefly on the investment of pharmaceutical companies in research and development (R&D). This process can be described as a cycle, where the success of one drug is necessary to stimulate the development and eventual success of a subsequent therapy. Specifically, this “innovation cycle” includes 3 major stages—drug innovation, reward to society (ie, patient access), and reinvestment of drug sales into the development of new drugs. Of note, this cycle is an incremental process, whereby failure to reward the initial development of a drug in a specific therapeutic area may have a negative impact on—or entirely halt— the rate of continued innovation in that field.

A Lengthy, Costly, and Risky Process The development of innovative new therapies is a lengthy, expensive, and risky process. The entire time from initial R&D through a drug’s regulatory approval can take between 10 and 15 years,1-3 at an estimated average cost ranging from $1.2 billion to more than $1.8 billion in the United States (including the cost of failures).4-6 In a 2011 report by BlueCross BlueShield, the annual aggregate spending on R&D by the pharmaceutical industry was estimated to be $12.6 billion on the development of new therapies.7 Despite these high costs, the risk for drug failure is significant: only 1 of thousands of screened compounds may eventually become an approved medicine after years of clinical testing. Furthermore, although the high prices associated with novel therapies continue to be criticized, it is estimated that only 3 in 10 approved drugs recover their R&D costs.8 This high risk underscores the importance of rewarding truly innovative medications to sustain ongoing drug development.

Patient Access Sustains R&D Innovation Although all stages of the innovation cycle are critical for ongoing drug development, patient access to treatment, naturally, has the greatest societal impact. For patients, reward for innovation comes in the form of the availability of cutting-edge medicines and drugs with improved efficacy and/or safety profiles. Access to new and innovative therapies provides additional benefits to society as a whole, such as improved population health and quality of life, reduced hospitalizations, increased

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productivity, and an increasing number of jobs.9 Because many patients cannot afford the drugs that they require, they may be supported through payer reimbursement by private and public insurance plans. These payers have a business responsibility (eg, as a result of tax funding, member premiums) to patients and to manufacturers to support innovation and to make breakthrough, high-efficacy drugs available to the individuals who need them. The provision of patient access is vital in driving the demand for and utilization of new drugs, and the maintenance of sales is increasingly necessary to stimulate R&D and to sustain the pharmaceutical marketplace.8,9

Disparate Innovation Cycles: Cancer versus Obesity To achieve the greatest health outcomes and to support the innovation cycle, promising new drugs must be rewarded across all therapeutic areas. A prime example of a successful innovation cycle is the R&D and subsequent utilization of oncology drugs. Recent data indicate that there are more pharmaceuticals under development for cancer than for any other therapeutic area, with cancer-targeted agents representing approximately 30% of all drugs currently in development in the United States.1,10 Major reasons for the strong interest in these therapies include a substantial unmet medical need and the high market recognition that cancer drugs receive for their innovation.

A report from the World Health Organization (WHO)’s International Agency for Research on Cancer recently warned of an imminent “human disaster,” based on the prediction that new cancer diagnoses will increase by 57% worldwide over the next 20 years, from 14 million cases annually in 2012 to 22 million cases annually in 2032.11 As a result, there is likely an enhanced willingness to approve and to reimburse oncology drugs, which continue to be rewarded by private and public payers, even in countries that use cost-effectiveness as a key criterion for clinical and policy decision-making.

Truly innovative therapies for cancer are also frequently approved in a short time frame through 1 of 4 expedited review and approval processes offered by the US Food and Drug Administration. These processes include fast tracking, breakthrough status, priority review, and accelerated approval.12 Taken collectively with disease burden, the incentives to reinvest in the development of innovative cancer treatments are significant.

Conversely, despite the epidemic status of obesity and

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its associated high risks for negative clinical and economic outcomes, the absence of innovative drug therapies targeting the condition is notable. According to the WHO, 11% of adults aged ≥20 years were obese in 2008, amounting to more than 200 million men and nearly 300 million women worldwide.13 Obesity is linked to many deleterious health effects, such as cardiovascular disease, a variety of musculoskeletal diseases, diabetes, and cancer.13 Moreover, obese individuals are at an elevated risk for early mortality: a recent meta-analysis reported an 18% increased risk for death in morbidly obese individuals compared with the general population.14 Not surprising, the management of obesity and its associated health consequences places an enormous financial burden on society, with annual medical costs reaching an estimated $190 billion in the United States in 2012.15 Despite its high prevalence and deleterious clinical and economic consequences, successful innovation in the treatment of obesity remains rare.16 According to an April 2014 personal e-mail communication from ­Evaluate Pharma, recent R&D data from its database indicate that only 190 drugs are currently under development to target obesity; in contrast, a 2013 report on drug development that was also using data from the EvaluatePharma database noted that 3436 drugs were undergoing evaluation for the treatment of cancer.1 This considerable disparity may relate to the common perception that obesity is a lifestyle condition that could and should be modified via diet and exercise alone.17 Furthermore, the unmet need associated with conditions such as obesity is often regarded as less severe and may be less well understood than that of cancer, making the measurement of a therapeutic value difficult.16,18 These factors may create challenges in terms of reimbursement, because payers may be reluctant to reimburse for medicines that treat obesity as a result of the previously mentioned perceptions of the disease.

Without the certainty of patient access and adequate return on investment, manufacturers may regard the risk associated with the development of anti-obesity drugs as too high. As such, the incremental nature of the innovation cycle becomes halted in the weight-loss pharmaceutical industry. This is a devastating situation for patients who experience significant morbidity, financial burden, and early mortality related to obesity.

Rewarding Innovation Improves Health Outcomes Given the financial pressures to maintain government and private budgets, cost-effectiveness research is increasingly being used to inform decision-making regarding the reimbursement of new pharmaceuticals. Although such research activities certainly support the allocation of scarce healthcare resources, they are also

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known to limit access to innovative medicines, including those targeting cancer and obesity.10,19,20 In addition, the use of price controls such as cost-­ effectiveness reduces patient access to medications, which in turn reduces utilization and revenue, thereby taking money out of R&D initiatives within the innovation cycle. It has been suggested that if the United States adopted price controls similar to those implemented in the rest of the world (eg, the United Kingdom, Canada, Australia), manufacturers would substantially reduce drug research, and the flow of new medicines would decrease by approximately 75% over the long-term.21 Drug pricing and reimbursement mechanisms must therefore adequately reward innovation for medications in all therapeutic areas to speed patient access, increase global health, and strengthen the incentives for the pharmaceutical industry to further invest in R&D. This will ensure that innovation will continue to advance to further improve the health outcomes of society as a whole. ■ Author Disclosure Statement Ms Saadi reported no conflicts of interest; Mr White is an employee of Johnson & Johnson.

References

1. Long G, Works J; for the Analysis Group. Innovation in the biopharmaceutical pipeline: a multidimensional view. January 2013. www.analysisgroup.com/uploadedFiles/Publishing/Articles/ 2012_Innovation_in_the_Biopharmaceutical_Pipeline.pdf. Accessed March 15, 2014.

2. International Federation of Pharmaceutical Manufacturers & Associations. Incremental innovation: adapting to patient needs. January 2013. www.ifpma.org/fileadmin/content/Publication/2013/ IFPMA_Incremental_Innovation_Feb_2013_Low-Res.pdf. Accessed March 15, 2014.

3. DiMasi JA, Hansen RW, Grabowski HG. The price of innovation: new estimates of drug development costs. J Health Econ. 2003;22:151-185.

4. DiMasi JA, Grabowski HG. The cost of biopharmaceutical R&D: is biotech different? MDE Manage Decis Econ. 2007;28:469-479.

5. Mestre-Ferrandiz J, Sussex J, Towse A; for the Office of Health Economics. The R&D Cost of a New Medicine. London, UK: Office of Health Economics; 2012. http://ohematerials.org/NMECost/ index.html#/0. Accessed March 15, 2014.

6. Paul SM, Mytelka DS, Dunwiddie CT, et al. How to improve R&D productivity: the pharmaceutical industry’s grand challenge. Nat Rev Drug Discov. 2010;9:203-214.

7. BlueCross BlueShield of North Carolina. In the spotlight: the pharmaceutical industry. Updated November 17, 2011. www.bcbsnc.com/assets/hcr/pdfs/spotlight_pharmaceuticals.pdf. Accessed March 15, 2014.

8. Troyer JL, Krasnikov AV. The effect of price regulation on innovation in the pharmaceutical industry. J Appl Bus Res. 2002;18:87-96.

9. Hassett KA. Price controls and the evolution of pharmaceutical markets. July 2004. www.who. int/intellectualproperty/news/en/Submission-Hassett.pdf. Accessed October 2, 2014.

10. Cheema PK, Gavura S, Migus M, et al. International variability in the reimbursement of cancer drugs by publically funded drug programs. Curr Oncol. 2012;19:e165-e176.

11. Stewart BW, Wild CP, eds. World Cancer Report 2014. Lyon, France: International Agency for Research on Cancer; 2014.

12. US Food and Drug Administration. Center for Drug Evaluation and Research. Novel new drugs 2013 summary. January 2014. www.fda.gov/downloads/drugs/developmentapprovalprocess/drug innovation/ucm381803.pdf. Accessed March 15, 2014.

13. World Health Organization. Obesity and overweight. Fact sheet. Updated August 2014. www.who.int/mediacentre/factsheets/fs311/en/. Accessed August 29, 2014.

14. Flegal KM, Kit BK, Orpana H, Graubard BI. Association of all-cause mortality with overweight and obesity using standard body mass index categories: a systematic review and meta-analysis.

JAMA. 2013;309:71-82.

15. Begley S. The costs of obesity. Huffington Post. April 30, 2012. www.huffingtonpost.com/ 2012/04/30/obesity-costs-dollars-cents_n_1463763.html. Accessed March 15, 2014.

16. Nguyen N, Champion JK, Ponce J, et al. A review of unmet needs in obesity management. Obes Surg. 2012;22:956-966.

17. Puhl RM, Heuer CA. Obesity stigma: important considerations for public health. Am J Public Health. 2010;100:1019-1028.

18. Hollis A. An efficient reward system for pharmaceutical innovation. Working paper. January 2005. http://keionline.org/misc-docs/drugprizes.pdf. Accessed March 15, 2014.

19. Rawson NS; for the Fraser Institute. Access to new oncology drugs in Canada compared with the United States and Europe. Fraser Alert. July 2012. www.fraserinstitute.org/uploadedFiles/ fraser-ca/Content/research-news/research/publications/access-to-new-oncology-drugs-in-canada.pdf.

Accessed March 15, 2014.

20. Veerman JL, Barendregt JJ, Forster M, Vos T. Cost-effectiveness of pharmacotherapy to reduce obesity. PLoS One. 2011;6:E26051.

21. Filson D. The impacts of price controls on the performance of the pharmaceutical industry.

February 27, 2007. www.cmc.edu/fei/papers/2007-01.pdf. Accessed March 15, 2014.

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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

CLINICAL

ORIGINAL RESEARCH

Evaluation of Dabigatran for Appropriateness of Use and Bleeding Events in a Community Hospital Setting Anastasia L. Armbruster, PharmD, BCPS; Katie S. Buehler, PharmD, BCPS; Sun H. Min, PharmD; Margaret Riley, PharmD; Michael W. Daly, PharmD, MSCI, BCPS BACKGROUND: Warfarin has been the predominant anticoagulant for the prevention of stroke and

Stakeholder Perspective, systemic embolism in patients with nonvalvular atrial fibrillation (NVAF). Its disadvantages are well-known page 383 and include a narrow therapeutic index, drug interactions, and the need for frequent monitoring.

Am Health Drug Benefits.

2014;7(7):376-384 www.AHDBonline.com Received June 26, 2014 Accepted in final form August 14, 2014

Disclosures are at end of text

Dabigatran etexilate, a direct thrombin inhibitor, presents less complexity in prescribing and has emerged as an alternate therapy to warfarin. Although dabigatran does not require routine monitoring, concerns associated with its use include the lack of a reversal agent, complex dose adjustments, and limited guidance to the management of drug interactions.

OBJECTIVES: The goals of this study are to describe and to evaluate the use of dabigatran at a community hospital to identify areas for improvement in its prescribing.

METHODS: This retrospective chart review of patients at a community hospital in St Louis, MO, included patients who received at least 1 dose of dabigatran between December 2010 and June 2012. The appropriateness of dabigatran was evaluated based on recommendations approved by the US Food and Drug Administration for stroke prophylaxis in the setting of NVAF. The composite end point of bleeding included hospital readmission within 1 year of receiving at least 1 dose of dabigatran at the study institution secondary to bleeding, bleeding associated with a decrease in hemoglobin level by ≥2 g/dL or transfusion of ≥2 units of blood, or a notation of bleeding in the patient’s medical record.

RESULTS: Of the 458 patients included in the evaluation, 76 (16.6%) patients receiving dabigatran were using an inappropriate regimen of this drug, based on dose and frequency on the first day of therapy of dabigatran or the presence of valvular disease. Many patients (42.3%) received at least 1 dose of a concomitant parenteral anticoagulant. The composite end point for bleeding was reported in 66 (14.4%) patients, including 23 (5%) with confirmed gastrointestinal bleeding.

CONCLUSIONS: High-risk medications such as dabigatran require monitoring of prescribing habits to improve patient safety and outcomes. Various initiatives, such as pharmacist interventions, therapeutic interchanges, and obtaining appropriate patient parameters, can be implemented in the practice setting to ensure the appropriate use of oral anticoagulants and improved patient outcomes.

O

ral anticoagulation has changed drastically in the past 4 years with the US Food and Drug Administration (FDA) approval of 3 new agents—dabigatran, rivaroxaban, and apixaban. Warfarin has had a primary role in oral anticoagulation therapy for many decades. Although its efficacy and safety have been established, therapy with warfarin is associated with significant challenges, including the need for frequent Dr Armbruster is Assistant Professor of Pharmacy Practice, Department of Pharmacy Practice, St Louis College of Pharmacy, MO; Dr Buehler is Assistant Professor of Pharmacy Practice, St Louis College of Pharmacy, MO; Dr Min is Staff Pharmacist, Walgreens Co, Longview, TX; Dr Riley is PGY-1 Pharmacy Resident, Indiana University Health, Indianapolis; Dr Daly is Clinical Pharmacy Manager, St Louis University Hospital, MO.

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monitoring, drug interactions, a delayed time to onset, and a narrow therapeutic index.1,2 The challenges associated with warfarin not only affect its efficacy, but they also impact patient satisfaction. These concerns have contributed to the development of novel oral anticoagulants, beginning with dabigatran etexilate.

Dabigatran etexilate, a direct thrombin inhibitor, was approved by the FDA in October 2010 and is the first novel oral anticoagulant approved to reduce the risk for stroke in patients with nonvalvular atrial fibrillation (NVAF).3 Results from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study demonstrated the superiority of dabigatran 150 mg orally twice daily compared with warfarin for the prevention of stroke and systemic embolism in patients with NVAF.4 In that study, the rate of major bleeding was similar between the agents; however, dabigatran demonstrated a

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Evaluation of Dabigatran Use in a Community Hospital Setting

lower risk for intracranial hemorrhage, but with an increased risk for major gastrointestinal (GI) bleeding, compared with warfarin.4 A recent analysis performed by the FDA confirmed these findings.5,6 In this analysis, compared with warfar­ in, dabigatran demonstrated lower rates of ischemic stroke, intracranial hemorrhage, and death; however, dabigatran was associated with a significant increase in major GI bleeding.5,6 In April 2014, dabigatran received new FDA indications for the treatment of patients with deep-vein thrombosis (DVT) and pulmonary embolism (PE) and for the risk reduction of recurrent DVT and PE in previously treated patients.

Two studies, RE-COVER and RE-COVER II, compared dabigatran 150 mg twice daily with warfarin for the treatment of DVT and PE after 5 to 10 days of parenteral anticoagulation. Both studies demonstrated dabigatran’s noninferiority to warfarin.7,8 When the RE-COVER study was initiated, da­bigatran was the only agent approved by the FDA for the risk reduction of recurrent venous thromboembolism (VTE).

In November 2011, rivaroxaban, a factor Xa inhibitor, was the second novel oral anticoagulant to receive FDA approval to reduce the risk for stroke in patients with NVAF.9 Results from the ROCKET AF trial demonstrated the noninferiority of rivaroxaban to war­ farin for the first occurrence of stroke or systemic embolism.10 In November 2012, rivaroxaban received an additional indication for the treatment of and reduction in the risk for recurrent VTE. Two studies, EINSTEIN-DVT and EINSTEIN-PE, compared rivaroxaban (at an initial dose of 15 mg twice daily for 3 weeks, followed by 20 mg once daily) with enoxaparin 1 mg/kg twice daily for at least 5 days with warfarin and then continued with warfarin after the target international normalized ratio (INR) of 2.0 to 3.0 was reached.11,12 Both studies demonstrated the noninferiority of rivaroxaban to warfarin in time to first recurrent DVT or PE event.11,12 In December 2012, the factor Xa inhibitor apixaban was the newest novel oral anticoagulant to receive FDA approval to reduce the risk for stroke in patients with NVAF.13 The ARISTOTLE trial compared apixaban 5 mg twice daily (or 2.5 mg twice daily in select patients) with warfarin.14 Apixaban was superior to warfarin for the primary end point of reducing the risks for stroke and systemic embolism. Superiority to warfarin was primarily attributable to reductions in hemorrhagic stroke and ischemic stroke with hemorrhagic transformation compared with warfarin.14 In AVERROES, patients with NVAF who were not candidates for therapy with warfarin were randomized to treatment with apixaban 5 mg twice daily (or 2.5 mg twice daily in select patients) or to aspirin 81 mg to 324

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KEY POINTS Anticoagulation has changed drastically in the past 4 years in the United States with the FDA approval of novel oral anticoagulants, starting with dabigatran in 2010, rivaroxaban in 2011, and apixaban in 2012. ➤ These new anticoagulants present a safe alternative to warfarin for the prevention of stroke and systemic embolism in the setting of nonvalvular atrial fibrillation (NVAF). ➤ However, although anticoagulation has been simplified with the novel oral drugs, many safety issues must be considered when prescribing these agents. ➤ This retrospective chart review at a community hospital analyzed the appropriateness use of dabigatran, the first novel anticoagulant to receive FDA approval for the treatment of NVAF. ➤ Of the 458 patients included in this study, 76 patients were prescribed an inappropriate, mostly too high, dose of dabigatran. ➤ Although dabigatran is only approved for the treatment of NVAF, 13 patients had valvular disease. ➤ The majority of the patients were also receiving concomitant medications that are known to have drug interactions with dabigatran. ➤ These results indicate that high-risk medications require better monitoring of prescribing habits to improve patient safety and outcomes. ➤

mg once daily.15 The primary objective of the study was to determine if apixaban was superior to aspirin for preventing the outcomes of stroke or systemic embolism.

This trial was stopped early on the basis of a prespecified interim analysis that showed significant reductions in stroke and systemic embolism with apixaban compared with aspirin, but apixaban was associated with a modest increase in major bleeding.15 The current guidelines for the treatment of atrial fibrillation provide a class I recommendation for warfarin (level of evidence A) and dabigatran, rivaroxaban, and apixaban (level of evidence B) for the prevention of thromboembolism in patients with a CHA2DS2-VASc score of ≥2.16 Dabigatran provides an effective alternative therapy to warfarin. It offers a predictable pharmacokinetic profile, which eliminates the need for routine monitoring of serum drug concentrations. Approximately 80% of da­ bigatran is excreted renally and requires dose reductions for patients with reduced creatinine clearance.17 Although dabigatran addresses some of the challenges asso-

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Table 1 Dabigatran Dosing Recommendations Indication Creatinine clearance Reduction in risk for stroke and systemic embolism in NVAF

150 mg orally

>30 mL/min

twice daily

75 mg orally

15-30 mL/min <15 mL/min

or dialysis

Dose

twice daily

Dosing recommendation cannot be provided

30-50 mL/min +

75 mg orally

dronedarone or systemic ketoconazole

twice daily

15-30 mL/min +

dronedarone or systemic ketoconazole

Avoid use

NVAF indicates nonvalvular atrial fibrillation.

Used with permission from Pradaxa (dabigatran etexilate mesylate) capsules [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; September 2014.

Table 2 Drugs Interacting with Dabigatran Pharmacodynamic interactions LMWH (enoxaparin, dalteparin)

Prasugrel

Fondaparinux

Ticagrelor

Heparin

Aspirin

Clopidogrel

NSAIDs (ibuprofen, naproxen, diclofenac, ketorolac)

Pharmacokinetic interactions P-gp/ABCB1 inducers (decrease concentration)

P-gp/ABCB1 inhibitors (increase concentration) Amiodarone

Nicardipine

Carbamazepine

Atorvastatin

Progesterone

Dexamethasone

Carvedilol

Propranolol

Prazosin

Quinidine

Rifampin

Cyclosporine

Quinine

St Johnâ&#x20AC;&#x2122;s wort

Dipyridamole

Ranolazine

Trazodone

Dronedarone

Ritonavir

Erythromycin

Tacrolimus

Itraconazole

Tamoxifen

Ketoconazole (systemic)

Verapamil

Clarithromycin

LMWH indicates low-molecular-weight heparin; NSAIDs, nonsteroidal anti-inflammatory drugs; P-gp, P-glycoprotein.

Source: Lexicomp. www.lexi.com (access requires fee payment).

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ciated with warfarin, there are remaining issues regarding the use of dabigatran.

Warfarin interacts with numerous medications, disease states, and a variety of foods containing vitamin K; however, there is a great deal of clinical experience and resources available to effectively manage many of war­ farinâ&#x20AC;&#x2122;s interactions.1 Unlike warfarin, dabigatran is not metabolized by cytochrome P450 enzymes and has fewer drug interactions. Although several drug interactions with dabigatran and P-glycoprotein inducers and inhibitors have been identified, little guidance has been provided on how to address them in practice.18 Additional concerns surrounding dabigatran include the lack of a reversal agent and the lack of availability of laboratory testing to determine its degree of anticoagulation activity. Dabigatran prolongs markers of coagulation, such as the activated partial thromboplastin time (aPTT) and ecarin clotting time, and may potentially impact INR values. The aPTT can only provide an approximation of the anticoagulation effect of dabigatran, and the INR is relatively insensitive to the degree of anticoagulation. The ecarin clotting time is a more specific parameter to determine the effect of anticoagulation19; however, most laboratories are not adequately equipped to perform the laboratory test. Without laboratory parameters to guide dosing adjustments, it is unclear how to balance the drug interactions that have been identified to potentially increase or decrease dabigatran serum concentrations. The lack of monitoring also makes it difficult to manage special populations that typically require dosage adjustments (eg, the elderly, obese patients, underweight patients, and those with renal dysfunction).

Since dabigatran became the first oral anticoagulant to be introduced to the US market, and the first to be included on hospital formularies, there has been a dramatic shift in the approach to anticoagulation. Laboratory markers of anticoagulation effect are no longer reliable, drug interactions require significantly less dose adjustments, and renal function continually needs to be addressed.20 The purpose of this study was to evaluate the use of dabigatran at a community hospital between December 2010 and June 2012 and to identify prescribing areas that can be improved to ensure appropriate use and patient outcomes.

Methods Participants and Design This retrospective chart review was performed at a 489-bed community hospital in St Louis, MO. Institutional Review Board approval was obtained before the start of data collection for the study. Data for patients who received at least 1 dose of dabigatran between December 2010 and May 2012 were evaluated. Patients

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without available data on serum creatinine, height, or weight were excluded from the evaluation.

Table 3 Patient Demographics

Data Collection A total of 533 eligible patients were identified from the pharmacy information system. The baseline demographic information was collected, including age, sex, race, length of stay, height, weight, serum creatinine, and creatinine clearance at the initiation of dabigatran therapy. The appropriateness of the initial regimen ordered was assessed based on the presence of valvular disease, dose, and frequency (Table 1).3 The concomitant use of antithrombotic therapies as well as P-glycoprotein inhibitors was documented to determine the potential for any association with increased risk for bleeding (Table 2). Patients were screened for readmission within 1 year to a system hospital secondary to any type of bleeding. Other bleeding parameters assessed included decreased hemoglobin level by ≥2 g/dL, transfusion of at least 2 units of blood, or notation of bleeding in the medical record; the composite end point of bleeding included these 4 criteria.

Although patients might have met more than 1 bleeding criterion, each patient was only included once in the composite bleeding analysis, unless therapy with dabigatran was reinitiated after the initial bleeding event.

Demographics

Patients (N = 458)

Age, yrs, mean (± SD) Male sex, N (%)

73 (± 13.1) 247 (54)

Race Caucasian, N (%)

419 (91.5)

Black, N (%)

18 (3.9)

Native American, N (%)

2 (0.4)

Other, N (%)

5 (1.1)

Unknown, N (%)

14 (3.1)

Mean length of hospital stay, days (± SD) Mean BMI, kg/m ± SD (median) 2

Mean weight, kg, mean ± SD (median)

4.9 (± 5.3) 29.9 ± 7.32 (29) 88.5 ± 26 (85)

Weight <50 kg, N (%)

12 (2.6)

>100 kg, N (%)

124 (27.1)

AST 3 × upper limit of normal, N (%)

7 (1.5)

ALT 3 × upper limit of normal, N (%)

8 (1.7)

Past medical history of liver disease, N (%)

12 (2.6)

Indication for dabigatran

Statistical Analysis The parameters that were evaluated in this analysis based on the data collected from the patients’ electronic medical records included demographic data, clinical indication for dabigatran use, concomitant medication use that could potentially interact with dabigatran (all medications listed in Table 2 plus warfarin), and bleeding.

Descriptive statistics were used to characterize the prescribing patterns of dabigatran. Differences in baseline demographics and concomitant medications between patients who experienced a bleeding event and those who did not were analyzed using the Student’s t-test for continuous data, the chi-square test, or the Fisher’s exact test for categorical data.

Atrial fibrillation, N (%)

426 (93)

VTE, N (%)

18 (3.9)

Aortic thrombus, N (%)

3 (0.65)

Pulmonary embolism, N (%)a

6 (1.3)

Cerebrovascular accident, N (%)

1 (0.22)

Renal artery infarct, N (%)

1 (0.22)

Femoral-popliteal bypass, N (%)

1 (0.22)

Orthopedic surgery prophylaxis (total knee replacement), N (%)

1 (0.22)

Factor V Leiden, N (%)

1 (0.22)

Results Of the 533 eligible patients identified for the study, 75 were excluded because of the inability to assess their renal function (ie, they had no record of serum creatinine level, height, or weight). Baseline demographics were collected on the 458 patients included in the analysis (Table 3). Of note, 12 (2.6%) patients weighed <50 kg and 124 (27.1%) patients weighed >100 kg.

The indications for patients’ dabigatran use are listed in Table 3. During the specified study time frame, dabigatran had not yet been approved for the treatment of or

Warfarin home medication, N (%)

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Outpatient prescribing Dabigatran home medication, N (%) Dabigatran continued at discharge, N (%)

208 (45.4) 32 (7) 397 (86.7)

Only 1 patient received 5-10 days of parenteral anticoagulant overlap.

ALT indicates alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; SD, standard deviation; VTE, venous thromboembolism. a

the reduction of risk for recurrent VTE. Therefore, those indications were considered off-label for this analysis.

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ssessment of Initial Dabigatran Regimen Table 4 A Appropriateness Dabigatran regimen Patients, N (%) Inappropriate regimen

76 (16.6)

Home medication inappropriately continued

41 (9)

Medication inappropriately initiated in hospital

35 (7.6)

Contraindicated due to renal function

8 (1.7)

Inappropriate dose

66 (14.4)

Inappropriate frequency

13 (2.8)

Bioprosthetic valve

12 (2.6)

Moderate or severe mitral stenosis

1 (0.2)

Of note, although dabigatran is only approved for the treatment of NVAF, 13 patients were deemed to have valvular disease, as defined by the presence of moderate or severe mitral stenosis on echocardiogram, or had a prosthetic heart valve. Taking these factors into consideration, along with creatinine clearance, 76 (16.6%) patients were treated with inappropriate regimens (Table 4).

Of the patients with an inappropriate dose of dabigatran, 50 were receiving too high of a dose based on their renal function. Nearly 8% of the patients had an inappropriate dabigatran regimen continued at home that had been initiated on admission to the hospital. Although there is no FDA-approved regimen that includes once-daily dosing of dabigatran, 13 patients received once-daily dosing.

Patients receiving dabigatran for an off-label indication were not evaluated in this study for appropriateness of use. Despite not having an FDA-approved indication for these conditions at the time this review was conducted, 18 (3.9%) patients received dabigatran treatment for VTE and 6 (1.3%) patients received dabigatran for PE. Furthermore, based on the RE-COVER and RE-COVER II trials and FDA-approved indication, patients should receive 5 to 10 days of a parenteral anticoagulant before the initiation of dabigatran.7,8 However, only 1 of the 6 patients receiving treatment for PE was appropriately treated with parenteral anticoagulation before initiating dabigatran therapy. Other off-label indications are listed in Table 3.

Table 2 includes all the potential drug interactions with dabigatran that were documented in this review.

Many patients were receiving at least 1 medication interacting with dabigatran; 204 (44.5%) patients were receiving at least 1 P-glycoprotein inhibitor, and 13 (2.8%) patients were receiving at least 1 P-glycoprotein inducer (Table 5). In addition, many patients received concurrent antithrombotic therapy while receiving ­dabigatran (Table 5).

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se of Concomitant Medications in Patients Table 5 U Receiving Dabigatran Patients, N Concomitant medication (%) Warfarin

9 (1.9)

Enoxaparin

120 (26.2)

Dalteparin

0

Fondaparinux

1 (0.2)

Heparin

73 (15.9)

Clopidogrel

44 (9.6)

Prasugrel

0

Ticagrelor

0

Aspirin 81 mg

181 (39.5)

162 mg

90 (19.7)

325 mg

2 (0.44)

Triple therapy (clopidogrel + aspirin)

35 (7.6)

Ibuprofen

6 (1.3)

Naproxen

0

Diclofenac

0

Ketorolac

1 (0.2)

Drug with interactions Amiodarone

81 (17.7)

Atorvastatin

41 (9)

Carvedilol

21 (4.6)

Dronedarone

15 (3.3)

Propranolol

1 (0.2)

Ranolazine

2 (0.4)

Verapamil

2 (0.4)

Trazodone

12 (2.6)

2 drug interactions

41 (9)

3 drug interactions

2 (0.4)

Overall, 42.3% of patients were administered at least 1 dose of heparin or enoxaparin concomitantly with dabigatran. For patients receiving concomitant heparin, the average number of doses administered was 7. Antiplatelet therapy was used in the majority of patients, and 60% of patients received a daily aspirin. Of note, 7.6% of the patients received “triple therapy” with aspirin, clopid­ ogrel, and dabigatran.

For the composite end point of bleeding, 66 (14.4%) unique patients experienced at least 1 bleeding event (Table 6). The most common confirmed source of bleed-

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ing was GI, which is consistent with data from the RE-LY trial.4 Patients who had a bleeding event were significantly more likely than patients who did not have bleeding to have an INR value of >1.1 (40.9% vs 22.7%, respectively; P = .002), a lower body weight (82.7 kg vs 89.6 kg; P = .016), and a longer length of stay (174 hours vs 108.3 hours; P <.005).

The length of hospital stay was most likely increased as a result of the treatment of active bleeding, or it could be attributed to more medically complex patients with comorbid conditions that are associated with an increased risk for bleeding. Other factors hypothesized to increase the risk for bleeding were also examined, including appropriate dosing in renal disease, drug interactions, concomitant anticoagulant use, and low body weight.

Those patients not receiving appropriate dosing of da­ bigatran for renal disease were not more likely to experience bleeding (16.7% patients were receiving excessive doses; P = .208), as observed in this analysis.

Discussion The third goal of the Hospital National Patient Safety Goals relates to the safe use of medications in the hospital.21 Reducing harm from anticoagulants is specifically highlighted within this goal.21 Although novel oral anticoagulants are not specifically mentioned, the complexity of anticoagulant dosing can be extrapolated to these agents. Many hospitals have well-established monitoring systems for patients receiving warfarin, including requirements for measuring daily INR values. Although there are no daily laboratory tests available to monitor these agents, there are important parameters to consider when initiating or continuing these drugs in the hospital.

To ensure the appropriate dosing of dabigatran, current, patient-specific data to calculate creatinine clearance22 are necessary.

In this analysis, 75 patients were excluded as a result of a lack of complete data to calculate creatinine clearance to assess the appropriateness of dabigatran dosing.

This illustrates one challenge pharmacists and other healthcare professionals may encounter when assessing the safety of dabigatran dosing. The dosing recommendations for dabigatran in the setting of renal disease are fairly complex and must take into consideration the indication and the concomitant use of P-glycoprotein inhibitors, such as dronedarone.

A 2013 article demonstrated the positive impact of a pharmacist-managed anticoagulation service.23 Physicians placed an electronic order delegating authority to the pharmacists for the management of dabigatran while the patient is in the hospital. During the review period, 46% of the patients required pharmacist intervention.23 This

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Table 6 Bleeding Events in Patients Receiving Dabigatran Bleeding

Patients/events, N (%)

Readmission for bleeding within 1 year

19 (4.1)

Bleeding noted during admission resulting in discontinuation

11 (2.4)

≥2 g/dL decrease in hemoglobin

38 (8.3)

Transfusion ≥2 units PRBC

18 (3.9)

Unique patients experiencing any bleeding

66 (14.4)

Confirmed bleeding source: GI

23 (5)

GI indicates gastrointestinal; PRBC, packed red blood cells.

illustrates one method to improve the safe use of anticoagulation in an inpatient setting. Another frequently used method is therapeutic interchange. These therapeutic interchanges are often approved by the institution’s Pharmacy & Therapeutics Committee. Such policies would allow pharmacists to adjust the dosing of anticoagulants without contacting a physician for a verbal order.

Anticoagulation has changed drastically in the United States in the past 4 years, starting with the approval of dabigatran in 2010, rivaroxaban in 2011, and apixaban in 2012. Ensuring that agents are prescribed based on their indications with supporting efficacy and safety data is another important factor. Novel oral anticoagulants are often approved by the FDA for a single indication and later receive added indication approvals as the drug is studied in additional clinical trials. It is important that prescribers and pharmacists are aware of all current indications or utilize supporting clinical trials when prescribing novel oral anticoagulants.

During the time of this analysis, the treatment of VTE was not an approved indication for dabigatran, although, as is shown in this analysis, it was prescribed for this indication. Although dabigatran can now be used for the treatment of VTE, it requires an initial 5 to 10 days of parenteral anticoagulation, which was not implemented in routine practice at this institution. One example of the risk of using dabigatran off-label is the Randomized, Phase II Study to Evaluate the Safety and Pharmacokinetics of Oral Dabigatran Etexilate in Patients After Heart Valve Replacement (RE-ALIGN), which was terminated early because of an excess number of thromboembolic and bleeding events in the cohort receiving dabigatran.24 The use of dabigatran in the patients with mechanical heart valves (before the results of this study were available) could have caused significant harm to patients.

The complexity of anticoagulation management increases because many hospitals have more than 1 novel

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oral anticoagulant on their formulary. Each agent varies in renal adjustment requirements, with rivaroxaban dosing varying even between indications. Apixaban recently received FDA approval for use in patients receiving hemodialysis; however, this was not part of the drug’s initial approval.13 It can be difficult to not only be aware of evolving indications, but to provide appropriate dosing recommendations as well.

Another prescribing concern highlighted by this analysis is the use of concomitant parenteral anticoagulation. DVT prophylaxis is important for the reduction of morbidity and mortality in hospitalized patients. However, it is not necessary to use parenteral anticoagulants in addition to novel oral anticoagulants because of the quick onset of an anticoagulant effect. This is an impor­ tant screening step when initiating a novel oral anticoagulant or when continuing home medications once patients are admitted to the hospital. Alerts incorporated into physician order entry or during pharmacy verification represent 1 step that could help to prevent concomitant anticoagulant use.

There are many situations during a hospitalization that can further increase a patient’s bleeding risk.

Acute renal failure can increase drug concentrations.

Many patients in this analysis were receiving dabigatran that was continued from home. Although the dose may be appropriate in the outpatient setting, it should be reassessed when patients present to the hospital.

Patients also frequently undergo procedures while admitted to the hospital. Each novel oral anticoagulant has unique recommendations to consider when discontinuing therapy because of a medical procedure. Although it may appear anticoagulation has been simplified by avoiding the complexities of warfarin, there are still many factors to consider for the safe use of novel oral anticoagulants.

Finally, it is also important to note that there is a significant increase in drug costs to hospitals, as well as to patients, as a result of the introduction of the novel oral anticoagulants. However, these costs may be offset by the savings in costs of laboratory monitoring, as well as the time saved by clinicians who monitor and adjust warfarin dosing based on daily INR values. The relative cost-effectiveness of dabigatran compared with warfarin is supported by a recent economic analysis evaluating data from the RE-LY trial.25

Limitations There are several limitations to this study. This is a retrospective chart review that only focuses on the use of dabigatran at a single community hospital. Dabigatran was the first novel oral anticoagulant to be introduced to hospital formulary and was in use for about 1 year before

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rivaroxaban was added to the formulary. Characterizing prescribing patterns and evaluating the appropriateness of rivaroxaban are currently being conducted at the same institution; rivaroxaban was not included in this analysis because of a limited number of patients at the time of the Institutional Review Board’s approval of this research.

The retrospective nature of this study allows for error in data abstraction from the patients’ charts. Because the patients were not prospectively being observed during their hospital stay, documentation by nurses and physicians was heavily relied on. This leaves room for bias in the interpretation of medical records, as well as allows for error in documentation at the time of patient hospitalization. Some patient data (eg, serum creatinine, height, weight) and a complete medical history for each patient were unable to be obtained.

In addition, the retrospective nature of the study makes it difficult to use similar bleeding criteria as a prospective analysis, especially when assessing decreases in hemoglobin and identifying sources of bleeding or rationale for drug discontinuation.

It should also be noted that 91.5% of the patients included in this study were Caucasian, which may limit the validity of these data for other institutions.

Conclusions The findings in this retrospective review highlight the difficulties of using dabigatran in patients admitted to the hospital. Potential future studies should include the continued review of dabigatran, as well as rivaroxaban and apixaban, once enough data are available to characterize prescribing patterns. When utilized appropriately, dabigatran has demonstrated superiority over warfarin for the prevention of systemic stroke and embolism in the setting of NVAF without having to monitor serum drug concentrations. However, with improved efficacy comes increased medication cost, various dosing regimens, and new challenges with maintaining safety in a hospital resulting from acute situations, such as changes in renal function, the initiation of novel medications, and the use of medical procedures.

Although dabigatran was the only novel oral anticoagulant included in this evaluation, similar process improvement plans can be extrapolated to rivaroxaban and apixaban, such as therapeutic interchanges for renal function, ensuring that appropriate patient data are collected at the time of admission, and physician education about new agents and indications as they are approved by the FDA. As the area of anticoagulation continues to evolve, it is imperative that hospitals institute monitoring systems to ensure the appropriate use of these highrisk medications. Although methods are well-established for safely monitoring warfarin, newer agents (eg, dabiga-

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tran) also pose a safety risk to patients and thus require careful monitoring by competent clinicians. ■ Acknowledgments JNT, TC, KMS, HCL, BKS, and PSC were responsible for writing the manuscript. JNT and TC validated the data. JNT is the guarantor of the quality and validity of this report. PSC provided clinical consultation.

Funding Source This study was supported by a Faculty Research Incentive Fund Grant from St Louis College of Pharmacy.

Author Disclosure Statement Dr Buehler participated in Pfizer’s Midwest Atrial Fibrillation Advisory Board meeting; Dr Armbruster, Dr Min, Dr Riley, and Dr Daly reported no conflicts of interest.

References

1. Holbrook AM, Pereira JA, Labiris R, et al. Systematic overview of warfarin and its drug and food interactions. Arch Intern Med. 2005;165:1095-1106.

2. Gage BF, Fihn SD, White RH. Management and dosing of warfarin therapy. Am J Med. 2000;109:481-488.

3. Pradaxa (dabigatran etexilate mesylate) capsules [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; September 2014.

4. Connolly SJ, Ezekowitz MD, Yusuf S, et al; for the RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139-1151. Erratum in: N Engl J Med. 2010;363:1875-1876.

5. US Food and Drug Administration. FDA drug safety communication: update on the risk for serious bleeding events with the anticoagulant Pradaxa (dabigatran).

November 2, 2012. Updated August 14, 2014. www.fda.gov/Drugs/DrugSafety/ ucm326580.htm. Accessed June 30, 2014.

6. US Food and Drug Administration. FDA Drug Safety Communication: FDA study of Medicare patients finds risks lower for stroke and death but higher for gastrointestinal bleeding with Pradaxa (dabigatran) compared to warfarin. May 13, 2014. www.fda.gov/Drugs/DrugSafety/ucm396470.htm. Accessed September 19, 2014.

7. Schulman S, Kearon C, Kakkar AK, et al; for the RE-COVER Study Group.

Dabigatran versus warfarin in the treatment of acute venous thromboembolism.

N Engl J Med. 2009;361:2342-2352.

8. Schulman S, Kakkar AK, Goldhaber SZ, et al; for the RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014;129:764-772.

9. Xarelto (rivaroxaban) tablets [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc; March 2014.

10. Patel MR, Mahaffey KW, Garg J, et al; for the ROCKET AF Investigators.

Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. ­ 2011;365:883-891.

11. Bauersachs R, Berkowitz SD, Brenner B, et al; for the EINSTEIN Investigators.

Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363:2499-2510.

12. Büller HR, Prins MH, Lensing AW, et al; for the EINSTEIN-PE Investigators.

Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366:1287-1297.

13. Eliquis (apixaban) tablets [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; August 2014.

14. Granger CB, Alexander JH, McMurray JJ, et al; for the ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation.

N Engl J Med. 2011;365:981-992.

15. Connolly SJ, Eikelboom J, Joyner C, et al; for the AVERROES Steering Committee and Investigators. Apixaban in patients with atrial fibrillation. N Engl J Med. 2011;364:806-817.

16. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients with Atrial Fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2014 Mar 28 [Epub ahead of print].

17. Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet. 2008;47:285-295.

18. Wittkowsky AK. Novel oral anticoagulants and their role in clinical practice.

Pharmacotherapy. 2011;31:1175-1191.

19. Gosselin RC, Dwyre DM, Dager WE. Measuring dabigatran concentrations using a chromogenic ecarin clotting time assay. Ann Pharmacother. 2013;47:1635-1640.

20. Chin PKL, Vella-Brincat JWA, Walker SL, et al. Dosing of dabigatran etexilate in relation to renal function and drug interactions at a tertiary hospital. Int Med J. 2013;43:778-783.

21. The Joint Commission. National Patient Safety Goals effective January 1, 2014: hospital accreditation program. 2013. www.jointcommission.org/assets/1/6/HAP_ NPSG_Chapter_2014.pdf. Accessed June 18, 2014.

22. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31-41.

23. Tedders KM, Lucey MF, Edwin SB. Evaluation of pharmacist-managed dabigatran in an inpatient setting. Ann Pharmacother. 2013;47:1649-1653.

24. Eikelboom JW, Connolly SJ, Brueckmann M, et al; for the RE-ALIGN Investigators. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med. 2013;369:1206-1214.

25. Kamel H, Johnston SC, Easton JD, Kim AS. Cost-effectiveness of dabigatran compared with warfarin for stroke prevention in patients with atrial fibrillation and prior stroke or transient ischemic attack. Stroke. 2012;43:881-883.

STAKEHOLDER PERSPECTIVE Accurate Prescribing Key to Safe Use of Anticoagulants in Patients with Nonvalvular Atrial Fibrillation

By Raymond L. Singer, MD, MMM, CPE Chief, Division of Cardiothoracic Surgery, Vice Chair, Quality and Patient Safety, Department of Surgery, Lehigh Valley Health Network

Atrial fibrillation (AF) is the most common arrhythmia in patients aged ≥65 years and is associated with a significant risk for thromboembolic stroke. Nonvalvular AF (NVAF) imposes a 5-fold increased risk for stroke compared with the overall population.1 PATIENTS: Warfarin is the most frequently prescribed antithrombotic medication for patients with

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NVAF. Warfarin is inexpensive and is well-tolerated; however, its use is associated with an increased risk for bleeding complications and must be constantly monitored. Moreover, patients taking warfarin must watch their diets, because many foods and medications interact with warfarin, which can impact its anticoagulation effect.

In the past few years, novel oral anticoagulants have Continued next page

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STAKEHOLDER PERSPECTIVE Continued been approved by the US Food and Drug Administration (FDA) as safe and effective alternatives to warfarin, including dabigatran, rivaroxaban, and apixaban. These drugs are direct thrombin and/or factor Xa inhibitors that do not require anticoagulation monitoring—as measured by prothrombin time and reported as an international normalized ratio—and are not associated with food or medication interactions.2 Early randomized, double-blind clinical trials suggest that these drugs may be more effective than warfarin for the prevention of stroke in patients with NVAF.3,4 In their retrospective claims analysis, Armbruster and colleagues discuss the use of dabigatran in 1 hospital setting.5 Of the 458 patients included in this analysis, 76 patients were prescribed dabigatran inappropriately, and many patients were receiving concomitant medications that interact with this anticoagulant, placing patients at unnecessary risk for potentially serious adverse events, and/or adversely affecting dabigatran’s efficacy.5 Although the newer oral anticoagulants are easier to manage, they are also substantially more expensive than warfarin and may not be covered by the patient’s insurance plan, which is a particular concern for patients with Medicare or Medicaid coverage. In addition, although the half-life of these drugs can be as little as 5 to 14 hours, patients need to understand that there are no antidotes for these drugs. Patients may be apprehensive about taking a drug that cannot be reversed even in an emergency setting. Patients must weigh the benefits and risks of antithrombotic medication for the treatment of NVAF. PAYERS: Although the newer agents are easier to prescribe and to monitor, the costs of these drugs remain high. Payers will need to balance the cost of these drugs with their safety profiles, efficacy, cost of monitoring, and most of all, the evidence for clinical superiority. Payers, too, must weigh the benefits and risks of antithrombotic medication for the treatment of NVAF in particular patients, in addition to cost.

PROVIDERS: As is clear from this present article

by Armbruster and colleagues, providers, including pharmacists who monitor patients using anticoagulants, must ensure that patients are properly receiving these medications according to treatment guidelines and FDA drug labeling information.5 They must care-

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fully ensure that these anticoagulants do not interact with other drugs their patients are using, and that the dose is prescribed correctly.5 Furthermore, although risk stratification schemes, such as CHADS2, CHA2DS2-VASc, and HAS-BLED, are beyond the scope of this perspective, they represent scoring guidelines that have been validated in many patients with NVAF. Based on these scores, a patient can be stratified as low, intermediate, or high risk for a thromboembolic event, and therefore be properly evaluated for the initiation of antithrombotic medication.1,6 In patients aged ≥65 years, it would be rare to have a CHADS2 or CHA2DS2-VASc of zero, and therefore the majority of patients will be treated. Furthermore, studies indicate that all women aged ≥65 years with NVAF should be treated, even with a score of zero, because of their observed increased risk for stroke.1,6 To reduce the risk for bleeding, providers must offer proper education and timely, consistent, and accurate monitoring to patients who are receiving antithrombotic medications. The education should include the importance of drug compliance, dietary restrictions, medication interactions, and lifestyle changes. Many thromboembolic and bleeding complications occur as a result of inconsistent monitoring and poor communication.

Because of the simplicity of monitoring, many providers prefer to use the newer oral antithrombotic agents as first-line therapy for patients with NVAF. However, cost can be an issue with these newer agents for patients whose insurance does not cover these medications. The lack of an antidote, too, may be a concern for the patient, and should be carefully considered by the provider. ■ 1. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2014 Mar 28.

[Epub ahead of print].

2. Spinler SA, Shafir V. New oral anticoagulants for atrial fibrillation. Circulation.

2012;126:133-137.

3. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139-1151.

4. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883-891.

5. Armbruster A, Buehler KS, Min SH. Evaluation of dabigatran for appropriateness of use and bleeding events in a community hospital setting. Am Health Drug Benefits.

2014;7:376-384.

6. Heidbuchel H, Verhamme P, Alings M, et al. EHRA practical guide on the use of new oral anticoagulants in patients wih non-valvular atrial fibrillation: executive summary. Eur Heart J. 2013;34:2094-2106.

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CLINICAL CLINICAL

ORIGINAL RESEARCH

Patient Preferences and Treatment Adherence Among Women Diagnosed with Metastatic Breast Cancer Marco daCosta DiBonaventura, PhD; Ronda Copher, PhD; Enrique Basurto, MSc; Claudio Faria, PharmD, MPH; Rose Lorenzo, BA Stakeholder Perspective, page 396

Am Health Drug Benefits.

2014;7(7):386-396 www.AHDBonline.com Received July 7, 2014 Accepted in final form September 16, 2014

Disclosures are at end of text

B

BACKGROUND: Given the various profiles (eg, oral vs intravenous administration, risk of hot flashes vs fatigue) of treatment options (eg, endocrine therapy, chemotherapy) for metastatic breast cancer (mBC), how patients value these attributes of their medications has implications on making treatment decisions and on adherence.

OBJECTIVES: To understand how patients trade off medication side effects with improved effectiveness and/or quality of life, to provide estimates of nonadherence among women with mBC, and to quantify the association of medication nonadherence with health outcomes.

METHODS: The study was a cross-sectional, Internet-based survey of 181 women diagnosed with mBC who were recruited from cancer-specific online panels (response rate, 7%). Treatment information, demographics, nonadherent behaviors, and quality of life assessed by the Functional Assessment of Cancer Therapy-Breast (FACT-B) were collected in the survey, and each respondent completed a choice-based conjoint exercise to assess patient preferences. The patients’ preferences were analyzed using hierarchical Bayesian logistic regression models, and the association between the number of nonadherent behaviors and the health outcomes was analyzed using general linear models.

RESULTS: The mean age of the patient sample was 52.2 years (standard deviation, ±9.1), with 93.9% of participants being non-Hispanic white. Results from the conjoint model indicated that effectiveness (overall survival) was of primary importance to patients, followed by side effects—notably alopecia, fatigue, neutropenia, motor neuropathy, and nausea/vomiting—and finally, dosing regimen. In all, 34.8% of survey respondents either discontinued their treatment or were nonadherent to their treatment regimen. Among those who have ever used oral chemotherapy (N = 95; 52.5%) and those currently using oral chemotherapy (N = 44; 24.3%), the number of nonadherent behaviors was significantly associated with a decrease in functional well-being (b [unstandardized regression coefficient] = –2.01 for patients who had ever used a targeted therapy and b = –3.14 for current users of a targeted therapy), FACT-General total score (b = –4.30 and b = –7.37, respectively), FACT-B total score (b = –3.93 and b = –6.11, respectively), and FACT trial outcome index (b = –5.22 and b = –8.63, respectively; all P <.05).

CONCLUSIONS: Patients were willing to accept substantial additional risks from side effects for gains in overall survival. Approximately 33% of women with mBC reported engaging in nonadherent behaviors.

Because forgetfulness and adverse events were among the most frequent reasons for nonadherence, these results suggest that less complex treatment regimens, as well as regimens with less toxic profiles, may be associated with improvements in adherence and, subsequently, could correspond to perceptible patient benefits.

reast cancer is the most common cancer diagnosed among women in the United States, with an estimated 232,000 new cases diagnosed annually.1 It is

Dr DiBonaventura is Vice President, Health Outcomes, Health Outcomes Practice, Kantar Health, New York, NY; Dr Copher is Associate Director, Health Economics and Outcomes Research, Eisai Inc, Woodcliff Lake, NJ; Mr Basurto is Senior Associate Methodologist, Kantar Health, New York, NY; Dr Faria is Director, Health Economics and Outcomes Research, Eisai Inc, Woodcliff Lake, NJ; and Ms Lorenzo is Senior Director of Research, Kantar Health, New York, NY.

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also the second most deadly cancer, accounting for nearly 40,000 deaths annually.1 The 5-year survival rates for early-stage breast cancer is between 84% for regional disease (ie, contained within the breast and lymph nodes) and 99% for localized disease (ie, contained within the breast); the survival rate drops to 24% in more advanced stages of the disease.2 Metastatic breast cancer (mBC) is defined as breast cancer that has spread to other parts of the body. Whereas less than 10% of women are initially diagnosed with mBC, approximately 33% of women who are treated for early-stage disease will progress to mBC.2,3 The majority of breast cancer metastases affect the lymph nodes, followed by bone, liver, and lung.4,5

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At present, mBC is incurable, and treatment is focused on arresting the disease and extending patient survival, as well as promoting quality of life (QOL) and ensuring adequate symptom management.3,4 Treatment strategies may include endocrine therapy (eg, exemestane); targeted therapies, such as anti-HER2 agents (eg, trastuzumab); and chemotherapy (eg, capecitabine).6 As a result of the currently incurable nature of mBC and the side-effect profile associated with various forms of therapy, investigators have explored the potential role of patient preferences in decision-making regarding their treatment goals and desired outcomes.7-11 For example, aggressive treatment may maximize the duration of survival but may also be associated with significant and burdensome side effects that impair QOL.3,4 Using the responses of 102 patients with breast cancer, Beusterien and colleagues recently revealed distinct preferences across side-effect profiles and a willingness to undergo more difficult treatment regimens to reduce the risk of more severe symptoms.7 Moreover, another study of 121 patients with breast cancer demonstrated the importance of a relatively minor survival benefit (as little as 3 months) for the perceived value of chemotherapy among patients with breast cancer, despite an increased risk for treatment toxicities.8 Further studies have shown a willingness of patients to trade a minor increase in disease recurrence risk for more convenient treatment regimens,9 as well as examining patient preferences for follow-up care10 and the ability for preferences to predict the eventual use of chemotherapy.11 To our knowledge, no study to date has examined patient preferences using a conjoint method in women with mBC. In part, this may be because it is difficult to recruit this patient population for research survey purposes. Several studies have been conducted that have focused on patients diagnosed with early-stage breast cancer.12,13 McQuellon and colleagues surveyed women diagnosed with early-stage disease to assess their preferences for the hypothetical treatment of mBC.14 Although there was a wide range of preference profiles among the women who were surveyed, they were once again consistently willing to trade the risk of major side effects and toxicities for a modest survival benefit.14 However, because that study was initiated nearly 20 years ago, treatment advances since the time of that study were not included in that analysis.

The primary objective of the current study is to provide an examination of contemporary treatments and to provide data on the treatment preferences of women with mBC to understand how these patients trade off side effects with increases in effectiveness and/or QOL. Patient preferences may have implications not only for treatment decision-making but also potentially for

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KEY POINTS Metastatic breast cancer (mBC) involves various drug regimens with different efficacy and side-effect profiles that may affect medication adherence. ➤ This is the first study to examine patient preferences in women with mBC. ➤ Of the 181 women with mBC surveyed, approximately 33% were nonadherent to their treatment regimen. ➤ Patients receiving hormone therapy reported the greatest nonadherence, followed by patients receiving an oral chemotherapeutic agent. ➤ Across all treatment modalities, forgetfulness (41.3%) and intolerance of side effects (36.5%) were the most common reasons for nonadherence. ➤ Although it is more convenient, women receiving oral chemotherapy were more likely to have significant declines in their health status. ➤ Patients are willing to trade substantial side-effect risks for gains in overall survival. ➤ The most important attributes of treatments were effectiveness and side effects; cost-related concerns were listed as the least important. ➤ The survey suggests that less complex and less toxic regimens may improve medication adherence and, ultimately, health outcomes. ➤

treatment adherence and follow-up care.15 If patient preferences and prescribed treatment regimens are misaligned, women diagnosed with breast cancer may become nonadherent, which could have implications for symptom management and for survival.15 To date, much of the research in this domain has focused on adherence to adjuvant therapy in patients with early-stage disease.16-18 A secondary objective of this study is to provide real-world evidence of nonadherence among women with mBC and to quantify the association with nonadherent behavior and health outcomes. We focused on adherence among patients receiving oral chemotherapy, because these agents are increasing in availability, and they represent a frequently self-administered treatment (as opposed to intravenous treatment, which is often not self-administered), and are thus more susceptible to nonadherent behaviors.

Methods Patient Sample and Procedures Qualitative interviews. An initial qualitative study was conducted to inform the participants of the survey.

A total of 10 telephone interviews were conducted using a structured discussion guide with women who were di-

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Table 1 Abbreviated Example of the Choice Task Q: Which treatment are you most likely to choose to treat your metastatic breast cancer?

Measurement Treatment A Treatment B Regimen

21-day cycle; 2- to 5-minute infusion on days 1 and 8

28-day cycle; 6- to 10-minute infusion on days 1, 8, and 15

Alopecia

48% chance of losing most or all of your hair, thinning of eyebrows/eyelashes; starts to grow back within 2-3 months after receiving chemotherapy

94% chance of losing most or all of your hair, thinning of eyebrows/eyelashes; starts to grow back within 2-3 months after receiving chemotherapy

Effectiveness

Has shown an additional survival benefit of 1 month

Has shown an additional survival benefit of 3 months

Quality of life

Difficulty performing work or other activities none of the time

Difficulty performing work or other activities all of the time

agnosed with mBC. Patients were invited to participate through cancer-specific online panels (eg, the Find A Cure Panel), which recruit members from cancer-oriented nonprofit Internet communities for the purpose of participating in research projects.

To be eligible to participate in the study, women had to report that they met the criteria, including being diagnosed with mBC, aged ≥18 years, and be proficient in the English language. Patients who never received treatment with a taxane (eg, paclitaxel, docetaxel) or who did not have health insurance, were covered by Medicaid, or who did not know their form of health insurance were excluded. These latter criteria were included to ensure sufficient treatment experience to put our hypothetical treatments into context. For research questions that were unrelated to the current study, the study focused on patients with private insurance types. Interviews lasted approximately 30 minutes and focused on the patient’s experience with previous treatments, as well as the frequency, severity, and tolerability of side effects.

Participant survey. The present study was a crosssectional, Internet-based survey of 181 women who were diagnosed with mBC. The inclusion and exclusion criteria of the women surveyed were identical to the qualitative participants. Potential participants were also invited from cancer-specific online panels, the same source used in the qualitative research. A total of 2500 panelists were e-mailed invitations to participate in the current study (response rate, 7%); those who clicked the invitation link were directed to the statement of informed consent, and, if consent was given, they were then directed to

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screening questions to determine eligibility; 28 respondents were ineligible: 21 because they had never received a taxane and 7 because of unknown reasons or for having Medicaid insurance coverage.

All participants who completed the survey were compensated with a $100 donation made in their name to a nonprofit charitable organization of their choice. For both the qualitative interview and the participant survey, all respondents provided informed consent and had their responses kept confidential. The protocol was approved by an Institutional Review Board (Essex IRB; Lebanon, NJ).

Survey Measures Demographics and health characteristics. All participants provided information about their age, race/ethnicity, marital status, college education, annual household income, employment, insurance type, and out-of-pocket (OOP) costs. Health-related information was also provided, such as height and weight, which was then converted to a body mass index category of underweight (<18.5 kg/ m2), normal weight (18.5 to <25 kg/m2), overweight (25 to <30 kg/m2), obese (≥30 kg/m2), or missing (for those participants who chose not to provide their weight). A family history of breast cancer, years diagnosed, specialty of diagnosing physician, stage at diagnosis, and months in metastatic stage were also reported.

Treatment history and adherence. The participants’ treatment modality experience was defined by surgery, intravenous chemotherapy, oral chemotherapy, radiation therapy, hormone therapy, clinical trial medication, and palliative care. The participants reported their experience in terms of previous treatment and current treatment. All women were asked whether they had been nonadherent to or had discontinued any of their previous treatments. For the participants who responded affirmatively for nonadherence, specific reasons for nonadherence or discontinuation were provided, and respondents were asked to indicate whether they engaged in the behavior.

Quality of life. The Functional Assessment of Cancer Therapy-Breast (FACT-B) was also included as a health-related QOL (HR-QOL) measurement instrument.19 The FACT-B includes the 7 subscales from the Functional Assessment of Cancer Therapy-General (FACT-G)—physical well-being, social well-being, family well-being, relationship with doctor, emotional well-being, functional well-being, trial outcome index— and the total score for the FACT-G. The FACT-B also includes a separate breast cancer subscale and a total score (FACT-B total score) that combines all of the subscales. For all of the subscales and total scores, higher values reflect better HR-QOL.

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Stated preferences and choice task. Participants rated the importance of various attributes (from 1, indicating “extremely important,” to 5, indicating “not at all important”) and completed a choice-based conjoint task consisting of 7 choice scenarios, each containing 2 profiles of hypothetical treatments. Participants then selected the treatment they preferred from the 2 choices based on the information in the profile; participants were told to assume that all other attributes of the medications that were not explicitly mentioned in the profiles were identical (Table 1).

For each profile of a hypothetical treatment in the choice scenarios, 11 different attributes were comprised of 8 safety attributes—including alopecia, motor neuropathy, myalgia/arthralgia, nausea/vomiting, fatigue, neutropenia, mucositis/stomatitis, and diarrhea—1 effectiveness attribute, 1 dosing regimen attribute, and 1 QOL attribute. The actual levels of each attribute varied with every hypothetical profile and across all choice scenarios. These attributes were identified from the preliminary qualitative research described earlier as well as an examination of past literature.

Given the number of unique attribute-level combinations (ie, profiles), a fractional factorial balanced incomplete block design was used. Kuhfeld’s SAS macros (SAS Institute; Cary, NC)20 were used to derive a set of orthogonal arrays that were 99.9% D-efficient with respect to parameter variance. The resulting instruments had orthogonal profiles and balanced attribute levels.

Statistical Analysis The choice tasks were analyzed using hierarchical Bayesian logistic regression models, whereas the regression models were parameterized using effects coding.

The resulting model coefficients are viewed as partworth utilities that also served as inputs to the relative importance analysis. To understand the relative importance of the attributes, deviations of the part-worth utilities from the overall expected value were calculated to create sums of squares for each individual attribute; for each attribute, the regression coefficients for each level of that attribute were squared and were summed together. The resulting sums of squares were divided by the attribute-specific degrees of freedom to generate a mean sum of squares (MSS) for each attribute. The relative importance of each attribute was calculated by dividing the MSS for that attribute by the sum of all MSS values for all attributes. The attributes with higher relative importance have a disproportionately larger MSS than other attributes, which is a result of large coefficients of the individual levels. The individual-level hierarchical Bayesian modeling was con-

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Table 2 Patient Demographics Patient sample (N = 181) Age, mean, yrs (± SD)

52.2 (± 9.1)

Non-Hispanic white, N (%)

170 (93.9)

Married, N (%)

136 (75.1)

College graduate, N (%)

130 (71.8)

Annual household income <$25,000, N (%)

11 (6.1)

$25,000 to <$50,000, N (%)

31 (17.1)

$50,000 to <$75,000, N (%)

28 (15.5)

≥$75,000, N (%)

86 (47.5)

Decline to answer, N (%)

25 (13.8)

Employment status Currently employed, N (%)

78 (43.1)

On leave from work, N (%)

15 (8.3)

Retired, N (%)

31 (17.1)

Other, N (%)

57 (31.5)

a

Health insurance Private insurance, N (%)

162 (89.5)

Medicare, N (%)

14 (7.7)

TRICARE, N (%)

5 (2.8)

Insurance coverage of breast cancer treatments Covers all of my breast cancer treatments, N (%)

139 (76.8)

Covers some of my breast cancer treatments, N (%)

40 (22.1)

Does not cover any of my breast cancer treatments, N (%)

1 (0.6)

Don’t know/not sure, N (%)

1 (0.6)

Body mass index Underweight, N (%)

5 (2.8)

Normal weight, N (%)

67 (37)

Overweight, N (%)

61 (33.7)

Obese, N (%)

42 (23.2)

Decline to provide weight, N (%)

6 (3.3)

Information not available.

SD indicates standard deviation.

a

ducted using Sawtooth’s CBC/HB v4.6.4 (Sawtooth Software; Orem, UT).

Because they were significantly related to adherence and associated with QOL, general linear models

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Table 3 Mean Out-of-Pocket Costs by Sociodemographic Categories OOP breast OOP breast cancer cancer treatphysician Sociodemographic Patients, ment cost, $ visit cost, $ category N (%) mean (± SD) mean (± SD) Total

OOP non– breast cancer treatment cost, $ mean (± SD)

OOP non– breast cancer physician visit costs, $ mean (± SD)

181 (100)

302.94 (± 784.68)

107.43 (± 200.23)

27.06 (± 50.9)

11.94 (± 27.23)

170 (93.92)

309.57 (± 806.86)

96.53 (± 145.67)

26.90 (± 52.08)

11.55 (± 27.53)

11 (6.08)

200.45 (± 261.55)

275.91 (± 574.32)

29.55 (± 27.88)

17.91 (± 22.34)

College graduate

130 (71.82)

322.12 (± 842.74)

103.77 (± 210.08)

26.22 (± 50.8)

14.55 (± 31.09)

Less than college graduate

51 (28.18)

254.04 (± 617.15)

116.76 (± 174.2)

29.22 (± 51.58)

5.27 (± 10.59)

<$25,000

11 (6.08)

120 (± 241.59)

144.09 (± 229.41)

20.18 (± 59.77)

0 (± 0)

$25,000 to <$50,000

31 (17.13)

172.52 (± 255.24)

122.58 (± 187.31)

28.55 (± 39.82)

9.03 (± 17.48)

$50,000 to <$75,000

28 (15.47)

385.96 (± 977.93)

110 (± 154.87)

23 (± 49.39)

9.29 (± 21.33)

≥$75,000

86 (47.51)

389.01 (± 963.77)

100.35 (± 231.35)

29.67 (± 56.51)

16.41 (± 33.78)

Decline to answer

25 (13.81)

156.08 (± 228.67)

94 (± 130.69)

23.8 (± 42.73)

8.40 (± 21.4)

No

159 (87.85)

307.43 (± 826.02)

90.22 (± 136.58)

27.24 (± 51.8)

12.76 (± 28.49)

Yes

22 (12.15)

270.45 (± 377.87)

231.82 (± 429.95)

25.77 (± 44.9)

6 (± 14.4)

Midwest

51 (28.18)

586.96 (± 1355.39)

142.45 (± 203.63)

19.98 (± 43.97)

6.47 (± 18.09)

Northeast

37 (20.44)

198.27 (± 309.54)

83.11 (± 114.98)

43.51 (± 76.27)

15.41 (± 43.67)

South

48 (26.52)

189.96 (± 361.34)

116.77 (± 298.61)

19.94 (± 39.64)

12.54 (± 18.91)

West

44 (24.31)

190.98 (± 290.85)

77.27 (± 89.94)

29.82 (± 40.43)

14.41 (± 26.06)

Race White Non-Hispanic white Education

Salary

Enrolled in an assistance program

Region of United States

Type of chemotherapy received at the time of the survey Oral

44 (24.31)

313.45 (± 708.69)

107.05 (± 146.02)

26.86 (± 40.52)

8.8 (± 13.09)

Intravenous

76 (41.99)

501.8 (± 1099.4)

108.16 (± 156.14)

27.16 (± 53.41)

12.75 (± 30.23)

NOTE: All costs are independent of one another (eg, costs of breast cancer and costs not related to breast cancer do not overlap).

OOP indicates out-of-pocket; SD, standard deviation.

controlling for age, race/ethnicity, education, and body mass index were used to estimate the relationship between the number of nonadherent behaviors and QOL measured with the FACT-B (unstandardized regression coefficients [ie, b] are provided, indicating the effect on the dependent variable [ie, QOL] with a 1-unit increase in the independent variable [ie, nonadherent behaviors]). The effect of adherence was examined separately among patients who had ever received an oral chemotherapy agent (N = 95) and those who were currently receiving an oral chemotherapy agent (N = 44).

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Results Demographics and Health History The mean age of the patient sample was 52.2 years (standard deviation [SD], 9.1) with 93.9% of participants reporting being non-Hispanic white. The patients were generally of high socioeconomic status, with 71.8% of participants reporting having a college degree, 47.5% reporting an annual household income of ≥$75,000, and 76.8% reporting that their insurance covers all of their treatments for breast cancer (Table 2).

The total monthly OOP costs per patient were approximately $303 (SD, $785) for treatments related to

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breast cancer and approximately $107 (SD, $200) for physician visits related to breast cancer (Table 3).

The OOP costs, particularly for the treatment of breast cancer, were higher among patients who were non-Hispanic white, were college educated, had a higher household income, and were not enrolled in a patient assistance program. Women in the Midwest United States (28.18%) reported the highest cancer-related OOP costs (ie, $586.96).

The patients had extensive previous treatment experience across treatment modalities (100% intravenous chemotherapy, 82.3% surgery, 77.4% hormone therapy, 71.3% radiation therapy, and 52.5% oral chemotherapy). The majority of participants (90.6%) were currently receiving treatment, with the most common treatment modalities being hormone therapy (47.5%), intravenous chemotherapy (42%), and oral chemotherapy (24.3%).

Patient Preferences When asked directly, the most important attributes of treatments for participants were related to effectiveness, followed by side effects. Cost-related attributes were the least important (Table 4).

Results from the conjoint model reaffirmed the primary importance of effectiveness, as indicated by overall survival, followed by side effects (the most notable of which were alopecia, fatigue, neutropenia, motor neuropathy, and nausea/vomiting), and, finally, dosing regimen (Table 5, Figure). For example, the logit column in Table 5 represents the strength (and direction) of the relationship between the presence of an attribute and selecting that treatment. Survival of 3 months (5.24), alopecia of 0% (1.70), and fatigue of 0% (1.19) had the highest positive logits, suggesting the strongest relationship with the probability of selection.

Post-hoc analyses investigated whether these preferences would vary by treatment experience (ie, rounds of chemotherapy). Our findings suggest that patient preference was remarkably consistent and did not vary by treatment experience. In our analyses, all attributes were rank ordered identically, and relative importance values of any given subgroup were within 2% to 3% of any other subgroup. For example, the relative importance of effectiveness attribute was highest for having received more than 6 rounds of chemotherapy (34.51%) and lowest for having received less than 2 rounds of chemotherapy (32.45%).

Adherence A total of 63 (34.8%) survey participants either discontinued their treatment or were nonadherent to their treatment regimen. Patients who had ever received hormone therapy (37.9%) reported the greatest level of

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Table 4 Stated Importance of Various Treatment Attributes Importance for all patients (N = 181), Treatment attribute mean (± SD) How well the treatment helps in slowing down the progression of the cancer

1.19 (± 0.44)

How these treatments can help in extending my life

1.22 (± 0.49)

How effective the treatment is compared with other treatments

1.41 (± 0.67)

The impact of the treatment on my overall quality of life

1.43 (± 0.59)

Appropriateness for the stage of my breast cancer

1.51 (± 0.74)

The severity of the treatment side effects

1.57 (± 0.72)

The impact of the treatment on my ability to perform daily activities

1.57 (± 0.68)

Ways to manage/cope with treatment side effects

1.62 (± 0.70)

Potential side effects

1.79 (± 0.82)

Potential safety risks

1.82 (± 0.80)

Long-term safety of the treatment

1.90 (± 0.91)

How the treatment actually works

1.95 (± 0.94)

The importance of following the prescribed dosing regimen

1.96 (± 1.05)

The impact of the treatment on my mental health/emotional well-being

1.97 (± 0.87)

How the treatment is administered/what the procedure involves

2.27 (± 1.07)

How long I would have to stay on the treatment

2.27 (± 1.11)

Other patients’ experiences with the treatments

2.51 (± 0.94)

How long the treatment has been available

2.78 (± 1.11)

Ways to help cover treatment costs provided by the pharmaceutical manufacturer

3.15 (± 1.37)

Cost of the treatment

3.24 (± 1.22)

Patient support programs provided by the manufacturer

3.42 (± 1.21)

Financial assistance for breast cancer treatment from a charity or research organization

3.43 (± 1.31)

NOTE: Rating scale was from 1 (extremely important) to 5 (not at all important).

SD indicates standard deviation.

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Table 5 Part-Worth Utilities from the Conjoint Task Attribute

Levels

Logit

SE

P value

Alopecia

0%

1.70

0.07

<.001

48%

–0.61

0.05

<.001

94%

–1.09

0.05

<.001

0%

0.80

0.04

<.001

4%

–0.24

0.02

<.001

10%

–0.56

0.02

<.001

0%

0.22

0.02

<.001

4%

–0.07

0.01

<.001

15%

–0.16

0.01

<.001

0%

0.80

0.04

<.001

4%

0.04

0.01

.004

15%

–0.84

0.04

<.001

0%

1.19

0.05

<.001

8%

–0.16

0.02

<.001

24%

–1.03

0.04

<.001

0%

1.05

0.05

<.001

Motor neuropathy

Myalgia/arthralgia

Nausea/vomiting

Fatigue

Neutropenia

Mucositis/stomatitis

–0.26

0.03

<.001

–0.79

0.05

<.001

0%

0.21

0.01

<.001

5%

–0.08

0.00

<.001

10%

–0.13

0.01

<.001

0%

0.31

0.02

<.001

5%

0

0.01

.699

15%

–0.31

0.02

<.001

No survival benefit

–4.98

0.19

<.001

Additional 1 month

–0.26

0.05

<.001

Additional 3 months

5.24

0.18

<.001

21-day cycle; oral tablets taken twice daily for first 2 weeks

0.30

0.01

<.001

21-day cycle; 2- to 5-minute infusion on days 1 and 8

0.16

0.01

<.001

21-day cycle; 3-hour infusion on day 1

0.05

0.01

<.001

28-day cycle; 6- to 10-minute infusion on days 1, 8, and 15

–0.02

0.01

.011

21-day cycle; 30-minute infusion on days 1, 8, and 15

–0.16

0.01

<.001

21-day cycle; 3-hour infusion on days 1, 8, and 15

–0.33

0.02

<.001

Difficulty performing work or other activities none of the time

0.99

0.04

<.001

Difficulty performing work or other activities some of the time

0.39

0.02

<.001

Difficulty performing work or other activities all of the time

–1.38

0.05

<.001

Diarrhea

Effectiveness

Regimen

9% 23%

Quality of life

SE indicates standard error.

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nonadherence, followed by patients who had ever received an oral chemotherapy agent (36.8%). Across all treatment modalities, forgetfulness (41.3%) and intolerance of side effects (36.5%) were the most common reasons for nonadherence among patients who reported their nonadherence or discontinuation (Table 6).

Among the patients who had ever received an oral chemotherapy agent (N = 95), the number of nonadherent behaviors (mean, 1.57) was used to predict HR-QOL (Table 7). Analogous models were also conducted among patients who were currently receiving a chemotherapy agent (N = 44). The number of nonadherent behaviors was significantly associated with a decrease in functional well-being (b = –2.01 for patients who had ever used a targeted therapy and b = –3.14 for current users of a targeted therapy), FACT-G total score (b = –4.30 and b = –7.37, respectively), FACT-B total score (b = –3.93 and b = –6.11, respectively), and FACT trial outcome index (b = –5.22 and b = –8.63, respectively; all P <.05).

Discussion The primary objective of this study was to assess patient preferences for the treatment of mBC, because most of the existing literature focused on preferences among women with early-stage breast cancer. Although our results were generally comparable with the results of patients with early-stage disease,7,8 we found that treatment effectiveness was rated as the most important attribute among women with mBC, nearly twice as much as alopecia, and more than 3 times more important than other side effects. The rank order of important attributes for a treatment is similar to the findings by Beusterien and colleagues8; however, the current study estimated a greater preference for treatment effectiveness and the avoidance of alopecia, and a lower preference for regimen and diarrhea. These findings help clarify the patient perspective of treatments for mBC, which, if aligned with prescribing patterns, may maximize treatment satisfaction and adherence.

A secondary objective of this study was to assess the level of nonadherence for women with mBC who are receiving an oral chemotherapy agent and to establish the relationship between nonadherence and QOL. Approximately 33% of women with mBC reported engaging in medication nonadherent behavior. This rate is consistent with previous reviews of treatment adherence in patients with breast cancer.21 However, given the fairly affluent and engaged patient population, it can be hypothesized that adherence levels in the overall population with mBC are even lower. Of note, even after adjusting for established predictors of QOL, the nonadherent behaviors of women receiving an oral chemother-

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Figure Relative Importance of Each Attribute Effectiveness

33.49% 21.32%

Alopecia Fatigue

12.46%

Neutropenia

10.37%

Quality of life

7.69%

Motor neuropathy

6.36%

Nausea/vomiting

6.18%

Diarrhea

1.08%

Myalgia/arthralgia

0.48%

Mucositis/stomatitis

0.43%

Dosing regimen

0.14% 0%

5%

10% 15% 20% 25% 30% 35% 40%

Relative importance

Table 6 Reasons for Patient Nonadherence Patients who discontinued/were nonadherent, N (%)

Reason stated Forgot to take medicines and/or keep treatment appointments

26 (41.3)

I could not tolerate the side effects

23 (36.5)

Other

19 (30.2)

Had family obligations/an event to attend

10 (15.9)

Side effects impacted my ability to perform daily activities

8 (12.7)

I was unable to enjoy everyday experiences

5 (7.9)

I could no longer afford the treatment

4 (6.4)

Treatment schedule was difficult to follow

3 (4.8)

I did not trust the medicine as it was still in clinical trials

1 (1.6)

a

I had to travel too far to get the treatment

0 (0)

Lack of support from family members/friend

0 (0)

I did not have someone to drive me to my treatment

0 (0)

Additional information not available.

a

apy agent were associated with significant decrements in health status.

Forgetfulness and adverse events were among the most common reasons for nonadherence, and these results suggest that a less complex treatment regimen and regimens with less toxic profiles may be associated with improvements in adherence, and subsequently could

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ssociation between the Number of Nonadherent Behaviors and FACT-B Scores Among Patients Who Ever Table 7 A Received or Currently Receive an Oral Chemotherapy Agent Social/ Breast Trial Physical family Emotional Functional FACT-G cancer FACT-B outcome well-being well-being well-being well-being total score subscale total score index b b b b b b b b Ever received an oral chemotherapy agent (N = 95) Number of nonadherent behaviors R2

–1.00 (95% CI, –2.39 to 0.4)

–0.90 (95% CI, –2.05 to 0.25)

–0.39 (95% CI, –1.56 to 0.79)

–2.01a (95% CI, –3.27 to –0.75)

–4.30a (95% CI, –8.12 to –0.48)

–0.92 (95% CI, –2.16 to 0.32)

–3.93a (95% CI, –7.12 to –0.73)

–5.22a (95% CI, –9.86 to –0.57)

0.12

0.13

0.03

0.16

0.12

0.14

0.14

0.13

Currently receiving an oral chemotherapy agent (N = 44) Number of nonadherent behaviors R2

–1.7 (95% CI, –3.76 to 0.36)

–1.56 (95% CI, –3.44 to 0.31)

–0.96 (95% CI, –2.64 to 0.72)

–3.14a (95% CI, –4.82 to –1.47)

–7.37a (95% CI, –12.98 to –1.75)

–1.27 (95% CI, –3.1 to 0.56)

–6.11a (95% CI, –10.72 to –1.5)

–8.63a (95% CI, –15.53 to –1.73)

0.23

0.13

0.14

0.30

0.22

0.18

0.22

0.21

P <.05. b indicates unstandardized regression coefficient; CI, confidence interval; FACT-B, Functional Assessment of Cancer Therapy-Breast; FACT-G, Functional Assessment of Cancer Therapy-General.

a

correspond to perceptible patient benefits. Other potential interventions may include greater education about potential side effects (which could mitigate the influence of side effects on nonadherence) and memory aids (eg, reminder systems). Further research is necessary to understand these potential interventions and their effectiveness in this patient population.

Targeted therapies have become increasingly important in the treatment of many cancers, including breast cancer.21 Such therapeutic agents are often taken orally and can often have less severe side effects than traditional chemotherapy regimens, which can improve patient outcomes.22 Although these advantages can increase adherence—because patients prefer oral therapies to those administered intravenously—medication adherence is complex. The complexity of adherence can be influenced by a multitude of patient- and care-based factors, including the prohibitive costs of targeted treatments for some patients.21 Research examining adherence to targeted oral medications in the context of breast cancer has shown that approximately 20% of patients are nonadherent, depending on the way in which adherence was measured.22-24 Furthermore, in a study of adherence to lapatinib, Kartashov and colleagues reported that nonadherence is associated with increased provider visits and suggested an increase in the cost of care.23 Further research is needed to enhance our understanding of the factors influencing adherence rates in the treatment of breast cancer, and to develop effective interventions in line with advances in the pharmaceutical industry.

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A literature search did not uncover any epidemiology study that could be useful to compare the general US population of patients receiving treatment for mBC against the sample in this current study.

Limitations The results of the current study should be examined within the context of its limitations. All data, including treatments and adherence information, were self-reported and could have been subject to recall biases and other self-presentation effects. The conjoint task is a simplifying hypothetical exercise to estimate how patients value certain attributes of treatments, and may differ with the inclusion of other relevant attributes or levels. For example, in actual decision-making, the true benefit or risks that will be experienced (eg, there is a probability of certain survival outcomes, but not a guaranteed 3-month survival) cannot be known with certainty. In addition, differences in analytical methods and attributes can also make it difficult to directly compare preference results from one study to another.

Of note, the relationship between nonadherence and QOL was presented in a single direction as nonadherence predicting QOL. It is possible that the relationship could be bidirectional (eg, QOL influencing adherence) or that there could be additional third variables that are not included in the current study that could explain the relationships observed here. In addition, detailed information on disease progression, treatment chronology, side effects experienced, and dosing adjustments was unavailable, so the context for the results on adherence

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is incomplete. For example, it is not known what the mechanism was for the relationship between nonadherence and health outcomes (eg, nonadherence leading to faster disease progression leading to poorer QOL).

Finally, the current study used a convenience sample of women with mBC. These women were generally of high socioeconomic status, and, because of their participation in online oncology panels, may be more engaged and/or knowledgeable about their condition and treatments, which may influence their preferences, adherence, and health outcomes.

Conclusion The current study suggests that the treatment preferences of women diagnosed with mBC, an understudied group in this context, are similar to the preferences of women diagnosed with early-stage disease. Among the patient sample surveyed, treatment effectiveness was of primary importance, an effect that did not appear influenced by other study variables. Further analysis revealed that approximately 33% of the women surveyed reported some degree of treatment nonadherence, which, in turn, was associated with impairment of QOL among patients receiving an oral chemotherapy agent. These results have important implications for treatment planning in the context of mBC, as well as reinforce the need to consider medication adherence in promoting QOL and desired treatment outcomes. ■ Acknowledgments The authors would like to thank Duncan Brown, PhD, for his contribution to the survey design and recruitment of respondents. Dr Brown was a full-time employee of Kantar Health at the time of the study. The authors would also like to thank Errol Philip, PhD, for his assistance with the literature review and editorial comments on the manuscript. Dr Philip is a paid consultant to Kantar Health.

Funding Source This study was funded by Eisai Inc. Author Disclosure Statement Dr DiBonaventura’s institution received research support from Eisai Inc; Dr Copher is an employee of Eisai Inc; Mr Basurto is a consultant to and received research support from Eisai; Dr Faria is an employee of Eisai; and Ms Lorenzo’s institution received research support from Eisai Inc.

References

1. American Cancer Society. Cancer facts & figures 2014. 2014. www.cancer.org/ acs/groups/content/@research/documents/webcontent/acspc-042151.pdf. Accessed March 14, 2014.

2. American Cancer Society. Breast cancer facts and figures 2013-2014. 2013. www. cancer.org/acs/groups/content/@research/documents/document/acspc-042725.pdf.

Accessed March 14, 2014.

3. Cardoso F, Fallowfield L, Costa A, et al; for the ESMO Guidelines Working Group. Locally recurrent or metastatic breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2011;22(suppl 6):vi25-vi30.

4. Beaumont T, Leadbeater M. Treatment and care of patients with metastatic breast cancer. Nurs Stand. 2011;25:49-56.

5. Gao S, Barber B, Schabert V, Ferrufino C. Tumor hormone/HER2 receptor status and pharmacologic treatment of metastatic breast cancer in Western Europe. Curr Med Res Opin. 2012;28:1111-1118.

6. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): breast cancer. Version 3.2014. April 1, 2014. www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed September 26, 2014.

7. Beusterien K, Grinspan J, Kuchuk I, et al. Use of conjoint analysis to assess breast cancer patient preferences for chemotherapy side effects. Oncologist. 2014;19:127134.

8. Beusterien K, Grinspan J, Tencer T, et al. Patient preferences for chemotherapies used in breast cancer. Int J Womens Health. 2012;4:279-287.

9. Alvarado MD, Conolly J, Park C, et al. Patient preferences regarding intraoperative versus external beam radiotherapy following breast-conserving surgery. Breast Cancer Res Treat. 2014;143:135-140.

10. Kimman ML, Dellaert BG, Boersma LJ, et al. Follow-up after treatment for breast cancer: one strategy fits all? An investigation of patient preferences using a discrete choice experiment. Acta Oncol. 2010;49:328-337.

11. Mandelblatt JS, Sheppard VB, Hurria A, et al; for the Cancer Leukemia Group B. Breast cancer adjuvant chemotherapy decisions in older women: the role of patient preference and interactions with physicians. J Clin Oncol. 2010;28:3146-3153.

12. Simes RJ, Coates AS. Patient preferences for adjuvant chemotherapy of early breast cancer: how much benefit is needed? J Natl Cancer Inst Monogr. 2001;30:146-152.

13. Fallowfield L, McGurk R, Dixon M. Same gain, less pain: potential patient preferences for adjuvant treatment in premenopausal women with early breast cancer.

Eur J Cancer. 2004;40:2403-2410.

14. McQuellon RP, Muss HB, Hoffman SL, et al. Patient preferences for treatment of metastatic breast cancer: a study of women with early-stage breast cancer. J Clin Oncol. 1995;13:858-868.

15. Magai C, Consedine N, Neugut AI, Hershman DL. Common psychosocial factors underlying breast cancer screening and breast cancer treatment adherence: a conceptual review and synthesis. J Womens Health (Larchmt). 2007;16:11-23.

16. Banning M. Adherence to adjuvant therapy in post-menopausal breast cancer patients: a review. Eur J Cancer Care (Engl). 2012;21:10-19.

17. Murphy CC, Bartholomew LK, Carpentier MY, et al. Adherence to adjuvant hormonal therapy among breast cancer survivors in clinical practice: a systematic review. Breast Cancer Res Treat. 2012;134:459-478.

18. Mayer EL, Partridge AH, Harris LN, et al. Tolerability of and adherence to combination oral therapy with gefitinib and capecitabine in metastatic breast cancer.

Breast Cancer Res Treat. 2009;117:615-623.

19. Bonomi AE, Cella DF, Hahn EA, et al. Multilingual translation of the Functional Assessment of Cancer Therapy (FACT) quality of life measurement system. Qual Life Res. 1996;5:309-320.

20. Kuhfeld WF. Marketing Research Methods in SAS: Experimental Design, Choice, Conjoint, and Graphical Techniques. SAS 9.2 Edition, MR-2010. Cary, NC: SAS Institute Inc; 2010. http://support.sas.com/techsup/technote/mr2010.pdf. Accessed April 15, 2014.

21. Geynisman DM, Wickersham KE. Adherence to targeted oral anticancer medications. Discov Med. 2013;15:231-241.

22. Weingart SN, Brown E, Bach PB, et al. NCCN Task Force Report: oral chemotherapy. J Natl Compr Canc Netw. 2008;6(suppl 3):S1-S14.

23. Kartashov A, Delea TE, Sharma PP. Retrospective study of predictors and consequences of nonadherence with lapatinib (LAP) in women with metastatic breast cancer (MBC) who were previously treated with trastuzumab. J Clin Oncol.

2012;30(15 suppl). Abstract e11067.

24. Addeo R, Vincenzi B, Riccardi F, et al. Multicenter observational study on adherence and acceptance of lapatinib treatment in patients with HER2+ metastatic breast cancer. J Clin Oncol. 2011;29(15 suppl). Abstract e11102.

Stakeholder Perspective next page

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STAKEHOLDER PERSPECTIVE Predicting Behavior: It’s a Matter of Preference

By Albert Tzeel, MD, MHSA, FACPE Regional Medical Director, Medicare Operations, North Florida, Humana, Jacksonville

In the well-known quip that has been attributed to individuals as diverse as the quantum physicist Niels Bohr and the extraordinary baseball manager Casey Stengel, both men are purported to have said, “I never make predictions, especially about the future.” Predictions, especially when they come to the ability and/or desire to adhere to a medical regimen of care, are highly dependent on a number of factors.

And so it is in the article by DiBonaventura and colleagues in this issue of American Health and Drug Benefits.1 Not long ago, the paternalistic aspect of medical care consisted of the physician prescribing a course of medical care that was incumbent on the patient to follow. Societal norms stipulated such behavior as a function of the asymmetric knowledge relationship between a physician and a patient. As patients became more empowered, they demanded a greater role in determining their own care, and we saw the genesis of the era of “shared decision-making.” As Mazur discusses in his book on shared decision-making, clarifying the notion of this type of decision-making includes, among other things, taking into account the risk preferences of patients.2 It is relatively easy for physicians and patients to believe that they can and will conform to certain therapies when they expect a relatively easy trade-off of side-effect tolerance versus gains in survival time. However, experience does not always mirror expectation.

One reason for this lack of congruence between plan and result may lie in behavioral economics. In their seminal article on prospect theory, Kahneman and Tversky posited and demonstrated that people make decisions based on the potential value of losses and gains rather than on the final outcome.3 In the article by DiBonaventura and colleagues, women with metastatic breast cancer were willing to trade increases in side effects for increases in life expectancy.1 Of course, one could also argue that prospect theory notes how people underweight the likelihood of

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high probability events (eg, side effects from medical treatment) while overvaluing the likelihood of lower probability events (eg, cure in overall survival). This may also explain some of the findings encountered in the current study by DiBonaventura and colleagues.

PAYERS: Payers understand these findings all too well. In addition to being a HEDIS (Healthcare Effectiveness Data and Information Set) measure, medication adherence is an area of great interest, because of its overall impact on cost and outcomes. It is well-documented that nonadherence to treatment, whether pharmacologic or otherwise, results in increased costs and worsened health. Many payers have thus developed specialty analytic units to study and address the conundrum why patients are nonadherent to therapy.

PATIENTS: People often make decisions without fully understanding the subconscious reasons why they have chosen to act as they do. If individual patients perhaps had more time or more inclination to truly share their real perspectives, it is very possible that there would be more adherence to treatment, or that more appropriate therapy decisions would be made in a shared manner in the first place. Of course, the key to this occurring is to study why it is not currently happening. As DiBonaventura and colleagues note, perhaps a decrease in the complexity of therapy may help in that endeavor.1 Although we can certainly all hope for more understanding of patients’ preferences and their role in successful care outcomes, what we cannot do, however, is predict that this will actually happen. ■ 1. DiBonaventura MdC, Copher R, Basurto E, et al. Patient preferences and treatment adherence among women diagnosed with metastatic breast cancer. Am Health Drug Benefits. 2014;7:386-396.

2. Mazur DJ. Shared Decision Making in the Physician-Patient Relationship. Tampa, FL: American College of Physician Executives; 2001:103.

3. Kahneman D, Tversky A. Prospect theory: an analysis of decision under risk.

Econometrica. 1979;47:263-291.

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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.

Readers are invited to submit articles that aim at improving the quality of patient care and patient well-being while controlling costs, enhancing the health of communities and patient populations, as well as other topics relevant to benefit design with specific implications to policymakers, payers, and employers.

Areas of High Interest: • Adherence Concerns • Benefit Design • Case Studies • Comorbidities and Cost Issues • Comparative Effectiveness Research • Decision-Making Tools • Ethics in Medicine • Health Economics Outcomes

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

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

Clinical Topics of High Interest: AGING—With the aging of the US population, there is a growing need for early implementation of outcomes-based preventive and therapeutic strategies for older people.

ALLERGIES—Allergies affect millions of Americans daily, resulting in a significant economic burden and human cost.

Under­treatment and lack of adherence are common obstacles to patient management.

AUTOIMMUNE DISORDERS—Rheumatic diseases and other autoimmune disorders are on the rise. Comparing the efficacy and safety of new therapies is key to improving patient outcomes and reducing costs.

CANCER CARE—The growing focus on high-cost biologic agents dictates an enhanced study of these therapeutic options and cost management.

CARDIOVASCULAR DISEASE—Outcomes-based research on appropriate therapies, cost comparisons, emerging prevention strategies, and best practices will enhance readers’ decision-making.

DIABETES, OBESITY—The ever-growing epidemics of these twin metabolic conditions mandate a thorough examination of best therapies, adherence issues, access, and prevention strategies.

GASTROINTESTINAL CONDITIONS—Managing GI conditions, such as hepatitis C, Crohn’s disease, and inflammatory bowel disorder, remains a challenge.

INFECTIOUS DISEASES—The spread of common and emerging pathogens within the hospital and in the community remains a major concern requiring increased vigilance.

MENTAL DISORDERS—Depression, bipolar disorder, and schizophrenia exert a huge financial and human burden on individuals, employers, and payers. Topics of interest include comparative effectiveness analyses, adherence, best practices, and reimbursement.

NEUROLOGIC DISORDERS—The central nervous system is associated with many complicated medical disorders and an enormous economic burden.

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

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

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.

In treating multiple myeloma

What is the value of ® VELCADE (bortezomib)? ▼ Overall survival advantage ▼ Defined length of therapy ▼ Medication cost If you DEfInE VALuE As An oVErALL surVIVAL ADVAntAgE: VELCADE (bortezomib) combination delivered a >13-month overall survival advantage A t 5-year median follow-up, VELCADE+MP* provided a median overall survival 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 overall survival advantage over MP that was not regained with subsequent therapies

If you DEfInE VALuE As DEfInED LEngth of thErApy: Results achieved using VELCADE twice-weekly followed by weekly dosing for a median of 50 weeks (54 planned)1

If you DEfInE VALuE As MEDICAtIon Cost: Medication cost is an important factor when considering overall drug spend. The Wholesale Acquisition Cost for VELCADE is $1568 per 3.5-mg vial as of January 2014 When determining the value of a prescription drug regimen, it may be worth considering medication cost, length of therapy, and dosing regimens. This list is not all-inclusive; there are additional factors to consider when determining value for a given regimen

▼ 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 on the next page of this advertisement.

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

Reference: 1. Mateos M-V, Richardson PG, Schlag R, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial.

J Clin Oncol. 2010;28(13):2259-2266. *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.

Brief Summary 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.

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. All rights reserved. Printed in USA V-12-0306a

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Health Economics Outcomes and Payers’ Perspectives The following summaries highlight some of the key posters presented at the Academy of Managed Care Pharmacy Nexus14 meeting on October 7-10, 2014, in

Boston, MA, focusing on findings with significant implications for payers, employers, providers, policy­ makers, patients, and other healthcare stakeholders.

Narcolepsy Associated with Increased Healthcare Utilization, Costs, and Reduced Productivity Narcolepsy is estimated to affect 1 of 2000 persons in the United States. Narcolepsy is characterized by reduced wakefulness and excessive daytime sleepiness, as well as other symptoms (eg, uncontrolled laughing), and can lead to a transient loss of muscle strength. The symptoms of narcolepsy can be controlled by the use of appropriate medications, but such medications do not cure the symptoms.

The symptoms of narcolepsy often affect a patient’s overall well-being as well as daytime productivity, including work-related productivity, and may affect other aspects of the patient’s health. A new population health study investigated the economic burden of this disease, including the patient’s total healthcare utilization, costs, and work productivity, based on self-reported outcomes.

Lead investigator Kathleen F. Villa, MS, Senior Director, Health Economics and Outcomes Research, Jazz Pharmaceuticals, Inc, and colleagues, used data for this analysis from responses to the 2011-2013 US National Health and Wellness Survey, a health-related survey conducted annually that represents a cross-section population in the United States. Specifically, this new analysis is based on responses from 75,000 respondents to the 2011 national survey, 71,157 respondents to the 2012 survey, and 75,000 respondents to the 2013 survey. Respondents who reported ever having been diagnosed with narcolepsy by a physician were matched with controls in a 1 to 2 ratio, based on baseline demographics and health-related risk behaviors (eg, smoking).

Components of the analyses included the impact of narcolepsy on resource utilization, impaired work and overall activity, and associated costs related to each of these components.

The study included a total of 437 patients with narcolepsy who had responded to the survey and were matched with 874 controls.

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Loss of work productivity and overall impaired activity were measured by the Work Productivity and Activity Impairment-General Health scale, which includes the following 4 productivity-related categories: • Absenteeism • Presenteeism • Overall work impairment • Activity impairment.

The analysis of healthcare costs included direct and indirect costs, calculated separately and together (ie, total costs); these were derived from data in the Medical Expenditure Panel Survey and the Bureau of Labor Statistics and were applied as unit costs to calculate resource utilization variables from the national survey.

Direct costs included emergency department visits, hospitalization, and physician office visits. Indirect costs were calculated for respondents who were employed and included absenteeism and presenteeism (independently and combined).

Compared with the utilization in the past 6 months reported by the controls, patients with narcolepsy reported healthcare utilization in the past 6 months that included significantly increased hospitalizations (mean, 0.27 vs 1.02, respectively; P <.001), increased emergency department visits (mean, 0.44 vs 1.22, respectively; P <.001), a greater number of office visits (mean, 4.08 vs 10.25, respectively; P <.001), and more visits to nonnarcolepsy specialists, such as psychiatrists (mean, 0.28 vs 0.72, respectively; P <.001).

Furthermore, compared with the controls, patients with narcolepsy reported significantly greater proportions of work-related missed time in the past week because of several reasons, including absenteeism (mean, 5.6% vs 17.4%, respectively; P <.001), presenteeism as reflected in loss of productivity while at work (mean, 17.5% vs 40.2%, respectively; P <.001), over-

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all work impairment (mean, 20.1% vs 45.5%, respectively; P <.001), and overall impaired activity (mean, 25.9% vs 50.9%, respectively; P <.001).

Overall, compared with persons without narcolepsy, patients with narcolepsy had significantly higher annual

These findings highlight the substantial economic burden associated with narcolepsy, including increases in healthcare utilization and costs, as well as reduced work productivity and overall impaired activity compared with the general population. healthcare costs, including indirect costs per person (mean, $9125 vs $19,852, respectively; P <.001), as well as direct costs per person (mean, $18,586 vs $54,136, respectively; P <.001). This translates to a mean annual total healthcare cost of $60,287 per patient with narcolepsy compared with $22,426 for matched persons without narcolepsy.

Specifically, the annual costs for physician office visits were a mean of $7388 for controls without narcolepsy compared with $20,590 for patients with narcolepsy, hospital costs were $6151 for the controls compared with $36,778 for patients with narcolepsy, and the costs for emergency department visits were a mean of $1112 for controls compared with $4769 for patients with narcolepsy.

These findings highlight the substantial economic burden associated with narcolepsy, including increases in healthcare utilization and costs, as well as reduced work productivity and overall impaired activity compared with the general population. Ms Villa and colleagues suggest that future research should focus on the impact of clinical comorbidities among patients with narcolepsy on the economic burden of this disease. “Further analyses are needed to distinguish the impact of medical comorbidities as well as treatment on these outcomes,” they concluded. n Source: Villa KF, Black J, Chervin RD, et al. Resource use, productivity loss, and economic burden of narcolepsy: results from the National Health and Wellness Survey. Poster presented at the Academy of Managed Care Pharmacy 2014 Nexus Meeting; October 7-10, 2014; Boston, MA.

Treatment Patterns and Total Healthcare Costs in Patients with Advanced Melanoma Melanoma is the fifth leading cancer in adults in the United States, with an estimated 76,100 new cases likely to be diagnosed this year. Advances in treatment have resulted in increased survival rates in patients with advanced, stage IV disease. A team of researchers investigated the new treatment patterns to calculate the impact on the associated health­­­­care costs.

All patients received at least 1 line of therapy; 31% received second-line treatment, 9% received third-line therapy, and 2% received fourth-line treatment.

Using claims data from the Truven Health MarketScan databases, a team of researchers from Truven Health Analytics and Bristol-Myers Squibb, led by Elisabetta Malangone of Truven Health Analytics, Bethesda, MD, studied treatment patterns and the cost of treating patients with melanoma.

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Patients with stage IV melanoma who had ≥1 inpatient claims or ≥2 outpatient visit claims with a first claim for metastatic melanoma (ie, index date) between October 1, 2010, and June 30, 2013, were included in this study if they had at least 6 months of continuous coverage before the index date.

A total of 643 patients with stage IV melanoma were included in the study (mean age, 58 years); 65% of the patients were male, and 27% had Medicare supplemental coverage.

All patients received at least 1 line of therapy; 31% received second-line treatment, 9% received thirdline therapy, and 2% received fourth-line treatment.

In all lines of treatment, ipilimumab was the most frequently used, with 34.4% of patients receiving it as first-line treatment, 37.2% receiving it for second-line treatment, 32.7% for third-line therapy, and 36.4% for fourth-line treatment.

The mean duration of first-line treatment was dependent on the type of medication used: 53 days for ipilimumab, 150 days for vemurafenib (which was the longest duration when introduced as first-line thera-

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py), 100 days for temozolomide, and 36 days for interleukin (IL)-2. The mean times from the initiation of first-line therapy to the initiation of second-line therapy were 182 days with ipilimumab, 153 days with vemurafenib, 163 days with temozolomide, and 146 days with IL-2.

The average total all-cause healthcare costs per-patient per-month (PPPM) during follow-up for patients with stage IV disease were: • $24,844 PPPM for all patients • $29,562 PPPM for first-line ipilimumab therapy (N = 218) • $20,823 PPPM for first-line vemurafenib therapy (N = 128).

The costs for patients receiving ipilimumab with >12 months of follow-up was an average of $12,897

PPPM after month 13 of treatment. That cost was $16,704 PPPM for patients receiving vemurafenib.

“Patients treated with first-line ipilimumab had higher expenditures initially, but lower average expenditures in the period beyond 12 months, while first-line vemurafenib patients had lower expenditures initially but higher average expenditures in the period beyond 12 months,” the investigators concluded. n Source: Malangone E, Hirji I, Hallmeyer S, et al. Trends in US treatment patterns and total health care expenditures of newly diagnosed advanced melanoma patients from a Medicare and commercially insured database, 2011-2013. Poster presented at the Academy of Managed Care Pharmacy 2014 Nexus Meeting; October 7-10, 2014; Boston, MA.

Clinical Pathways Can Improve the Use of Antipsychotic Medications in Patients with Schizophrenia Schizophrenia is estimated to affect slightly more than 1% of the US population. This condition is characterized by delusions, hallucinations, incoherence, disorganized behavior, and affective flattening. The disease is described as an idiosyncratic syndrome, and its symptoms, such as increased severity or impending disease relapse, may be idiosyncratic in nature and may not represent a group of patients with this debilitating condition. Studies have shown that a lack of adherence to antipsychotic medications can increase relapse rates and can lead to increased health resource utilization and poor prognosis.

A new study investigated the use of treatment pathways as a potential tool toward the improvement of prescribing appropriate antipsychotic medications to patients with schizophrenia, to reduce the use of ineffective treatments and the increased costs of using inappropriate treatments. Joseph Tkacz, MS, of Health Analytics, Columbia, MD, and colleagues used medical and pharmacy claims data to investigate the patient treatment history and medication use patterns, with the goal of finding treatment patterns or pathways that could improve treatment success and reduce the associated costs for patients with schizophrenia.

The study included 2666 patients with a diagnosis of schizophrenia who were members of an Aetna health plan, with medical and pharmacy coverage between 2010 and 2013. The index diagnosis date was defined as the first event in the form of (1) an inpatient hospitalization with an International Classification of Diseases,

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Ninth Edition, Clinical Modification (ICD-9-CM) schizophrenia diagnosis code 295.xx on the claim, or (2) the first of 2 outpatient visits within 1 year for a patient with an ICD-9-CM schizophrenia diagnosis code on the claim. Patients diagnosed solely with an ICD-9-CM schizophreniform disorder (295.4) or with schizoaffective type (295.7) were excluded from the analysis. To participate in the study, patients had to be eligible continuously for 2 years after the study index date.

Studies have shown that a lack of adherence to antipsychotic medications can increase relapse rates and can lead to increased health resource utilization and poor prognosis.

During the 2-year study, patients were divided into 4 groups based on their antipsychotic regimen, including (1) a long-acting injectable medication group; (2) an oral concurrent group of patients receiving 2 oral antipsychotics concurrently; (3) an oral switch group, which included patients using >1 oral antipsychotic agent at different times; and (4) an oral stable group, which included patients using 1 oral antipsychotic medication and who had a supply of ≥90 days.

The oral stable group was used as the gold standard of treatment. The mean performance of that

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group during the postindex period was used as the primary comparator.

Of note, the patients’ ages differed significantly by group. The patients in the long-acting injectable group and the oral switch group were significantly younger than the patients in the oral stable group, and the patients in the oral concurrent group were significantly older than the patients in the oral switch group (P <.05).

Specifically, after treatment initiation, emergency department visits decreased in all 4 groups, with the greatest reduction seen in the long-acting injectable group, followed by the oral switch group.

Overall, 6 patient instability events were measured in each 90-day quarter, including: • Inpatient psychiatric hospitalizations • Psychiatric emergency department visits • Use of another psychiatric medication • Other psychiatric behavior • Change in the frequency of schizophrenia-related outpatient visits • Proportion of covered days for antipsychiatric medication.

The results showed a growing number of patient instability events before the index event, with the ­ long-acting injectable group and the oral switch group demonstrating the greatest numbers of schizophrenia-related events before starting the treatment regimen. After the initiation of treatment, all groups showed a decrease in the number of psychiatric-related events, with few exceptions.

A group-based effect was seen on the change in total instability events with the initiation of treatment in all

groups. The long-acting injectable group showed the greatest reduction in total events, followed by the oral switch group and then the oral stable group. The oral concurrent group showed the least reduction in events across the different measurements analyzed. The overall difference in event reduction between the long-acting injectable and the oral concurrent groups was significant (P <.05). Patients who were switched from their initial treatment to a long-acting injectable showed the greatest reduction in psychiatric-related events.

Specifically, after treatment initiation, emergency department visits decreased in all 4 groups, with the greatest reduction seen in the long-acting injectable group, followed by the oral switch group; again, the least change was seen in the concurrent oral group. Similarly, the concurrent oral group showed an increase in inpatient hospitalization, whereas the other 3 groups showed a decrease in hospitalization, with the oral switch group showing the greatest decrease. A reduction in other psychiatric behaviors was also seen after the index group date, with the greatest decrease again seen with the long-acting group, followed by the oral switch group.

Perhaps not surprising, the decrease in hospitalization in the 3 groups noted above was associated with an increase in outpatient visits.

The investigators concluded that the patient instability events identified in this study “may be useful in the development of case finding tools to facilitate matching patients to the most effective and efficient treatment available.” n Source: Tkacz J, Brady BL, Waters HC, et al. An examination of clinical pathways among a sample of patients with schizophrenia treated with antipsychotic medication: a retrospective analysis of commercial health plan claims data. Poster presented at the Academy of Managed Care Pharmacy 2014 Nexus Meeting; October 7-10, 2014; Boston, MA.

Cost Implications of Therapies to Manage Obesity: A Budget Impact Analysis Understanding the utilization patterns and cost of a drug can assist health plans to determine the relative value of adding a specific agent to the plan’s formulary and the potential benefits to patients. A recent study analyzed the cost implications for US payers of adding naltrexone-bupropion to a plan’s formulary for the treatment of patients with obesity in the United States, using a budget impact model.

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Naltrexone-bupropion is an extended-release, fixed-dose combination therapy recently approved by the US Food and Drug Administration (FDA) for the treatment of obesity and weight management as an adjunct to a reduced calorie diet and an enhanced physical activity program. Other anti-obesity drugs currently approved by the FDA include phentermine, lorcaserin, phentermine-topiramate, and other

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agents (including orlistat).

Using a pharmacy budget impact model, the investigators analyzed the economic impact of adding this anti-obesity medication to a formulary during 3 years for a hypothetical health plan with 1 million members.

A secondary analysis included a plan with 500,000 members. The estimates for the number of patients who would be eligible for anti-obesity therapies were based on the US National Health and Wellness Survey (NHWS), a self-reported, cross-sectional survey of the US population.

Based on the NHWS, a 1-million member plan would include 627,467 patients who are obese or overweight. Of these, only an estimated 3360 patients would be receiving an anti-obesity medication in the first year. This number was projected to increase by 9.6% in the second year and by 11.3% in the third year, for a total of 4098 patients.

The market share of the combination of naltrexone-bupropion was estimated to be 5.4% in year 1, 7.7% in year 2, and 8.6% in year 3, based on current market shares of phentermine (80%), lorcaserin (5.4%), phentermine-topiramate (6.7%), and 7% from other agents.

By adding naltrexone-bupropion to current anti-­ obesity therapies on the formulary, the total budget impact would be $1,863,877 in year 1, $2,137,873 in year 2, and $2,430,471 in year 3. Without the addition of this combination therapy to the formulary, the total budget impact would be $1,529,952 in year 1, $1,606,766 in year 2, and $1,763,833 in year 3.

For a plan size of 1 million members, adding naltrexone-bupropion to the formulary would result in a per-member per-month (PMPM) cost of $0.03; for a

population of 500,000 members, the PMPM cost would be $0.04.

Overall, the addition of naltrexone-bupropion to the anti-obesity therapies on a formulary would result in a cost of less than $0.05 PMPM. The investigators note that this analysis does not include the cost implications of treatment discontinuation; therefore, it is likely that the budget impact of adding this combination therapy would be even lower than the current PMPM estimated cost. The investigators conclude that “there may be additional relevant costs to a health plan that have not been captured in this analysis, including cost offsets associated with fewer health-related complications as a result of weight loss from anti-obesity medications.” n

For a plan size of 1 million members, adding naltrexone-bupropion to the formulary would result in a per-member per-month (PMPM) cost of $0.03; for a population of 500,000 members, the PMPM cost would be $0.04.

Source: Gordon J, McEwan P, Bron M, Ward T. The economics of anti-obesity treatment: evaluating the budget impact to payers in the United States associated with new and existing anti-obesity medications. Poster presented at the Academy of Managed Care Pharmacy 2014 Nexus Meeting; October 7-10, 2014; Boston, MA.

Real-World Healthcare Utilization and Medical Costs Lower with Dabigatran than with Warfarin in Patients with Nonvalvular Atrial Fibrillation Approximately 2.6 million Americans are diagnosed with atrial fibrillation, and 95% of them have nonvalvular atrial fibrillation (NVAF). The recently approved novel oral anticoagulants are increasingly used as an alternative to warfarin therapy in the treatment of patients with NVAF. This new retrospective cohort study compared real-­ world all-cause healthcare resource utilization and associated medical (excluding pharmacy) costs in ­ ­patients with newly diagnosed NVAF who initiated therapy with warfarin or with dabigatran, the first FDA approved novel oral anticoagulant, between

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October 1, 2009, and September 30, 2013.

Data were collected from the electronic medical record (EMR) database of Humedica, which includes information for more than 30 million members across 38 states.

After matching for baseline demographics, 1945 patients with newly diagnosed NVAF who were newly treated with dabigatran or with warfarin were included in each cohort. The patients’ mean age was 70 years, and 58% were male. All patients had ≥1 EMR encounter 12 months before the index date, which was defined as the date of first prescription fill for

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­da­bigatran or for warfarin.

The all-cause per-patient per-year (PPPY) mean number of hospitalizations was lower with dabigatran than with warfarin (1.07 vs 1.20, respectively; P <.001); similarly the mean number of emergency department visits and physician office visits were lower with dabigatran than with warfarin (0.36 vs 0.51 and 10.64 vs 18.13, respectively; P <.001).

The all-cause per-patient per-year mean number of hospitalizations was lower with dabigatran than with warfarin (1.07 vs 1.20, respectively; P <.001); similarly the mean number of emergency department visits and physician office visits were lower with dabigatran than with warfarin.

Furthermore, the patients receiving dabigatran had a significantly shorter hospital stay compared with those receiving warfarin (4 days vs 4.6 days, respectively; P <.001).

The mean direct medical costs PPPY for hospitalization were $10,513 with dabigatran versus $17,768 with warfarin; the mean PPPY emergency department costs were $374 versus $531, respectively; and for office visits the costs were $2712 versus $4622, respectively (all P <.001). The mean total medical costs were also lower with dabigatran ($13,600) compared with warfarin ($22,920; P <.001).

Lead investigator Matthew Sussman, MA, Boston Health Economics, Waltham, MA, and colleagues noted that the cost data were not available in the EMR database and “had to be imputed from an external data source.” Furthermore, they added, “pharmacy costs could not be assessed due to the insufficiency of NDC [National Drug Code] data for each observed prescription in the EMR data set.” n Source: Sussman M, Sutherland S, Ghate S, et al. Allcause healthcare resource utilization and associated medical costs among newly diagnosed non-valvular atrial fibrillation patients treated with dabigatran or warfarin within integrated healthcare delivery networks. Poster presented at the Academy of Managed Care Pharmacy 2014 Nexus Meeting; October 7-10, 2014; Boston, MA.

Payers’ Perspectives on Accountable Care Organizations in Oncology Accountable care organizations (ACOs) have been promoted as a potential way to deliver cost-effective patient care. However, its embracement in cancer care has been slow, in part because the ACO model is a departure from the fee-for-service model that is common in oncology.

A team of researchers from Xcenda has conducted a survey of its payer members in the Managed Care Network (MCN), which includes payers in commercial health plans, Medicare Advantage/prescription drug plans, Medicaid health plans, integrated healthcare delivery systems, and pharmacy benefit managers. Together, MCN members, which consist mainly of medical and pharmacy directors, represent approximately 100 million covered lives in a variety of regional and national health plans.

Two electronic surveys were sent to MCN payer members; a total of 48 members responded to the June 2012 survey and 58 payers responded to the January 2014 survey. The questions were focused on the health plan’s current and future involvement in ACOs and their potential strategies for implementing an oncology-specific ACO. Furthermore, the survey presented

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details of an oncology ACO pilot program to gauge the interest of payers in such a program. The requirements for the proposed pilot program included: • Provide 24/7 access to care for patients with cancer • Offer preventive and/or survivorship care • Encourage patients and families to actively participate in the patient’s care • Coordinate cancer care across medical facilities, including primary care and electronic health records • Actively monitor or manage adverse events.

Payers would provide a monthly management fee to participating offices and practices. Participant oncologists will also be able to share in any payer cost-savings resulting from the pilot ACO. The investigators compared the responses between 2012 and 2014 to determine any difference in trends between these 2 periods. Overall, compared with 2012, payers expressed less interest in an oncology pilot ACO; in 2012, 50% of payers reported no plans to implement such an ACO; that percentage was up by 16% in 2014, with 66% of payers reporting no such plans. In 2012, 13% of survey responders reported their plans have already implemented an

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oncology ACO compared with only 10% in 2014; similarly, whereas 38% of 2012 respondents reported a plan to implement an oncology ACO in the next 12 months to 18 months, only 24% reported such a plan in 2014 (a 14% reduction in plans to implement an oncology ACO).

A similar trend was seen with regard to implementing an oncology medical home. In 2012, 8% of plans had implemented an oncology medical home; by 2014, that number was at 12%. As for their plans to establish an oncology medical home in the next 12 to 18 months, compared with 44% of payers who reported such plans in 2012, only 16% reported such a plan in 2014, a 24% reduction in interest in the oncology medical home.

These findings reveal a clear reduction in the interest of managed care health plans regarding oncology-specific programs as a way to manage their members who have cancer. The investigators sug-

gest that “more research is needed to understand why payer interest in oncology ACO models is decreasing when overall interest in ACOs as a cost savings method is increasing.” n

These findings reveal a clear reduction in the interest of managed care health plans regarding oncology-specific programs as a way to manage their members who have cancer.

Source: Knight JM, Denno M, Allen L, et al. Managed care perspectives on accountable care organization implementation: focus on oncology. Poster presented at the Academy of Managed Care Pharmacy 2014 Nexus Meeting; October 7-10, 2014; Boston, MA.

Prognostic Test Cost-Effective in Patients with Early-Stage Lung Adenocarcinoma Patients with early-stage non–small-cell lung cancer (NSCLC) have poor prognosis: 40% of patients with stage I NSCLC and 66% of patients with stage II disease will die within 5 years of diagnosis. A team of investigators who have studied the benefits of a new prognostic test for lung adenocarcinoma suggest that this “may indicate some of these patients may be high risk and would benefit from adjuvant chemotherapy (ACT),” which has been shown to reduce the risk for disease recurrence in patients with stage II but not ­stage I NSCLC. The team of researchers from the University of Utah, College of Pharmacy, in Salt Lake City; Myriad Genetic Laboratories, Inc, Salt Lake City; and Harvard School of Public Health, Harvard University, Boston, investigated the cost-benefit of a recently introduced test for early-stage NSCLC. Developed

by Myriad Genetics and known as “myPlan Lung Cancer,” this prognostic test has been shown to predict the mortality risk in patients with early-stage NSCLC with adenocarcinoma histology and can guide the decision about the use of ACT in this patient population.

The team developed a Markov model to compare the cost-utility of using the prognostic test versus a standard-of-care strategy in patients with early-stage NSCLC. The base case model included 10,000 pa-

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tients; the probability of receiving ACT with either standard of care or after the prognostic test was estimated based on a survey of 101 physicians who treated patients with NSCLC and varied by disease stage and risk stratification; the cost outcomes were calculated in 2011 US dollars, and cost-effectiveness was measured by quality-adjusted life-years and incremental cost-­ effectiveness ratio (ICER). Patients were classified as high risk if their 5-year mortality risk on the prognostic test was more than 22%.

Based on this base case model, a total of 42.6% of the patients with early-stage NSCLC received ACT in the prognostic test arm compared with 27.3% of patients who received ACT in the standard-of-care arm.

In this model, the overall lifetime cost of patients using the prognostic test was $131,528 compared with $121,914 for patients in the standard-of-care arm. The ICER for the prognostic test versus the standard of care was $34,334. A simulation analysis showed that the prognostic test was cost-effective in 65.9% of patients willing to pay a threshold of $50,000 and in 89.1% of patients willing to pay a threshold of $100,000, which are generally considered acceptable thresholds based on previous research.

One-way sensitivity analysis suggested that the largest driver of cost-effectiveness was not having cancer after receiving ACT. The investigators con-

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cluded that “the results of this study suggest that using the prognostic test to guide ACT decisions in NSCLC is cost-effective compared to a SoC [standard-of-care] approach according to globally ­ ­accepted thresholds.” n

Source: Stenehjem DD, Bellows BK, Kaldate R, et al.

Cost-utility analysis of a prognostic test for early stage non-small cell lung cancer (NSCLC). Poster presented at the Academy of Managed Care Pharmacy 2014 Nexus Meeting; October 7-10, 2014; Boston, MA.

Workplace Onsite Pharmacy Improves Medication Adherence of Employees Medication nonadherence is a well-known factor that is linked to worsening health outcomes, increased healthcare utilization, and associated costs. Employers are increasingly offering services to improve their employees’ well-being.

A team of researchers from Cerner Corporation investigated the long-term impact of an onsite pharmacy at its Kansas, MO, offices on medication adherence among its employees. Kathleen M. Aguilar, MPH, of Cerner Research Services, Culver City, CA, and colleagues performed a retrospective analysis of pharmacy claims data between January 1, 2009, and December 31, 2011.

Members with a pharmacy claim for asthma, depression, diabetes, hyperlipidemia, or hypertension were followed for 365 days after the first prescription fill between these dates. Participants had to have 6 months of health plan coverage before the first prescription fill after January 1, 2009, and continuing coverage for the next full year.

Medication possession ration (MPR) was calculated for the total drug supplied for 365 and 730 days. A

total of 2498 employees were included in the analysis.

Overall, the results showed that employees who used the onsite pharmacy were more likely to fill their prescriptions and adhere to their medication regimen.

Across all types of drugs, the average MPR was significantly higher for patients using the onsite pharmacy than for those using offsite pharmacy services (P <.001); this was true at 365 days and at 730 days.

In addition, the average number of days to discontinuation of all drug types was also significantly greater for employees using the onsite pharmacy than for those using an offsite pharmacy (P <.001).

Ms Aguilar and colleagues concluded, “The association of improved medication adherence with onsite pharmacy use was found across the included chronic conditions.” n Source: Aguilar KM, Hou Q, Miller RM. Impact of onsite pharmacy on medication adherence: an updated analysis. Poster presented at the Academy of Managed Care Pharmacy 2014 Nexus Meeting; October 7-10, 2014; Boston, MA.

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VISIT THE NEW ONLINE RESOURCE FOR THE ENTIRE MULTIPLE MYELOMA CARE TEAM

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Value-Based Care in Myeloma delivers exclusive interviews and perspectives related to cost, quality, and access issues.

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