AHDB DECEMBER 2014 by Dalia Buffery

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

VOLUME 7, NUMBER 9

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

EDITORIAL

Maintaining Medication Quality David B. Nash, MD, MBA BUSINESS

Budgetary Impact of Adding Riociguat to a US Health Plan for the Treatment of Patients with Pulmonary Arterial Hypertension or Chronic Thromboembolic Pulmonary Hypertension ™

Chakkarin Burudpakdee, PharmD; Anshul Shah, MS; Vijay N. Joish, PhD; Christine Divers, PhD; Avin Yaldo, PhD Stakeholder Perspective: Is It Time for Risk-Sharing Contracts In Specialty Pharmacy? By Atheer A. Kaddis, PharmD CLINICAL

Diagnosis and Treatment of Bipolar Disorders in Adults: A Review of the Evidence on Pharmacologic Treatments Michael W. Jann, PharmD, FCP, FCCP Stakeholder Perspective: Bipolar Disorders: Balancing Formulary Management and Clinical Outcomes for a Vulnerable Patient Population By Gary M. Owens, MD CONTINUING EDUCATION

Evolution in the Value-Based Care of Rheumatologic Diseases: A Prospectus for Managed Care Pharmacists Douglas Burgoyne, PharmD; Joseph F. Merola, MD, MMSC; Jonathan Kay, MD

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EDITORIAL BOARD EDITOR-IN-CHIEF

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

PAYER-PROVIDER FINANCES

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

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

PERSONALIZED MEDICINE

SPECIALTY PHARMACY

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

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

American Health & Drug Benefits

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

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DECEMBER 2014

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PUBLISHING STAFF Senior Vice President/Group Publisher Nicholas Englezos nenglezos@the-lynx-group.com Directors, Client Services Joe Beck jbeck@the-lynx-group.com Zach Ceretelle zceretelle@the-lynx-group.com Ron Gordon rgordon@the-lynx-group.com Editorial Director Dalia Buffery dbuffery@the-lynx-group.com Senior Associate Editor Lilly Ostrovsky Associate Editor Lara J. Lorton Editorial Assistant Cara Guglielmon Production Manager Cara Nicolini Founding Editor-in-Chief Robert E. Henry

EDITORIAL

475 Maintaining Medication Quality David B. Nash, MD, MBA BUSINESS

479 Budgetary Impact of Adding Riociguat to a US Health Plan for the Treatment of Patients with Pulmonary Arterial Hypertension or Chronic Thromboembolic Pulmonary Hypertension Chakkarin Burudpakdee, PharmD; Anshul Shah, MS; Vijay N. Joish, PhD; Christine Divers, PhD; Avin Yaldo, PhD 486 Stakeholder Perspective: Is It Time for Risk-Sharing Contracts In Specialty Pharmacy? By Atheer A. Kaddis, PharmD CLINICAL

489 Diagnosis and Treatment of Bipolar Disorders in Adults: A Review of the Evidence on Pharmacologic Treatments Michael W. Jann, PharmD, FCP, FCCP 499 Stakeholder Perspective: Bipolar Disorders: Balancing Formulary Management and Clinical Outcomes for a Vulnerable Patient Population By Gary M. Owens, MD Continued on page 474

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TABLE OF CONTENTS

(Continued)

CONTINUING EDUCATION

508 Evolution in the Value-Based Care of Rheumatologic Diseases: A Prospectus for Managed Care Pharmacists Douglas Burgoyne, PharmD; Joseph F. Merola, MD, MMSC; Jonathan Kay, MD CORRECTION

487 Impact of the New ACC/AHA Guidelines on the Treatment of High Blood Cholesterol in a Managed Care Setting

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EDITORIAL

Maintaining Medication Quality David B. Nash, MD, MBA Editor-in-Chief, American Health & Drug Benefits; Founding Dean, J Â efferson School of Population Health, Philadelphia, PA

have had the privilege of serving on the Pharmacy and Therapeutics (P&T) committee at Thomas Jefferson University Hospital for nearly a quarter of a century, and I serve as Chair for its Medication Quality subcommittee. I have enjoyed my longtime service on both committees, and have reported on their work to readers of American Health & Drug Benefits.1 I am confident that tying the work of the P&T committee to the overall delivery of high-value healthcare is an imporÂ tant annual exercise. As such, at the close of 2014, it would be beneficial to review the recent annual report from the subcommittee and make some broad recommendations for 2015 and beyond. The work of the Medication Quality subcommittee is divided into several discrete segments. The first involves a detailed review of adverse drug events, from surveillance and prevention perspectives. The second involves a critical review of medication through a standardized process, sometimes called Medical Use Evaluation (MUE). The third is the day-to-day work of reviewing protocols and policies regarding medication use in our healthcare system, and finally, critical activities that ensure regulatory compliance. Let us examine each of these in turn. Regarding adverse drug event prevention and surveillance, our committee worked hard in this past academic year to examine the quarterly medication events and adverse drug reaction reports. We made specific recommendations, as appropriate, and reviewed the logs for the documentation of system improvements that were made in response to events. Our adverse drug reaction reports reveal a stable system, with very little perturbation throughout the year. Sometimes our work leads to a root cause analysis on a department-specific basis. For example, house officers in the Department of Medicine did a root cause analysis this past year relating to medication reconciliationâ&#x20AC;&#x201D;clearly a critically important issue. Finally, we also reviewed and evaluated reports from the Chemotherapy Event Review committee. Clearly, we want to deliver these toxic medications in the safest way possible. Vigilance and ongoing system evaluation are important tools in ensuring patient safety.

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With regard to MUE, 2014 was a busy year. We reviewed quarterly reports of, for example, proton pump inhibitors, parenteral nutrition, and related medications. We routinely compared our performance in the use of proton pump inhibitors and parenteral nutrition with our colleagues across the membership of UHC (formerly known as the University HealthSystem Consortium). We are lucky to have this national comparative data set on hospitals similar to ours, because it provides ongoing benchmarks to help in evaluating our performance. We also reviewed quarterly reports of the use of rescue drugs. For example, how often do we need to use dextrose for insulin overdose or naloxone for an opioid overdose? We compared favorably with the UHC members in these subcategories. Within the MUE category, we also sometimes pose difficult questions. For example, how can we more appropriately dispense drugs such as zolpidem, which, by all accounts are overly prescribed by physicians? This is one of our more difficult tasks as we seek to choose wisely and create higher value for our patients. We also hope to avoid increasingly common drug interactions. Through one MUE review, we discovered that our use of combination antifungal medications for invasive fungal infections was not in compliance with nationally recommended guidelines, which led us to make recommendations to our colleagues in the Infectious Disease subcommittee and up through the chain of command to various clinical department chairs. We revisit these issues months, and sometimes years, later to see how we are doing. In short, self-evaluation, measurement, and closure of the feedback loop are the critical tools that characterize the MUE process. Of course, in a place of our scope and size (an urban academic medical center with 3 sites and 957 acute care beds), the annual review of standing policies and protocols is always a good idea. It is incredible to consider the number of policies that are under our purview, including investigational drugs, controlled substances, deletion of drugs from the formulary, documentation of vaccine administrations, policies on verbal orders, and policies for educating patients on drug interaction. Any time a clinical department alters a standing protocol

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involving the administration of a pharmaceutical agent, our subcommittee swings into action and must give final approval to a standing protocol-driven, evidence-based guideline anywhere in the institution.

I am curious about your P&T committee and its subcommittee structure. How does your organization review adverse drug events, MUEs, and standing policies and procedures? Finally, regarding activities that ensure compliance with regulatory requirements, we respond on a regular basis to scores of external requests for information. At any moment, our hospital could be inspected by officials from the city, state, Medicare, or accrediting bodies. One of the many areas I am most proud of is our ongoing compliance with what we refer to as “double signatures”—the requirement that 2 people sign off— for certain high-risk medications. This is especially critical in the chemotherapy arena. It turns out that

compliance with the medication reconciliation monitors remained high this past academic year, and we are constantly tinkering with this system to ensure the highest possible level of medication safety. Looking back on my nearly 25 years of service on both committees, I am proud of our team. I want to especially note the tremendous support that our committee gets from Craig Senholzi, RPh, MBA, and Brian Swift, PharmD, MBA. I am grateful to these 2 leaders, as well as to many unnamed others who contribute their time, energy, and expertise on a monthly basis to help ensure that our patients are safe. Of course, safety is a cornerstone of delivering value; I see it as central to the mission of our complex academic medical center. I am curious about your P&T committee and its subcommittee structure. How does your organization review adversedrug events, MUEs, and standing policies and procedures? As always, feel free to reach out to me at david.nash@jefferson.edu. We can all continue to learn from one another. n

Reference

1. Nash DB. Hardworking P&T committees. Am Health Drug Benefits. 2012;5:330.

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BUSINESS

ORIGINAL RESEARCH

Budgetary Impact of Adding Riociguat to a US Health Plan for the Treatment of Patients with Pulmonary Arterial Hypertension or Chronic Thromboembolic Pulmonary Hypertension Chakkarin Burudpakdee, PharmD; Anshul Shah, MS; Vijay N. Joish, PhD; Christine Divers, PhD; Avin Yaldo, PhD BACKGROUND: Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are chronic, debilitating, and life-threatening conditions. Riociguat is the first and only pharmacotherapy approved by the US Food and Drug Administration (FDA) for the treatment of PAH and for CTEPH in patients who are either inoperable or have persistent pulmonary hypertension after surgery. OBJECTIVE: To estimate the budgetary impact of adding riociguat to a US health plan’s formulary for the treatment of patients with PAH or CTEPH using a budget impact analytic model. METHODS: A customizable, Microsoft Excel–based decision analytic tool was developed to estimate the impact of riociguat on per-member per-month (PMPM) and per-member per-year (PMPY) bases in Medicare and non-Medicare health plans. The economic impact was calculated based on 1 million insured lives, published prevalence estimates of PAH and CTEPH, pharmacotherapy-eligible patients with PAH or CTEPH, administration costs, and monitoring costs related to pharmacotherapy. The drug costs were based on wholesale acquisition costs, and the medical costs were derived from Truven Health MarketScan claims data and the Medicare 2013 Clinical Diagnostic Laboratory Fee Schedule and Physician Fee Schedule. The market share for approved treatments was based on a tracking study of physicians treating patients with PAH or CTEPH. A sensitivity analysis was used to test the model’s robustness. RESULTS: In a hypothetical plan population of 1 million members, the model estimated that 7 patients with PAH and 2 patients with CTEPH would be suitable for pharmacotherapy. Overall, 3 patients (1 with PAH and 2 with CTEPH) were receiving riociguat in a health plan consisting of patients with commercial and with Medicare insurance coverage. The incremental PMPY and PMPM costs for providing insurance coverage for riociguat were $0.27 and $0.02, respectively, for non-Medicare and Medicare health plans. Sensitivity analyses indicated that the budget impact increased by $0.01 PMPM, with a 25% increase in base-case parameter values. CONCLUSION: Riociguat is a first-in-class and the only FDA-approved treatment for patients with PAH or CTEPH—2 debilitating, chronic, and life-threatening conditions with poor prognosis. This drug offers health plans an effective and safe treatment option, with a minimal economic impact. The financial impact to a health plan of providing coverage for riociguat in the first year of treatment was as low as $0.02 PMPM. The real-world budget impact of riociguat needs to be measured using real-world evidence to validate our results.

Dr Burudpakdee is Principal, IMS Health, Fairfax, VA, and Research Assistant Professor, University of North Carolina at Charlotte; Mr Shah is Senior Analyst, Market Access Solutions, LLC, Raritan, NJ; Dr Joish is Director, Health Economics and Outcomes Research, Bayer HealthCare Pharmaceuticals Inc; Dr Divers is Director, Health Economics and Outcomes Research, Bayer HealthCare Pharmaceuticals Inc; Dr Yaldo is Director, Health Economics and Outcomes Research, Bayer HealthCare Pharmaceuticals Inc, Whippany, NJ.

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Chakkarin Burudpakdee, PharmD

Stakeholder Perspective, page 486

Am Health Drug Benefits. 2014;7(9):479-487 www.AHDBonline.com Received October 6, 2014 Accepted in final form November 14, 2014

Disclosures are at end of text

ulmonary arterial hypertension (PAH) and chro nic thromboembolic pulmonary hypertension (CTEPH), the 2 subtypes of pulmonary hyperten sion, are chronic, debilitating, and life-threatening condi tions. Despite the differences in etiologies between PAH and CTEPH, both are primarily characterized by vascular remodeling that results in progressive right heart failure and death.1-3 Based on a recent US analysis of risk stratifi cation in patients with PAH, the 1-, 3-, and 5-year surviv

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KEY POINTS Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are debilitating, progressing, and lifethreatening conditions. ➤ Despite improved outcomes with prostacyclin analogs, endothelin receptor antagonists, and PDE-5 inhibitors, PAH remains a progressive and fatal disease, with poor survival. ➤ Riociguat is an oral, first-in-class soluble guanylate cyclase stimulator and is the only FDA-approved agent for the treatment of patients with either condition—PAH or CTEPH. ➤ This is the first budget impact analysis of adding riociguat to a US health plan for the treatment of patients with PAH or CTEPH. ➤ In this analysis, the per-member per-year cost of adding riociguat to the treatment regimen was $0.27 and the per-member per-month (PMPM) cost was $0.02. ➤ A sensitivity analysis indicated that the economic impact increased by $0.01 PMPM, with a 25% increase in base-case parameter values. ➤ This study shows that providing insurance coverage for this first-in-class, effective treatment for patients with PAH or CTEPH, has a minimal economic impact on a health plan. ➤

al rates are 92%, 75%, and 66%, respectively.4 Similarly, in a UK-based study conducted between 2001 and 2006, the 1- and 3-year survival rates for patients with inopera ble CTEPH were 82% and 70%, respectively.5 In the United States, the prevalence of PAH per 1 million individuals is estimated to be 109 patients in persons aged <65 years, and 451 patients in older persons aged ≥65 years.6 The prevalence of CTEPH per 1 million individuals is estimated to be 63 patients in persons aged <65 years and 1007 patients among older persons aged ≥65 years.6 However, the true prevalence of PAH and of CTEPH is difficult to measure, because of the underdiag nosis and misdiagnosis of these diseases, and the lack of specific International Classification of Diseases, Ninth Edition, Clinical Modification codes for these 2 conditions.6,7 The existing strategies that are approved by the US Food and Drug Administration (FDA) for the treatment of PAH involve the use of prostacyclin analogs, such as treprostinil and iloprost (including inhaled, injectable, or oral prostanoids); endothelin receptor antagonists, such as ambrisentan and bosentan; and/or phosphodiesterase (PDE)-5 inhibitors. Although not approved by the FDA

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for PAH, calcium channel blockers, in particular L-type calcium channel blockers (eg, nifedipine), can be effec tive, but they are only safe for patients who respond to a one-time vasodilator challenge (ie, vasoreactive-positive patients).8 Despite improved outcomes with prostacyclin analogs, endothelin receptor antagonists, and PDE-5 in hibitors, PAH remains a progressive and fatal disease, with poor survival rates.4 In patients with CTEPH, the treatment of choice is pulmonary endarterectomy; however, in 20% to 40% of patients, CTEPH is deemed to be inoperable. In addi tion, 10% to 20% of patients who undergo pulmonary endarterectomy have persistent or recurrent pulmonary hypertension after surgery.9-11 In these patients, there is a significant unmet need for an effective alternative treatment to surgical intervention or for a bridging therapy before pulmonary endarterectomy. The safety and efficacy of riociguat, an oral, first-in-class soluble guanylate cyclase stimulator, have been evalu ated in 2 phase 3 randomized controlled clinical trials, 1 trial in patients with PAH12 and 1 trial in patients with CTEPH.13 Riociguat has a dual mode of action of increasing the sensitivity of soluble guanylate cyclase to nitric oxide and directly stimulating the soluble gua nylate cyclase independent of nitric oxide availability, which can increase hemodynamic and exercise capacity in patients with PAH.12,13 In October 2013, riociguat was approved by the FDA for the treatment of adults with PAH (World Health Or ganization [WHO] Group 1) to improve exercise capacity and WHO functional class and to delay the clinical wors ening, and for the treatment of patients with inoperable or with persistent or recurrent CTEPH (WHO Group 4) to improve exercise capacity and WHO functional class.14 The objective of the present study was to measure the economic impact of adding riociguat to the drug formulary of a US health plan for the treatment of pa tients with PAH who are inoperable or who have per sistent or recurrent CTEPH.

Methods Model Overview An interactive, Microsoft Excel–based budget impact model was developed to evaluate the per-member permonth (PMPM) and per-member per-year (PMPY) budgetary impacts of providing coverage of riociguat for pharmacotherapy-eligible patients with PAH or CTEPH. The model has 4 major components: (1) population, which estimates the pharmacotherapy-eligible patients with PAH or CTEPH in a health plan of 1 million cov ered lives; (2) treatment, which distributes eligible pa tients across different pharmacotherapies based on best practice; (3) resource utilization, which quantifies the

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Budgetary Impact of Adding Riociguat to a US Health Plan

Figure 1 Flow Diagram to Determine Who Will Be Starting or Switching Statin Therapies Patients with PAH

Patients with CTEPH

Prevalence, 12.5 per 1 million individuals

Prevalence, 3.2 per 1 million individuals

Vasoreactive-positive patient proportion, 46%

Vasoreactive-negative patient proportion, 54%

Inoperable patient proportion, 36.4%

Pharmacotherapy-eligible patients with PAH Prevalence, 7 per 1 million individualsa

Pharmacotherapy-eligible patients with CTEPHc Prevalence, 2 per 1 million individuals

Operable patient proportion, 62.9%

Post-PEA residual pulmonary hypertension patient proportion, 12.5%b

Pharmacotherapy-eligible patients with PAH = total covered lives * prevalence of PAH * proportion of vasoreactive-negative patients. b 12.5% of patients undergoing surgery for CTEPH; assumes all operable patients undergo surgery. c Pharmacotherapy-eligible patients with CTEPH = (total covered lives * prevalence of CTEPH * proportion of inoperable patients) + [(total covered lives * prevalence of CTEPH) * proportion of operable patients] * proportion of patients post-PEA with residual pulmonary hypertension. CTEPH indicates chronic thromboembolic pulmonary hypertension; PAH, pulmonary arterial hypertension; PEA, pulmonary endarterectomy. a

healthcare resources utilized with treatment; and (4) cost, which applies unit costs to resources to estimate the PMPM and PMPY costs of treating patients before and after adding riociguat to a health plan drug formulary. The costs in this analysis were for the drugs, drug ad ministration, and drug monitoring. All costs were reported in 2013 US dollars, and no discounting of future cost was taken into account. The parameter estimates and costs for all model inputs were based on the published sources. The budget impact of riociguat was calculated as an increase in annual expenditure for treating with riocig uat pharmacotherapy-eligible patients with PAH or CTEPH, in terms of the PMPM and PMPY costs, the total annual expenditure, and the cost per therapeutic class. The PMPY costs were calculated by dividing the total expenditure by the total covered lives in the plan, and the PMPM costs were calculated by further divid ing the PMPY cost by 12. The cost impact of adding riociguat was calculated from a US health plan perspective, including patients with and without Medicare coverage, over a 1-year pe riod. The model did not make any claims of safety and/ or efficacy for the therapies included in the analysis.

Patient Population and Treatments Eligibility for pharmacotherapy was determined based on the American College of Cardiology Founda

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tion/American Heart Association guidelines for PAH.1 PAH-specific pharmacotherapy is recommended for patients with negative vasoreactive status. For patients with CTEPH, pharmacotherapy is recommended for inoperable patients and for patients with residual dis ease after undergoing surgery. The population estimates for pharmacotherapy- eligible patients aged ≥18 years with PAH or CTEPH who were considered in the analysis are shown in Figure 1. Because no US-specific published prevalence data for PAH and CTEPH were identified, various estimates from European registries were used to calculate the de fault prevalence data in patients with PAH or CTEPH. In this model, the prevalence of PAH was estimated to be 12.5 per 1 million individuals based on an aver age of estimates reported in the United Kingdom and Ireland (6.6 per 1 million individuals),15 France (15 per 1 million individuals),16 and Spain (16 per 1 million individuals).17 Similarly, a prevalence of 3.2 per 1 mil lion individuals for CTEPH was derived from a Span ish registry in the absence of US-specific data on CTEPH.17 It was assumed that all pharmacotherapy- eligible patients with PAH or CTEPH were receiving treatment and were fully adherent to the treatment and monitoring recommendations. Based on the epidemiology of PAH and CTEPH pre sented in Figure 1, a plan with 1 million covered lives would

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Table 1 P harmacotherapy-Eligible Patient Distribution in a US Health Plan Patients, Patients, without adding with adding Medication class riociguat,a N riociguat,b N sGC stimulator monotherapy (riociguat)

1 with PAH, 2 with CTEPH

PDE-5 inhibitor monotherapy (sildenafil)

ERA monotherapy (ambrisentan/bosentan)

ERA + PDE-5 inhibitor (ambrisentan/bosentan + sildenafil)

Bayer’s survey; data on file.18 Model assumption. CTEPH indicates chronic thromboembolic pulmonary hypertension; ERA, endothelin receptor antagonist; PAH, pulmonary arterial hypertension; PDE, phosphodiesterase; sGC, soluble guanylate cyclase. a

Table 2 M odel Drug Cost Inputs Monthly drug cost, WAC (2013),19 $

Medication class sGC stimulator monotherapy (riociguat)

7500.00

PDE-5 inhibitor monotherapy (sildenafil)

90.90

ERA monotherapy (ambrisentan/bosentan)

6644.18

ERA + PDE-5 inhibitor (ambrisentan/bosentan + sildenafil)

6375.08

ERA indicates endothelin receptor antagonist; PDE, phosphodiesterase; sGC, soluble guanylate cyclase; WAC, wholesale acquisition cost.

consist of approximately 7 patients with PAH and 2 pa tients with CTEPH who were eligible for pharmacotherapy. The treatment options considered in the analysis were based on FDA-approved pharmacotherapies, in cluding prostacyclin analogs (ie, treprostinil, iloprost), endothelin receptor antagonists (ie, ambrisentan, bosentan), and a PDE-5 inhibitor (ie, sildenafil). Com bination therapies of up to 2 molecules were included in the analysis, along with the monotherapies. The distribution of treatments was based on the re sults of a national survey from a tracking study of patients with PAH or CTEPH. The study was conducted in the United States in 2012 by Bayer to assess treatments that are often used in clinical practice for patients with PAH.18 This unpublished study included a survey of 160 US physicians who were actively involved in drug ther apy decisions for the treatment of patients with PAH, as well as 800 patient records from these physicians.18 The budget impact analysis was performed at the ther apeutic class level; the therapeutic classes included solu ble guanylate cyclases (riociguat), PDE-5 inhibitors

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(sildenafil), endothelin receptor antagonists (ambrisen tan and bosentan), systemic prostacyclin analogs (subcu taneous treprostinil), and inhaled prostacyclin analogs (iloprost and treprostinil). Because of the rarity of PAH, and the currently low market share of PCAs, no patients were treated with prostacyclin analogs in the base-case scenario. The rest of the therapeutic classes represented approximately 81% of the PAH drug treatment market.18 Table 1 shows the number of patients who received each class of medication, with and without the addition of riocig uat to a US health plan. Because of the lack of FDA- approved therapies for CTEPH before the FDA approval of riociguat, it was assumed that riociguat was the only pharmacotherapy indicated for the treatment of CTEPH.

Drug Costs The drug costs were based on the published 2013 wholesale acquisition costs (WAC),19 and were calculat ed based on the recommended dosages in the package inserts of the drugs (Table 2). The monthly cost of a PDE-5 inhibitor was based on the price of generic silden afil, whereas the cost of endothelin receptor antagonists was an average price of ambrisentan and bosentan. The model assumed no out-of-pocket pharmacy ex penses by patients with PAH or CTEPH. Background therapy, such as anticoagulants and diuretics, were not included in the model, because these therapies were rec ommended for all patients who received treatment and, therefore, were nondifferential in terms of a budget im pact.1 For drug acquisition costs, the model used only generic costs when available, and did not account for rebates and dispensing fees in the drug cost calculations. Drug Monitoring Costs The annual drug monitoring costs were calculated based on the FDA package insert resource requirements for drug monitoring. The annual monitoring costs for riociguat were based on 12 urine pregnancy tests (for females only) and 12 office visits.14 The annual moni toring costs for endothelin receptor antagonists repre sented the average costs for ambrisentan and bosentan; ambrisentan required 12 urine pregnancy tests and 5 hemoglobin tests,20 and bosentan required 12 urine pregnancy tests, 4 hemoglobin measurements, and 12 liver function tests.21 The non-Medicare cost units were derived from 2012 claims data in the Truven Health MarketScan database; the Medicare cost units were derived from the Medicare 2013 Clinical Diagnostic Laboratory Fee Schedule and the Medicare 2013 Physician Fee Schedule; the costs from claims data were adjusted to 2013 dollars.22 Table 3 shows the unit costs for each recommended monitoring resource, by payer. Table 4 shows the annu

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al monitoring cost per patient for each medication class, based on the unit costs and the package insert recommended frequencies.

Sensitivity Analysis One-way sensitivity analysis was performed on the key model parameters to assess the robustness of the analysis. The prevalence of PAH and CTEPH, and data on riociguat’s market share were adjusted by ±25% to test the impact of base-case estimates on the budget im pact results. Our base-case analysis assumed that riocig Table 3 P ayer-Specific Unit Cost of Drug Monitoring Resources Unit cost, Unit cost, Monitoring Billing non-Medicare, Medicare, resource code $24 $24,29 Liver function test

80076

17.49

11.23

Urine pregnancy test

81025

16.26

8.70

Hemoglobin measurement

85018

5.27

3.26

Office visit

99215

110.67

142.90

Table 4 P ayer-Specific Per-Patient Per-Year Monitoring Costs, by Medication Class Non-Medicare Medicare Medication class plan, $ plan, $ sGC stimulator (riociguat)

1523.10

1819.20

PDE-5 inhibitor (sildenafil)

0.00

1651.73

1901.25

ERA (ambrisentan/bosentan)

ERA indicates endothelin receptor antagonist; PDE, phosphodiesterase; sGC, soluble guanylate cyclase.

uat was used as monotherapy; therefore, we also assessed the robustness of the analysis when riociguat was admin istered in combination with an endothelin receptor an tagonist or a prostacyclin analog for patients with PAH. In a non-Medicare plan, the costs of subcutaneous prostacyclin analog (drug costs and administration costs) were calculated to be $1178.53 in the first month and $6626.56 monthly for the rest of the treatment.19,23,24 For a Medicare plan, these costs were $1421.29 for the first month and $6423.56 monthly for the rest of the treatment.19,23,25 The costs of inhaled prostacyclin analogs (ie, drug costs and inhalation device costs) were $18,187.59 for the non-Medicare plan19,24,26,27 and $18,759.28 for the Medicare plan19,25-28 for the first month and $17,043.21 monthly18,24-28 for the rest of the treat ment for Medicare and non-Medicare plans separately.

Results Base-Case Analysis: Non-Medicare Plan Based on our model, we estimated that 7 patients with PAH and 2 patients with CTEPH were eligible for pharmacotherapy. When riociguat was added to the health plan formulary, we assumed that 1 patient with PAH switched from treatment with a PDE-5 inhibitor to riociguat, and 2 patients with CTEPH received treat ment with riociguat, currently the only FDA-approved treatment for patients with CTEPH. Table 5 reports the total annual expenditures (drug costs and drug monitoring costs) at the therapeutic class level, with and without riociguat included on the plan formulary. Among patients with PAH or CTEPH who were receiving pharmacotherapy, the estimated total annual expenditure increased from $328,807 to $600,654 when adding riociguat to the formulary. At a per-mem ber level, the cost impact to the health plan of adding riociguat was $0.02 PMPM and $0.27 PMPY (Table 5).

Table 5 B udget Impact of Adding Riociguat for a Non-Medicare Plan PMPM cost, $ Treatment options

Total annual expenditure, $

PMPY cost, $

Without riociguat

With riociguat

Without riociguat

With riociguat

sGC stimulator

0.00

0.02

0.00

0.27

PDE-5 inhibitor

0.00

0.01

0.00

5454

4363

1.7

0.7

ERA

0.03

0.32

323,353

98.3

53.8

Total

0.03

0.05

0.33

0.60

328,807

600,654

100.0

Incremental change in budget

0.02

Without riociguat

With riociguat

Total annual expenditure, %

0.0

0.27

271,847

272,938

Without riociguat

With riociguat

0.0

45.4

—

ERA indicates endothelin receptor antagonist; PDE, phosphodiesterase; PMPM, per-member per-month; PMPY, per-member per-year; sGC, soluble guanylate cyclase.

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Table 6 Budget Impact of Adding Riociguat for a Medicare Plan PMPM cost, $ Treatment options

PMPY cost, $

Total annual expenditure, $

Without riociguat

With riociguat

Without riociguat

With riociguat

sGC stimulator

0.00

0.02

0.00

0.27

0.0

273,509

0.0

45.4

PDE-5 inhibitor

0.00

0.01

0.00

5454

4363

1.7

0.7

ERA

0.03

0.32

323,928

98.3

53.8

Total

0.03

0.05

0.33

0.60

329,382

601,800

100.0

Budget impact

0.02

0.27

Without riociguat

With riociguat

Total annual expenditure, % Without riociguat

272,418

With riociguat

—

ERA indicates endothelin receptor antagonist; PDE, phosphodiesterase; PMPM, per-member per-month; PMPY, per-member peryear; sGC, soluble guanylate cyclase.

with an inhaled prostacyclin analog, the cost impact to the health plan was $0.04 PMPM and $0.48 PMPY.

Figure 2 One-Way Sensitivity Analysis Riociguat market share CTEPH prevalence PAH prevalence $0.01

$0.02

$0.03

Maximum Minimum

US dollars

CTEPH indicates chronic thromboembolic pulmonary hypertension; PAH, pulmonary arterial hypertension.

Base-Case Analysis: Medicare Plan Similarly, for a Medicare plan, the estimated total annual expenditure increased from $329,382 to $601,800 with the addition of riociguat to the formu lary in patients with PAH or CTEPH who received pharmacotherapy (Table 6). The cost impact of adding riociguat was $0.02 PMPM and $0.27 PMPY; these amounts were similar to the results among patients in a non-Medicare plan (Table 6). Sensitivity Analysis One-way sensitivity analysis demonstrated that the PMPM cost impact of riociguat increased by $0.01, with a 25% increase in the base-case values for the riociguat market share and the prevalence of CTEPH and PAH. The PMPM cost impact was unchanged when data pa rameters were decreased by 25% (Figure 2). The combination of riociguat and an endothelin receptor antagonist or riociguat plus a subcutaneous prostacyclin analog (ie, treprostinil) for the treatment of PAH resulted in a PMPM cost of $0.03 and a PMPY cost of $0.35. When riociguat was used in combination

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Discussion On a daily basis, patients with PAH and CTEPH may experience debilitating symptoms, such as short ness of breath, fatigue, chest discomfort, palpitations, lightheadedness, and syncope, that can impair quality of life.30,31 Furthermore, despite current treatments for patients with PAH, this condition continues to pro gress and is associated with poor outcomes.4 The recent FDA approval of riociguat provides a new treatment option for patients with PAH or CTEPH, with a new mechanism of action that has been shown to improve clinical outcomes.12 In this budgetary impact model, the costs of includ ing riociguat on the formulary for patients with PAH and for patients with inoperable or with persistent or recurrent CTEPH were estimated for a hypothetical US health plan with 1 million members. Of these, an esti mated 7 patients with PAH and 2 patients with CTEPH were eligible for pharmacotherapy. It was fur ther assumed that 1 patient with PAH would switch from a PDE-5 inhibitor to riociguat, and 2 patients with CTEPH would receive treatment with riociguat. The findings from this budget impact model suggest that adding riociguat to a formulary plan, either Medicare or a non-Medicare plan, offers a new treatment option for managing patients with PAH and CTEPH, with a budget increase estimated at $0.02 PMPM and $0.27 PMPY. To our knowledge, this is the first study to evaluate the budget impact of adding riociguat to a formulary in a US health plan. Limitations The results of this analysis should be interpreted in light of several study limitations. First, the findings are

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specific to a disease population of patients aged ≥18 years, which reflects our epidemiology data, and these findings may not apply to all age-groups. Furthermore, because of a lack of specific US preva lence estimates, the actual budget impact may vary for a plan with different numbers of patients with PAH and CTEPH who receive pharmacotherapy, although this may be unlikely because of the small number of patients with these diseases. In addition, a large proportion of the incremental expenditure in our findings is associated with using riociguat for patients with CTEPH where there were no previously indicated treatments. The actual budget impact to health insurance plans may be lower if pa tients currently receive medications that are not indi cated for CTEPH. The market share assumptions used in this model are based on a patient survey of 800 patients with PAH18 and may not reflect real-world clinical practice. Because of the rarity of these diseas es, and the data from the patient survey, our base-case analysis assumed that no patients received prostacy clin analogs or riociguat in combination with another therapy. Furthermore, in our model we assumed that all pa tients were 100% adherent to pharmacotherapy and had stable disease over the course of treatment. The costs of drug-related adverse events, birth control, and disease complications, as well as the costs related to disease monitoring were not taken into consideration. Moreover, the model accounts for drug monitoring recommendations from package inserts that may not reflect real-world clinical practice. Another key limitation pertains to the exclusion of member costs in the base-case scenario presented here. It was assumed that all patients had met their deductible limits and that no maximum out-of-pocket caps apply. However, these factors are unlikely to have any sig nificant impact on our results, because few patients are expected to be diagnosed and become eligible for phar macotherapy in a typical health plan. The budget im pact model did not account for any safety or efficacy data for any of the therapies that were included. An evaluation of the cost-effectiveness of riociguat, with outcomes expressed as change in WHO functional class and time to clinical worsening, would provide addition al supportive evidence for the value of riociguat for the treatment of patients with PAH or CTEPH.

Conclusions PAH and CTEPH are rare but chronic, progressing, and life-threatening conditions. Riociguat is the first and only pharmacotherapy approved by the FDA for the treatment of patients with either of these condi

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tions who are either inoperable or who have persistent pulmonary hypertension after surgery. Based on the budgetary impact model, the budget impact to a health plan of reimbursing the use of riocig uat in the first year is projected to be $0.02 PMPM for patients with PAH or CTEPH, which translates to an increase of 82.7% in drug spending for the first year for these patients. The real-world economic impact of rio ciguat needs to be studied using real-world data to val idate the results of this model. ■ Acknowledgment The authors would like to acknowledge Rohini Sharma from Communications Symmetry for her assis tance in the preparation of this manuscript. Funding Source This study was funded by Bayer Healthcare Pharmaceuticals. Author Disclosure Statement Dr Burudpakdee was employed by Market Access Solutions when this study was conducted; Mr Shah is an employee of Market Access Solutions, LLC, which received funding from Bayer for this study; Dr Joish, Dr Divers, and Dr Yaldo are employees of Bayer HealthCare.

References

1. McLaughlin VV, Archer SL, Badesch DB, et al; for the American College

Cardiology Foundation Task Force on Expert Consensus Documents; the of American Heart Association; the American College of Chest Physicians; the American Thoracic Society, Inc; the Pulmonary Hypertension Association. ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association. J Am Coll Cardiol. 2009;53:1573-1619. 2. Hoeper MM, Mayer E, Simonneau G, Rubin LJ. Chronic thromboembolic pulmonary hypertension. Circulation. 2006;113:2011-2020. 3. Klepetko W, Mayer E, Sandoval J, et al. Interventional and surgical modali ties of treatment for pulmonary arterial hypertension. J Am Coll Cardiol. 2004;43(12 suppl S):73S-80S. 4. Thenappan T, Shah SJ, Rich S, et al. Survival in pulmonary arterial hyper tension: a reappraisal of the NIH risk stratification equation. Eur Respir J. 2010;35:1079-1087. 5. Condliffe R, Kiely DG, Gibbs JS, et al. Improved outcomes in medically and surgically treated chronic thromboembolic pulmonary hypertension. Am J Respir Crit Care Med. 2008;177:1122-1127. 6. Kirson NY, Birnbaum HG, Ivanova JI, et al. Prevalence of pulmonary arteri al hypertension and chronic thromboembolic pulmonary hypertension in the United States. Curr Med Res Opin. 2011;27:1763-1768. 7. Said Q, Martin BC, Joish VN, et al. The cost to managed care of managing pulmonary hypertension. J Med Econ. 2012;15:500-508. 8. Sitbon O, Humbert M, Jaïs X, et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation. 2005;111: 3105-3111. 9. Kim NH. Riociguat: an upcoming therapy in chronic thromboembolic pul monary hypertension? Eur Respir Rev. 2010;19:68-71. 10. Galiè N, Kim NH. Pulmonary microvascular disease in chronic thrombo embolic pulmonary hypertension. Proc Am Thorac Soc. 2006;3:571-576. 11. Mayer E. Surgical and post-operative treatment of chronic thromboembolic pulmonary hypertension. Eur Respir Rev. 2010;19:64-67. 12. Ghofrani H-A, Galiè N, Grimminger F, et al; for the PATENT-1 Study Group. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013;369:330-340. 13. Ghofrani H-A, D’Armini AM, Grimminger F, et al; for the CHEST-1

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Study Group. Riociguat for the treatment of chronic thromboembolic pulmo nary hypertension. N Engl J Med. 2013;369:319-329. 14. Adempas (riociguat) tablets [prescribing information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc; September 2014. 15. Ling Y, Johnson MK, Kiely DG, et al. Changing demographics, epidemiol ogy, and survival of incident pulmonary arterial hypertension: results from the pulmonary hypertension registry of the United Kingdom and Ireland. Am J Respir Crit Care Med. 2012;186:790-796. 16. Humbert M, Sitbon O, Chaouat A, et al. Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med. 2006;173:10231030. 17. Escribano-Subias P, Blanco I, López-Meseguer M, et al; for the REHAP investigators. Survival in pulmonary hypertension in Spain: insights from the Spanish registry. Eur Respir J. 2012;40:596-603. 18. Bayer survey. Bayer PAH and CTEPH treatment tracking study; US data 2012. Unpublished. 19. Price Rx. Medi-Span Master Drug Data Base. Wolters Kluwer Health. www. medispan.com/drug-pricing-analysis-pricerx/. Accessed October 15, 2013. 20. Letairis (ambrisentan) tablets [prescribing information]. Foster City, CA: Gilead Sciences, Inc; May 2014. 21. Tracleer (bosentan) tablets [prescribing information]. South San Francisco, CA: Actelion Pharmaceuticals US, Inc; October 2012. 22. US Bureau of Labor Statistics. Producer Price Index data. Commodities and

industries. www.bls.gov/data/. Accessed August 6, 2013.

23. Remodulin (treprostinil) injection [prescribing information]. Research

Triangle Park, NC: United Therapeutics Corporation; February 2011.

24. Truven Health MarketScan Commercial Database. January 2012-September

2012.

25. Centers for Medicare & Medicaid Services. Durable Medical Equipment,

Prosthetics/Orthotics, and Supplies (DMEPOS) 2013 Fee Schedule. www.cms. gov/Medicare/Medicare-Fee-for-Service-Payment/DMEPOSFeeSched/ DMEPOS-Fee-Schedule.html. Accessed July 15, 2013. 26. Tyvaso (treprostinil) inhalation solution [prescribing information]. Re search Triangle Park, NC: United Therapeutics Corporation; April 2013. 27. Ventavis (iloprost) inhalation solution [prescribing information]. South San Francisco, CA: Actelion Pharmaceuticals US, Inc; April 2012. 28. American Medical Association. CPT Code/Relative Value Search. https:// ocm.ama-assn.org/OCM/CPTRelativeValueSearch.do?submitbutton=accept. Accessed August 10, 2013. 29. Centers for Medicare & Medicaid Services. 2013 Clinical Diagnostic Labora tory Fee Schedule. National limit. www.cms.gov/Medicare/Medicare-Fee-for- Service-Payment/ClinicalLabFeeSched/clinlab.html. Accessed October 23, 2013. 30. Auger WR, Kim NH, Trow TK. Chronic thromboembolic pulmonary hy pertension. Clin Chest Med. 2010;31:741-758. 31. Halank M, Einsle F, Lehman S, et al. Exercise capacity affects quality of life in patients with pulmonary hypertension. Lung. 2013;191:337-343.

STAKEHOLDER PERSPECTIVE

Is It Time for Risk-Sharing Contracts In Specialty Pharmacy? By Atheer A. Kaddis, PharmD Senior Vice President, Sales and Business Development, Diplomat Specialty Pharmacy, Flint, MI

he majority of my career as a pharmacist has been spent in the managed care setting, with responsi bility for co-chairing a Pharmacy and Therapeutics committee, as well as for formulary development for a large health plan. Discussions regarding risk-sharing con tracts and even outcomes-based contracting have been taking place between health plans and pharmaceutical manufacturers for years, with very few contracts actually being implemented.1 The past 7 years of my career have been spent within a specialty pharmacy, which has al lowed me to see that very little progress has been made in risk-sharing contracts for specialty pharmaceuticals. Is it time for a change? In the article by Burudpakdee and colleagues in this issue of American Health & Drug Benefits,2 the authors provide information on the budgetary impact of adding a new drug, riociguat, to a health plan’s formulary for the treatment of patients with pulmonary arterial hyperten sion or with chronic thromboembolic pulmonary hyper tension. Using a budget impact analytic model, the au thors estimate that the financial impact of adding riociguat to a health plan’s formulary would only be ap proximately $0.02 per member per month. With such a cost, why would any health plan not add this new drug to formulary? Let us ponder this question.

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PAYERS/DRUG MANUFACTURERS: Pharma ceutical manufacturer development and subsequent US Food and Drug Administration (FDA) approvals of new molecular entities (NMEs) have been impressive. As of December 11, 2014, the FDA had approved 35 NMEs this year compared with only 27 NMEs in 2013.3 Of the 35 new drug approvals this year, 15 were for treatment of rare diseases (diseases that affect 200,000 or fewer Amer icans). The previous “high” was 13 new drugs for rare diseases approved in 2012. Although this may be beneficial to all healthcare stakeholders, patients, and society at large, there is also a cost that must be taken into consideration as new thera pies coming to market—especially those for rare dis ease—carry a significant price tag. For example, riociguat has a monthly drug cost of $7500, based on the 2013 wholesale acquisition cost (WAC).2 Previously FDA- approved competitor therapies—ambrisentan and bosen tan—have a monthly drug cost of $6644.13 (also based on the 2013 WAC).2 In addition, most health plans place specialty pharmaceuticals into a specialty tier on their formularies, and apply the same coinsurance metrics across all specialty drugs. Health plans then rely heavily on utilization management strategies to manage specialty pharmaceuticals within their formularies.4

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STAKEHOLDER PERSPECTIVE Continued Based on the analysis by Burudpakdee and colleagues,2 it is my observation that riociguat presents an excellent opportunity for a risk-sharing contract between the drug manufacturer and a health plan. The reasons are that this medication has a higher monthly cost than other drugs in its category; it has a budget impact analytic model already developed,2 which will help forecast the financial impact on a health plan; it will probably be relegated to a coinsurance benefit design; and it will be strongly managed through utilization management strategies. The concern that health plans will likely have is with regard to the potential overprescribing or inappropriate use of this medication. Therefore, why not put some skin into the game, and share some of the risk when there is

overprescribing or inappropriate use, in exchange for lessened restrictions on this therapy? It is worth a discussion, at the very least. ■ 1. Coulton L, Annemans L, Javier J, et al. Risk-sharing schemes worldwide: a landscape analysis of health outcomes-based reimbursement agreements. Poster presented at the ISPOR 4th Asia-Pacific Conference; September 5-7, 2010; Phuket, Thailand. 2. Burudpakdee C, Shah A, Joish VN, et al. Budgetary impact of adding riociguat to a US health plan for the treatment of patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension. Am Health Drug Benefits. 2014;7:479-487. 3. Hamburg MA. 2014 drug approvals: speeding novel drugs to the patients who need them. FDA Voice. December 11, 2014. http://blogs.fda.gov/fdavoice/index. php/2014/12/2014-drug-approvals-speeding-novel-drugs-to-the-patients-whoneed-them. Accessed December 10, 2014. 4. EMD Serono. EMD Serono Specialty Digest, 9th edition: managed care strategies for specialty pharmaceuticals. 2013. www.amcp.org/EMDSeronoSpecialty Digest9th.pdf. Accessed December 10, 2014.

CORRECTION

n the article “Impact of the New ACC/AHA Guidelines on the Treatment of High Blood Cholesterol in a Managed Care Setting” published in November 2014 (Vol 7, No 8, pages 430-443), the study period was January 1, 2013, to December 31, 2013, rather than November 1, 2012, to October 31, 2013. In addition, the total study population was 14,114,500, rather than 25,705,722; the commercial population was 4,402,866, rather than

14,661,302; the Medicaid population was 2,173,914, rather than 3,313,910; and the Medicare population was 7,537,720, rather than 7,730,510. These population data affect the percentages cited in the body of the article and are also appearing in Table 3, Table 4, and Figure 2, which are corrected below. The overall results and conclusion of the study have not been affected. The article is corrected at www.AHDBonline.com. ■

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

Percent of population

8.9% 6.4% 4.3%

7.9%

Commercial

Medicare

Medicaid

Total population

4.8% 3.3% 2.0%

1.8% 0.3% Patients who qualify for but are not receiving any cholesterol-lowering medications

Population by health plan type

0.1%

0.9%

0.6%

Patients receiving nonstatin cholesterollowering medications

0.6%

1.6%

0.4% Patients receiving a low-intensity statin

0.7%

Patients receiving a moderate-intensity statin

Patients who qualify for but are not receiving any cholesterol-lowering medications, N (%)

Patients receiving nonstatin cholesterol-lowering medications, N (%)

Patients receiving a lowintensity statin, N (%)a

Patients receiving a moderate- intensity statin, N (%)a 71,992 (1.6)

Commercial (N = 4,402,866)

187,242 (4.3)

12,440 (0.3)

27,252 (0.6)

Medicaid (N = 2,173,914)

39,984 (1.8)

2584 (0.1)

9342 (0.4)

14,889 (0.7)

Medicare (N = 7,537,720)

670,018 (8.9)

70,993 (0.9)

248,729 (3.3)

594,489 (7.9)

Total population (N = 14,114,500)

897,244 (6.4)

86,017 (0.6)

285,323 (2.0)

681,370 (4.8)

See Table 1 for statin dosing intensity information.

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CORRECTION

n the article “Impact of the New ACC/AHA Guidelines on the Treatment of High Blood Cholesterol in a Managed Care Setting” published in October 2014 (Vol 7, No 7, pages 430-443), the study period was January 1, 2013, to December 31, 2013, rather than November 1, 2012, to October 31, 2013. In addition, the total study population was 14,114,500, rather than 25,705,722; the commercial population was 4,402,866, rather than

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

Percent of population

8.9% 6.4% 4.3%

7.9%

Commercial

Medicare

Medicaid

Total population

4.8% 3.3% 2.0%

1.8% 0.3% Patients who qualify for but are not receiving any cholesterol-lowering medications

Population by health plan type

0.1%

0.9%

0.6%

Patients receiving nonstatin cholesterollowering medications

0.6%

1.6%

0.4% Patients receiving a low-intensity statin

0.7%

Patients receiving a moderate-intensity statin

Patients who qualify for but are not receiving any cholesterol-lowering medications, N (%)

Patients receiving nonstatin cholesterol-lowering medications, N (%)

Patients receiving a lowintensity statin, N (%)a

Patients receiving a moderate- intensity statin, N (%)a 71,992 (1.6)

Commercial (N = 4,402,866)

187,242 (4.3)

12,440 (0.3)

27,252 (0.6)

Medicaid (N = 2,173,914)

39,984 (1.8)

2584 (0.1)

9342 (0.4)

14,889 (0.7)

Medicare (N = 7,537,720)

670,018 (8.9)

70,993 (0.9)

248,729 (3.3)

594,489 (7.9)

Total population (N = 14,114,500)

897,244 (6.4)

86,017 (0.6)

285,323 (2.0)

681,370 (4.8)

See Table 1 for statin dosing intensity information.

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Table 3 Baseline Cholesterol-Lowering Medication Utilization Patients in a commercial plan, Patients receiving cholesterol-lowering N (%) medications (N = 4,402,866) Statin users, by dosing intensitya

Patients in a Medicare plan, N (%) (N = 7,537,720)

Total population, N (%) (N = 14,114,500)

Low-intensity statin

54,503 (13.20)

18,684 (21.90)

497,458 (14.60)

570,645 (14.60)

Moderate-intensity statin

287,968 (69.80)

59,556 (69.70)

2,377,955 (69.70)

2,725,480 (69.70)

High-intensity statin

70,329 (17.00)

7196 (8.40)

535,758 (15.70)

613,283 (15.70)

Total

412,800 (9.380)

85,436 (3.93)

3,411,171 (45.25)

3,909,407 (27.70)

Total

45,327 (1.030)

10,159 (0.47)

364,656 (4.84)

420,142 (2.98)

Bile acid– binding resins

10,285 (12.39)

1629 (9.06)

92,151 (15.89)

104,065 (15.29)

Cholesterol absorption inhibitors

13,800 (16.62)

1573 (8.74)

141,624 (24.43)

156,997 (23.06)

Fibrates

42,835 (51.59)

12,430 (69.09)

279,033 (48.13)

334,298 (49.10)

Niacin

10,300 (12.41)

2120 (11.78)

64,621 (11.15)

77,041 (11.32)

Omega-3 fatty acids

15,204 (18.31)

1899 (10.56)

62,893 (10.85)

Total

83,024 (1.89)

17,990 (0.83)

579,786 (7.69)

680,800 (4.82)

Total

450,497 (10.23)

93,267 (4.29)

3,626,301 (48.11)

4,170,065 (29.54)

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

Patients in a Medicaid plan, N (%) (N = 2,173,914)

All cholesterol-lowering medication usersc

79,996 (11.75)

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

48,796 (3.00)

15,211 (5.10)

213,098 (8.70)

277,105 (6.40)

230,743 (14.40)

41,289 (13.90)

761,533 (31.20)

1,033,565 (23.80)

1,605,973 (36.48)

297,051 (13.66)

2,442,821 (32.41)

4,345,845 (30.79)

See Table 1 for statin dosing intensity definitions. b These patients are receiving a statin and a nonstatin cholesterol-lowering medication, and these counts are not mutually exclusive of the patients counted under the statin and the nonstatin cholesterol-lowering medication user groups. c Unique members who are receiving any cholesterol-lowering medications. a

Table 4 Projected Cholesterol-Lowering Medications Utilization Patients in a commercial plan, Patients receiving cholesterol-lowering N (%) medications (N = 4,402,866) Statin users, by dosing intensitya

Patients in a Patients in a Medicaid plan, Medicare plan, N (%) N (%) (N = 2,173,914) (N = 7,537,720)

Total population, N (%) (N = 14,114,500)

Low-intensity statin

27,252 (4.4)

9342 (7.3)

248,729 (6.0)

285,323 (5.8)

Moderate-intensity statin

392,928 (64.2)

90,642 (70.8)

2,566,826 (61.8)

3,050,396 (62.3)

High-intensity statin

192,302 (31.4)

28,021 (21.9)

1,336,627 (32.2)

1,556,950 (31.8)

Total

612,482 (13.91)

128,005 (5.89)

4,152,182 (55.09)

4,892,668 (34.66)

Statin and nonstatin cholesterol-lowering medication usersb

Total

0 (0)

Nonstatin cholesterol-lowering medication users

Bile acid– binding resins

5667 (22.4)

1000 (19.1)

48,163 (33.4)

54,831 (31.4)

Cholesterol absorption inhibitors

4801 (19.0)

378 (7.2)

41,549 (28.8)

46,728 (26.8)

All cholesterol-lowering medication usersc

0 (0)

Fibrates

13,270 (52.5)

4204 (80.1)

77,550 (53.8)

95,024 (54.4)

Niacin

3901 (15.4)

790 (15.1)

21,231 (14.7)

25,922 (14.8)

Omega-3 fatty acids

7018 (27.8)

535 (10.2)

16,180 (11.2)

23,733 (13.6)

Total

25,257 (0.57)

5247 (0.24)

144,137 (1.91)

174,641 (1.24)

Total

637,739 (14.48)

4,296,319 (57.00)

5,067,309 (35.90)

133,252 (6.13)

Patients aged 40-75 years not receiving cholesterol-lowering medications With diabetes claims

0 (0)

With hypertension claims, but no diabetes medication claim

92,297 (6.51)

Overall total

1,418,731 (32.22)

0 (0) 16,516 (6.42) 257,067 (11.83)

0 (0)

304,613 (17.18)

413,426 (11.99)

1,772,803 (23.52)

3,448,601 (24.43)

See Table 1 for statin dosing intensity definitions. These patients are receiving a statin and a nonstatin cholesterol-lowering medication, and these counts are not mutually exclusive of the patients counted under the statin and the nonstatin cholesterol-lowering medication user groups. c Unique members who are receiving any cholesterol-lowering medications. a

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CLINICAL

REVIEW ARTICLE

Diagnosis and Treatment of Bipolar Disorders in Adults: A Review of the

Evidence on Pharmacologic Treatments Michael W. Jann, PharmD, FCP, FCCP BACKGROUND: Patients with bipolar disorder are exceptionally challenging to manage because of the dynamic, chronic, and fluctuating nature of their disease. Typically, the symptoms of bipolar disorder first appear in adolescence or early adulthood, and are repeated over the patient’s lifetime, expressed as unpredictable recurrences of hypomanic/manic or depressive episodes. The lifetime prevalence of bipolar disorder in adults is reported to be approximately 4%, and its management was estimated to cost the US healthcare system in 2009 $150 billion in combined direct and indirect costs. OBJECTIVES: To review the published literature and describe the personal and societal burdens associated with bipolar disorder, the impact of delays in accurate diagnosis, and the evidence for the clinical effectiveness of available pharmacologic therapies. METHODS: The studies in this comprehensive review were selected for inclusion based on clinical relevance, importance, and robustness of data related to diagnosis and treatment of bipolar disorder. The search terms that were initially used on MEDLINE/PubMed and Google Scholar were restricted to 1994 through 2014 and included “bipolar disorder,” “mania,” “bipolar depression,” “mood stabilizer,” “atypical antipsychotics,” and “antidepressants.” High-quality, recent reviews of major relevant topics were included to supplement the primary studies. DISCUSSION: Substantial challenges facing patients with bipolar disorder, in addition to their severe mood symptoms, include frequent incidence of psychiatric (eg, anxiety disorders, alcohol or drug dependence) and general medical comorbidities (eg, diabetes, cardiovascular disease, obesity, migraine, and hepatitis C virus infection). It has been reported that more than 75% of patients take their medication less than 75% of the time, and the rate of suicide (0.4%) among patients with bipolar disorder is more than 20 times greater than in the general US population. Mood stabilizers are the cornerstone of treatment of bipolar disorder, but atypical antipsychotics are broadly as effective; however, differences in efficacy exist between individual agents in the treatment of the various phases of bipolar disorder, including treatment of acute mania or acute depression symptoms, and in the prevention of relapse. CONCLUSION: The challenges involved in managing bipolar disorder over a patient’s lifetime are the result of the dynamic, chronic, and fluctuating nature of this disease. Diligent selection of a treatment that takes into account its efficacy in the various phases of the disorder, along with the safety profile identified in clinical trials and in the real world can help ameliorate the impact of this devastating condition.

ipolar disorder is a chronic, relapsing illness characterized by recurrent episodes of manic or depressive symptoms, with intervening periods that are relatively (but not fully) symptom-free. Onset occurs usually in adolescence or in early adulthood, although onset later in life is also possible.1 Bipolar disorder has a lifelong impact on patients’ overall health status, quality of life, and functioning.2 This disorder has 2 major types—bipolar disorder I and bipolar disorder II.3 Bipolar disorder I is defined by epi-

Dr Jann is Professor and Chair, Department of Pharmaco therapy, University of North Texas System College of Pharmacy, University of North Texas Health Sciences Center, Fort Worth, TX.

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Stakeholder Perspective, page 499

Am Health Drug Benefits. 2014;7(9):489-499 www.AHDBonline.com Received May 27, 2014 Accepted in final form November 25, 2014

Disclosures are at end of text

sodes of depression and the presence of mania, whereas bipolar disorder II is characterized by episodes of depression and hypomania. Therefore, the main distinction between the 2 types is the severity of manic symptoms: full mania causes severe functional impairment, can include symptoms of psychosis, and often requires hospitalization; hypomania, by contrast, is not severe enough to cause marked impairment in social or occupational functioning, or to necessitate hospitalization.3 Longitudinal studies show that patients with bipolar disorder of either type experience symptomatic depression at least 3 times more frequently than symptomatic mania or hypomania (Figure 1).4-9 The lifetime prevalence of bipolar disorder in adults in the United States is reported to be 3.9%.10

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KEY POINTS Bipolar disorder is a dynamic and serious condition that can have a lifelong impact on a patient’s overall health status, quality of life, and functioning. ➤ The treatment of bipolar disorder is challenging and costs the US healthcare system an estimated >$30 billion in direct expenditures and >$120 billion in indirect costs annually. ➤ Delayed diagnosis can result in worsening clinical outcomes and increased costs; early recognition of this condition can reduce the total per-patient costs by as much as $2316 annually. ➤ Considering the possibility of bipolar disorder in patients with depressive disorders is critical to improving outcomes and reducing costs of treatment. ➤ Despite the introduction of new therapies for bipolar disorder, treatment outcomes remain less successful than for major depressive disorder; the use of antidepressants for this condition remains controversial. ➤ Medication nonadherence is perhaps the most significant contributor to poor outcomes in this patient population; monotherapy may help improve adherence in some patients. ➤ The selection of an appropriate treatment that takes into account efficacy as well as safety can help to ameliorate the devastating impact of bipolar disorder. ➤

Bipolar disorder has an enormous economic impact on the US healthcare system.11,12 The estimated total direct cost of bipolar disorder (including inpatient costs, outpatient costs, pharmaceuticals, and community care) in the United States in 2009 was $30.7 billion.11 In addition, the adverse impact of bipolar disorder on functioning and quality of life translates to a substantial total indirect healthcare cost resulting from the loss of employment, loss of productivity, sick leave,13 and uncompensated care that is estimated at more than $120 billion annually.11 From a managed care perspective, bipolar disorder is among the most costly of all mental health conditions. In a major study of commercial insurance claims data from 1996 of almost 1.7 million individuals, although only 3% of patients with a mental health claim were identified with bipolar disorder, these patients accounted for 12.4% of the total plan expenditures.14 High cost was driven largely by a disproportionate rate of inpatient admissions for bipolar disorder versus all other behavioral health claimants (39.1% vs 4.5%, respectively), resulting in a cost of $1.80 for inpatient care per

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every dollar of outpatient treatment cost.14 Another large study of healthcare utilization and costs from 2004 to 2007 compared 122 patients with bipolar disorder with patients with other psychiatric conditions, including 1290 patients with depression, 2770 with asthma, 1759 with coronary artery disease, and 1418 with diabetes.12 The patients with bipolar disorder had higher adjusted mean costs per member per month (approximately $1700) than all other groups, including depression (approximately $1300), with the exception of patients who had both diabetes and coronary artery disease (with approximately $2000 per member per month).12 Despite the advent of lithium therapy more than 60 years ago,15 the introduction of other pharmacotherapies and the development of disease-specific behavioral approaches,16 and a generally greater awareness of bipolar disorder, treatment outcomes remain less satisfactory than the outcomes for major depressive disorder (MDD) in all sectors of the US healthcare system, including Figure 1 Total Time Ill in First 2 Years After the Index Episode

Judd et al (2002)5 (N = 146)

M-type D-type Total

Post et al (2003)7 (N = 258) Joffe et al (2004)8 (N = 138) Paykel et al (2006)9 (N = 204) Baldessarini et al (2010)4 (N = 303)

(Total morbidity, 54%; D/M, 3.0)

Overall, 5 studies (N = 1049) 0

100

Time ill, %

M-type: mania, hypomania, psychosis; D-type: depression, dysthymia, dysphoric mixed states. Reprinted with permission from Baldessarini RJ, Salvatore P, Khalsa H-M, et al. Morbidity in 303 first-episode bipolar I disorder patients. Bipolar Disord. 2010;12:264-270.

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managed care.2 This represents a challenge and an opportunity for managed care to focus on this disorder to improve outcomes and to reduce healthcare costs. This review article presents the clinical evidence supporting best practice for the diagnosis and treatment of bipolar disorder. The review highlights what little is known about the most effective ways to address specific clinical challenges in caring for patients with bipolar disorder and identifies recent research that documents innovative approaches to improving the effectiveness of care in this setting.

Study Selection Methodology Studies were selected for inclusion in this review based on a comprehensive literature search initially using MEDLINE/PubMed and Google Scholar, and was restricted to the years 1994 to the present. The search terms included “bipolar disorder,” “mania,” “bipolar depression,” “mood stabilizer,” “atypical antipsychotics,” and “antidepressants.” For the sections on diagnosis, treatment, and key challenges, articles were selected for inclusion from the extensive literature based on the clinical judgment of the author, using the conventional criteria of relevance, importance, and robustness of data. In selecting studies for inclusion, a broad representation of topics was sought, while limiting the total number of references on any given topic; high-quality, recent reviews of major topics were included to supplement the primary studies. Diagnosis A diagnosis of bipolar disorder is obvious when a patient presents with florid mania but is challenging when the initial presentation includes depressive symptoms; studies generally report that 50% or more of patients initially present with depression.3,17-20 Primarily because unipolar depression (ie, MDD) is more common than bipolar depression, and because bipolar depression lacks pathognomonic features, bipolar disorder is often incorrectly identified as MDD.21 Among patients who are eventually diagnosed with bipolar disorder, approximately 70% reportedly had an initial misdiagnosis and more than 33% remained misdiagnosed for 10 years or more.22 Delay in diagnosis is a particular problem in women with bipolar disorder type II, because the symptoms of hypomania may not be very apparent.23 Moreover, misdiagnosis during the postpartum period is common; in a study of 56 women referred for postpartum depression, 54% were later rediagnosed with bipolar disorder.24 The delayed recognition of bipolar disorder has adverse clinical and healthcare cost consequences.21,25,26 From a clinical perspective, patients with bipolar disor-

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der who are treated with antidepressants alone (the standard of care for MDD) are less likely to have an appropriate response and are at risk for manic switch or cycle acceleration (ie, increased frequency of mood episodes over time).27,28 From a health economic perspective, care is likely to be more costly in patients with delayed diagnosis of bipolar disorder than in those diagnosed early. In an analysis from the California Medicaid program, 2 groups of patients with bipolar disorder were compared: those who were diagnosed with bipolar disorder at initial presentation and those who had a delayed diagnosis during a 6-year follow-up.26 Patients with a delayed diagnosis of bipolar disorder represented almost twice as many cases as those with initially recognized bipolar disorder (28.2% vs 14.5%, respectively), and the annualized total cost per patient in the delayed group was $2316 higher in the sixth year compared with the cost for patients whose disease was initially recognized as bipolar disorder (P <.001). Moreover, costs for patients with bipolar disorder and a delayed diagnosis increased by $10 monthly before the correct diagnosis (P <.001) and decreased by $1 afterward (P = .006 for the change in slope).26 Thus, the consideration of the possibility of bipolar disorder in patients with depressive disorders is critical to improving outcomes and reducing the costs of care of patients with bipolar disorder. Screening each patient for a history of mania and hypomania on their initial presentation of depressive symptoms is an early step toward the recognition of bipolar disorder.29 Validated instruments that can be used include the Mood Disorder Questionnaire,30 the Composite International Diagnostic Interview, version 3.0,31 and the Primary Care Evaluation of Mental Disorders Patient Health Questionnaire.32 Clinical screening can be supplemented with electronic health record (EHR)-based case findings, in which information collected by self-report or a healthcare assistant is entered into the EHR and is screened for possible indicators of bipolar disorder.33 These tools help to ensure that the clinician recognizes patients who are more likely to have bipolar disorder, help assist in directing the clinical interview, and can encourage active follow-up for any emerging symptoms of bipolar disorder. In a study modeling the clinical outcome and cost-effectiveness over 5 years of administering the Mood Disorder Questionnaire to all patients first presenting with symptoms of MDD, screening resulted in an increase in diagnostic accuracy for bipolar disorder, with an additional 38 cases identified per 1000 patients screened and a per-patient savings of $1937, for a total annual budgetary savings of more than $1.9 million.34

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Pharmacologic Treatment Pharmacologic treatments for bipolar disorder include the conventional mood stabilizers (eg, lithium, valproate, lamotrigine, and carbamazepine) and most of the currently marketed atypical antipsychotics.2,21 A detailed review of randomized controlled trials (RCTs) and observational studies for every agent in the treatment of each of the phases of bipolar disorder is beyond the scope of this review; rather, a summary of the most important findings of the aggregated evidence is presented from systematic reviews and meta-analyses,15,35 as well as the results of recent studies that address previous gaps in the literature.36,37 It is relevant to note that the level of trial evidence varies for the different pharmacotherapies that are approved for the treatment of bipolar disorder. Some of these agents have evidence of efficacy in acute mania, others in acute bipolar depression, and a limited number of therapies have efficacy at both poles of the disease spectrum. Some therapies demonstrate efficacy only in acute episodes, whereas others show efficacy as maintenance therapy. Mood Stabilizers Lithium has been the foundation of treatment of bipolar disorder for over 60 years,2,15,38 but its efficacy in the prevention and treatment of bipolar depression is limited, and it is not rapidly effective for acute mania.15 In a systematic review of RCTs with a lithium arm that were published between 1970 and 2006, lithium had a significant prophylactic effect for all relapses (random effects relative risk [RR], 0.65; 95% confidence interval [CI], 0.50-0.84) and manic relapses (RR, 0.62; 95% CI, 0.40-0.95) but not for depressive relapses (RR, 0.72; 95% CI, 0.49-1.07).15 Notably, lithium remains the only agent proved to reduce the risk for suicide in patients with bipolar disorder.39 Sodium valproate is the most frequently used antiepileptic mood stabilizer for patients with bipolar disorder. In the BALANCE trial, a 2-year active controlled trial, 330 patients were receiving maintenance therapy with lithium or valproate, or the combination of both; the primary outcome was time to first mood episode.40 Although the combination performed best, lithium was more effective than valproate alone (hazard ratio [HR] for the primary outcome, 0.71; 95% CI, 0.51-1.00; P = .047).40 A nationwide observational study conducted in Denmark from 1995 to 2006 of 4268 patients who received lithium or valproate for the treatment of bipolar disorder found a higher rate of adding medications or switching to another drug among patients receiving valproate compared with lithium (HR, 1.86; 95% CI, 1.59-2.16) and a higher rate of hospitalization (HR, 1.33; 95% CI, 1.18-1.48).41

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Lamotrigine is the mood stabilizer with the best evidence for bipolar depression prophylaxis.28 Published data on the use of lamotrigine for acute depression in patients with bipolar disorder are inconsistent, but a meta-analysis did find significant efficacy for a higher dose of 200 mg/day.28,42 Each of the mood stabilizers presents significant safety issues. Lithium has a narrow therapeutic window that leads to the requirement for regular monitoring of serum concentrations; it can be fatal in overdose, and is associated with progressive renal insufficiency and hypothyroidism.21,43 Valproate is associated with hepatotoxicity, whereas lamotrigine is linked with rash and Stevens-Johnsonâ&#x20AC;&#x201C;like syndrome.21,44,45 Valproate and lithium are both teratogenic.46

Atypical Antipsychotics A vast body of evidence supports the use of atypical antipsychotics in the treatment of bipolar disorder.35 The most established role for this class is in the treatment of acute mania. All approved atypical antipsychotics (with the exception of lurasidone) have been shown to be effective in the treatment of manic episodes of bipolar disorder I.35 In contrast, only quetiapine (immediate-release and extended-release formulations) has the highest level (level 1) of evidence for efficacy as monotherapy for bipolar I or II depression.35 More recently, quetiapine was also shown to reduce the symptoms of depression in acute mixed episodes of bipolar II hypomania.36 One single trial of the combination agent of olanzapine and fluoxetine shows the efficacy of this agent in bipolar I depression28; lurasidone was approved in 2013 by the US Food and Drug Administration (FDA) for the treatment of adults with bipolar I depression.47 Other atypical antipsychotics, including aripiprazole, have not shown efficacy in trials of patients with bipolar depression.48 The safety and tolerability of atypical antipsychotics are well characterized in the literature.49,50 The adverse effects of atypical antipsychotics differ between indiÂ vidual agents. In a meta-analysis of 48 RCTs in which Âat least 2 atypical antipsychotics were compared and risperidone served as the index medication, weight gain was significantly increased with olanzapine (odds ratio [OR], 2.139; 95% CI, 1.764-2.626) and was decreased with ziprasidone (OR, 0.466; 95% CI, 0.317-0.657); extrapyramidal symptoms were decreased with quetiapine (OR, 0.441; 95% CI, 0.129-0.910).50 Atypical antipsychotics as a class have a propensity to contribute to metabolic risk in patients with bipolar disorder, and monitoring strategies have been proposed to prevent, minimize, or detect symptoms early so that appropriate measures can be taken.49

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Aripiprazole, risperidone, valproate, ziprasidone

Lithium, valproate, carbamazepine, aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone

Mania

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Severely ill: lithium/ valproate + antipsychotic Less severely ill: lithium, valproate, antipsychotic

Severe: antipsychotic, valproate

Mild: lithium, carbamazepine

Quetiapine, lithium/ valproate + pramipexole, valproate, antidepressants Bipolar II depression Quetiapine, quetiapine XR

Quetiapine

Bipolar I depression Lithium, lamotrigine, quetiapine, quetiapine XR, lithium/valproate + SSRI, olanzapine + SSRI, lithium + valproate, lithium/ valproate + bupropion

Severely ill: lithium/ valproate + antipsychotic Less severely ill: lithium, valproate, antipsychotic

Lithium, lamotrigine

Quetiapine, lamotrigine, SSRI or other antidepressant (not TCA)

Bipolar depression

Bipolar II d足 epression

Bipolar I 足depression

Quetiapine, lamotrigine, lithium

Bipolar depression

Acute treatment Depression

Lithium, aripiprazole, quetiapine, valproate, olanzapine

Mania

Lithium, lamotrigine (limited efficacy in preventing mania), quetiapine, risperidone LAI, aripiprazole, lithium/valproate + quetiapine, lithium/ valproate + risperidone, LAI lithium/valproate + aripiprazole or lithium/valproate + ziprasidone

Aripiprazole, lamotrigine, lithium, quetiapine

Any episode

Quetiapine, lamotrigine

Depression

Lithium, lamotrigine, quetiapine

Bipolar II disorder

Lamotrigine, quetiapine

Aripiprazole, lithium, quetiapine Bipolar I disorder

Depression

Lithium, lamotrigine; lithium/valproate + quetiapine

Mania

Lithium, olanzapine; lithium/valproate + quetiapine

Agent effective in acute Agent effective in acute phase; monotherapy phase; monotherapy advised advised

Mania

Lithium, valproate, carbamazepine, oxcarbazepine Severely ill: lithium/ valproate + antipsychotic Less severely ill: lithium, valproate, antipsychotic

Mild: lithium, carbamazepine Severe: antipsychotic, valproate

No specific recommendations

Valproate, carbamazepine, olanzapine, aripiprazole, risperidone, ziprasidone

Mixed states

Maintenance

LAI indicates long-acting injection; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant; XR, extended release.

APA (2002)21

BAP (2009)52

CANMAT Lithium, valproate, (2013)38 aripiprazole, olanzapine, quetiapine, quetiapine XR, risperidone, ziprasidone, asenapine, paliperidone XR, lithium/valproate + aripiprazole, lithium/ valproate + olanzapine, lithium/valproate + quetiapine, lithium/ valproate + risperidone, lithium/valproate + asenapine

WFSBP (2009, 2010, 2013)55-57

VAD/DoD (2010)54

Guideline

Table Guideline Recommendations for the First-Line Treatment of Bipolar Disorder

Diagnosis and Treatment of Bipolar Disorders in Adults

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Antidepressants The use of antidepressants as pharmacotherapy for bipolar disorder is the area of greatest controversy related to this disease.27,51 In a random-effects meta-analysis of 10 studies that included 2226 patients with unipolar depression and 863 patients with bipolar disorder, antidepressant responses did not differ between the 2 groups (pooled RR, 1.05; 95% CI, 0.96-1.15; P = .34).51 However, the risk rate for a switch to mania was 2.5% weekly in patients with bipolar depression compared with 0.28% in patients with unipolar depression. Antidepressants are not FDA-approved for the treatment of bipolar disorder, with the exception of fluoxetine in combination with olanzapine, although antidepressants are frequently prescribed in clinical practice for the depressive symptoms of bipolar disorder. The current guidelines21,38,52 are generally consistent in making the recommendations listed in the Table regarding antidepressant use in bipolar depression, indicating that selective serotonin reuptake inhibitors

(other than paroxetine) and bupropion may be used as ﬁrst-line treatments in patients with bipolar disorder with no history of rapid cycling and without concomitant manic symptoms, but always in conjunction with a mood stabilizer or an atypical antipsychotic. Antidepressants should be tapered and discontinued after full remission of depression; the role of antidepressants in maintenance treatment is unclear.27,28

Treatment Guidelines Treatment guidelines are a critical source for the rational pharmacotherapy of bipolar disorder.21,52 The American Psychiatric Association guidelines for bipolar disorder have not been updated since 2002, and therefore do not include data that became available more recently.21 In a systematic overview of the current international guidelines for bipolar disorder conducted in 2011, the recommendations with the greatest degree of consensus and best evidence for first-line treatment were the use of (1) lithium, divalproex, or an atypical

Figure 2A Canadian Network for Mood and Anxiety Treatments Mania Algorithm Assess safety/functioning Establish treatment setting D/C antidepressants Rule out medical causes D/C caffeine, alcohol, and illicit substances Behavioral strategies/rhythms, psychoeducation

Step 1

Review general principles and assess medication status

Not receiving medication or first-line agent

Step 2

Initiate/optimize, check compliance

Initiate lithium, DVP, AAP, or 2-drug combination

Receiving first-line agent

Atypical antipsychotic

Lithium or DVP

2-drug combination (lithium or DVP + AAP)

No response

Step 3

Add-on or switch therapy

Add or switch to AAP

Add or switch to lithium or DVP

Replace 1 or both agents with other first-line agents

No response

Step 4

Add-on or switch therapy

Replace 1 or both agents with other first-line agents

Consider adding or switching to second- or third-line agents

No response

Step 5

Consider adding levetiracetam, phenytoin, mexiletine, omega-3 fatty acids, calcitonin, rapid tryptophan depletion, allopurinol, amisulpride

Add-on novel or experimental agents

AAP indicates atypical antipsychotic; D/C, discontinue; DVP, divalproex. Reprinted with permission from Yatham LN, Kennedy SH, Parikh SV, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2013. Bipolar Disord. 2013;15:1-44.

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Figure 2B Canadian Network for Mood and Anxiety Treatments Bipolar Depression Algorithm Assess safety/functioning Behavioral strategies/rhythms Psychoeducation

Step 1

Review general principles and assess medication status

On DVP

On OLZ, RIS, ARI, or ZIP

Add SSRIa/BUP or add/switch to lithium, LAM, or QUE

Add SSRI,a lithium or LAM, or switch to lithium, LAM or QUE

On first-line agent

Not on medication

Step 2

Initiate/optimize, check compliance

LAM

Lithium

QUE

OLZ + SSRIa

Lithium or DVP + SSRIa/BUP

Lithium + DVP

No response

Step 3

Add-on or switch therapy

Add/switch to lithium or QUE

Add SSRIa/ BUP or add/ switch to LAM or QUE

No response

Add SSRI, lithium or LAM or switch to lithium, LAM or OLZ + SSRIa

Switch to QUE, QUE + SSRI,a lithium, lithium + SSRIa/BUP or LAMb

Switch lithium or DVP to QUE or OLZ or switch SSRIa/ BUP to LAMc

Add SSRIa/ BUP or switch lithium or DVP to LAM or QUE

Step 4

Add-on or switch therapy

Replace 1 or both agents with alternate first- or second-line agents

No response

Step 5

Consider ECT, third-line agents, and novel or experimental options

Add-on or switch therapy

Except paroxetine. Or switch the SSRI to another SSRI. c Or switch the SSRI or BUP to another SSRI or BUP. ARI indicates aripiprazole; BUP, bupropion; DVP, divalproex; ECT, electroconvulsive therapy; LAM, lamotrigine; OLZ, olanzapine; QUE, quetiapine; RIS, risperidone; SSRI, selective serotonin reuptake inhibitor; ZIP, ziprasidone. Reprinted with permission from Yatham LN, Kennedy SH, Parikh SV, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2013. Bipolar Disord. 2013;15:1-44. a

antipsychotic, for acute mania; (2) divalproex or an atypical antipsychotic, for mixed episodes (ie, manic and depressed symptoms together); (3) quetiapine, olanzapine/fluoxetine combination, or lamotrigine, for bipolar depression; and (4) group or individual psychological education should be offered to all patients with bipolar disorder.53 The Table provides a summary of first-line pharmacotherapy recommendations from a selected set of comprehensive guidelines.21,38,52,54-57 However, implementation of the guidance in any treatment algorithm for bipolar disorder is challenging, because of the multiple factors involved in drug selection, drug interactions, adverse side effects, and patient adherence (Figure 2A and Figure 2B).38

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Major Challenges in the Treatment of Bipolar Disorder In addition to the importance of implementing an expeditious diagnosis, evidence-based prescribing, and cost-effective therapies, other challenges must be recognized and addressed in the treatment of patients with bipolar disorder to improve treatment outcome. Treatment Nonadherence Nonadherence to treatment is perhaps the most significant contributing factor to poor outcome in patients with bipolar disorder.58,59 Medication possession ratio (MPR) has been used to assess treatment adherence. MPR is the ratio of the number of days that an antipsychotic medication, for example, was filled

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compared with the total number of days during the follow-up period. An MPR of 1 indicates that for a medication prescribed for a patient over a given time, prescriptions were filled 100% of that period. A priori MPR percentage thresholds of 70% to 80% have been set to define adherence versus nonadherence; a threshold of 75% or 80% represents a level of adherence that is associated with better outcomes in patients with bipolar disorder.58-61 In one study with 1973 commercially insured patients, the mean MPR was only 0.46 (SD, ±0.32); patients whose MPR was ≥0.75 had a lower risk for allcause rehospitalization (OR, 0.73; 95% CI, 0.58-0.92) and mental health–related rehospitalization (OR, 0.76; 95% CI, 0.60-0.96).58 Similarly, among 1399 commercially insured patients, reduced adherence (<80%) to traditional mood-stabilizing therapy was associated with a greater risk for emergency department visits (OR, 1.98; 95% CI, 1.38-2.84) and inpatient hospitalizations (OR, 1.71; 95% CI, 1.27-2.32).59 In one of the largest studies of its type, using claims data from the 2000-2006 PharMetrics database (a large US database of commercial health plans), 78.7% of the 7769 patients with bipolar disorder had an MPR <0.75. An MPR ≥0.80 was associated with a reduction in risk for mental health–related hospitalization (OR, 0.82; 95% CI, 0.70-0.95), and an MPR ≥0.90 was also associated with a reduction in the risk for a mental health– related emergency department visit (OR, 0.71; 95% CI, 0.54-0.91).60 Similar findings have been reported in Medicaid-insured populations.61 Because adherence tends to worsen with the addition of each medication to a pharmacotherapeutic regimen, monotherapy may be considered a practical option in patients with poor adherence.62,63

Psychiatric Comorbidities Patients with bipolar disorder are predisposed to other comorbid psychiatric disorders at higher rates than patients with other psychiatric disorders.64,65 Anxiety disorders and alcohol or drug dependence are particularly common comorbidities, with major consequences for treatment outcome and increased cost.64,66 Comorbidity is the rule rather than the exception in bipolar disorder,64,65 with approximately 66% of patients having 1 comorbid mental health diagnosis and approximately 66% having 2 other conditions.66 These comorbid psychiatric conditions are associated with longer episodes of bipolar illness64,66; shorter time in remission (ie, euthymia)64,66; polypharmacy, with the potential for drug interactions67; and an increase in related problems, such as poor treatment compliance and suicidality.65

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General Medical Comorbidities Patients with bipolar disorder also have a high rate of other medical comorbidities, including diabetes, cardiovascular disease, obesity, migraine, and hepatitis C virus (HCV) infection.66,68 In a Veterans Administration (VA) study, patients with bipolar disorder had a higher prevalence of diabetes than patients in a national VA cohort (17.2% vs 15.6%, respectively; P = .0035) and of HCV (5.9% vs 1.1%, respectively; P <.001).68 Several reasons can potentially account for this increased burden of medical illness, including shared biologic predisposition (eg, migraine), comorbid substance misuse (HCV), as well as adverse effects of treatment (obesity and diabetes).69 Not surprisingly, medical comorbidities are associated with a significant increase in the total cost of care.70,71 Suicide Suicide is more frequent among patients with bipolar disorder than among patients with any other psychiatric or general medical disorder.72,73 Suicide among patients with bipolar disorder is estimated to occur at an annual rate of 0.4% (1 for every 250 individuals with bipolar disorder), which is more than 20 times than in the general US population.73 In the Epidemiologic Catchment Area database, which is still one of the best US databases regarding the epidemiology of psychiatric disorders, the lifetime rate of suicide attempts for persons with bipolar disorder was 29.2%—almost twice the rates of MDD (15.9%) and other Diagnostic and Statistical Manual of Mental Disorders, Third Edition– defined Axis I disorder (4.2%).72 Suicide attempts are very costly.74 In a study using data from the PharMetrics Integrated Outcomes Database (1995-2005), the total costs for 352 patients with bipolar disorder who attempted suicide were compared between the years after and before the first suicide attempt. The mean healthcare cost for the 1 year after the suicide attempt was $25,012 versus $11,476 for the 1 year before (P <.001). During the month after the suicide attempt, a large increase was reported in inpatient and emergency services, followed by enduring long-term increases in medication and outpatient costs.74 Women of Childbearing Age Women of childbearing age comprise a special population requiring vigilance by caregivers and healthcare providers.75 In a prospective observational study of 89 pregnant women with bipolar disorder who were euthymic at the time of conception, 71% had at least 1 recurrence of a bipolar episode during pregnancy; depression was the most common type of recurrence (38%), followed by mixed states (29%), hypomania (17%), and

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Diagnosis and Treatment of Bipolar Disorders in Adults

mania (7%). Those who discontinued pharmacotherapies were at twice the risk for a recurrence as those who continued therapy, had a recurrence earlier, and their illness was almost 5 times as long; abrupt treatment withdrawal posed the greatest risk.75 Given the demonstrated teratogenic risk associated with antiepileptic drugs and with lithium, atypical antipsychotics are an essential treatment option in this vulnerable population.76 Close coordination between obstetric, psychiatric, and primary medical care providers during pregnancy is critical.

Conclusion The lifetime management of patients with bipolar disorder is challenging, because of the dynamic, chronic, and fluctuating nature of this disease. The healthcare costs for patients and their caregivers are enormous from psychosocial and economic perspectives. It is incumbent on healthcare professionals to reduce the burden of bipolar disorder. Pharmacologic treatment is the mainstay of treatment for patients with bipolar disorder. Although mood stabilizers have been the cornerstone of therapy, the availability of atypical antipsychotics has significantly modified the approach to care. Individual atypical antipsychotic medications have been shown to be effective for acute mania/hypomania, for acute depression, and for maintenance treatment (of mania and depression), and have been incorporated into many treatment guidelines. The diligent selection of a specific agent that takes into account its efficacy in the various phases of bipolar disorder, along with its safety profile, can help to ameliorate the impact of this devastating condition. ■ Acknowledgment Editorial support for the preparation of the manuscript was provided by Bill Wolvey of PAREXEL. Funding Source Funding for writing this review article was provided by AstraZeneca. Author Disclosure Statement Dr Jann is on the Speaker’s Bureau for Janssen Pharmaceuticals.

References

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5. Judd LL, Akiskal HS, Schettler PJ, et al. The long-term natural history of the weekly symptomatic status of bipolar I disorder. Arch Gen Psychiatry. 2002;59:530537. 6. Judd LL, Akiskal HS, Schettler PJ, et al. A prospective investigation of the natural history of the long-term weekly symptomatic status of bipolar II disorder. Arch Gen Psychiatry. 2003;60:261-269. 7. Post RM, Denicoff KD, Leverich GS, et al. Morbidity in 258 bipolar outpatients followed for 1 year with daily prospective ratings on the NIMH life chart method. J Clin Psychiatry. 2003;64:680-690. 8. Joffe RT, MacQueen GM, Marriott M, Trevor Young L. A prospective, longitutinal study of percentage of time spent ill in patients with bipolar I or bipolar II disorders. Bipolar Disord. 2004;6:62-66. 9. Paykel ES, Abbott R, Morriss R, et al. Sub-syndromal and syndromal symptoms in the longitudinal course of bipolar disorder. Br J Psychiatry. 2006;189:118-123. 10. National Institutes of Health. National Institute of Mental Health. Statistics. www.nimh.nih.gov/health/statistics/prevalence/bipolar-disorder-among-adults. shtml. Accessed December 1, 2014. 11. Dilsaver SC. An estimate of the minimum economic burden of bipolar I and II disorders in the United States: 2009. J Affect Disord. 2011;129:79-83. 12. Williams MD, Shah ND, Wagie AE, et al. Direct costs of bipolar disorder versus other chronic conditions: an employer-based health plan analysis. Psychiatr Serv. 2011;62:1073-1078. 13. Zimmerman M, Galione JN, Chelminski I, et al. Sustained unemployment in psychiatric outpatients with bipolar disorder: frequency and association with demographic variables and comorbid disorders. Bipolar Disord. 2010;12:720-726. 14. Peele PB, Xu Y, Kupfer DJ. Insurance expenditures on bipolar disorder: clinical and parity implications. Am J Psychiatry. 2003;160:1286-1290. 15. Geddes JR, Burgess S, Hawton K, et al. Long-term lithium therapy for bipolar disorder: systematic review and meta-analysis of randomized controlled trials. Am J Psychiatry. 2004;161:217-222. 16. Scott J, Colom F. Psychosocial treatments for bipolar disorders. Psychiatr Clin North Am. 2005;28:371-384. 17. Baldessarini RJ, Tondo L, Visioli C. First-episode types in bipolar disorder: predictive associations with later illness. Acta Psychiatr Scand. 2014;129:383-392. 18. Daban C, Colom F, Sanchez-Moreno J, et al. Clinical correlates of first-episode polarity in bipolar disorder. Compr Psychiatry. 2006;47:433-437. 19. Perugi G, Micheli C, Akiskal HS, et al. Polarity of the first episode, clinical characteristics, and course of manic depressive illness: a systematic retrospective investigation of 320 bipolar I patients. Compr Psychiatry. 2000;41:13-18. 20. Suppes T, Leverich GS, Keck PE Jr, et al. The Stanley Foundation Bipolar Treatment Outcome Network: II. Demographics and illness characteristics of the first 261 patients. J Affect Disord. 2001;67:45-59. 21. Hirschfeld RM, Bowden CL, Gitlin MJ, et al; for the work group on bipolar disorder; American Psychiatric Association. Practice guideline for the treatment of patients with bipolar disorder. Second edition. April 2002. http://dbsanca.org/docs/ APA_Bipolar_Guidelines.1783155.pdf. Accessed April 23, 2013. 22. Hirschfeld RMA, Lewis L, Vornik LA. Perceptions and impact of bipolar disorder: how far have we come? Results of a national depressive and manic-depressive association 2000 survey of individuals with bipolar disorder. J Clin Psychiatry. 2003;64:161-174. 23. Scott J, Leboyer M. Consequences of delayed diagnosis of bipolar disorders. Encephale. 2011;37(suppl 3):S173-S175. 24. Sharma V, Khan M, Corpse C, Sharma P. Missed bipolarity and psychiatric comorbidity in women with postpartum depression. Bipolar Disord. 2008;10:742-747. 25. Kamat SA, Rajagopalan K, Pethick N, et al. Prevalence and humanistic impact of potential misdiagnosis of bipolar disorder among patients with major depressive disorder in a commercially insured population. J Manag Care Pharm. 2008;14:632-642. 26. McCombs JS, Ahn J, Tencer T, Shi L. The impact of unrecognized bipolar disorders among patients treated for depression with antidepressants in the fee-forservices California Medicaid (Medi-Cal) program: a 6-year retrospective analysis. J Affect Disord. 2007;97:171-179. 27. Ghaemi SN, Ostacher MM, El-Mallakh RS, et al. Antidepressant discontinuation in bipolar depression: a Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) randomized clinical trial of long-term effectiveness and safety. J Clin Psychiatry. 2010;71:372-380. 28. Vieta E, Locklear J, Günther O, et al. Treatment options for bipolar depression: a systematic review of randomized, controlled trials. J Clin Psychopharmacol. 2010;30:579-590. 29. Hirschfeld RMA. Screening for bipolar disorder. Am J Manag Care. 2007;13(7 suppl):S164-S169. Erratum in: Am J Manag Care. 2008;14:76. 30. Hirschfeld RMA. The Mood Disorder Questionnaire: a simple, patient-rated screening instrument for bipolar disorder. Prim Care Companion J Clin Psychiatry. 2002;4:9-11. 31. Kessler RC, Üstün TB. The World Mental Health (WMH) Survey Initiative Version of the World Health Organization (WHO) Composite International Diagnostic Interview (CIDI). Int J Methods Psychiatr Res. 2004;13:93-121. 32. Spitzer RL, Kroenke K, Williams JB; for the Patient Health Questionnaire Primary Care Study Group. Validation and utility of a self-report version of PRIME-MD: the PHQ primary care study. JAMA. 1999;282:1737-1744.

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33. Gill JM, Chen YX, Grimes A, Klinkman MS. Using electronic health record– based tools to screen for bipolar disorder in primary care patients with depression. J Am Board Fam Med. 2012;25:283-290. 34. Menzin J, Sussman M, Tafesse E, et al. A model of the economic impact of a bipolar disorder screening program in primary care. J Clin Psychiatry. 2009;70:1230-1236. 35. Derry S, Moore RA. Atypical antipsychotics in bipolar disorder: systematic review of randomised trials. BMC Psychiatry. 2007;7:40. 36. Suppes T, Ketter TA, Gwizdowski IS, et al. First controlled treatment trial of bipolar II hypomania with mixed symptoms: quetiapine versus placebo. J Affect Disord. 2013;150:37-43. 37. Sachs GS, Nierenberg AA, Calabrese JR, et al. Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med. 2007;356:1711-1722. 38. Yatham LN, Kennedy SH, Parikh SV, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2013. Bipolar Disord. 2013;15:1-44. 39. Baldessarini RJ, Tondo L, Davis P, et al. Decreased risk of suicides and attempts during long-term lithium treatment: a meta-analytic review. Bipolar Disord. 2006;8(5 pt 2):625-639. Erratum in: Bipolar Disord. 2007;9:314. 40. Geddes JR, Goodwin GM, Rendell J, et al; for the BALANCE investigators and collaborators. Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label trial. Lancet. 2010;375:385-395. 41. Kessing LV, Hellmund G, Geddes JR, et al. Valproate v. lithium in the treatment of bipolar disorder in clinical practice: observational nationwide register- based cohort study. Br J Psychiatry. 2011;199:57-63. Erratum in: Br J Psychiatry. 2011;199:343. 42. Geddes JR, Calabrese JR, Goodwin GM. Lamotrigine for treatment of bipolar depression: independent meta-analysis and meta-regression of individual patient data from five randomised trials. Br J Psychiatry. 2009;194:4-9. 43. Grandjean EM, Aubry J-M. Lithium: updated human knowledge using an evidence-based approach: part III: clinical safety. CNS Drugs. 2009;23:397-418. 44. Powell-Jackson PR, Tredger JM, Williams R. Hepatotoxicity to sodium valproate: a review. Gut. 1984;25:673-681. 45. Seo H-J, Chiesa A, Lee S-J, et al. Safety and tolerability of lamotrigine: results from 12 placebo-controlled clinical trials and clinical implications. Clin Neurophar macol. 2011;34:39-47. 46. Iqbal MM, Sohhan T, Mahmud SZ. The effects of lithium, valproic acid, and carbamazepine during pregnancy and lactation. J Toxicol Clin Toxicol. 2001;39:381-392. 47. Loebel A, Cucchiaro J, Silva R, et al. Lurasidone monotherapy in the treatment of bipolar I depression: a randomized, double-blind, placebo-controlled study. Am J Psychiatry. 2014;171:160-168. 48. Thase ME, Jonas A, Khan A, et al. Aripiprazole monotherapy in nonpsychotic bipolar I depression: results of 2 randomized, placebo-controlled studies. J Clin Psychopharmacol. 2008;28:13-20. Erratum in: J Clin Psychopharmacol. 2009;29:38. 49. Newcomer JW. Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review. CNS Drugs. 2005;19(suppl 1):1-93. 50. Edwards SJ, Smith CJ. Tolerability of atypical antipsychotics in the treatment of adults with schizophrenia or bipolar disorder: a mixed treatment comparison of randomized controlled trials. Clin Ther. 2009;31(pt 1):1345-1359. 51. Vázquez G, Tondo L, Baldessarini RJ. Comparison of antidepressant responses in patients with bipolar vs. unipolar depression: a meta-analytic review. Pharmaco psychiatry. 2011;44:21-26. 52. Goodwin GM; for the Consensus Group of the British Association for Pyschopharmacology. Evidence-based guidelines for treating bipolar disorder: revised second edition—recommendations from the British Association for Psychopharmacology. J Psychopharmacol. 2009;23:346-388. 53. Connolly KR, Thase ME. The clinical management of bipolar disorder: a review of evidence-based guidelines. Prim Care Companion CNS Disord. 2011;13. 54. Department of Veterans Affairs; Department of Defense; the Management of Bipolar Disorder Working Group. VA/DoD Clinical Practice Guideline for Management of Bipolar Disorder in Adults. May 2010. www.healthquality.va.gov/ guidelines/MH/bd/bd_305_full.pdf. Accessed December 5, 2014. 55. Grunze H, Vieta E, Goodwin GM, et al; for the WFSBP Task Force on Treatment Guidelines for Bipolar Disorders. The World Federation of Societies of Bio-

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logical Psychiatry (WFSBP) guidelines for the biological treatment of bipolar disorders: update 2012 on the long-term treatment of bipolar disorder. World J Biol Psychiatry. 2013;14:154-219. 56. Grunze H, Vieta E, Goodwin GM, et al; for the WFSBP Task Force on Treatment Guidelines for Bipolar Disorders. The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the biological treatment of bipolar disorders: update 2010 on the treatment of acute bipolar depression. World J Biol Psychiatry. 2010;11:81-109. 57. Grunze H, Vieta E, Goodwin GM, et al; for the WFSBP Task Force on Treatment Guidelines for Bipolar Disorders. The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the biological treatment of bipolar disorders: update 2009 on the treatment of acute mania. World J Biol Psychiatry. 2009;10:85-116. Erratum in: World J Biol Psychiatry. 2009;10:255. 58. Hassan M, Lage MJ. Risk of rehospitalization among bipolar disorder patients who are nonadherent to antipsychotic therapy after hospital discharge. Am J Health Syst Pharm. 2009;66:358-365. 59. Lew KH, Chang EY, Rajagopalan K, Knoth RL. The effect of medication adherence on health care utilization in bipolar disorder. Manag Care Interface. 2006;19:41-46. 60. Lage MJ, Hassan MK. The relationship between antipsychotic medication adherence and patient outcomes among individuals diagnosed with bipolar disorder: a retrospective study. Ann Gen Psychiatry. 2009;8:7. 61. Rascati KL, Richards KM, Ott CA, et al. Adherence, persistence of use, and costs associated with second-generation antipsychotics for bipolar disorder. Psychi atr Serv. 2011;62:1032-1040. 62. Burton SC. Strategies for improving adherence to second-generation antipsychotics in patients with schizophrenia by increasing ease of use. J Psychiatr Pract. 2005;11:369-378. 63. Thase ME. Quetiapine monotherapy for bipolar depression. Neuropsychiatr Dis Treat. 2008;4:21-31. 64. Grant BF, Stinson FS, Hasin DS, et al. Prevalence, correlates, and comorbidity of bipolar I disorder and axis I and II disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions. J Clin Psychiatry. 2005;66:1205-1215. 65. Baldassano CF. Illness course, comorbidity, gender, and suicidality in patients with bipolar disorder. J Clin Psychiatry. 2006;67(suppl 11):8-11. 66. Kessler RC, Nelson CB, McGonagle KA, et al. The epidemiology of co-occurring addictive and mental disorders: implications for prevention and service utilization. Am J Orthopsychiatry. 1996;66:17-31. 67. McIntyre RS, Konarski JZ, Yatham LN. Comorbidity in bipolar disorder: a framework for rational treatment selection. Hum Psychopharmacol. 2004;19:369-386. 68. Kilbourne AM, Cornelius JR, Han X, et al. Burden of general medical conditions among individuals with bipolar disorder. Bipolar Disord. 2004;6:368-373. 69. Weber NS, Fisher JA, Cowan DN, Niebuhr DW. Psychiatric and general medical conditions comorbid with bipolar disorder in the National Hospital Discharge Survey. Psychiatr Serv. 2011;62:1152-1158. 70. Guo JJ, Keck PE Jr, Li H, et al. Treatment costs and health care utilization for patients with bipolar disorder in a large managed care population. Value Health. 2008;11:416-423. 71. Kasteng F, Eriksson J, Sennfält K, Lindgren P. Metabolic effects and cost-effectiveness of aripiprazole versus olanzapine in schizophrenia and bipolar disorder. Acta Psychiatr Scand. 2011;124:214-225. 72. Chen Y-W, Dilsaver SC. Lifetime rates of suicide attempts among subjects with bipolar and unipolar disorders relative to subjects with other axis I disorders. Biol Psychiatry. 1996;39:896-899. 73. Tondo L, Isacsson G, Baldessarini RJ. Suicidal behaviour in bipolar disorder: risk and prevention. CNS Drugs. 2003;17:491-511. 74. Stensland MD, Zhu B, Ascher-Svanum H, Ball DE. Costs associated with attempted suicide among individuals with bipolar disorder. J Ment Health Policy Econ. 2010;13:87-92. 75. Viguera AC, Whitfield T, Baldessarini RJ, et al. Risk of recurrence in women with bipolar disorder during pregnancy: prospective study of mood stabilizer discontinuation. Am J Psychiatry. 2007;164:1817-1824. 76. McKenna K, Koren G, Tetelbaum M, et al. Pregnancy outcome of women using atypical antipsychotic drugs: a prospective comparative study. J Clin Psychiatry. 2005;66:444-449.

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Diagnosis and Treatment of Bipolar Disorders in Adults

STAKEHOLDER PERSPECTIVE

Bipolar Disorders: Balancing Formulary Management and Clinical Outcomes for a Vulnerable Patient Population By Gary M. Owens, MD President, Gary Owens Associates

PATIENTS: Bipolar disorders are a major health concern, with significant lifelong social and occupational impairment to patients, and poor prognosis. It is estimated that the lifetime prevalence of clinical bipolar spectrum disorders is approximately 3% to 7% of the US population, and the average age of onset is 15 to 30 years.1,2 Astoundingly, the prevalence of bipolar disorders may be just slightly less than the prevalence of asthma (8%) in adult patients.3 In addition to the debilitating clinical burden on patients, there is also significant cost associated to patients and to the healthcare system with this disorder, in large part secondary to its substantially elevated morbidity and mortality rates, which are largely due to associated cardiovascular disease, metabolic syndrome, substance abuse or misuse, and potential for physical self-harm from reckless or impulsive behaviors or suicide. MEDICAL/PHARMACY DIRECTORS: As noted in the review article by Dr Jann in this issue of American Health & Drug Benefits,4 payers recognize that this disorder brings both clinical and economic challenges. The managment of bipolar disorder has evolved over the past decade, as new treatments and new evidence for the use of atypical antipsychotics and other agents emerge. Payers are certainly aware of the changing treatment environment, and they are challenged to keep up with these changes as they expand beyond even the most recent treatment guidelines. As Dr Jann notes, “Although mood stabilizers have been the cornerstone of therapy, the availability of atypical antipsychotics has significantly modified the approach to care.”4 This makes it a challenge for payers, who must optimize current formularies to take advantage of the availability of low-cost generic drugs yet maintain access to essential treatments for this important patient population. Management of the treatments for bipolar disorder includes generics-first programs, preferred brand drugs step therapy, and prior authorization of the atypical antipsychotics. Although these programs are essential to

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sound formulary management, recent studies have cast some doubt on the overall effectiveness of these efforts.5,6 For example, Zhang and colleagues provide evidence for a small decrease in pharmacy expenditures associated with formulary restrictions for patients with bipolar disorder, but this was associated with an increase in treatment discontinuation.5 More recently, a 2014 study by Seabury and colleagues concluded that formulary restrictions resulted in medical cost increases that eliminated much, if not all, of the possible savings among atypical antipsychotic users with schizophrenia or with bipolar disorder.6 Because of this growing evidence, it is important for payers to continuously assess their clinical management programs for this disease category to ensure that they are optimizing cost management and not creating negative clinical impact on this vulnerable patient population. Payers can also make substantial contributions to the multidisciplinary team who are caring for patients with bipolar disorder. Specific pharmacy programs can serve as medication information resources such as providing medication counseling, counseling on lifestyle modifications to ensure optimal clinical response to therapies, and monitoring of patients on issues of medication compliance and the consequences of nonadherence. By taking these steps, payers will ensure that they are providing the optimum balance of clinical and economic outcomes for this population. ■ 1. Goodwin FK, Jamison KR. Manic-Depressive Illness: Bipolar Disorders and Recur rent Depression. 2nd ed. New York, NY: Oxford University Press; 2007.

2. Malhi GS, Adams D, Cahill CM, et al. The management of individuals with bipolar disorder: a review of the evidence and its integration into clinical practice. Drugs. 2009;69:2063-2101. 3. Centers for Disease Control and Prevention. FastStats: asthma. Updated July 14, 2014. www.cdc.gov/nchs/fastats/asthma.htm. Accessed December 12, 2014. 4. Jann MW. Diagnosis and treatment of bipolar disorders in adults: a review of the evidence on pharmacologic treatments. Am Health Drug Benefits. 2014; 7:489-499. 5. Zhang Y, Adams AS, Ross-Degnan D, et al. Effects of prior authorization on medication discontinuation among Medicaid beneficiaries with bipolar disorder. Psychiatr Serv. 2009;60:520-527. 6. Seabury SA, Goldman DP, Kalsekar I, et al. Formulary restrictions on atypical antipsychotics: impact on costs for patients with schizophrenia and bipolar disorder in Medicaid. Am J Manag Care. 2014;20:e52-e60.

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499

CONTINUING EDUCATION

Supplement

Evolution in the Value-Based Care of Rheumatologic Diseases: A Prospectus for Managed Care Pharmacists Faculty Douglas Burgoyne, PharmD President VRx Pharmacy Services, LLC Salt Lake City, UT

Release date: December 15, 2014 Expiration date: December 31, 2015 Estimated time to complete activity: 1.0 hour Target Audience This activity is directed toward pharmacists who are involved in the management of patients with rheumatologic diseases. Educational Objectives After completing this activity, the participant should be better able to: • Review the current management options in rheumatoid arthritis and psoriatic arthritis • Discuss the potential clinical implications of existing and emerging novel biologic therapies on the treatment paradigm for rheumatologic diseases • Utilize optimal, value-based management approaches to patients with rheumatoid arthritis and psoriatic arthritis • Provide accurate and appropriate counsel as part of the treatment team Faculty Douglas Burgoyne, PharmD President, VRx Pharmacy Services, LLC Salt Lake City, UT Joseph F. Merola, MD, MMSC Director of Clinical Trials Co-Director, Center for Skin and Related Musculoskeletal Diseases Brigham and Women’s Hospital Instructor, Harvard Medical School, Boston, MA Jonathan Kay, MD Director of Clinical Research, Rheumatology Professor of Medicine University of Massachusetts Medical School UMass Memorial Medical Center, Worcester, MA Pharmacist Continuing Education Accreditation Statement Postgraduate Institute for Medicine is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Credit Designation Postgraduate Institute of Medicine designates this continuing education activity for 1 contact hour(s) (0.1 CEU) of the Accreditation Council for Pharmacy Education. (Universal Activity Number 0809-9999-14-227-H01-P) Type of Activity: application System Requirements PC Windows 7 or above Flash Player v10.0 or higher Internet Explorer v9.0 or higher

MAC MAC OS X 10.6 or higher Flash Player v10.0 or higher Latest version of Firefox,

Joseph F. Merola, MD, MMSC Director of Clinical Trials Co-Director, Center for Skin and Related Musculoskeletal Diseases Brigham and Women’s Hospital Instructor, Harvard Medical School Boston, MA Latest version of Firefox, Google Chrome, or Safari Adobe Acrobat Reader v7.0 or higher*

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*Required to view printable (PDF) version of the lesson. Disclosure of Conflicts of Interest Postgraduate Institute for Medicine (PIM) requires instructors, planners, managers, and other individuals who are in a position to control the content of this activity to disclose any real or apparent conflict of interest (COI) they may have as related to the content of this activity. All identified COI are thoroughly vetted and resolved according to PIM policy. PIM is committed to providing its learners with high-quality CME/CE activities and related materials that promote improvements or quality in healthcare and not a specific proprietary business interest of a commercial interest. The faculty reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME/CPE activity: Name of Faculty or Presenter

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Douglas Burgoyne, Consultant to AstraZeneca, BristolPharmD Myers Squibb, Novo Nordisk, Purdue, Sanofi, and XenoPort. Joseph F. Merola, Advisory Board for AbbVie, Amgen, MD, MMSC Eli Lilly, and Novartis; Consultant to AbbVie, Amgen, Biogen Idec, Eli Lilly, and Novartis; Investigator for Amgen, Biogen Idec, and Pfizer; Licensed Outcome Measure for AbbVie; Research funding from Biogen Idec. Jonathan Kay, MD Consultant to AbbVie, Alexion Pharmaceuticals, Amgen, AstraZeneca, Bristol-Myers Squibb, Crescendo Bioscience, Eli Lilly, Epirus Biopharmaceuticals, Genentech, Hospira, Janssen Biotech, PanGenetic B.V., Pfizer, Roche Laboratories, Samsung Bioepis, and UCB Inc. The following PIM planners and managers—Laura Excell, ND, NP, MS, MA, LPC, NCC; Trace Hutchison, PharmD; Samantha Mattiucci, PharmD, CCMEP; and Jan Schultz, MSN, RN, CCMEP—hereby state that they or their spouse/life partner do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months. Center of Excellence Media, LLC: Susan Berry hereby states that she or her spouse/life partner do not have any financial relation-

Jonathan Kay, MD Director of Clinical Research, Rheumatology Professor of Medicine University of Massachusetts Medical School UMass Memorial Medical Center Worcester, MA ships or relationships to products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months. Disclosure of Unlabeled Use This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. Postgraduate Institute for Medicine and Center of Excellence Media, LLC, do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of any organization associated with this activity. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings. Disclaimer Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed in this activity should not be used by clinicians without evaluation of patient conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities. Instructions for Credit There is no fee for this activity. To receive credit after reading this CE activity in its entirety, participants must complete the posttest and evaluation. The posttest and evaluation can be completed online at http://ce.lynxcme.com/COE175. Upon completion of the evaluation and scoring 75% or better on the posttest, you will immediately receive your certificate online. If you do not achieve a score of 75% or better on the posttest, you will be asked to take it again. Please retain a copy of the certificate for your records. If you have any questions regarding the CE certification for this activity, please contact Postgraduate Institute for Medicine at: information@pimed.com or 303-799-1930. Pharmacists: Upon successfully completing the posttest with a score of 75% or better and the activity evaluation form, transcript information will be sent to the NABP CPE Monitor Service within 4 weeks. Media: Printed report

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heumatologic diseases, such as rheumatoid arthritis (RA) and psoriatic arthritis (PsA), are chronic inflammatory disorders that are associated with severe disability and, consequentially, negative impact on quality of life (QOL). Dramatic advancements seen in the treatment of rheumatoid diseases largely stem from the advent of biologic agents. However, the costs of therapy are significant, underscoring the importance and need for the practice of value-based care. This educational activity provides highlights of a live symposium from the Academy of Managed Care Pharmacy meeting held in Boston, MA, on October 7-10, 2014, which focused on the evolution of value-based care of rheumatologic diseases, including clinical and pharmacoeconomic assessments of conventional and biologic disease-modifying antirheumatic drugs (DMARDs) in the treatment of patients with RA or PsA.

In addition, the current treatment armamentarium of bDMARDs includes 5 US Food and Drug Administration (FDA)-approved tumor necrosis factor (TNF) inhibitors (adalimumab, certolizumab, etanercept, golimumab,

Dramatic advancements seen in the treatment of rheumatoid diseases largely stem from the advent of biologic agents. and infliximab), the cytotoxic T-lymphocyte–associated protein-4 T-cell costimulation blocker abatacept, the anti-CD20 monoclonal antibody (mAb) rituximab, the interleukin (IL)-1 receptor antagonist inhibitor anakinra, the anti–IL-6 receptor mAb tocilizumab, and the oral Janus kinase/signal transducer and activator of transcription inhibitor tofacitinib (Table 1).4-11 Over the last decade, the treatment paradigms for RA have evolved significantly, with authoritative guidelines and emerging clinical data advocating the initiation of intensive therapy earlier in the course of disease and the use of a treat-to-target management strategy. To attain

Optimization of Conventional and Biologic Disease-Modifying Antirheumatic Drug Use in Rheumatoid Arthritis RA is an autoimmune disease characterized by inflammation of the joints, accompanied by proliferation of the synovium and the progressive erosion of cartilage and bone, leading to severe disability and premature mortality.1 In 2010, a colTable 1 Biologic Disease-Modifying Antirheumatic Drugs Approved for Management of Rheumatoid Arthritis and Psoriatic Arthritis laboration between the American College of Rheumatology (ACR) and Drug Mechanism of action FDA approval year the European League Against Rheu4-9 Rheumatoid arthritis matism (EULAR) resulted in new Anti-TNF 2002 Adalimumab classification criteria for RA that emAnti-TNF 2008 Certolizumab pegol phasized the need for early diagnosis Anti-TNF 1998 Etanercept based on the extent of joint involveAnti-TNF 2009 Golimumab ment, serology (rheumatoid factor Anti-TNF 1999 and anticitrullinated protein antiInfliximab CD28 2005 body), acute-phase reactants (erythAbatacept rocyte sedimentation rate [ESR] and Anti-CD20 1997 Rituximab C-reactive protein), and duration of IL-1 receptor 2001 Anakinra symptoms (<6 weeks or ≥6 weeks).2 IL-6 receptor 2010 Tocilizumab Based on the important pathogenJAK/STAT TKI 2012 Tofacitinib ic roles of proinflammatory cytokines Psoriatic arthritis4,5,10,11 in RA, a number of powerful convenAnti-TNF 2002 tional DMARDs (cDMARDs) and Etanercept Anti-TNF 2005 biologic DMARDs (bDMARDs) Adalimumab have become available. In this era of Anti-TNF 2005 Infliximab targeted biologic therapies, methoAnti-TNF 2009 Golimumab trexate (MTX) still reigns as an “anAnti-TNF 2013 Certolizumab pegol chor drug” and the gold standard for PDE4 inhibitor 2014 Apremilast treatment of RA, either as monotherAnti–IL-12/IL-23 2013 Ustekinumab apy or in combination with various biologic agents, attesting to its efficaFDA indicates US Food and Drug Administration; IL, interleukin; JAK, Janus kinase; PDE4, phosphodiesterase 4; STAT, signal transducer and activator of cy, acceptable safety profile, low cost, 3 transcription; TKI, tyrosine kinase inhibitor; TNF, tumor necrosis factor. and decades of clinical experience.

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Table 2 Radiographic Progression During 2 Years in the TEAR Trial Difference in modified Sharp score at week 102

Patients, n

Baseline (mean ± SD)

Week 48 (mean ± SD)

Week 102 (mean ± SD)

Immediate combination therapy

330

7.0 ± 14.9

7.9 ± 15.9

7.5 ± 15.7

1.1 ± 6.4

Step-up to combination therapy

236

6.2 ± 13.4

7.3 ± 14.6

6.2 ± 8.7

1.2 ± 4.1

MTX monotherapy

2.9 ± 3.5

2.9 ± 3.6

2.6 ± 2.9

0.2 ± 1.1

Treatment group

(mean ± SD)

P values across treatment groups were significant at week 48 (P=.0321) and week 102 (P=.0074), as was the change in modified Sharp score at week 102 (P=.0467). MTX indicates methotrexate; SD, standard deviation; TEAR, Treatment of Early Aggressive Rheumatoid Arthritis. Sources: O’Dell JR, et al. Arthritis Rheum. 2013;65:1985-1994; Moreland LW, et al. Arthritis Rheum. 2012;64:2824-2435.

the treatment goal of remission or low disease activity, therapy should be adjusted when no improvement is noted by at most 3 months after the start of treatment or when the target has not been reached by 6 months.12 The 2013 EULAR guidelines clarified that intensive therapy in early RA does not imply commencing therapy with bDMARDs before cDMARDs, and advised that cDMARD monotherapy or a combination of cDMARDs should be used in DMARD-naive patients, and that MTX should be part of the first treatment strategy.12

Currently, tocilizumab is the only biologic agent that has demonstrated superiority as monotherapy over MTX in MTX-naive patients with RA. The guidelines further state that bDMARDs may be initiated in combination with MTX if treatment target is not achieved with cDMARD approaches or if poor prognostic factors are present.12 In addition, the EULAR guidelines broadly consider that abatacept, tocilizumab, rituximab, and the 5 FDA-approved TNF inhibitors exhibited similar efficacy and safety and recommended switching to another bDMARD upon failure of a first bDMARD. The guidelines further recommend the preferential use of a bDMARD in combination with MTX over bDMARD monotherapy,12 because the approved biologic agents have demonstrated reduction of disease activity, improvement of functional disability, and retardation of radiographic progression, either alone13 or in combination with MTX.14,15 Currently, tocilizumab is the only biologic

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agent that has demonstrated superiority as monotherapy over MTX in MTX-naive patients with RA.16 Several trials have assessed whether it is better to intensively treat all patients with early RA using combination therapy comprising bDMARD plus MTX or triple therapy with cDMARDs, such as MTX, sulfasalazine, and hydroxychloroquine immediately, or to delay administration of combination therapy following an inadequate response to MTX monotherapy.17-20 The 2-year follow-up assessment of the randomized SWEFOT (Swedish Farmacotherapy) trial involving patients with MTX-refractory early RA showed that the proportion of patients who achieved a EULAR-defined good response was numerically higher in those who were treated with MTX plus infliximab compared with those who received cDMARD triple therapy, although this difference was not significant (38% vs 31%, respectively; P=.204).17 However, the radiologic disease progression was significantly greater in patients treated with conventional therapy compared with those who were treated with biologic therapy (change in modified Sharp score mean, 7.23 vs 4.00; P=.009).17 The randomized, 4-arm TEAR (Treatment of Early Aggressive Rheumatoid Arthritis) trial of 755 patients with early, poor-prognosis RA evaluated 2 immediate treatment approaches with either cDMARD triple therapy (MTX + sulfasalazine + hydroxychloroquine) or MTX plus etanercept combination therapy, and 2 delayed treatment approaches in which treatment escalation to one of the combination therapies was applied at 24 weeks after inadequate response to MTX monotherapy, based on a disease activity score in 28 joints using the ESR (DAS28ESR) ≥3.2.18,19 Overall, no differences were seen in the mean DAS28-ESR between patients randomized to triple therapy and those randomized to MTX plus etanercept,

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Figure Response Rates at 1 Year in the AMPLE Trial 100

Primary end point

90 Proportion of patients with ACR20 response, %

regardless of whether patients received immediate combination therapy or step-up from MTX monotherapy. In this trial, approximately 28% of patients continued to use MTX monotherapy based on a DAS28-ESR â&#x2030;¤3.2, confirming that a subset of patients attain disease control with MTX alone. However, at 102 weeks, immediate combination therapy with either strategy was more effective than initial MTX monotherapy, underscoring the benefits of combination therapy. Of note, patients who received initial MTX monotherapy and subsequent step-up to combination therapy had DAS28-ESR values at week 48 and radiographic progression at week 102 similar to those who received immediate combination therapy, which validated the traditional step-up approach (Table 2).18,19 Along the same vein, the 48-week, double-blind, noninferiority RACAT (RA: Comparison of Active Therapies) trial concluded that triple therapy (MTX + sulfasalazine + hydroxychloroquine) was noninferior to MTX plus etanercept in terms of DAS28 response at 48 weeks, in patients with active RA who had an inadequate response to MTX (DAS28 â&#x2030;Ľ4.4).20 In this study, patients who did not show an improvement in DAS28 at 24 weeks (DAS28 decrease <1.2) were allowed to switch from one arm to the other, resulting in significant improvements in both groups. Taken together, the findings from the TEAR and the RACAT trials support the use of cDMARD triple therapy as a low-cost alternative to the combination of MTX plus bDMARD. In addition, in patients with early RA, the initial use of MTX monotherapy with a biologic or a nonbiologic DMARD added on as needed after 6 months of disease persistence is a rational approach.18-20 Recently, in treating patients with bDMARDs, there has been interest in evaluating the potential withdrawal of the biologic agent when reaching low disease activity or remission. Understandably, this paradigm shift in the treatment of RA would have favorable pharmacoeconomic implications in addition to obvious safety and convenience benefits.21 For example, a systematic review of 10 eligible studies evaluating discontinuation of TNF inhibitors in patients achieving low disease activity or remission suggested that this approach was possible in 24% to 81% of patients without a resultant increase in disease activity; heterogeneous inclusion criteria and highly variable outcome definitions across studies contributed to the wide range of the results.22 However, there are currently no markers to predict which patients may be candidates for discontinuation of anti-TNF therapy once desirable clinical outcomes are achieved. A number of studies have compared bDMARDs directly. For example, the AMPLE (Abatacept Versus Adalimumab Comparison in Biologic-Naive RA Subjects with Background Methotrexate) trial concluded that subcutaneous abatacept or adalimumab (adminis-

80 70

64.8%

63.4%

206/318

208/328

Abatacept

Adalimumab

60 50 40 30 20 10 0

ACR indicates American College of Rheumatology; AMPLE, Abatacept Versus Adalimumab Comparison in Biologic-Naive RA Subjects with Background Methotrexate. Sources: Schiff M, et al. Ann Rheum Dis. 2014;73:86-94; Weinblatt ME, et al. Arthritis Rheum. 2013;65:28-38.

tered with MTX) showed comparable ACR improvement responses (Figure), as well as improvement in functional disability and inhibition of radiographic progression at 2 years.23,24 Although the rates of adverse events and serious adverse events were similar between the 2 treatment groups, adalimumab therapy was associated with a higher rate of discontinuation and a higher

Recently, in treating patients with bDMARDs, there has been interest in evaluating the potential withdrawal of the biologic agent when reaching low disease activity or remission. incidence of serious infections (including 2 cases of tuberculosis) compared with abatacept therapy.23 Conversely, the randomized, double-blind, phase 4 ADACTA (Tocilizumab Monotherapy Versus Adalimumab Monotherapy for Treatment of Rheumatoid Arthritis) trial reported that tocilizumab monotherapy was superior to adalimumab monotherapy in producing a significantly greater change from baseline in DAS28, DAS28 remission, and DAS28 low disease activity at week 24 in patients with RA for whom MTX was deemed ineffective or inappropriate.25 The safety profiles were consistent with those previously reported for these 2 agents.25 However, it must be noted that a higher dose of tocilizumab (8 mg/kg

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intravenous monthly) was used in this trial than the doses used in other trials with this agent, and adalimumab monotherapy is known to be less effective than adalimumab plus MTX; both of these factors may have skewed the results in favor of tocilizumab.15,26

Treatment Paradigms in Psoriatic Arthritis PsA is a chronic, systemic, inflammatory disease that is associated with significant joint involvement (peripheral and spinal) in conjunction with a spectrum of extra-articular manifestations, including enthesitis and dactylitis, as well as involvement of the skin and nails.27 Such broad articular and nonarticular phenotypes of PsA have a debilitating impact on patientsâ&#x20AC;&#x2122; function and QOL, which were shown to be nearly equivalent to the function and QOL scores reported by patients with RA.28 Although the general prevalence of PsA in the United States is estimated to be 0.25%, it is considerably higher among patients with psoriasis, with a prevalence rate of up to 42%.29,30 Skin disease typically precedes joint disease in patients with PsA, with approximately 75% to 80% of affected patients developing joint complications 7 to 12 years from the onset of psoriasis to the diagnosis of PsA, although in 10% to 15% of patients, PsA may precede psoriasis.30 Moreover, PsA is associated with an elevated risk for cardiovascular disease and metabolic syndrome, conferring an increased risk for mortality.31 In fact, the prevalence of metabolic syndrome among patients with PsA in one study was observed to be higher (58.1%) than the prevalence among the general population (35.2%) reported by the Third National Health and Nutrition Examination Survey.32

The management of PsA can pose a clinical challenge as a result of diverse and often simultaneous clinical manifestations, requiring multidisciplinary treatment. The heterogeneous clinical presentation of PsA is accompanied by a variable disease course, with some patients experiencing mild, chronic disease whereas others show severe, rapid, erosive joint disease.27 Timely diagnosis and appropriate therapeutic intervention are of paramount importance, because persistent inflammation, progressive joint damage, and marked functional impairment and disability can occur in the absence of effective therapy.17 However, the management of PsA can pose a clinical challenge as a result of diverse and often simultaneous clinical manifestations, requiring multidisciplinary treatment.

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Two treatment guidelines, 2012 EULAR and 2009 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis, have been released for the management of PsA.33,34 Whereas the immediate treatment target is to achieve clinical remission or at least low disease activity, long-term treatment goals are to maintain health-related QOL, reduce skin and joint signs and symptoms, and prevent or attenuate structural damage. Treatment recommendations from both guidelines indicate that patients with mild-to-moderate disease may be treated with nonsteroidal anti-inflammatory drugs and intra-articular corticosteroid injections as adjunctive therapy for control of joint (but not skin) symptoms. For patients with more severe disease, cDMARD therapy (ie, MTX, sulfasalazine, leflunamide, or cyclosporine) is indicated at an early stage, whereas biologic agents with or without cDMARDs may be considered if the response to cDMARDs is considered inadequate, and as first-line therapy in patients with extensive involvement of skin and joints. The 2012 EULAR guidelines in particular recommend switching to a second anti-TNF agent in patients whose disease fails to improve after treatment with a TNF inhibitor.33 However, in contrast to RA, current evidence does not support the use of a combination of TNF inhibitors and cDMARDs in patients with PsA.29,33 Currently, 5 TNF inhibitors (adalimumab, certolizumab, etanercept, golimumab, and infliximab), the antiIL-12/23 mAb ustekinumab, and the phosphodiesterase 4 inhibitor apremilast have shown efficacy in PsA and have been approved by the FDA for this indication.30,33 The guidelines note that despite the lack of direct head-tohead comparisons among the available TNF inhibitors, no apparent differences in efficacy for joint involvement have emerged with these agents, whereas the efficacy of etanercept on skin involvement may be lower than the other TNF antagonists.33 A meta-analysis of an indirect comparison of adalimumab, etanercept, golimumab, and infliximab in PsA revealed no significant differences in effectiveness among these agents.35 However, the study noted that golimumab yielded the highest relative risk for the PsA response criteria, whereas etanercept and infliximab showed the greatest benefit for Health Assessment Questionnaire improvements, and infliximab was most effective in yielding psoriasis area and severity index improvements.35 Taken together, these findings show that an individualized approach to drug selection, based on disease severity and tissue manifestations, is critical in the treatment of PsA.

Clinical and Pharmacoeconomic Assessments in Value-Based Care of Rheumatologic Diseases Although bDMARDs have redefined the treatment paradigm in rheumatologic diseases, it is undisputed that

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the treatment costs incurred by these agents are substantial. According to the 2014 CVS/Caremark Book of Business spending trend analysis, RA was the therapeutic category with the largest specialty drug spending.36 Currently, the 5 approved TNF inhibitors represent approximately $20 billion in annual sales.37 These facts have led to a growing interest in evaluating the value of bDMARDs in the treatment of RA and PsA, specifically, to determine whether the efficacy benefits, reductions in healthcare use, decreases in productivity losses, and improvements in QOL achieved with these agents warrant the increased drug costs compared with cDMARDs. Toward this end, several cost-effectiveness analyses of anti-TNF drugs for RA have been conducted. Zalesak and colleagues recently published a systematic review of market research and cost-effectiveness studies designed to assess clinical, functional, and economic outcomes associated with specialty drug treatments versus the previous standard of care.38 They showed that compared with conventional DMARDs, bDMARDs had significant therapeutic benefit in addition to being costeffective, with incremental cost-effectiveness ratios (ICERs) of $47,500 per quality-adjusted life-year (QALY).38 Overall, whereas the costs of anti-TNF agents were clearly higher than those of traditional DMARDs, the former resulted in a higher number of QALYs.38 In another analysis that used the Birmingham Rheumatoid Arthritis Model, which takes into account QOL and mortality indices, TNF inhibitors were most costeffective when used as last active therapy after the use of less expensive conventional DMARDs, rather than firstline use.39 Comparing TNF inhibitors, the ICER for infliximab was significantly higher than the ICERs for etanercept or adalimumab, regardless of whether it was used as first-line therapy or later.39 In terms of first-line combination therapy, the ICERs associated with MTX plus a TNF inhibitor were considerably higher than those generated with monotherapy.39 Consistent with these results, the cost-effectiveness analysis of the SWEFOT trial showed that the infliximab-treated group accumulated higher drug and healthcare costs compared with the group randomized to conventional nonbiologic therapy, compounded by higher societal costs as a result of productivity losses being similar between the groups.40 Finally, sequential therapy with 2 TNF antagonists has been shown to have the same order of cost-effectiveness as single-agent therapy.39 Many of the conclusions from these cost-effectiveness analyses are consistent with emerging clinical data and guideline recommendations. A few persistent questions relevant to value-based care in rheumatologic diseases include: • Is there a significant clinical benefit of biologic agents over conventional agents?

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• Should biologic drugs be offered only after patients show inadequate response to less expensive conventional therapies? • Can biologic drugs be discontinued once remission or low disease activity is achieved? • Which patients should receive biologic agents instead of conventional therapies?

Taken together, these findings show that an individualized approach to drug selection, based on disease severity and tissue manifestations, is critical in the treatment of PsA. In addition to optimization of currently existing biologic agents to gain cost benefits, another approach is to develop effective but cheaper biologic alternatives. This has led to the development of biosimilars, which are biologic drugs that are structurally similar but not identical to the reference agent, and show no clinically meaningful differences in terms of safety, purity, and potency.41 This concept has taken root because the US patents for several biologic agents for RA (including abatacept, adalimumab, infliximab, rituximab, and tocilizumab) have expired or are expected to expire over the next few years.42 Although the efforts to introduce biosimilars for the treatment of RA are expected to provide cost-savings and, possibly, increased access to biologic agents, several hurdles remain to be overcome to achieve this goal. Foremost is the need to establish the clinical bioequivalence in terms of efficacy and safety of a biosimilar and its parent compound, followed by their interchangeability in clinical practice.41,42

Conclusion The advent of biologic DMARDs has brought us closer to being able to achieve disease remission and repair of structural damage in RA and PsA, but these agents incur significant costs, necessitating further cost-effectiveness analyses. Balancing the cost considerations with the clinical outcomes suggests that cDMARDs should remain as first-line therapies in RA and PsA within a treat-to-target framework, whereas biologic agents should be used subsequent to the failure of treatment with cDMARDs, to achieve optimal clinical, functional, and economic outcomes in rheumatologic diseases. Acknowledgment Sabeeha Muneer, PhD, contributed to the development of this article.

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