October 2008, Vol 1, No 8 by Dalia Buffery

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™ OCTOBER 2008

VOLUME 1, NUMBER 8

EDITORIAL

Writing Research Articles on Benefit Design and Policy William E. Fassett, BSPharm, MBA, PhD; Charles R. Phillips, PharmD, PhD REGULATORY

Cutting Through the Politics: Presidential Candidates’ Healthcare Platforms and Impact on Health Benefits Peyton Howell, MHA BUSINESS ™

Medication Therapy Management Goes Hi-Tech: Implementing Automated Software Improves Pharmacy Efficiency Adrienne Giordano, PharmD; Carrie Holden, PharmD; Cathrine Misquitta, PharmD, BCPS

Cost-Effectiveness of Second-Generation Antihistamines and Montelukast in Relieving Allergic Rhinitis Nasal Symptoms Michael J. Goodman, PhD; Mehul Jhaveri, PharmD; Kim Saverno, RPh; Kellie Meyer, PharmD; Brian Nightengale, PhD CLINICAL

Evaluation and Management of Diabetes Mellitus Quang Nguyen, DO; Loida Nguyen, PharmD; James Felicetta, MD DEPARTMENTS ◆ Generic Drug Trends ◆ FDA Watch

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EDITORIAL

Writing Research Articles on Benefit Design and Policy William E. Fassett, BSPharm, MBA, PhD; Charles R. Phillips, PharmD, PhD

eaders of American Health & Drug Benefits (AHDB) are invited to submit research articles relevant to benefit design. Successful publication of an author’s research arises from selecting a journal whose readers’ needs and interests match the topic of the manWilliam E. Fassett uscript. Health and drug benefit administrators and policy makers need reliable information predicting how changes in benefit design will affect healthcare outcomes and the behaviors of stakeholders. A successful manuscript clearly addresses a current issue of importance to a national audience of drug policy makers and administrators, reports results that are reliable and justified by the design and conduct of the research, and exhibits characteristics of good writing. Aspiring authors may see achieving publication of a manuscript as a daunting task. The act of writing is hard work—Gene Fowler is reputed to have said, “Writing is easy: all you do is sit staring at a blank sheet of paper until drops of blood form on your forehead.”1 Having submitted the manuscript, the author faces possible rejection. For example, American Psychological Association journals in 2006 reported an overall rejection rate of 78%, ranging from 34% for the Journal of Comparative Psychology to 89% for JEP: Learning, Memory, and Cognition.2 Does this mean that an author must submit 2 or 3 articles to get 1 published? In fact, it does not—the publication process is not a crapshoot. Successful authors are repeatedly successful; many experienced authors find that virtually all their manuscripts reach publication. Repeatedly successful authors apply several key principles in their work.3,4 Many of these principles can help authors who submit manuscripts to AHDB.

Dr Fassett is Professor of Pharmacy Law and Ethics, and Vice Chair, Department of Pharmacotherapy, College of Pharmacy, Washington State University, Spokane; Dr Phillips is Assistant Dean of Assessment and Associate Professor, Social and Administrative Sciences, College of Pharmacy and Health Sciences, Drake University, Des Moines, IA.

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A Solid Foundation Every successful manuscript serves a particular need or answers a question of interest to the intended audience. Key to a successful article is welldesigned research or scholarship. Four important tasks face the researcher. First, it is critical to Charles R. Phillips understand the current state of knowledge in the area selected for study, and this means to fully understand the current literature. The researcher, then, frames a research question that will add new information to the literature. Each type of question requires a particular approach, which means implementing solid research methods while designing the study. Finally, the researcher must make sure that the source of information or study population is appropriate to yield reliable results that have meaning to the intended audience. List as authors all persons who participate significantly in the creation of the manuscript and acknowledge minor contributions. Putting one’s name on a ghostwritten article is a violation of publication ethics.5 Write for the Intended Reader AHDB readers are policy makers and administrators responsible for implementing health and drug benefit programs. They aim to deliver the greatest value to health plan stakeholders. They seek to maximize healthcare outcomes for patients while minimizing costs to payers, which involves evaluating incentives, products, and services that are included in the benefit package. Articles submitted to the journal must provide information relevant to these concerns. Understand, Summarize the Literature The researcher is a member of a community of individuals interested in answering important questions about a particular area. Journals seek to publish new and unique findings of interest to their readers, and do not wish to publish material previously revealed elsewhere, whether by the same or different authors. Therefore, the aspiring author must be up to date on the current literature relevant to the proposed study.

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The author must summarize the literature, identify where new information is needed, and explain why his or her study fits that need.

A Clear Research Question A clearly defined research question is essential and may propose new theory, seek to correct current thinking, ask about new methods of research, or ask how current theory applies in actual practice. The investigator must clearly define the intervention or policy change and the outcome measures that will assess the intervention’s effect. Examples of specific research questions common to benefit design include: • How will pharmacy spending and utilization change from implementing a plan or a public policy change (multitiered copayments, mandatory generic substitution, coinsurance, prior authorization, formularies)? • How will medical spending and utilization change as a result of a plan or a public policy change? • How will a proposed change affect health outcomes?6 • Which intervention or product produces the best benefit-to-cost ratio, the most cost-effective outcome, or the highest quality-adjusted life extension? The researchers must carefully choose the interventions to study, how to measure the outcomes, and the perspective to use for the analysis. Should they base pharmacy costs on the cost to the plan, the patient, or even society? Should they define costs as per member per month, as total out of pocket, or some other measurement? The researchers need to be explicit about their measurements to be able to specifically address the research question. Match the Method to the Question To answer the research question, it is essential to implement well-designed and accepted research methods. Whether the research question deals with cost containment, utilization control, medical therapy management, or outcomes management, each research approach has specific practices. Each of the accepted designs used by researchers studying pharmacy benefits follows rules of design and measurement.6 Some of these research approaches are: • Clinical trials, retrospective reviews of pharmacy claims data during and after benefit design changes, pharmacoeconomic studies to compare competing alternatives • Cross-section studies that depict utilization and spending under current conditions, retrospective and prospective studies assessing risk

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October 2008

• Longitudinal and time-series studies that track outcome changes over time. There is no perfect study, but to obtain valid, reliable, and usable results, the appropriate research design has the fewest and least-fatal design flaws.

Use Appropriate Sample If results are going to be applicable to a reader’s population, the sample or source of information must be generalizable to a wider group of people than just those studied. When a study’s results are not generalizable, they are merely an interesting anecdote that requires more study in other populations. A sample of patients similar to those served by the readers of the journal has a greater chance of publication. A sample skewed by demographics—such as elderly or Medicaid populations, or by unique interventions unlikely useful to others7—limits the impact of their results and jeopardizes the study’s publication. Other common problems are samples that are too small for adequate statistical testing, and bias introduced by the sampling method. For example, internet surveys do not reach people who lack adequate computer access,8 and telephone surveys often miss low-income or young people.9 Follow the Author Guidelines Carefully Each journal has identified a potential audience and has a plan that defines the types of articles sought and the style and format of the journal. The guidelines for authors set forth the criteria for acceptance derived from this plan. Research articles in AHDB are judged at the outset according to these guidelines and must follow the required format. The AHDB guidelines are relatively general, so it is helpful here to describe a typical outline for a research article. At least the following sections should be present: Abstract: The abstract provides the reader with a concise summary of the article. The abstract must include the objective, methods, results, and conclusions. Readers must be able to learn from the abstract the key study results and decide whether the article is applicable to their environment and, therefore, worthy of further review. Introduction: The introduction must concisely summarize the literature and the importance of the research question to the reader. It should identify key gaps in current knowledge and suggest how the proposed study addresses those gaps. An introduction that is beyond a page or so is generally too long. Methods: The methods section should inform the

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Writing Research Articles

reader of the nature of the study sample, geographic location of the study, and the data collection time frame. The design of the study is described, and relevant statistical tests must be disclosed. The author must explain how the survey instrument was developed and validated. When human subject research is involved, the author must document the nature of Institutional Review Board approval. Include appropriate references that justify the particular methods used in the study. The methods section should be sufficient to allow another researcher to replicate the study. Results: This section presents the study findings. It should show results that address the research questions and objectives, as well as any results supporting the validity of the data. In general, reserve interpretations of the findings or comments on weaknesses or strengths of the data for the discussion section. Discussion: The discussion explains how the author interprets the results in the context of current knowledge. It should also mention potential limitations of the study. Conclusion: The author’s conclusions should comment on additional implications of the study, and if the study met its intended purpose. The author should explain the applicability of the results to health and benefit design and implementation. In general, the conclusions section should be a brief summary that encapsulates the study findings and their meaning.

Revise, Revise, Revise Rejected manuscripts fail for 2 major reasons (and often for both): (1) the article is conceptually unsound in the design and conduct of the study; and (2) the article is poorly organized and written. Sometimes an otherwise acceptably designed study is rejected because the author fails to describe it clearly and fully. We recommend that an author revise a manuscript at least 3 times before submitting it for publication. Revise first for clarity and organization. This should include asking another colleague to review the article and comment on any major missing pieces, overall organization, and if the colleague understands the author’s descriptions and conclusions. Revise next for conciseness. Journals have limited space and readers have limited time. Most journals specify upper limits for word counts; AHDB’s target for peer-reviewed articles is 3000 words. AHDB generally limits abstracts to 250 words and references to 30. Finally, revise to conform to the journal’s format and style guidelines. Ensure correct citation of every reference, and verify that all data and figures are correct and

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accurate. References must be numbered consecutively and listed at the end of the article. Figures and tables should be placed after the references. Successful authors usually must revise the manuscript again after peer review. When the editors ask the author to make these changes, congratulations are in order. The peer reviewers and editors have found the article generally appropriate and suitable for publication, subject to the revisions. Perform this revision promptly, and comply with all the suggestions. Look forward to seeing the manuscript in print. ■ References 1. Brainy Quote: Gene Fowler quotations. http://www.brainy quote.com/ quotes/authors/g/gene_fowler.html. Accessed August 10, 2008. 2. American Psychological Association. Summary Report of Journal Operations, 2006. 2007. http://www.apa.org/journals/statistics/2006 operations. pdf. Accessed August 10, 2008. 3. Nahata MC. Tips for writing and publishing an article. Ann Pharmacother. 2008;42:273-277. 4. Emerald Group Publishing Limited. How to…survive peer review and revise your paper. http://info.emeraldinsight.com/ authors/guides/ review.htm?part=1. Accessed August 10, 2008. 5. DeAngelis CD, Fontanarosa PB. Impugning the integrity of medical science: the adverse effects of industry influence. JAMA. 2008;299:1833-1835. 6. Goldman DP, Joyce GF, Zheng Y. Prescription drug cost sharing: associations with medication and medical utilization and spending and health. JAMA. 2007;298:61-69. 7. Joyce GF, Escarce JJ, Solomon MD, et al. Employer drug benefit plans and spending on prescription drugs. JAMA. 2002;288:1733-1739. 8. Hartford K, Carey R, Mendonca J. Sampling bias in an international internet survey of diversion programs in the criminal justice system. Eval Health Prof. 2007;30:35-46. 9. Blumberg SJ, Luke JV. Coverage bias in traditional telephone surveys of low-income and young adults. Public Opin Quart. 2007;71:734-749.

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OCTOBER 2008

VOLUME 1, NUMBER 8

™

EDITORIAL

Writing Research Articles on Benefit Design and Policy William E. Fassett, BSPharm, MBA, PhD; Charles R. Phillips, PharmD, PhD

REGULATORY

Cutting Through the Politics: Presidential Candidates’ Healthcare Platforms and Impact on Health Benefits Peyton Howell, MHA Stakeholder Perspective by Joseph R. Antos, PhD

BUSINESS

Medication Therapy Management Goes Hi-Tech: Implementing Automated Software Improves Pharmacy Efficiency Adrienne Giordano, PharmD; Carrie Holden, PharmD; Cathrine Misquitta, PharmD, BCPS Stakeholder Perspective by Scott R. Taylor, RPh, MBA

Cost-Effectiveness of Second-Generation Antihistamines and Montelukast in Relieving Nasal Symptoms of Allergic Rhinitis Michael J. Goodman, PhD; Mehul Jhaveri, PharmD; Kim Saverno, RPh; Kellie Meyer, PharmD; Brian Nightengale, PhD Stakeholder Perspective by Michael F. Murphy, MD, PhD

Publisher Nicholas Englezos nick@engagehc.com 732-992-1884 Associate Publisher Maurice Nogueira maurice@engagehc.com 732-992-1895 Editorial Director Dalia Buffery dalia@AHDBonline.com 732-992-1889 Associate Editor Lara J. Reiman 732-992-1892 Senior Production Manager Robyn Jacobs Director of Human Resources Blanche Marchitto President Brian F. Tyburski brian@engagehc.com Editor-in-Chief Robert E. Henry rhenry@AHDBonline.com 732-992-1885

CLINICAL

Mission Statement

Evaluation and Management of Diabetes Mellitus

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

Quang Nguyen, DO; Loida Nguyen, PharmD; James Felicetta, MD Stakeholder Perspective by Thomas McCarter, MD, FACP

American Health & Drug Benefits is included in the following indexing and database services: Cumulative Index to Nursing and Allied Health Literature (CINAHL)

Contact Information: For reprints, subscription information, and editorial queries, please contact: editorial@AHDBonline.com

EBSCOhost research databases (EBSCO)

Continued on page 6

AMERICAN HEALTH & DRUG BENEFITS

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

October 2008

T: 732-992-1880 F: 732-992-1881

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DEPARTMENTS

GENERIC DRUG TRENDS Presidential Candidates Strong Supporters of Greater Access to Generics and Biosimilars Dalia Buffery, MA, ABD

FDA WATCH New Reporting System for Potential Safety Concerns of Drugs on the Market Mark Senak, JD

Business/Government Editor Kip Piper, MA, CHE President, Health Results Group kpiper@AHDBonline.com Actuary David Williams Clinical Research Nirav R. Shah, MD, MPH Samuel M. Silver, MD, MPH Michael A. Weber, MD Employers Alberto M. Colombi, MD, MPH Arthur F. Shinn, PharmD, FASCP F. Randy Vogenberg, RPh, PhD

Executive Summaries

CAPTION CONTEST

Clinical Editor Thomas McCarter, MD, FACP Chief Clinical Officer Executive Health Resources tmccarter@AHDBonline.com

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Health Information Technology J.B. Jones, ABD, MBA Healthcare Outcomes Gary M. Owens, MD Managed Care & Government Affairs Sharad Mansukani, MD

Managed Markets Marketing Jeffrey A. Bourret, MS, RPh, FASHP Charles E. Collins, Jr, MS, MBA

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Outcomes Research Gordon M. Cummins, MS Timothy S. Regan, BPharm, RPh

• Hospitalized elderly lack understanding

Patient Advocacy William E. Fassett, PhD, RPh, MBA

WEB EXCLUSIVE of generic equivalence • Caption Contest

Pharmacoeconomics Jeff Jianfei Guo, BPharm, MS, PhD

American Health & Drug Benefits, ISSN 1942-2962 (print); ISSN 1942-2970 (online), is published 9 times a year by Engage Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205B, Monroe Township, NJ 08831. Copyright © 2008 by Engage Healthcare Communications, LLC. All rights reserved. American Health & Drug Benefits and The Peer-Reviewed Forum for Evidence in Benefit Design are trademarks of Engage Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher. Printed in the United States of America. Address all editorial correspondence to: editorial@AHDBonline.com, Telephone: 732-992-1889. Fax: 732-992-1881. American Health & Drug Benefits, 241 Forsgate Drive, Suite 205B, Monroe Township, NJ 08831. POSTMASTER: CORRESPONDENCE REGARDING SUBSCRIPTIONS OR CHANGE OF ADDRESS should be directed to CIRCULATION DIRECTOR, American Health & Drug Benefits, 241 Forsgate Drive, Suite 205B, Monroe Township, NJ 08831. Fax: 732-992-1881. YEARLY SUBSCRIPTION RATES: One year: $99.00 USD; Two years: $149.00 USD; Three years: $199.00 USD. Permission requests to reprint all or part of any article published in this journal should be addressed to REPRINT PERMISSIONS DEPARTMENT, Engage Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205B, Monroe Township, NJ 08831. The ideas and opinions expressed in American Health & Drug Benefits do not necessarily reflect those of the Editorial Board, the Editors, or the Publisher. Publication of an advertisement or other product mentioned in American Health & Drug Benefits should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturers about any features or limitations of products mentioned. Neither the Editors nor the Publisher assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication.

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October 2008

Pharmacy Benefit Design Jan E. Berger, MD, MJ Joel V. Brill, MD Paul A. Polansky, BSPharm, MBA Scott R. Taylor, RPh, MBA Pharmacy & Specialty Products James T. Kenney, RPh, MBA Policy & Public Health Joseph R. Antos, PhD Alex A. Hathaway, MD, MPH, FACPM Jack E. Fincham, PhD, RPh Reimbursement Policy Michael Schaffer, PharmD, MBA Grant D. Lawless, MD, BSPharm, FACP Research & Development Michael F. Murphy, MD, PhD Wayne A. Rosenkrans, Jr, PhD

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REGULATORY

Cutting Through the Politics: Presidential Candidates’ Healthcare Platforms and Impact on Health Benefits Peyton Howell, MHA Healthcare reform is one of the top issues for the presidential elections this year, and both candidates have proposed a wide range of health policy changes that could be the most important changes to the delivery of care in the country since the creation of Medicare and Medicaid in the 1960s. This article provides a summary analysis of the healthcare platforms of the presidential candidates. Specifically, the major components of their published health plan proposals are broken out and compared using the language and descriptions from the candidates. The article also highlights several healthcare reform proposals from health advocacy organizations, as well as insights from medical directors and pharmacy directors across more than 50 major managed care health plans. By framing the issues, the article provides a basis for consideration of more detail as healthcare reform recommendations are developed by Congress in 2009. [AHDB. 2008;1(8):8-14.]

e are in the final stretch of the presidential elections, and both the Democratic and Republican conventions are now behind us. After the August break, Congress was back in Washington for only 3 weeks starting September 8, making it unlikely for any new healthcare legislation to be passed until after we have a new administration. This year, Congress has been challenged to reach consensus on healthcare legislation although members were able to override a veto and pass the Medicare Improvements for Patients and Providers Act of 2008, which corrected a cut this July in Medicare reimbursement for physician services. Although there seems to be partisan agreement that many aspects of our healthcare system need significant reform, the challenge of resources to fund such reforms seems to have created a paralyzing environment for the next president. The debate on the future of healthcare in the United States continues among healthcare professionals, as evidenced in recent publications,1-5 and will remain a key issue for the presidential elections. The present article is intended to provide a straightforward analysis of the healthcare platforms of the presidential candidates, as

Ms Howell is President, Consulting Services & Health Policy, AmerisourceBergen Specialty Group, Frisco, TX.

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October 2008

well as highlight several healthcare reform proposals from health advocacy organizations. The article also includes views on healthcare reforms from a group of about 50 decision makers in managed care health plans surveyed during 2 meetings of Managed Care Network (MCN) in June and in September 2008. The reality is that we are likely to see health reforms ultimately emerge to include a combination of the reform proposals rather than the platform of the president-elect alone. Congressional debate will ultimately determine the specific healthcare reform proposals, and therefore the balance of power within Congress will have a key impact on healthcare reform. This analysis will focus on key health reform components and avoid labeling such reforms in political terms. When possible, exact quotes and descriptions from the candidates’ healthcare proposals and summaries available on the campaigns’ websites have been used.

Key Areas of Proposed Health Reform Policies Overall, both healthcare plans are focused on leveraging the existing private healthcare market, but both also preserve existing Medicare and Medicaid systems in general (Table 1). Both candidates recognize the need for broader health reforms that focus on prevention and disease

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management. McCain specifically states that he would like to reform Medicare to be more oriented to diagnostic care, preventive care, and care coordination. There has been bipartisan interest in these objectives but crafting and funding such changes has been a challenge. Obama’s proposals will face key funding obstacles, such as “filling in” the Medicare Part D “donut hole” (a gap in annual drug coverage), which has expanded the debate on the “underinsured.”

KEY POINTS

Main Differences between the 2 Proposals Areas of greatest difference between the 2 candidates involve (1) the role of federal government and use of mandates, and (2) Medicare- and Medicaid-specific reforms, including mandates or requirements to participate in a healthcare reform initiative (Table 2). However, both proposals are largely focused on private insurance–based reforms, which is very different from the “socialized medicine” type concerns we often have been hearing debated. One area of debate is whether the Obama plan would leverage a private-payer model similar to federal employees under the Federal Employees Health Benefits (FEHB) program or whether it would advocate for a government-run Medicare model that individuals could buy into, which would likely be opposed by moderates from both parties. The McCain plan is focused on removing the current bias toward employer-sponsored health insurance and instead moving to individual tax credits that would create lower-cost options for healthy families, but the key concerns of this plan are for families with some form of existing healthcare issues.6 This is a major overhaul of current tax code incentives and one of the key,

▲ Despite the crucial differences in their approaches, the 2

▲ Both presidential candidates have proposed health policy

changes that could introduce the most sweeping revisions to US healthcare since the inception of Medicare. ▲ We are likely to see reforms that will combine a plethora of

proposals issued by different organizations rather than the platform of the president-elect alone. ▲ The balance of power within Congress will have a key

impact on healthcare reform. candidates agree on (1) transparency and price reporting, (2) comparative effectiveness, and (3) the role of health information technology. ▲ It is essential for decision makers in healthcare to monitor

the details of any reform proposal and stay engaged in the process. Results of a recent survey presented in this article reflect positions taken by 50 medical and pharmacy directors.

most-costly benefits provided by the majority of employers. More analysis and data are needed on the likely impact of this change from an individual perspective and from a corporate perspective. Many experts fear that a shift away from employer incentives to provide health insurance would do little to address the needs of the uninsured.7 A recent analysis by The Commonwealth Fund indicates that we could see more “underinsured patients” as individuals opt for less-expensive plans with significant out-of-pocket risks in the form of large deductibles and coinsurance since those plans would likely more closely match the proposed tax credits.8

Table 1 Comparison of Key Components of Proposed Health Plans Plan component Mandated coverage?

Obama Yes, for children only

McCain No

Medicaid/SCHIP expansion? Tax credits/subsidies

Yes Tax credit (for premiums greater than certain percentage of income only) All firms offer coverage or contribute a percentage of payroll New private and public plan options

No Tax credit ($2500 for individual, $5000 for family)

Employer-shared responsibility Private insurance markets

No change in tax code basis Purchase private individual insurance in any state

SCHIP indicates State Children’s Health Insurance Program. Adapted from Collins SR, Kriss JL. Envisioning the future: the 2008 presidential candidates’ health reform proposals. http://www.commonwealthfund.org/publications/publications_show.htm?doc_id=647708.

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REGULATORY

Table 2 Role of Federal Government in Health Insurance and Coverage: Key Differences in the 2 Proposals Obama plan Supports significant federal oversight of healthcare Will create a “national health plan” with “guaranteed eligibility” and “comprehensive benefits” like the FEHB program

McCain plan Does not support government-mandated, governmentfunded, or government-controlled healthcare Will provide all individuals with a $2500 tax credit ($5000 for families) toward purchase of health insurance

Will require employers to make “meaningful contribution” to the cost of quality health coverage, or be required to contribute a percentage of payroll to the national plan

Will change the tax code to shift away from employer-sponsored health insurance

Will establish a “National Health Insurance exchange” to regulate plans and create rules for plans (eg, stable premiums regardless of health status)

Will increase competition by allowing individuals to purchase health insurance across state lines and across groups/associations

Estimated cost: $50 billion-$65 billion annually

Will give states flexibility and encourage alternative forms of access and insurance

FEHB indicates Federal Employee Health Benefits.

Table 3 Areas of Similarities between the 2 Proposals Obama

McCain Specific Medicare and Medicaid Proposals Wants to “require companies to send Medicare Reforms Medicare to compensate for diagnostic, beneficiaries a full list of the drugs and fees prevention, and care coordination they paid the previous year” Wants to fill in the Medicare Part D “donut hole” Gives states flexibility to encourage Medicaid competition Supports expansion of Medicaid, SCHIP Transparency and Price Would require “full transparency” on prices, Supports “more public information” on quality, costs medical outcomes, quality of care, costs, prices Comparative Effectiveness Supports research to determine “which drugs, No specific proposal is identified as comparative devices, and procedures are the best diagnostic effectiveness, but supports “more public information” and treatment options” on medical outcomes, quality of care, costs, prices Health Information Technologies Invest $10 billion annually over next 5 years “Promote rapid deployment of 21st-century information for the “adoption of standards-based electronic” systems,” including telemedicine in areas where access medical records to providers is limited SCHIP indicates State Children’s Health Insurance Program.

The Obama plan is focused on employer mandates to reduce the number of uninsured to a level where government efforts can nearly close the gap on the uninsured.9 Mandates are one of the areas of criticism and concern regarding the Obama plan. The plan is focused on reducing the number of uninsured (espe-

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cially children and young adults) but would not initially eliminate all of the uninsured. This plan proposes a private insurance model similar to that available to those in the FEHB program, but one area of concern is whether a Medicare opt-in model would be created that private payers could not compete with.

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Presidential Candidates’ Healthcare Platforms

Areas of Agreement between the 2 Proposals Despite the many differences, there are several areas where the 2 platforms seem aligned (Table 3), including (1) transparency and price reporting, (2) comparative effectiveness, and (3) health information technology (HIT). With regard to transparency and price reporting, their public statements appear similar. However, it is unclear how this transparency could affect health plans, for example, or if it would be limited to prices for services and products (hospitals, physicians, pharmacy). Clearly, both candidates advocate for more access to such data, yet more details or specifics are needed from both to get to some conclusions. Similarly, both candidates are likely to support new focus on comparative effectiveness as a resource to maximize the value of our healthcare expenditures and improve access to information on health outcomes and best practices. There appears to be bipartisan support to expand comparative effectiveness, as well as to its eventual use in coverage and payment policies. This appears to be an area where the candidates are more aligned than not, and thus the creation of some form of mechanism to collect, analyze, and share health outcomes resources, including cost-effectiveness data, is likely. But integrating such data into coverage limitations and reductions is clearly more controversial. HIT has been a hot topic in Washington, and again we see both candidates supportive of such technologies as a means to gain new long-term cost-efficiencies and potential quality improvements. Obama’s plan has released more specific details regarding investments he would propose to support electronic medical records (EMRs), whereas McCain has talked more broadly to expand coverage for technologies such as telemedicine. Health policy analysts have expressed concern regarding the significant investment costs of HIT compared with realistic gains in quality or costs, particularly given the overall budget challenges the country faces in Washington, but there is bipartisan agreement that the government must create some form of incentives for providers to move more quickly toward HIT investments.

types of programs would eventually be implemented. One example that has received favorable attention is recommendations proposed by America’s Health Insurance Plans (AHIP), which suggests incremental reforms that would provide cost savings to the existing system. AHIP has separately proposed a healthcare reform proposal to address the broader (and more costly) issues of the uninsured. AHIP proposes a 5-point strategy for reducing healthcare costs and insurance premiums that it estimates would save $145 billion by 2015. The plan’s key recommendations are: 1. Create a national entity to compare the clinical and cost-effectiveness of new technologies 2. Facilitate leadership to encourage adoption of EMRs and other HIT 3. Create an independent administrative process to resolve medical liability disputes 4. Implement payment reforms to reward quality and value 5. Support the implementation of incentives and other strategies to promote healthy behavior and prevent disease. It is useful to review these AHIP recommendations, because they appear aligned with both Obama’s and McCain’s proposals in these areas, and thus point to opportunities for bipartisan support. Other proposals released from a variety of states and national associations and coalitions include: • Federation of American Hospitals • Health Coverage Coalition for the Uninsured • National Federation of Independent Businesses • American Academy of Family Physicians • Service Employees International Union • Healthcare Leadership Council • Families USA • American Medical Association • AARP. Based on a review of these proposals, core information has been collected on some of the key proposals; a summary of these plans appears in Table 4. Overall, most proposals appear to more closely advocate for health reforms that include components of both presidential candidates.

Other Healthcare Reform Proposals With a high probability of some form of significant healthcare reform in the next 4 years, a wide range of health policy organizations have begun to develop their own proposals and recommendations.10,11 Some proposals reflect more of a bipartisan blend of healthcare reforms and therefore could be models of what

Private Health Plans’ Perspectives on Healthcare Reform During a meeting of MCN in June 2008 and again in September 2008, more than 50 medical and pharmacy directors from a wide range of private health plans were surveyed about their perspectives regarding the presidential elections and the potential for health-

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that mandates are used to cover uninsured

• Not specific, but assume

Yes

Based on low income in tax code

restructuring tax code to benefit lower-income people • Insurance market reforms to encourage individual choice and insurers to establish affordable coverage policies • The plan diminishes the role of employers

• Covers the uninsured by

AMA

eligibility to those <100% FPL • Enroll individuals/ currently eligible for coverage under a public plan but not to participating

• Expand Medicaid

4 specific tax code changes

access and quality via 5 goals: Encourage research on what works Change incentives to promote better care Empower consumers and providers Promote wellness Create public–private

• Lowers costs and improves

BCBSA

Advocates use of SCHIP and Medicaid dollars to provide premium assistance for working individuals to purchase insurance through their employer

Significant changes

primarily through private insurance with public programs as a safety net • Improves quality and affordability • Fosters innovation through better coordinated care, HIT, patient literacy, coverage solutions and financial incentives and reimbursement

• Covers all Americans

HLC

Note: Summary analysis is based on published policy statements. AHA indicates American Hospital Association; AHIP, America’s Health Insurance Plans; AMA, American Medical Association; BCBSA, BlueCross BlueShield Association; HIT, health information technology; HLC, Healthcare Leadership Council; FPL, federal poverty level; SCHIP, State Children’s Health Insurance Program.

assume that mandates are used to cover uninsured

• Not specific, but

coverage to those kids in families <200% FPL • All adults <100% FPL would become eligible for Medicaid

• Increases SCHIP

Public program expansion (eg, Medicaid, SCHIP)

Yes

Some form of employer mandates?

Yes

Not clear; have assumed mandates to fund

Yes

For low-income people

5 goals: Prevention More efficient care More affordable care Access to health information Universal coverage

• Proposal is built on

• Increases eligibility

for public programs to: • Facilitate consumer purchase of health insurance with pretax pretax dollars • Provide subsidies up to 400% FPL • Support states’ proposals for access

AHA

AHIP

Some form of individual mandate?

Tax credit provisions

Plan summary (Not comprehensive, intended for overview purposes only, based on public statements)

Health reform proposals

Table 4 Health Reform Proposals by Various Organizations

Presidential Candidates’ Healthcare Platforms

Figure 1 If the Elections Were Held Today, Who Do You Think Would Win? June

Figure 3 In What Timeframe Do You Anticipate Some Type of Reform? June

September

September 8%

10% 23%

40%

47%

60%

53%

N = 49 Obama McCain

September

66%

N = 48 1-2 yrs

Figure 2 Do You Expect to See Incremental Healthcare Reform or a Major Overhaul? June

67%

N = 55

Source: Managed Care Network Meeting on June 8, 2008, Washington, DC; September 13, 2008, Salt Lake City, UT.

26%

2-5 yrs

N = 55 Never

Source: Managed Care Network Meeting on June 8, 2008, Washington, DC; September 13, 2008, Salt Lake City, UT.

Figure 4 Assuming Democratic-Controlled Senate and Congress Continues, Which Candidate Would Lead to the Best Healthcare Reform for the Country? September

7% 28%

28% 72%

93% Barack Obama

N = 47 Incremental reform

N = 55 Major overhaul

Source: Managed Care Network Meeting on June 8, 2008, Washington, DC; September 13, 2008, Salt Lake City, UT.

care reforms. Responses to 4 questions are shown in Figures 1-4. The findings from this survey suggest that decision makers across private health plans and managed care organizations see a greater potential for major healthcare reform than most other industry experts MCN has surveyed. These thought leaders are at the cutting edge of managed care, so they may also be more open to such reforms. It is expected that any type of reform would occur during the second half of a new administration— whether incremental or a major overhaul.

Conclusions Both presidential candidates have included healthcare reform as core components of their campaigns.

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43%

30%

John McCain No significant difference

N = 54

Source: Managed Care Network Meeting, September 13, 2008, Salt Lake City, UT.

Their approaches overall are significantly different and will affect patients, employers, providers, and payers very differently. It is therefore essential for decision makers in healthcare to continue to monitor the details of healthcare reform proposals by the candidates and by other organizations and to stay engaged in the process. ■

References 1. Baker CD, Caplan A, Karen D, et al. Health of the nation—coverage for all Americans. N Engl J Med. 2008;359:777-780. 2. Oberlander J. The partisan divide—the McCain and Obama plans for US health care reform. N Engl J Med. 2008;359:781-784. 3. Buchmueller T, Glied SA, Royalty A, Swartz K. Cost and coverage implications of the McCain plan to restructure health insurance. Health Aff. 2008;27:W472-W481. 4. Antos J, Wilensky G, Kuttner H. The Obama plan: more regulation, unsustainable spending. Health Aff. 2008;27:W462-W471.

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REGULATORY

5. Pauly MV. Blending better ingredients for health reform. Health Aff. 2008;27:W482-W491. 6. www.johnmccain.com/healthcare. Accessed September 15, 2008. 7. Schoen C, Davis K, Collins SR. Building blocks for reform: achieving universal coverage with private and public group health insurance. Health Aff. 2008;27:646-657. 8. Collins SR, Kriss JL. Envisioning the future: the 2008 presidential candidates’ health reform proposals. http://www.commonwealthfund.org/

publications/publications_show.htm?doc_id=647708. Accessed September 15, 2008. 9. www.barackobama.com/issues/healthcare. Accessed September 15, 2008. 10. Kaiser Family Foundation. American public’s reactions to buying health insurance on their own, 2008. June 26, 2008. www.kaiserfamily foundation.org. Accessed September 15, 2008. 11. www.health08.org. Accessed September 15, 2008.

Stakeholder Perspective Health Reform and the Next President PAYERS: Senators Barack Obama and John McCain offer sharply different visions of health sector reform, but they share the same general policy objectives. Both presidential candidates support expanding government subsidies to increase the number of people who have health insurance. Both candidates argue that health insurance must become more affordable. Both candidates embrace changes, such as expanded use of health information technology and improved management of high-cost patients, which could improve efficiency in healthcare delivery. Both candidates avoid admitting that their visions can only be had at a price—requiring higher taxes to finance subsidies, substantial new investments to implement health system improvements, and changes in the way healthcare is practiced. This is the stuff of political campaigns, long on promises and short on implementation. The differences between the candidates are worth examining. Senator Obama emphasizes business as usual, albeit with larger subsidies and more regulations. His 2 “big” ideas—organizing the nongroup insurance market along the lines of the Federal Employees Health Benefits program and requiring employers to contribute to worker health benefits or pay a new tax (“play or pay”)—focus on expanding coverage. At least in the near term, affordability means higher subsidies, not lower cost. The centerpiece of Senator McCain’s reform is replacing the current income tax exclusion with a flat tax credit, which would eliminate the bias in favor of more expensive coverage. The tax proposal would make purchases in the nongroup market more attractive, but it does not spell the end of employer coverage. The McCain proposal would reshape federal subsidies to dampen the growth of health spending. Which strategy would be more effective in reaching the goals shared by both candidates? Unfortunately, we

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may never know. Prospects for major health reform have declined sharply with the unprecedented disruption of financial markets whose potential impact is only beginning to be realized. Faced with a nearly $500-billion budget deficit and demands for federal investments in energy, education, infrastructure development, and defense, the next president will have little ability to mount a major health reform. Incremental reforms are possible but they will largely be financed by reducing other health outlays. Congressional attention will focus first on extending (and probably expanding) the State Children’s Health Insurance Program. By the end of 2009, Congress must also find a face-saving way to delay a scheduled 20% reduction in Medicare physician fees. Those 2 priorities will cut into the money left to be redirected to reform. We are likely to see the imposition of “best price” discounts on Medicare Part D drugs purchased by dualeligibles, and payments to Medicare Advantage plans will be reduced. Congress will intensify its interest in “follow-on” biologics, but safety concerns (heightened by recent reports of tainted milk products from China and possible contamination of generic drugs produced by Ranbaxy) have deflated interest in drug importation as a way to reduce the cost of pharmaceuticals. Although health reform will not take center stage next year, progress will be possible. Decisions made over the next 4 years will lay the foundation for major reforms in the future. The next president can make a difference in healthcare, although the credit (or blame) might well go to his successor. Joseph R. Antos, PhD Wilson H. Taylor Scholar in Healthcare and Retirement Policy American Enterprise Institute

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4HE BUILDING BLOCKS OF ALL WE DO !N AMBITIOUS TEAM OF IN COUNTRIES !N EXTENSIVE ARRAY OF FORMULATIONS GENERICS TO MARKET ON THE WAY 4HE GENETICS BEHIND OUR GENERICS

4O LEARN MORE CALL !CTAVIS CUSTOMER SERVICE AT OR VISIT US AT WWW ACTAVIS US

BUSINESS

Medication Therapy Management Goes Hi-Tech: Implementing Automated Software Improves Pharmacy Efficiency Adrienne Giordano, PharmD; Carrie Holden, PharmD; Cathrine Misquitta, PharmD, BCPS

Background: With the Centers for Medicare & Medicaid Services mandate that all Medicare Part D benefit sponsors must offer members a medication therapy management program, pharmacists were facing new challenges of data collecting using software applications that had limited use for the new program. Objective: Health Net pharmacists initiated an automated software application to increase the efficiency of the medication therapy management program, the integrity of the member profiles, and the ability to provide accurate reporting of drug-related issues. Methods: Pharmacists were integral contributors to the automated software program; they Carrie Holden developed the clinical algorithms, screen layout and transitions, and program functionality. Together with a programming company—Cognizant Technology Solutions—they created a web-based software application to accommodate an increasing number of eligible members and ensure accuracy of the information; they also performed testing of the final product. Results: The new program includes member demographics and qualifying parameters that are uploaded monthly. All drug-related problems are now displayed and updated automatically by the software application. Assessment questions are answered and saved within the software, and reporting functions allow for quick and accurate results. Consequently, the number of drug regimen reviews and drug problems identified has increased by more than 300%. Conclusion: The automated software application is capable of maintaining and updating medication claims, sending and receiving faxes to physicians and pharmacies, and allows for documentation of patient-specific freeform text. Each profile is extensive and allows the pharmacist to get all necessary information from a single source. [AHDB. 2008;1(8):16-23.]

n 2006, the Centers for Medicare & Medicaid Services’ (CMS) ruling went into effect, mandating that all Medicare Part D prescription benefit sponsors must offer their members a medication therapy management (MTM) program.1 Among other requirements, CMS mandates Part D sponsors to have an MTM program to reduce the risk of adverse events and ensure optimum therapeutic outcomes for targeted beneficiaries through improved medication use.1 CMS gives basic guidelines of requirements for eligibility into the program. The patient must be taking multiple (*2) Part D medications and have multiple (*2) chron-

Dr Giordano is Clinical Pharmacist, Dr Holden is Clinical Pharmacist, and Dr Misquitta is Director of Pharmacy, all with Health Net Clinical Pharmacy Services, Rancho Cordova, CA.

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ic diseases. Each MTM program identifies how many and which medications and diseases will be used in determining eligibility; a member must also have a likely annual drug spending of *$4000.1 Health Net’s 2006-2008 MTM program defines eligibility as *5 chronic medications, which includes any medication with a *60-day supply in a 90-day period and *3 chronic diseases from these conditions—heart failure or hypertension, chronic obstructive pulmonary disease or asthma, diabetes, hyperlipidemia, and depression. All diagnoses are inferred from drug therapy by necessity, because medical claims data are not available for Part D–only members.

New MTM Program, Old Software After CMS published the MTM requirements in 2005, Health Net asked a multidisciplinary team—

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comprised of pharmacists, physicians, psychologists, and nurses—to develop its MTM program based on several sources: a consensus statement from 11 national organizations2; published results from an executive session between the Academy of Managed Care Pharmacy and the American Society of Health-System Pharmacists3; and a standard stepwise process (Table 1). Health Net leveraged internal strengths and an existing software tool that had been designed to assist case managers with tracking the status and progress of mental health patients. The pharmacists adapted this tool for MTM use to enter patient-specific notes in freeform text, create custom assessments, document problems, goals, interventions, and outcomes in a readily reportable format, and track and assign patients to a work queue. The pharmacists assisted in devising the custom assessments about overall health status, medication compliance, and access to healthcare issues. Data were captured in predefined fields to facilitate reporting. MTM nurses used the information gathered in each assessment to triage patients for appropriate disease management, assistance program, or behavioral healthcare purposes. Questions in the compliance assessments helped determine if patients were having adverse reactions, had difficulty with copayments, required additional education, or would benefit from a reduced tablet burden. As appropriate, the nurses scheduled patient calls with the MTM pharmacists to assist in changing drug regimens and facilitate communication with their physicians (Table 2). The pharmacists established categories of problems, goals, and interventions to enter into the existing system. For example, with the broad problem category therapeutic duplication, the linked goal could be to remove a duplicated drug, as in a patient taking 2 angiotensinconverting enzyme (ACE) inhibitors who should be taking only 1. The intervention may then be to educate the patient or contact the physician. Outcomes were categorized as “achieved,” “not achieved,” or “no longer relevant,” and coded manually by the pharmacist (Table 3). With technical staff already dedicated to maintaining the software, creating the custom assessments, and providing monthly reports, the original tool seemed a suitable solution for a new program that was designed from scratch.

Illustrative Case Report The following case illustrates the impact of the multidisciplinary approach and workflow used in an MTM program.

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KEY POINTS ▲ With the mandate to provide MTM programs to Medicare

Part D beneficiaries, pharmacists faced new challenges of collecting important patient-specific medication information using old, inefficient, and costly systems. ▲ Mired in manual procedures with the old software, pharma-

cists at Health Net completed about 200 MTM reviews monthly of members joining the program, although they had an average of 1500 potential members becoming eligible each month. ▲ The new automated MTM program—created in cooperation

between pharmacists and a programming company— increased pharmacy efficiency significantly; drug regimen reviews and drug problems identified increased by 300%. ▲ Health Net pharmacists now review 50 member profiles

daily compared with 50 weekly reviews with the old software system. ▲ Part D sponsors would benefit from customizing their MTM

programs to cover the large spectrum of eligibility criteria, enrollment methods, and intervention types.

A 71-year-old woman living alone received a letter inviting her to participate in the MTM program. She called the program and scheduled a call with an MTM nurse. Before the nurse returned the call, pharmacists evaluated the member’s drug regimen. She had pharmacy claims for glipizide, metformin, amlodipine, atorvastatin, paroxetine, and famotidine; she had no claims for an ACE inhibitor and had not been compliant with her amlodipine regimen. The pharmacist provided a list of questions for the nurse to validate doses and diagnoses and listed potential drug therapy recommendations. When the nurse contacted the member, she complained of headaches and nausea, as well as difficulty getting to see her doctor. She reported that her blood pressure was 210/90 mm Hg. The nurse arranged for an appointment with the member’s primary care physician and facilitated transportation, as well as educated the member on the importance of medication adherence. The pharmacist faxed the medication recommendations to the physician’s office before the visit. An ACE inhibitor was added by the physician as recommended by the MTM pharmacist. At follow-up with the MTM nurse a few weeks later, the patient’s blood pressure had dropped to 162/85 mm Hg. Participation in the MTM program led to positive outcomes for this member. The nurse’s interventions, the pharmacist’s review, and the coordination with the patient’s physician led to optimizing her medication therapy.

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Table 1 Stepwise Process for Developing an MTM Program Step

Program component

Health Net description

Define program purpose

Define program goals and measurable objectives

Develop high-level workflow

Customize support systems

5 6 7

Implement program Document interventions Measure outcomes

Provide an integrated approach, across all involved parties, to ensure that effective and safe medication treatments are delivered with optimal medical and economic value Identify and resolve any DRPs Identify and resolve any medication compliance issues Identify and resolve any provider access issues Send member outreach letters Perform drug regimen review Perform clinical assessments Provide member education Contact provider and recommend changes Measure results Develop clinical assessment tools with easily reportable fields Define specific problems, goals, and interventions Enroll members who call in response to invitation letter See “Illustrative Case Report,” page 17 Participation rate Total MTM eligible members as of 6/30/06: 6539 Total number of opted-in members as of 6/30/06: 64 Program participation: <1% Effectiveness of program* Sample Active MTM MTM eligible, not groups participant enrolled in program Members, N 59 129 Mean problems 1.71 1.88 per member, N DRP resolution† 98% 27%

Conduct continuous quality improvement efforts

Based on the difference in resolution rate between groups and the low level of participation, the MTM team revised member recruitment techniques to increase participation.

Source: Gedey RJ, Giordano A, Redline S, et al. Overview of a comprehensive medication therapy management program (MTMP) with preliminary outcome data. California J Health-System Pharmacy. 2007;19(suppl 1):9. † No statistical analysis performed. MTM indicates medication therapy management; DRPs, drug-related problems.

Mired in Manual Procedures Early into the effort, however, the MTM pharmacists realized that the adapted software had significant limitations. Although medication claims history was available, it was not conducive to a comprehensive drug regimen review. It also was not possible to build drug-related problem (DRP)-identifying algorithms into the system. Without these features, the potential existed for pharmacist variability in each review. The notes in freeform text were long and duplicative. Documenting the prob-

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lems, goals, and interventions took place in separate systems, which required pharmacists to search through many screens to form a full clinical picture and determine what required follow-up. The system could not create or store any external communications. Virtually the entire MTM process was manual. Pharmacists had to copy medication claims onto custom files, identify DRPs by hand, create a quick-reference list of all documented DRPs to simplify patient follow-up calls, and print faxes sent to and received

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Table 2 Sample Questions from the Assessment Questionnaires Question Do you take any over-the-counter medicine, herbs, or natural products for headache, muscle pain, nausea, constipation, diarrhea, others? Does any of your medicine(s) make you feel sick? Do you feel confident about how and when you should take your medication? Do you get your medicine filled at more than 1 pharmacy? How many times in the past month (or week) have you forgotten to take your medicine? For which of the following reasons do you need help getting a regular supply of your medicine?

Answer type Yes/No

Purpose Evaluate for DRPs for medications not found in claims history

Yes/No Yes/No

Evaluate for adverse drug events Trigger compliance assessment

Yes/No

Determine if there are care coordination issues

Drop-down

Assist with drug regimen review for potential therapeutic alternatives Determine if access may be affecting compliance and what type of intervention would best assist the patient Determine if other barriers exist to patient obtaining care

Multiple selection

Do you have other difficulties accessing either pharmacy and/or PCP services?

Yes/No

DRPs indicates drug-related problems; PCP, primary care physician.

Table 3 Sample Drug-Related Problems, Goals, and Intervention Type

members was 865, 7.8% of the 11,124 eligible members, with the success of DRP resolution more than 95%. As a result, Health Net Pharmaceutical Services (HNPS) planned to increase enrollment to be able to improve more member lives. In 2007, CMS approved a hybrid opt-in/opt-out enrollment methodology, in which ACE indicates angiotensin-converting enzyme; ARB, angiotensin receptor blocker. high-risk members were automatically enrolled in the profrom physicians. The pharmacists used multiple systems gram. “High-risk” was defined by HNPS as any member to incorporate procedures, but the systems did not comwith *10 chronic medications or who is being treated municate well with each other. The pharmacists with drugs indicated for Alzheimer’s disease, psychoses, also maintained hard copy files for each opt-in member or peripheral vascular disease. Since the manual and created, printed, and faxed documents manually. process could not handle increased enrollment, HNPS Mired in these manual procedures, the pharmacists leaders agreed to automate the program, with the ulticompleted an average of 50 reviews each week. mate goal of incorporating all the systems and processAlthough this amounted to 200 reviews monthly, an es into a comprehensive software application. average of 1500 members were becoming eligible for Automating the MTM the MTM program each month. The need for automaThe MTM team considered several options. The tion became apparent. first was to evaluate the possibility of enhancing the Health Net’s original MTM program enrollment existing tool and incorporating external algorithms and method was opt-in, with welcome letters sent to eligiinternal print fulfillment. Since the original tool was ble members inviting them to participate. By the end of developed by a vendor and was used by multiple health 2006, the total number of actively enrolled MTM Problems Drug–drug interaction

Goals Educate patient Educate provider Change regimen Gaps in care Educate patient Add ACE/ARB in diabetes Add ACE/ARB in heart failure Add beta-blocker in heart failure Add statin in diabetes Add controller agent in asthma

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Interventions Patient contact Call to patient Letter to patient Physician contact Fax Call Disease management referral

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plans, customized changes were severely limited. The second option was to purchase software from a vendor that specialized in MTM program–specific tools. Although it was possible to incorporate customized changes, and several evidence-based algorithms were available, it would have required too many changes to the current business flow. The team would still require some use of the original software to communicate with MTM, and the cost was somewhat prohibitive. The third option was to create customized software within Health Net. The team chose the third option because: • The software would fit the workflow • It could be modified as Part D and MTM evolved • One system could incorporate all aspects of the program • Customized reports could be created • Cost was reasonable. The MTM pharmacists worked in conjunction with a programming company—Cognizant Technology Solutions—to build a new automated system. The pharmacists discussed every aspect of their process with business analysts, answering questions such as: What is being done? Why is it being done? What is expected of the new system? The pharmacists documented all aspects of the planned project to ensure they captured all functions appropriately.

Whenever a member requires contact or needs an updated review, the workflow queue eliminates the need for manual tracking. The system captures and updates medication claims and updates DRPs each month. A key function of the new system is DRP identification. For the DRPs originally identified manually, the pharmacists devised algorithms based on specific drugs or drug classes, refill patterns, member demographics, current evidence-based best practices, formulary status, generic availability, and standard quality metrics. After the pharmacists created and documented the business rules based on typical drug regimen review and patient–pharmacist interactions, the pharmacists determined which data to store in the system and how to display data, where to make entries, what to store as predefined fields for reporting purposes, what notes should be specific, and how to queue priority reviews. Similar to the original program, the pharmacists cre-

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ated prompts and specific questions that the nurses could use to assess patients’ reaction to therapies and determine the severity of a drug interaction or agerelated contraindication. Nurses could enter responses into the system in a standard format that easily incorporated the back-end database. The pharmacists then determined the best way to order and filter data, how to create manual entries with standardized text to facilitate future reporting, and how to flag entries as manual versus automated. They devised an automatic reminder system for members requiring follow-up review and created all of the reporting requirements, including CMS-mandated reports of eligibility and plan involvement information, plus reports for member intervention tracking to monitor the MTM program’s success, and procedural reports to track the number of members reviewed in a specified time period. The new software was released in May 2007. Each month, based on eligibility requirements, members load into the system automatically and claims are run through a series of predefined algorithms. Specific DRPs that the system recognizes are displayed on the member homepage for pharmacists to review and act on. The specific interventions and goals for each member are also captured. Whenever a member requires contact or needs an updated review, the workflow queue eliminates the need for manual tracking. The system captures and updates medication claims and updates DRPs each month. Its scalability enables the addition of other medications, such as herbals, overthe-counter, or other classes that the MTM pharmacists learn a patient is taking. The system reports program results easily and generates, sends, and receives physician and pharmacy faxes automatically as well. The system homepage displays all eligible members and serves as a work queue for the MTM pharmacists. Members can be filtered to view by those requiring initial review, callbacks, or follow-up reviews. The member homepage (Figure) displays the identified DRPs and the general category, such as drug–drug interaction, medication descriptions, and the medications that triggered the DRP, based on the clinical algorithms. The system currently identifies DRPs once monthly, but the pharmacist’s review can occur at any time until the following month, so a potential lag of updated information exists, depending on when the reviews occur. Therefore, the pharmacist reviews current medication claims to ensure there are no new medications that could have triggered another DRP and that the DRPs are still current. Using different

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tabs, the pharmacist can view medication claims, specific goals and interventions made, in- and outbound fax, and any notes from behavioral health coaches who have spoken with the member. The pharmacist can leave notes for the next reviewing pharmacist, and there is an area for documenting allergy information.

Results: Benefits of Automated MTM The new automated system increased Health Net’s MTM program efficiency of review consistency, customized algorithms to identify DRPs, reduction of human error, enhanced reporting, electronic data storage with the elimination of the need for hard copies, and the ability to perform far more reviews. The team’s average member reviews has increased from 50 weekly reviews to 50 per day. Health Net’s current MTM program has changed from a hybrid opt-in/opt-out program in 2007 to an entirely opt-out program in 2008, capturing data from every eligible member, at least until they request to be omitted. The 2008 program includes customized letters sent to each member after the pharmacist’s review. And as a result of the constant increase in Medicare population, the number of eligible members for Health Net’s 2008 MTM is estimated to exceed 80,000. The current goal of the 6 full-time MTM pharmacists increased from 50 reviews per day by 3 pharmacists combined to 60 reviews per day by each pharmacist. Further automation is in progress to facilitate these additional member reviews (Table 4). Future Goals The current system still involves several manual applications, which interferes with efficiency and patient outcomes, such as a potential 1-month lag between DRP identification or review. Our pharmacists are working on system enhancements to allow for a 1-day lag with DRPs. Member eligibility will be virtually instantaneous, as the system will link to the Health Net eligibility system, eliminating the need for phar-

Figure MTM Member Homepage: Drug-Related Problems

macists to manually verify eligibility. Intervention outcomes will be tracked automatically. For example, when a noncompliance issue is identified and the intervention is to educate the patient on compliance, the system will follow up to determine whether compliance improved. If the goal is to fill a therapeutic gap (eg, controller medications in asthma), the system will evaluate claims to see if the specific class of medications was initiated. The system will incorporate in patient-specific letters all DRPs that it identifies and the pharmacists verify. The system will store letters in a daily queue and send the files to a central distribution center for print fulfillment. The system also will store the letters within each patient profile so the pharmacists can refer specifically to what the members receive if they call with questions. By the end of 2008, the MTM pharmacists expect the results to far surpass those of the first 2 years combined. Because it is now an opt-out program, the participation rate should be well above 95%. And

Table 4 MTM Program Eligible and Participating Members Program variable Enrollment method Intervention method MTM program eligible Member participating in MTM, N Member enrollment, %

2006

2007

2008

Opt-in* Telephonic/fax

Opt-in/opt-out high-risk Telephonic/fax

11,124 865 7.8

58,123 4471 7.7

Opt-out Letter/telephonic/fax ~80,000 anticipated ~76,000 anticipated >95 anticipated

By mid-2006, the MTM program switched to an opt-in/opt-out high-risk enrollment method. MTM indicates medication therapy management.

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although the percentage of DRP resolution remains unknown, the magnitude of results should far exceed previous results simply by the number of lives that will be touched in 2008.

The computer algorithms developed to identify specific DRPs have significantly shortened the review time of the MTM pharmacists, while ensuring interventions correspond to evidence-based medicine. Implications for MTM Programs MTM programs cover a large spectrum of eligibility criteria, enrollment methods, and intervention types. Any of these aspects can be customized to meet the needs and fit the budget of the Part D provider. In 2008, the Academy of Managed Care Pharmacy (AMCP) published an update to its 2006 consensus statement4 on MTM programs, which included results from its new validation study.5 In the updated statement it was noted that MTM programs are still in a formative stage, with no specific “best practices” or quality assurance standards, but the important features and operational aspects outlined in the document should be considered when developing or modifying MTM programs.5 Using a multidisciplinary team within a health plan to coordinate care has several advantages, including referral to disease management, home healthcare and behavioral health services, documentation of member participation in other clinical quality improvement programs, automatic drug approvals, authorizations and overrides within the benefit, and treating the patient as a whole. The disadvantage is the lack of face-to-face communication, which was encouraged in the first MTM program consensus statement4 and was removed from the second version.5 The assessments outlined here have enabled our MTM staff to drill down to specific underlying causes of DRPs and tailor interventions to meet member needs. The computer algorithms developed to identify specific DRPs have significantly shortened the review time of the MTM pharmacists, while ensuring interventions correspond to evidencebased medicine. The link of all operational aspects through the use of one system greatly increased the number of members who could be served. Incorporating faxes, letters, telephonic notes, assessments, and interventions ensures that all communications are appropri-

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ately documented and care is individualized. These aspects are all in line with the elements outlined by the AMCP.5 With a lack of medical claims data available for Part D members, full pharmacoeconomic analyses of programs are not yet possible. As a result, surrogate markers such as the resolution of DRPs serve as a measurable way to determine if program objectives are being met. Programs have shifted away from opt-in enrollment methods (51.0% in 2006 compared with 14.6% in 2008).6 Automation is one way to provide an opt-out program to a large number of members while maintaining the integrity of individualized patient care. Other plans use a variety of automated customized features in their MTM programs. According to McMahan, Humana includes a cost-saving calculator to inform members of the magnitude of cost-saving opportunities.7 Programs evaluating the transition to automation should consider several factors in choosing a platform or deciding to build software internally, including: • Does the software enable the MTM program to meet its overarching purpose? • Are significant changes to business processes required to utilize the software? • Is the software customizable to meet the existing program structure? • Does the software allow for end-user outcomes reporting? • Does the software facilitate CMS reporting? • Will the software enable the program to provide services to a larger number of members? • How are interventions recorded and tracked in the system? • Is there sufficient support staff to manage upgrades or issues? Approximately 50% of MTM programs use internal staff only.6 For programs using community or consultant pharmacists, a software system should also facilitate billing for services rendered.

Conclusions Health information technology can assist in determining member risk levels and stratifying patients into appropriate interventions. Pharmacy data are recognized in the industry as being timely, accurate, and easy to use for data mining. Integrating pharmacy data into personal health records and introducing MTM recommendations through secure health plan websites can be an effective way to reach out to members. In Health Net’s MTM program, automation enabled outreach to more eligible members, while continuing high-touch

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telephone support, without significantly increasing the cost to administer the program. The new automated software has allowed the program to maintain and update medication claims more efficiently, enhanced the communication between physicians and pharmacies, and provided all the necessary patient-specific information from a single source. ■ References 1. Subpart D—cost control and quality improvement requirements for Part D plans. Fed Regist. 2005;70:4540-4541. CFR §423.150/153/156/ 159/162/165. http://frwebgate.access.gpo.gov/cgibin/getpage.cgi? position =all&page=4540&dbname=2005_register. Accessed September 14, 2008.

2. Bluml B. Definition of medication therapy management: development of profession-wide consensus. J Am Pharm Assoc (2003). 2005;45: 566-572. 3. Summary of the executive sessions on medication therapy management programs. Bethesda, Maryland, June 14 and August 18, 2004. J Manag Care Pharm. 2005;11:179-186. 4. Curtiss FR. Sound Medication Therapy Management Programs 2006 Consensus Document. 2006; 12(suppl):S1-S15. 5. Curtiss FR. Sound Medication Therapy Management Programs, Version 2.0 with Validation Study. J Manag Care Pharm. 2008;14(suppl b):S2-S42. 6. Center for Medicare & Medicaid Services. Medicare Part D Medication Therapy Management (MTM) Programs 2008 Fact Sheet. Revised March 19, 2008:1-13. http://www.cms.hhs.gov/Prescription DrugCovContra/ Downloads/MTMFactSheet.pdf. Accessed September 14, 2008. 7. McMahan R. Operationalizing MTM through the use of health information technology. J Manag Care Pharm. 2008;14(2 suppl):S18-S21.

Stakeholder Perspective Automated MTM Programs PAYERS: With the advent of medication therapy management (MTM) programs for Medicare Part D Plans in 2006 came an additional challenge and opportunity for pharmacists to take action on behalf of their plan members. The Health Net MTM program details progressive and positive team approach to deliver optimal pharmaceutical care to members using automated systems. In designing a program that addresses the complex nature of pharmacy management, including documentation, follow-up on drug-related problems (DRPs) and closing the loop with providers and patients, the 2008 upgrades using technology are noteworthy advances. Several key factors have allowed Health Net to set up a scalable and sustainable solution that may also be an option for other MTM programs: creating documentation shortcuts, following evidence-based guidelines, and extensive process upgrades as the program continued to grow; applying algorithms, automated management reports, nurse support, and various media formats for communication and engaging patients—with a 95% rate of fulfillment, a tremendous rate in this population. Many payers applied much simpler approaches, but those lack the level of attention and benefit demonstrated in Health Net’s MTM program. Payers have also experienced capacity and capability gaps that made MTM a considerable obstacle to overcome. The program outlined in this article offers advantages for patients with DRPs in a systematic and prioritized manner. Health Net may benefit from presenting the eco-

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nomic/business case to deliver and implement this program in terms of per member per month and cost avoidance. The business case should also include the amount of plan resources needed to implement the technology solution and provide lessons learned for others in the industry. This effort is an exceptional clinical and business approach to MTM and needs to be applauded. Additional variables that may improve the adoption of this approach include patient satisfaction, educational techniques for working with Medicare Part D members to educate and communicate effectively, and ultimately payers moving quickly to paying for performance outcomes, which would greatly enhance the overall result of this program. The Centers for Medicare & Medicaid Services, the Academy of Managed Care Pharmacy, and managed care pharmacists recognize the tremendous effort and benefit that pharmacists working on the team represent in this endeavor and the value that pharmacy MTM can provide in an organized, creative, and progressive environment. Providing even greater evidence and support for the value of pharmaceutical care and creating the benchmark for this service provision, Health Net may consider applying similar methods to commercial populations as the business case evolves. Scott R. Taylor, RPh, MBA Executive Director, Industry Relations Geisinger Health System, Henry Hood Center for Health Research, Danville, PA

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GENERIC DRUG TRENDS

Presidential Candidates Strong Supporters of Greater Access to Generics and Biosimilars By Dalia Buffery, MA, ABD

t the 2008 Annual Policy Conference of the Generic Pharmaceutical Association (GPhA), held in September in Washington, DC, advisors to the presidential candidates Barack Obama and John McCain told GPhA members that both candidates agree on the urgent need to increase access to generic medications—including generic biologics (referred to as biosimilars or follow-on biologics1)—as a way to control the ever-escalating US healthcare costs. Dora Hughes, Health Policy Advisor to Obama, and Douglas Holtz-Eakin, Senior Policy Advisor to McCain, noted that expanding the use of generics by physicians and by patients is among the top of their healthcare priorities. Kathleen Jaeger, GPhA’s President and CEO, reiterated that message to GPhA members during the meeting, saying, “As American families increasingly struggle with rising healthcare costs, both parties are talking about increasing access to affordable generic—and biogeneric—medicines.”2

Setting a new pathway for an FDA approval process for biosimilars may soon become a reality in the new administration, regardless of who the president is.

“We know that expanding the use of generics and eliminating barriers to that goal must be a centerpiece of any health reform effort,” said Ms Hughes at the meeting, elaborating on Obama’s position.3 Commenting on McCain’s approach to generics, Mr Holtz-Eakin noted, “Controlling healthcare costs has to be the imperative of any effective healthcare reform.”3 Both Ms Hughes and Mr Holtz-Eakin said that the 2 candidates recommend that the US Food and Drug Administration (FDA) should move as fast as possible to make biologic agents available as generics, believing that the 14-year period of exclusivity that had been

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October 2008

suggested by pharmaceutical companies is much too long, and that their respective candidates support a much shorter exclusivity period. According to Mr Holtz-Eakin, “Senator McCain’s instincts are to make the period as short as possible so that you can get products to market more quickly.”3 As for Obama’s approach, noted Ms Hughes, “14 years (of data exclusivity), as requested by the biotech industry, is excessively long…we’re tilted toward the shorter period.”3 There is currently no pathway for an FDA approval process of biosimilars in the United States. Several proposals that were put up for debate in Congress last year were rejected for one reason or another, all reflecting a basic disagreement between traditional pharmaceutical and generic drug manufacturers. An article published in Pharmaceutical Business Review Online notes that “it is now likely that the legislative pathway allowing approval of biosimilars will be in place by the end of 2010.”4 The author adds, “Given the potential influence of a new president, the exclusivity period for biologics may be significantly shorter than the 14 years that the branded firms are hoping for.” 4 With the continuing increase in the number and cost of biologic agents, setting a new pathway for an FDA approval process for biosimilars may soon become a reality in the new administration, regardless of who the president is. ■

References 1. Heinrichs MJ, Owens GM. Where generics and biologics meet. Am Health & Drug Benefits. 2008;1(5):21-26. 2. Generic Pharmaceutical Association. Senior advisors to presidential candidates affirm support for increased access to generic medicine and creation of FDA approval pathway for biogenerics. September 18, 2008. http://www.gphaonline.org/AM/Template.cfm?Section=Press_Releases &TEMPLATE=/CM/ContentDisplay.cfm&CONTENTID=4804. Accessed October 6, 2008. 3. Advisers to major presidential candidates discuss positions on reimportation, generics, biotechnology medications. Medical News Today. September 22, 2008. http://www.medicalnewstoday.com/printerfriendly news.php?newsid=122278. Accessed October 6, 2008. 4. Ignjatovic T. Biosimilars: US presidential candidates pledge support. Pharmaceutical Business Review Online. September 23, 2008. http://www. pharmaceutical-business-review.com/article_feature_ print. asp?guid= C75DF183-16A0-4976-B49A-DB91E2B89E32. Accessed October 6, 2008.

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Cultivated with Care. To ensure that every Mylan product is manufactured to uncompromising standards, we have carefully and painstakingly refined our systems and controls for more than 45 years. With the acquisition of the Generics Business of Merck KGaA, we now have a global team of professionals that shares our passion for perfection. As we look to the future, we will be guided by the principles that have earned us the trust and respect of pharmacists throughout the United States. After all, our roots are firmly planted in our conviction to make proven medicine more affordable for the patients who need them.

800-RX-MYLAN www.mylan.com ÂŠ2008 Mylan Inc.

MYNMKT228

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Objective: Allergic rhinitis imposes a significant health and economic burden both on individuals and the healthcare system. Second-generation prescription antihistamines, levocetirizine, fexofenadine, and desloratadine, and the leukotriene receptor antagonist, montelukast, differ in their ability to relieve common rhinitis symptoms. The purpose of this study was to compare the cost-effectiveness of prescription agents based on their effectiveness in relieving nasal symptoms. Methods: Effectiveness was measured as the composite of nasal symptoms, including congestion, rhinorrhea, and sneezing, from clinical studies that compared each of the 4 comparators to placebo. Direct costs included prescription therapy and rhinitis-related physician Michael J. Goodman office visits. Physician office visit costs were collected from an analysis of the PharMetrics insurance claims database. Sensitivity analyses were conducted using a Monte Carlo simulation to assess the robustness of the average and incremental cost-effectiveness ratios. Results: The cost per clinically significant improvement of nasal symptoms for levocetirizine was less than for the other model comparator agents. The incremental cost-effectiveness ratio for levocetirizine dominated montelukast and desloratadine and was lower than either branded or generic fexofenadine. Conclusion: Levocetirizine is a cost-effective therapy for the relief of nasal symptoms of allergic rhinitis. [AHDB. 2008;1(8):26-34.]

llergic rhinitis (AR) is one of the most common chronic conditions in the United States, affecting approximately 40 million people.1 Although AR is rarely considered a severe medical condition, its bothersome symptoms, such as sneezing, rhinorrhea, and congestion, can negatively affect important domains of quality of life, including sleep, social interaction, and work.2-7 In a recent large national survey of adults with AR, 78% of those surveyed indicated that nasal congestion was a moderately or extremely bothersome symptom of AR.5 Other nasal

Dr Goodman is Director, Xcenda, Palm Harbor, FL; Dr Jhaveri is Manager, Health Outcomes, sanofi-aventis, Bridgewater, NJ; Ms Saverno is a PhD student in Pharmaceutical Economics, Policy, and Outcomes, University of Arizona College of Pharmacy, Tucson, AZ, and an analyst, Xcenda, Palm Harbor, FL; Dr Meyer is Associate Director, Xcenda, Palm Harbor, FL; and Dr Nightengale is Vice President, Xcenda, Palm Harbor, FL.

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October 2008

symptoms often cited as moderately to extremely bothersome included runny nose (62%), postnasal drip (61%), and repeated sneezing (51%).5 As such, the goal of therapy is to relieve the symptoms associated with AR. Antihistamines have long been a mainstay of AR therapy. Second-generation antihistamines (SGAs) are some of the most widely prescribed medications in the United States and cause fewer adverse effects, including sedation and anticholinergic activity, than first-generation antihistamines.8 The prevalence of AR results in significant economic burden associated with symptom treatment.5-7,9 Estimates of the economic burden of AR in the United States range from $1.4 billion to nearly $6 billion in direct costs annually.7,8,10 Goetzel and colleagues estimated that allergies were the fifth most expensive condition for employers when factors such as presenteeism, absenteeism, and direct medical costs were all taken into account.11 These estimates probably understate the full economic impact because they do not

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consider spending on over-the-counter (OTC) products. One estimate of spending on prescription and nonprescription AR agents placed the cost at more than $6 billion annually (in 2000 US dollars).10 Despite the sizable economic burden of AR, there are no studies that compare the cost-effectiveness of the different SGAs or alternative oral AR therapies, such as the leukotriene-receptor antagonist montelukast (Singulair). Only 1 cost-effectiveness study has considered SGAs, but that study compared the choice of SGAs to older, first-generation antihistamines that produced a significant sedating effect.12 Current treatment patterns call for more advanced modeling that directly compares the economic outcomes of treatment patterns with newer agents. The current analysis was designed to assess the cost-effectiveness of reducing nasal symptoms with the recently US Food and Drug Administration (FDA)-approved SGA levocetirizine (Xyzal) relative to other prescription SGAs and to montelukast, which is FDA-approved for seasonal AR treatment.

Methods The goal of this study was to inform US formulary and clinical decision makers in managed care organizations about the relative cost-effectiveness of treatments for AR. Since it is common for payers to exclude OTC products from prescription benefit coverage, this study was limited to products available by prescription during the first quarter of 2008. The analysis included the SGAs levocetirizine, desloratadine (Clarinex), and fexofenadine (Allegra; branded and generic), and montelukast. The model was constructed using a 1-year time frame. The target population for this analysis was patients diagnosed with AR and treated with a single prescription therapy for symptom relief. The model excluded patients with asthma requiring daily corticosteroid treatment and focused on the use of SGAs and a leukotriene receptor antagonist as monotherapy for the treatment of AR. Although combination therapy with an SGA and montelukast is occasionally used to treat the symptoms of AR, combination therapy was excluded in this analysis because this would introduce additional heterogeneity into the model. The effectiveness measure chosen as the basis for this model was a composite nasal symptom score (NSS), defined as the average effect size for each comparator versus placebo for 3 nasal symptoms: rhinorrhea, nasal congestion, and sneezing. Improvement in composite NSS was chosen as the outcome measure of interest because of the documented burden of nasal symptoms in patients with AR.5 Other AR symptoms, such as ocular

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KEY POINTS ▲ The direct costs of allergic rhinitis to the US economy are

estimated at $1.4 billion to $6 billion annually. ▲ In 2004, allergies were estimated to represent the fifth most

expensive condition for employers when considering presenteeism, absenteeism, and direct medical costs. ▲ The goal of this study was to inform US formulary and

benefit design decision makers about the relative costeffectiveness of available treatments for allergic rhinitis. ▲ In this first cost-effective comparison of the various second-

generation antihistamines and the leukotriene-receptor antagonist montelukast, levocetirizine had the lowest average cost per clinically significant improvement in nasal symptom score, followed by generic fexofenadine.

and nasal itching, were not included because of insufficient information in published clinical trials to calculate an effect size for each comparator or because the measure differed across model comparator agents. To estimate treatment effectiveness, we calculated the standardized mean difference (SMD) for each study reporting a significant improvement in study drug compared with placebo. Relevant studies were identified by searching MEDLINE from 1950 to May 2007 using the comparator names levocetirizine, fexofenadine, desloratadine, and montelukast, in combination with the terms nasal symptoms, allergic rhinitis, rhinitis, congestion, obstruction, rhinorrhea, discharge, sneezing, itching, pruritus, and NSS. Additional studies were located by reviewing the reference lists of applicable articles. Trials investigating the efficacy of at least 1 of the model comparator agents in patients with AR were included in the model. In addition, trials had to be randomized, blinded, placebo-controlled, and exclude individuals with asthma requiring daily corticosteroid use. Studies had to have patients rate the severity of at least 1 of the following individual nasal symptoms throughout the duration of the trial on an ordinal scale: congestion, rhinorrhea, or sneezing. Outcomes that were physicianreported or that comprised more than 1 symptom (ie, nasal/eye itching) were excluded. Trials had to be a minimum of 7 days to be included in the analysis. Furthermore, studies had to disclose patient-reported individual symptom score results for study inclusion. When clinical trials reported individual symptom scores at various time points throughout a study, it was decided a priori to extract data from the latest time period for data analysis. Studies involving patients aged younger than 12 years were excluded because not all end points

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Table 1 Nasal Symptom Score Standardized Mean Differences, 95% CI Levocetirizine

Fexofenadine (generic)

Fexofenadine (brand)

Desloratadine

Montelukast

Nasal congestion Sneezing

–0.366 (–0.495, –0.236)

–0.250 (–0.344, –0.157)

–0.241 (–0.320, –0.162)

–0.173 (–0.225, –0.121)

–0.402 (–0.532, –0.273)

–0.327 (–0.419, –0.236)

–0.309 (–0.383, –0.235)

–0.211 (–0.263, –0.159)

Rhinorrhea

–0.408 (–0.538, –0.278)

–0.289 (–0.375, –0.202)

–0.228 (–0.300, –0.157)

–0.190 (–0.242, –0.138)

Average

–0.392

–0.289

–0.259

–0.191

CI indicates confidence interval.

Table 2 Model Inputs

Treatment arm Levocetirizine Desloratadine Fexofenadine (generic) Fexofenadine (branded) Montelukast

Annual drug cost, $*

Annual medical cost, $† Total cost, $

Effectiveness, marginal probability of significant improvement in NSS, $‡

Effectiveness, probability of significant improvement in NSS, $‡

203

284

487

249

326

575

168

326

494

216

326

542

275

356

631

Annual drug cost assumes 90-day therapy annually and daily wholesale acquisition cost. Annual outpatient allergy visit costs based on an analysis of the PharMetrics database. The fourth column shows the marginal effect given treatment with the target drug (the fifth column minus 33%). The fourth column was used in the costeffectiveness analysis calculations. The fifth column shows the proportion of the population with a mean below the threshold after treatment at baseline. NSS indicates nasal symptom score. † ‡

were available for pediatric patients. Data were extracted from studies only when the total daily dose was the FDA-approved total daily dose for the age-group of patients included in that particular study. A total of 25 clinical trials met the inclusion criteria (Appendix, page 33)13-37; an additional 27 studies were excluded. The SMD between the comparator and the placebo group was calculated for each study using the following equation: SMD =

Difference in mean outcome between comparator and placebo Standard deviation

The pooled SMD across all studies was calculated as the weighted average of the studies for that model comparator agent, where the weight for each study was the inverse of the variance (1/variance). To convert the

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individual symptom score SMD into a usable measure for the cost-effectiveness ratio, a composite NSS was created as the average of the SMD for nasal congestion, rhinorrhea, and sneezing. The composite NSS represents improvement in standard deviation units. For the cost-effectiveness analysis, this measure was converted to the probability of clinically significant improvement, which required 3 steps. First, the baseline mean and standard deviation for each symptom were calculated from published clinical trials and averaged to form a composite mean and standard deviation. Second, the postintervention mean was calculated as the baseline mean plus the SMD multiplied by the baseline standard deviation: Postintervention mean = baseline mean + (SMD baseline standard deviation).

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Third, the postintervention mean was translated into the probability of significant improvement by comparing the proportion of the study population below the clinically significant improvement threshold at baseline to the proportion of the study population below the threshold, given use of each of the comparators. The threshold for significant improvement in nasal symptoms has not been well-defined. For the purposes of our model, a 25% placebo-adjusted improvement from baseline in the composite NSS was defined as the threshold for clinically significant improvement. The proportion of the population meeting or exceeding a 25% reduction over placebo in the baseline mean was calculated as the area under the normal curve. The marginal probability of significant improvement was defined as the marginal difference in the proportion of the population that was below the threshold for significant improvement. For example, if, at baseline, 30% of the population was below the significant improvement threshold, and after treatment with drug X 50% of the population was below the significant improvement threshold, then the marginal probability of clinically significant improvement was 20%. Drug costs for the model were calculated as the expected days of therapy per year multiplied by the daily wholesale acquisition cost.38 The model assumed 90 days of therapy for a calendar year. The costs of AR-related physician office visits were calculated from an analysis of the proprietary PharMetrics dataset for a 1-year period from July 1, 2005, to June 30, 2006. Patients were included in the analysis if they had a diagnosis of AR without a diagnosis of asthma. Treatment groups were created based on the first treatment agent. An analysis found limited switching. Pharmacy and outpatient visit costs were inflated to 2007 dollars by Bureau of Labor Statistics series CUUR0000SAM.39 Levocetirizine was approved in May 2007 and was not available in the United States during the period in which the PharMetrics data were captured; therefore its costs were imputed using a linear fit of the effect size for the composite NSS to the physician office visit costs for the other model comparator agents. Laboratory costs are often billed as part of the physician office visit, so they are not a separate component. Inpatient costs were not included because they would rarely be observed as a result of AR. Indirect costs were not included in the model because productivity has not been assessed in clinical trials for all comparators. Models were run separately, including just drug costs and drug costs plus the cost of AR-related office visits.

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Results of the comparative cost-effectiveness analysis are presented as average and incremental ratios, including 95% confidence intervals (CIs). The average costeffectiveness is calculated as the ratio of costs to the probability of clinically significant improvement. The incremental cost-effectiveness ratio (ICER) is calculated as the ratio of the difference in cost to the difference in the probability of clinically significant improvement for any comparator relative to levocetirizine. ICER =

Costlevocetirizine –Costdesloratadine Effectivenesslevocetirizine –Effectivenessdesloratadine

To understand the variability in the cost-effectiveness estimates, a Monte Carlo simulation was performed. The SMD and the total cost were varied by ±10%. Random draws were run 1000 times using Microsoft Excel 2003, Service Pack 2. The 95% CIs for the cost-effectiveness ratios were calculated as the 26th and 974th ordered values in the simulation. Significance for a cost-effectiveness ratio is defined by whether the CI overlaps the point estimate for the cost-effectiveness ratio. Significance for an ICER is defined as a CI around the point estimate that does not overlap 0.0.

Results The effectiveness of the model comparator agents (as measured in the 25 studies13-37) is shown in Table 1. The effectiveness of each agent is presented as the SMD relative to placebo (95% CI). All comparators showed statistically significant improvement in the 3 NSSs compared with placebo (all statistically significant). Table 2 presents the annual drug and medical costs by model comparator agent and the effectiveness of each agent. The imputed medical visit costs of levocetirizine were lower than the other comparators. Montelukast medical visit costs were higher than for the other comparators. Annual AR drug therapy costs, assuming 90 days of therapy, ranged from $168 to $275. Results of this decision-analytic model for AR using combined prescription drug and AR-related physician office visit costs are shown in Table 3. (Results from the prescription drug–only model were similar.) Costeffectiveness ratio is defined as the cost per clinically significant improvement in composite nasal symptoms. Levocetirizine had the lowest average cost per clinically significant improvement in NSS, followed by generic fexofenadine. The average cost-effectiveness ratio for levocetirizine was significantly lower compared with all other model comparator agents.

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Table 3 Cost-Effectiveness Ratios for Treating Nasal Symptoms Treatment arm Levocetirizine Desloratadine Fexofenadine (generic) Fexofenadine (brand) Montelukast

Significant symptom improvement: CER, $

95% CI: CER, $

4343 8190 6236 6841 12,556

(3712, 5075) (7013, 9611) (5305, 7342) (5824, 7992) (10,717, 14,694)

ICER, $ n/r

95% CI: ICER, $ n/r

–2107 –205 –1658 –2335

(–4586, –82) (–3134, 2389) (–5393, 797) (–4064, –858)

CER indicares cost-effectiveness ratio; CI, confidence interval; ICER, incremental CER; n/r, not calculated/reference group.

The Figure shows the ICER for each model comparator agent relative to levocetirizine. Negative ICERs can reflect either lower cost and higher effectiveness or higher cost and lower effectiveness, so they are conventionally reported as dominated to avoid confusion. The comparisons between levocetirizine and montelukast and between levocetirizine and desloratadine are significant. The remaining ICERs overlapped zero. Another way to put these ICERs in context is to examine how many times the simulated ICER was negative, which indicated that levocetirizine dominated the comparator in that simulation. In the comparison between levocetirizine and branded fexofenadine, the simulated ICER was negative 898 times (90%). In the comparison between levocetirizine and generic fexofenadine, the ICER was negative 576 times. ICERs that are positive require a tradeoff between cost and effectiveness.

Discussion To our knowledge, this is the first time the costeffectiveness of individual SGAs and montelukast has been compared for the relief of nasal symptoms of AR. This is surprising given the prevalence and economic impact of AR symptoms. As the most prevalent respiratory condition in the United States, AR affects approximately 20% of the US population.40 The symptoms of AR are often bothersome, resulting in decreased quality of life. A national survey revealed that 66% of AR sufferers polled felt that AR had some effect on their daily lives.5 The model results in this article, indicating a significant difference in the costeffectiveness of the different SGAs and montelukast for the treatment of AR, can assist managed care decision makers in determining economically efficient AR treatment options. This current analysis was designed to assess the costeffectiveness of levocetirizine compared with other oral

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prescription medications available for AR symptom management. One of the reasons that such an analysis has not been undertaken before now may be due to the lack of standard outcome measures across AR studies. The symptoms of AR manifest in myriad ways, including itchy and watery red eyes, itchy palate, nasal congestion, rhinorrhea, nasal pruritus, and sneezing. Most clinical trials of AR measure efficacy in terms of improvement from baseline in a composite NSS. The difficulty in comparing composite NSS across clinical trials is that the composite NSS is often a uniquely defined set of symptoms for each clinical trial. To overcome this obstacle, we chose to synthesize a composite NSS based on 3 individual scores often reported in the literature—nasal congestion, rhinorrhea, and sneezing. The clinical trial designs used to construct the composite nasal symptoms differed in several ways: (1) The populations ranged in age from 12 to 75 years; (2) the observation time varied from 7 days to 6 months; (3) we did not include studies conducted in environmental exposure units that measured outcomes over very short intervals; and (4) the studies were not designed as head-to-head comparisons. Nasal congestion has been reported as a bothersome symptom by patients with AR.5 Although some may argue that nasal congestion should not be part of the NSS for an evaluation of SGAs because decongestants or intranasal steroids are superior at relieving nasal congestion, there are instances when decongestants or intranasal steroids may not be the appropriate or preferred therapy. For example, because decongestants can cause difficulty sleeping, an antihistamine or montelukast may be the preferred therapy for night-time relief of AR symptoms. Furthermore, decongestants are not recommended for use in individuals with high blood pressure, thyroid disease, or those taking certain antidepressants. Finally, some patients do not want to take steroids or prefer an oral drug to an intranasal spray; in

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Cost-Effectiveness of Antihistamines and Montelukast

such cases, an antihistamine or montelukast may be prescribed even to a patient with nasal congestion. To make the denominator of the cost-effectiveness ratio more meaningful for decision makers, we converted the SMD in our composite NSS to the probability of a clinically significant improvement (defined a priori as at least a 25% improvement in NSS over placebo). This method accounts for the placebo effect often observed during AR clinical trials. Because we compared the placebo-adjusted change from baseline, our results are generally conservative. This model indicated that levocetirizine is more effective and less costly than montelukast and desloratadine for the management of nasal symptoms of AR in patients without asthma requiring daily corticosteroid use. Because the 95% CIs of the ICERs comparing levocetirizine to branded and generic fexofenadine cross zero, levocetirizine does not have complete dominance over these comparators. Thus, a tradeoff is warranted in some cases, taking into account the higher effectiveness of levocetirizine compared with the lower cost of generic fexofenadine. Although a number of prescription and OTC medications are approved for AR symptom relief, the objective of this analysis was to assess the cost-effectiveness of SGAs and montelukast, relative to levocetirizine. Only comparators available by prescription were included because the model perspective was that of a managed care organization; many health plans do not reimburse for OTC medications. Cetirizine (Zyrtec) was excluded because it became available OTC at the end of 2007. The generalizability of our results to the overall population of patients with AR may be limited by our decision to exclude clinical trials that enrolled patients with AR and concomitant asthma requiring daily corticosteroid use. It is estimated that nearly 40% of those with allergies also have asthma.9 And between 60% and 78% of patients with asthma have AR.9 Montelukast is indicated for the management of asthma and AR, whereas the SGAs are not FDA-approved for asthma. Therefore, we chose to eliminate studies involving patients with asthma requiring daily corticosteroids so as to not bias the results with respect to montelukast. Because the majority of AR patients are not asthmatic and/or do not require daily steroid inhalation, our results likely apply to a substantial portion of patients with AR who would be seen in a managed care population. The model included direct costs only, specifically drug costs and costs of outpatient physician office visits

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Figure Incremental Cost-Effectiveness Ratios

Note: A treatment is said to be dominated if an alternative exists that is more effective and less costly. for AR. Studies indicate a sizable amount of the economic burden associated with AR is due to lost productivity from absenteeism and presenteeism.11,41 In an employee survey, Lamb and colleagues found that employees with AR were absent roughly 3.6 days annually because of AR and lost 2.3 hours per workday in productivity when symptoms were present.41 Indirect costs were excluded from the analysis because of lack of relevant data substantiating differences between comparators. This may be because most AR clinical trials are of a short duration. Costs associated with lack of effectiveness and adverse events are also not accounted for in this model. The lack of a standardized outcome measure across AR trials presented some challenges. Because we specifically defined the 3 individual symptoms that served as the basis of our composite NSS, some data concerning the efficacy of each comparator agent may not have been fully captured. Our choice to use common nasal symptoms as the basis of the effectiveness measure does not take into account AR symptoms that affect other body parts (eg, eyes, palate, or throat). Construction of a synthetic NSS created a point estimate of the effect size versus placebo for each model comparator agent without CIs. Therefore, a sensitivity analysis, which varied the effect size and the cost estimates by a defined percentage, was undertaken to assess the robustness of the model results. This differs somewhat from what could have been done if the model used a single symptom score and an exact CI around the effectiveness estimate. Conversely, the CI around individual symptom scores is dependent on sample

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size; so if only a few small studies provide data on a symptom, they would have wide CIs that overstate what would be observed in larger trials. Additional trials of these agents would tighten all CIs and strengthen our conclusions.

Conclusions Levocetirizine is cost-effective for the relief of nasal symptoms of AR in patients without severe asthma compared with other second-generation prescription antihistamines and the leukotriene receptor antagonist, montelukast. The ICERs of levocetirizine versus the other model comparator agents showed that it dominated montelukast and desloratadine and was favorable compared with the other products. â&#x2013; Acknowledgments/Funding This study was funded by UCB, Inc, and sanofi-aventis US, LLC. Laurie Kozbelt and Jeanne Hawkins of Xcenda, LLC, Palm Harbor, Florida, provided technical assistance in conducting this study and producing this article. Disclosure Statement Dr Goodman, Ms Saverno, Dr Meyer, and Dr Nightengale are all consultants for Xcenda. Dr Jhaveri is an employee at sanofi-aventis. References 1. Hay JW, Leahy M. Cost and utilization impacts of oral antihistamines in the California Medi-Cal program. Value Health. 2005;8:506-516. 2. Juniper EF, Guyatt GH. Development and testing of a new measure of health status for clinical trials in rhinoconjunctivitis. Clin Exp Allergy. 1991;21:77-83. 3. Juniper EF, Guyatt GH, Griffith LE, et al. Interpretation of rhinoconjunctivitis quality of life questionnaire data. J Allergy Clin Immunol. 1996;98:843-845. 4. Juniper EF, Rohrbaugh T, Meltzer EO. A questionnaire to measure quality of life in adults with nocturnal allergic rhinoconjunctivitis. J Allergy Clin Immunol. 2003;111:484-490. 5. Nathan RA. The burden of allergic rhinitis. Allergy Asthma Proc. 2007;28:3-9. 6. Schoenwetter WF, Dupclay L Jr, Appajosyula S, et al. Economic impact and quality-of-life burden of allergic rhinitis. Curr Med Res Opin. 2004;20:305-317. 7. Malone DC, Lawson KA, Smith DH, et al. A cost of illness study of allergic rhinitis in the United States. J Allergy Clin Immunol. 1997;99:22-27. 8. Reed SD, Lee TA, McCrory DC. The economic burden of allergic rhinitis: a critical evaluation of the literature. Pharmacoeconomics. 2004;22:345-361. 9. Crown WH, Olufade A, Smith MW, et al. Seasonal versus perennial allergic rhinitis: drug and medical resource use patterns. Value Health. 2003;6:448-456. 10. Stempel DA, Woolf R. The cost of treating allergic rhinitis. Curr Allergy Asthma Rep. 2002;2:223-230. 11. Goetzel RZ, Long SR, Ozminkowski RJ, et al. Health, absence, disability, and presenteeism cost estimates of certain physical and mental health conditions affecting U.S. employers. J Occup Environ Med. 2004;46:398-412. 12. Sullivan PW, Follin SL, Nichol MB. Transitioning the second-generation antihistamines to over-the-counter status: a cost-effectiveness analysis. Med Care. 2003;41:1382-1395. 13. Bachert C, Bousquet J, Canonica GW, et al, for the XPERT Study

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October 2008

Group. Levocetirizine improves quality of life and reduces costs in longterm management of persistent allergic rhinitis. J Allergy Clin Immunol. 2004;114:838-844. 14. Berger WE, Schenkel EJ, Mansfield LE. Safety and efficacy of desloratadine 5 mg in asthma patients with seasonal allergic rhinitis and nasal congestion. Ann Allergy Asthma Immunol. 2002;89:485-491. 15. Berger WE, Lumry WR, Meltzer EO, et al. Efficacy of desloratadine, 5 mg, compared with fexofenadine, 180 mg, in patients with symptomatic seasonal allergic rhinitis. Allergy Asthma Proc. 2006;27:214-223. 16. Bernstein DI, Schoenwetter WF, Nathan RA, et al. Efficacy and safety of fexofenadine hydrochloride for treatment of seasonal allergic rhinitis. Ann Allergy Asthma Immunol. 1997;79:443-448. 17. Bronsky EA, Falliers CJ, Kaiser HB, et al. Effectiveness and safety of fexofenadine, a new nonsedating H1-receptor antagonist, in the treatment of fall allergies. Allergy Asthma Proc. 1998;19:135-141. 18. Casale TB, Andrade C, Qu R. Safety and efficacy of once-daily fexofenadine HCl in the treatment of autumn seasonal allergic rhinitis. Allergy Asthma Proc. 1999;20:193-198. 19. Chervinsky P, Philip G, Malice MP, et al. Montelukast for treating fall allergic rhinitis: effect of pollen exposure in 3 studies. Ann Allergy Asthma Immunol. 2004;92:367-373. 20. Ciebiada M, GĂłrska-Ciebiada M, DuBuske LM, et al. Montelukast with desloratadine or levocetirizine for the treatment of persistent allergic rhinitis. Ann Allergy Asthma Immunol. 2006;97:664-671. 21. Ciprandi G, Cirillo I, Vizzaccaro A, et al. Levocetirizine improves nasal obstruction and modulates cytokine pattern in patients with seasonal allergic rhinitis: a pilot study. Clin Exp Allergy. 2004;34:958-964. 22. Ciprandi G, Cirillo I, Vizzaccaro A, et al. Desloratadine and levocetirizine improve nasal symptoms, airflow, and allergic inflammation in patients with perennial allergic rhinitis: a pilot study. Int Immunopharmacol. 2005;5:1800-1808. 23. Howarth PH, Stern MA, Roi L, et al. Double-blind, placebo-controlled study comparing the efficacy and safety of fexofenadine hydrochloride (120 and 180 mg once daily) and cetirizine in seasonal allergic rhinitis. J Allergy Clin Immunol. 1999;104:927-933. 24. Kurowski M, Kuna P, Gorski P. Montelukast plus cetirizine in the prophylactic treatment of seasonal allergic rhinitis: influence on clinical symptoms and nasal allergic inflammation. Allergy. 2004;59:280-288. 25. Meltzer EO, Jalowayski AA, Vogt K, et al. Effect of desloratadine therapy on symptom scores and measures of nasal patency in seasonal allergic rhinitis: results of a single-center, placebo-controlled trial. Ann Allergy Asthma Immunol. 2006;96:363-368. 26. Nayak AS, Schenkel E. Desloratadine reduces nasal congestion in patients with intermittent allergic rhinitis. Allergy. 2001;56:1077-1080. 27. Nayak AS, Philip G, Lu S, et al, for the Montelukast Fall Rhinitis Investigator Group. Efficacy and tolerability of montelukast alone or in combination with loratadine in seasonal allergic rhinitis: a multicenter, randomized, double-blind, placebo-controlled trial performed in the fall. Ann Allergy Asthma Immunol. 2002;88:592-600. 28. Patel P, Philip G, Yang W, et al. Randomized, double-blind, placebocontrolled study of montelukast for treating perennial allergic rhinitis. Ann Allergy Asthma Immunol. 2005;95:551-557. 29. Philip G, Malmstrom K, Hampel FC, et al, for the Montelukast Spring Rhinitis Study Group. Montelukast for treating seasonal allergic rhinitis: a randomized, double-blind, placebo-controlled trial performed in the spring. Clin Exp Allergy. 2002;32:1020-1028. 30. Potter PC. Levocetirizine is effective for symptom relief including nasal congestion in adolescent and adult (PAR) sensitized to house dust mites. Allergy. 2003;58:893-899. 31. Pradalier A, Neukirch C, Dreyfus I, et al. Desloratadine improves quality of life and symptom severity in patients with allergic rhinitis. Allergy. 2007;62:1331-1334. 32. Raphael GD, Angello JT, Wu MM, et al. Efficacy of diphenhydramine vs desloratadine and placebo in patients with moderate-to-severe seasonal allergic rhinitis. Ann Allergy Asthma Immunol. 2006;96:606-614. 33. Salmun LM, Lorber R. 24-hour efficacy of once-daily desloratadine therapy in patients with seasonal allergic rhinitis. BMC Fam Pract. 2002;3:14.

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34. Simons FE, Prenner BM, Finn A Jr. Efficacy and safety of desloratadine in the treatment of perennial allergic rhinitis. J Allergy Clin Immunol. 2003;111:617-622. 35. van Adelsberg J, Philip G, Pedinoff AJ, et al, for the Montelukast Fall Rhinitis Study Group. Montelukast improves symptoms of seasonal allergic rhinitis over a 4-week treatment period. Allergy. 2003;58:1268-1276. 36. van Adelsberg J, Philip G, LaForce CF, et al; Montelukast Spring Rhinitis Investigator Group. Randomized controlled trial evaluating the clinical benefit of montelukast for treating spring seasonal allergic rhinitis. Ann Allergy Asthma Immunol. 2003;90:214-222. 37. Wilson AM, Haggart K, Sims EJ, et al. Effects of fexofenadine and desloratadine on subjective and objective measures of nasal congestion

in seasonal allergic rhinitis. Clin Exp Allergy. 2002;32:1504-1509. 38. RED BOOK for Windows, Volume 46. 2007. 39. US Department of Labor Bureau of Labor Statistics. Most Requested Statistics. Consumer Price Index. http://data.bls.gov/cgi-bin/survey most?cu. Accessed January 22, 2008. 40. American Academy of Allergy, Asthma, and Immunology. Allergy Statistics. http://www.aaaai.org/media/resources/media_kit/allergy_statistics. stm. Accessed January 17, 2008. 41. Lamb CE, Ratner PH, Johnson CE, et al. Economic impact of workplace productivity losses due to allergic rhinitis compared with select medical conditions in the United States from an employer perspective. Curr Med Res Opin. 2006;22:1203-1210.

Appendix Studies Included in This Analysis Author, date Bachert, 200413 Berger, 200214 Berger, 200615 Bernstein, 199716 Bronsky, 199817 Casale, 199918 Chervinsky, 200419 Ciebiada, 200620 Ciprandi, 200421 Ciprandi, 200522 Howarth, 199923 Kurowski, 200424 Meltzer, 200625 Nayak, 200126 Nayak, 200227 Patel, 200528 Philip, 200229 Potter, 200330 Pradalier, 200731 Raphael, 200632 Salmun, 200233 Simons, 200334 van Adelsberg (spring), 200335 van Adelsberg (fall), 200336 Wilson, 200237

Compound(s) Levocetirizine Desloratadine Desloratadine Fexofenadine Fexofenadine Fexofenadine Fexofenadine Montelukast Desloratadine Levocetirizine Montelukast Desloratadine Levocetirizine Desloratadine Levocetirizine Fexofenadine Montelukast Desloratadine Desloratadine Montelukast Montelukast Montelukast Levocetirizine Desloratadine Desloratadine Desloratadine Desloratadine Montelukast

NO. 8

257 166 257 260 141 138 287

Congestion

Nasal itch

Rhinorrhea

Sneezing

x x

x NS x x

x x x x

20 20 20 10 10 10 10 211 11 108 172 155 1002 348 150 234 190 171 337

x x NS x x x x x x x x NS

x x

x x x

x x x x x x x x

522

Montelukast

448

Desloratadine Fexofenadine

All studies required patients with allergic rhinitis.

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Treated patients, N

Ocular itching x

x x x x

NS indicates not significant (P <.05).

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Stakeholder Perspective Relieving Nasal Symptoms: Uncommon Excellence in a Common Clinical Condition Scholarly and rigorous, richly annotated with relevant references, with very precise descriptions of methodology and every assumption used within the analysis, this article represents one of the only published analyses of economic burden using prospective, placebo-controlled trial data for this class of frequently used compounds. Although analyses regarding use and cost of new-generation antihistamines have been presented elsewhere using retrospective database review (eg, Lee J, et al. Am J Manag Care. 2001;7:S103-S112), cost-effectiveness data presented using clinical trials data are the first for second-generation antihistamines and montelukast and provide an exceptional example of methodological rigor applied to a ubiquitous clinical condition. The perspective for the analysis was that of a managed care decision maker within the United States with the intent of informing formulary and clinical decision makers. A composite of patient-reported outcomes, as opposed to physician-reported measures, was used as the dependent variable, a threshold for clinically important change was defined, and fully justified assumptions regarding drug cost as well as pharmacy and outpatient visit cost are included. Only adult patients using monotherapy without asthma and daily corticosteroid treatment are considered. The absence of clinical trial data for certain parameters, such as the indirect costs of absenteeism and presenteeism, precluded their incorporation in the model, thus adhering to the standard for methodological rigor adopted by the authors, while retaining the managed care perspective as intended. Appropriate to the perspective adoptive, only prescription medication was considered. The number of trials/compound, the number of subjects within each study used to estimate effectiveness, the

number of key individual nasal symptoms reported/study, and the comparability of the patient population in each of the studies in the database are presented. Sensitivity analyses varying the effect size of each medication and cost estimates qualify the interpretation. Results provide insight regarding cost-effectiveness for second-generation antihistamines versus the leukotriene receptor antagonist, montelukast, in allergic rhinitis. However, it is the approach to this question, as much as the result of the analysis that warrants attention. The limitations of the database, in fact, provide insights for cooperative research among multiple stakeholders. By appreciating the algorithm used in cost-effectiveness analyses, the design of prospective clinical trials for investigational agents can be significantly informed. Patient characteristics, including the type and severity of comorbid conditions and permitted concomitant medication optimized for detection of an effect in a clinical trial population, may not be as informative for evaluating healthcare utilization in a clinical care environment as they can eschew patients disproportionately contributing to those estimates. Similarly, outcome measures suitable for registration purposes may be incomplete for cost-effectiveness modeling. Knowledge of optimal parameters for model construction can be captured by clinical trialists a priori, in the design stage of a registration program, substantially facilitating the perspective of multiple stakeholders. Michael F. Murphy, MD, PhD Chief Medical and Scientific Officer Worldwide Clinical Trials Chadds Ford, Pennsylvania

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Early and intensive treatment can help patients reach their A1C goal Are your plan members not taking their type 2 diabetes medications? s Many patients are not reaching the ADA A1C target goal of <7%, and many are stopping their medications.1,2

Recent data show a drop in the use of oral antidiabetic medications3 2,500

TRx (000s)

2,400 2,300 2,200

OAD TRx 4 week moving avg

Trend (Pre-NEJM)

2,100 2,000 3/16/2007

Days

6/6/2008

The need for early treatment s Because many patients already have chronic complications at the time of diagnosis, treatment plans must be aggressive from the start to optimally manage type 2 diabetes.4 s Long-term beneﬁts of diabetes medications can only be realized if patients adhere to their treatment regimen.2

“Early, intensive intervention has the potential to get patients to glycaemic goals more quickly and be more effective at keeping them at goal...” 5

References: 1. Hoerger TJ, Segel JE, Gregg EW, Saaddine JB. Is glycemic control improving in U.S. adults? Diabetes Care. 2008;31:81-86. 2. Rodgers K. Ensuring compliance in patients with diabetes. In: Diabetes: Disease Management Guide. 4th ed. Montvale, NJ: Thomson PDR; 2004:501-505. 3. Data on ﬁle, Takeda Pharmaceuticals North America, Inc. 4. Cornell SA. Clinical case study: achieving long-term control of insulin resistance. J Manag Care Pharm. 2007;13(suppl B):S11-S15. 5. Goldstein BJ, Gomis R, Lee H-K, Leiter LA, on behalf of the Global Partnership for Effective Diabetes Management. Type 2 diabetes—treat early, treat intensively. Int J Clin Pract. 2007;61(suppl 157):16-21. ©2008 Takeda Pharmaceuticals North America, Inc.

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FDA WATCH

New Reporting System for Potential Safety Concerns of Drugs on the Market Mark Senak, JD

n early September, the US Food and Drug Administration (FDA) sent out a press release posting the first quarterly report titled “Potential Signals of Serious Risks/New Safety Information Identified by the Adverse Event Reporting System (AERS),” listing the potential safety issues of drugs currently on the market. This action is in conformance with direction provided by Congress in accordance with Title IX, Section 921, of the Food and Drug Administration Amendments Act of 20071 (see Sidebar). It is long in direction and attempts to promote transparency in the pursuit of public health safety, but the impacts and effects are entirely unclear for drug manufacturers and prescribers, as are the benefits to patients. Dr Janet Woodcock, Director of the FDA’s Center for Drug Evaluation and Research, said, “My message to patients is this: Don’t stop taking your medicine. If your doctor has prescribed a drug that appears on this list,

Title IX, Section 921 of the Food and Drug Administration Amendments Act 2007 (FDAAA) (121 Stat. 962) amends the Federal Food, Drug and Cosmetic Act (FDCA) to add a new subsection (k)(5) to section 505 (21 U.S.C. 355). Title IX, Section 921 in FDAAA, among other things, directs FDA to “conduct regular, bi-weekly screening of the Adverse Event Reporting System [AERS] database and post a quarterly report on the Adverse Event Reporting System Web site of any new safety information or potential signal of a serious risk identified by Adverse Event Reporting System within the last quarter.” When a potential signal of a serious risk is identified from AERS data, it will be posted in the required report in the quarter in which it is first identified. A potential signal of a serious risk may in some cases constitute new safety information as defined in FDAAA (newly created section 505-1(b)(3) of the FDCA) which includes, among other things, information derived from adverse event reports about a serious risk associated with use of a drug that FDA has become aware of since the drug was approved or, for drugs that have REMS, since the REMS was required or last assessed. FDA will post each potential signal of a serious risk in the quarter in which it is first identified. If additional new safety information is developed concerning a potential signal that has already been posted, it will be addressed by FDA in new safety communications, but will not appear again as a new quarterly posting. Reprinted from http://www.fda.gov/cder/aers/potential_signals/ default.htm#insert.

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Octoberr 2008

you should continue taking it unless your doctor advises you differently.”2 For drug companies, this presents one more milestone for which to plan in addition to those already in existence, such as: • Clinical trial announcements • New drug application submissions and acceptances • Advisory committee meetings • FDA decisions and, if positive, launches • Postmarketing commitments • High-profile adverse events • Warning letters In addition, the existence of periodic unexpected crises (such as the discovery that an investigator is not in fact a doctor or an investigation by an irascible member of Congress) is interwoven throughout all phases of drug production. With the publication of this new list, yet one more crisis has been added. The ramifications of the publication of this list are unclear, but it does raise many questions. The FDA published the first report of 20 drugs on Friday, September 5,3 which put it into the news cycle on Saturday.4 The first list did earn prominence in the media, but what will be the impact when the list is posted regularly? Will the media publish it—either mainstream or trade publications? Will lawyers collect them for use as evidence in malpractice suits? Will disease-specific medical societies gather those that pertain to their membership and reprint them? Will the potential concerns affect the outlook of analysts? Will the reports have an impact on stocks (hence, the Friday afternoon posting)? It is too early to tell; however, the answer to at least some of these questions is quite probably affirmative. How does a marketed drug end up on this new list? The FDA makes the process clear on its website, in the section that houses the report: “FDA staff in the Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER) regularly examine the AERS database as part of routine safety monitoring. When a potential signal of a serious risk is identified from AERS data, it is entered as a safety issue into CDER’s Document Archiving, Reporting, and Regulatory Tracking System (DARRTS) or into CBER’s

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FDA WATCH

Table

Potential Signals of Serious Risks Identified by Adverse Event Reporting System (AERS), January-March 2008

Product Name: Active Ingredient (Trade) or Product Class Arginine Hydrochloride Injection (R-Gene 10) Desflurane (Suprane) Duloxetine (Cymbalta) Etravirine (Intelence) Fluorouracil Cream (Carac) and Ketoconazole Cream (Kuric) Heparin Icodextrin (Extraneal) Insulin U-500 (Humulin R) Ivermectin (Stromectol) and Warfarin Lapatinib (Tykerb) Lenalidomide (Revlimid) Natalizumab (Tysabri) Nitroglycerin (Nitrostat) Octreotide Acetate Depot (Sandostatin LAR) Oxycodone Hydrochloride Controlled-Release (OxyContin) Perflutren Lipid Microsphere (Definity) Phenytoin Injection (Dilantin) Quetiapine (Seroquel) Telbivudine (Tyzeka) Tumor Necrosis Factor Blockers

Potential Signal of Serious Risk/New Safety Information Pediatric overdose due to labeling/packaging confusion Cardiac arrest Urinary retention Hemarthrosis Adverse events due to name confusion Anaphylactic-type reactions Hypoglycemia Dosing confusion Drug interaction Hepatotoxicity Stevens-Johnson syndrome Skin melanomas Overdose due to labeling confusion Ileus Drug misuse, abuse, and overdose Cardiopulmonary reactions Purple glove syndrome Overdose due to sample pack labeling confusion Peripheral neuropathy Cancers in children and young adults

Reprinted from http://www.fda.gov/cder/aers/potential_signals/potential_signals_2008Q1.htm#list.

Therapeutics and Blood Safety Branch Safety Signal Tracking (SST) system. Potential signals of serious risks are normally based upon groups of AERS reports, although a single AERS report could lead to further evaluation of a potential safety issue.”1 But in fact, the actual list provides very little information or insight for patients, and does not direct patients to resources that could provide detailed information. The drugs are listed first by generic and then by brand name (Table). What follows is a very brief description of the potential signal, which may be a classic example of where a little information could potentially become a dangerous thing. How many instances were there, what other drugs were the people taking, what percentage have been affected, what does the drug treat? Answers to these questions may be found only with further research on the part of the patient and may even involve the filing of a Freedom of Information Act request. Perhaps most important, one may ask how a drug named on the list gets off of the list. Apparently it does not. According to the Fact Sheet issued by the FDA, “if a drug appears on the AERS-based quarterly report, it means that FDA has begun an analysis to determine whether there is a safety problem. However, depending on the level of analysis completed, it may be too early to know whether there is a safety problem, and FDA’s

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analysis may ultimately conclude that there is no safety problem. As the FDA completes its analysis of drugs on the list, if a safety problem is found, the agency will take action to protect consumers.”5 There is no mention of any procedure to vindicate a drug once the safety issue is found to be unrelated to the compound. Maybe this is yet another manifestation of the current environment that emphasizes risk over benefit. There is no vindication, only condemnation. References 1. Potential signals of serious risks/new safety information identified by the adverse event reporting system (AERS). Updated September 11, 2008. http://www.fda.gov/cder/aers/potential_signals/default.htm#insert. Accessed September 14, 2008. 2. FDA to Post Quarterly Report of Potential Safety Issues. September 5, 2008. http://www.fda.gov/bbs/topics/NEWS/2008/NEW01881.html. Accessed September 14, 2008. 3. Potential signals of serious risks/new safety information identified by the adverse event reporting system (AERS)—January-March 2008. September 5, 2008. http://www.fda.gov/cder/aers/potential_signals/ potential_signals_2008Q1.htm. Accessed September 14, 2008. 4. Brown D. FDA to list drugs being investigated: complaints will be posted quarterly. Washington Post. September 6, 2008:A02. http://www.washingtonpost.com/wp-dyn/content/article/2008/09/05/ AR2008090503409.html. Accessed September 14, 2008. 5. Fact Sheet on FDA’s Quarterly Report of Potential Safety Issues. http://www.fda.gov/oc/factsheets/aers.html. Accessed September 14, 2008.

Mr Senak is Senior Vice President at Fleishman-Hillard in Washington, DC, and writes the Eye on FDA blog at www.eyeonfda.com.

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THE MEDICATION PRESCRIBED FOR LAURA MAY NOT WORK FOR SCOTT. Open Access. Because different people have different needs. Bristol-Myers Squibb supports open and unrestricted access to mental health medications. For people with mental illness, having access to newer and potentially more effective medications can be a crucial component of treatment.

1 in 4 adults suffer from a diagnosable mental disorder in any given year.1 Open access is especially important in the treatment of mental disorders because the response to therapy can vary greatly from individual to individual and from one medication to the next. Restrictions in the form of prior authorizations and preferred lists may have the unintended consequences of jeopardizing patient health while failing to reduce costs.

SUPPORT OPEN ACCESS AND GIVE PROVIDERS THE FREEDOM TO FIND THE MOST APPROPRIATE MEDICATION FOR EACH INDIVIDUAL. 1. National Institute of Mental Health. Available at: http://www.nimh.nih.gov/healthinformation/statisticsmenu.cfm. Accessed August 7, 2006.

D6-K0176Q October 2006 AA444678/10-06

CLINICAL

Evaluation and Management of Diabetes Mellitus Quang Nguyen, DO; Loida Nguyen, PharmD; James Felicetta, MD

Diabetes mellitus is a major public health problem with tremendous medical and economic burdens. It is the seventh leading cause of death and the number one cause of end-stage renal disease, adult blindness, impotence, and nontraumatic lower-limb amputation in the United States. People with diabetes are 2 to 4 times more likely to suffer from stroke or from cardiovascular disease, and are twice as likely to die compared with age-matched individuals without diabetes. Diabetes cost the United States around $174 billion in 2007, $58 billion of which was related to disability, work loss, and early mortality. Although there is currently no known cure for diabetes, much progress has been made over the past 2 decades to Quang Nguyen improve the diagnosis and management of diabetes. Evidence has shown that applying aggressive interventions early can prevent or delay progression to microvascular complications that increase the mortality rate in diabetes. The authors review the guidelines for optimal evaluation of diabetes mellitus and discuss the current and emerging therapeutic options available in the United States. [ADHB. 2008;1(8):39-48.] iabetes mellitus is a chronic and devastating disease, affecting 8% of the US population.1 Despite recent advances in diagnostic and therapeutic options, the incidence of diabetes continued to rise in 2007. According to the Centers for Disease Control and Prevention, approximately 24 million Americans are currently diagnosed with diabetes, an increase of 3 million over the past 2 years, and another 57 million are classified as having prediabetes.1 About one third of the people with diabetes remain undiagnosed. Worldwide, the prevalence of diabetes is projected to reach 366 million people by the year 2030.2 Major increases in both macrovascular and microvascular complications can be projected on the basis of this growing prevalence. Indeed, recent studies have reported that life expectancy is reduced in patients with diabetes, with an estimated risk of death about twice that of the general population of similar age.1,3 Men and women who are diagnosed with diabetes before the age of 40 have an average life expectancy reduction of 12 and 19 years, respectively.4

The cost of diabetes to the US healthcare system is staggering; it was estimated to be around $174 billion in direct ($116 billion) and indirect ($58 billion) costs in 2007.1 Data from the United Kingdom Prospective Diabetes Study Group, the Diabetes Control and Complications Trial, and the Kumamoto study have clearly shown that early and aggressive glycemic interventions can reduce the risk of microvascular complicationsâ&#x20AC;&#x201D;retinopathy, nephropathy, and neuropathyâ&#x20AC;&#x201D; of diabetes.5-7 Despite this knowledge, studies continue to show that most Americans with diabetes are not achieving the recommended treatment goals. Recent data from the National Health and Nutrition Examination Survey reported that only one third of diabetic patients are at goal with regard to glycemic and blood pressure control, and only half are meeting their cholesterol goals.8 It is hopeful that the availability of published guidelines and algorithms will aid physicians to bring more patients to the desired glycemic, blood pressure, and lipid goals.

Dr Q. Nguyen is Assistant Professor, Department of Endocrinology, Diabetes, and Metabolism, University of Nevada School of Medicine, Reno; Dr L. Nguyen is a Clinical Pharmacy Specialist, VA Sierra Nevada Health Care System, Reno; Dr Felicetta is Chairman, Department of Medicine, Carl T. Hayden VA Medical Center, and Professor of Clinical Medicine, University of Arizona, Tucson.

Diagnosis The American Diabetes Association (ADA) currently recognizes 4 classifications of diabetes: type 1 diabetes, type 2 diabetes, other specific types of diabetes due to other causes, and gestational diabetes. Diagnostic criteria for diabetes mellitus are listed in Table 1. Fasting plasma glucose (FPG) continues to be

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KEY POINTS ▲ Approximately 24 million Americans are currently diag-

nosed with diabetes, an increase of 3 million over the past 2 years; 57 million have prediabetes. ▲ The cost of diabetes to the US healthcare system in 2007

was estimated to be $174 billion, which included direct ($116 billion) and indirect ($58 billion) costs. ▲ Early, aggressive glycemic interventions can reduce

progression to retinopathy, nephropathy, and neuropathy; nevertheless, most Americans with diabetes are not reaching treatment goals. ▲ Patients with diabetes should receive aggressive blood

pressure lowering to reduce cardiovascular events. ▲ Evidence has shown that metformin, orlistat, acarbose, and

troglitazone successfully reduce the progression of impaired glucose tolerance and impaired fasting glucose to diabetes, although to a lesser degree than diet and exercise. ▲ Lifestyle modifications remain the best treatment for type 2

diabetes, but most patients will not be able to follow a rigid diet and exercise regimen and will eventually require antihyperglycemic medications.

the diagnostic test of choice for diabetes.9 Recent studies, however, have indicated that hemoglobin (Hb) A1C may be a more stable,10 convenient (ie, does not require fasting), and noninferior test compared with FPG.11 An HbA1C screening review panel has recently evaluated the current literature on this topic and concluded that HbA1C should be “incorporated into criteria for screening and diagnosing diabetes.”12 As assays for HbA1C testing become more reliable and less expensive, it is possible that HbA1C will be accepted as an alternative screening and diagnostic test in the future.

Screening Routine screening for type 1 diabetes is currently not recommended by any organization. Due to the low incidence and the lack of known preventive measures for type 1 diabetes, screening for this disease in healthy people is not cost-effective. In contrast, many experts believe that screening for type 2 diabetes is indicated because of the long—7 years—presymptomatic phase often seen in this population.12 Although microvascular complications may take years to develop, macrovascular morbidity and mortality are significantly elevated in individuals before the diagnosis of diabetes is made.13 The ADA currently recommends that screening be considered in all individuals ≥45 years of age. If normal, the screening test should be repeated every 3 years. For individuals with 1 or more risk factors for type 2 diabetes (Table 2), screening should be done at any age.9 FPG is the screening test of choice for the ADA and the American Heart Association,14 whereas the 2hour oral glucose tolerance is the preferred test for the American Association of Clinical Endocrinologists (AACE).15 In contrast, the US Preventive Services Task Force (USPSTF) has recently updated their diabetes screening recommendations and concluded that the evidence is still insufficient to recommend for or against routine screening of asymptomatic adults for prediabetes or type 2 diabetes. The only population where screening is indicated, according to the USPSTF, is people whose blood pressure is >135/80 mm Hg. Convincing evidence has demonstrated that aggressive lowering of blood pressure in patients with diabetes reduces the incidence of cardiovascular events and mortality.16

Table 1 Diagnostic Criteria for Diabetes Mellitus Fasting plasma Classification glucose, mg/dL Normal <100 Prediabetes Impaired fasting glucose *100-125 Impaired glucose tolerance

Diabetes

*126†

2-h oral glucose tolerance test, mg/dL*

Random plasma glucose, mg/dL

<140

*140-199 *200†

>200‡

*75-g

glucose dose. Abnormal test must be repeated on subsequent day. Must occur with hyperglycemic symptoms: polydipsia, polyphagia, polyuria, blurred vision. Source: Executive summary: standards of medical care in diabetes—2008. Diabetes Care. 2008;31(suppl 1):S5-S54. † ‡

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Prevention Prevention of progression to diabetes is essential, considering the serious medical and economic consequences of the disease and the lack of cure. Several clinical trials have demonstrated that lifestyle modifications alone or in conjunction with pharmacologic therapies can prevent or delay the development of type 2 diabetes. Individuals who lose 7% of their body weight and maintain 150 minutes of exercise weekly can reduce the rate of progression from impaired glucose tolerance (IGT) to diabetes by 58%.17 Studies have demonstrated that the use of several pharmacologic agents—metformin,17 orlistat,18

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acarbose,19 and troglitazone20—can successfully reduce the progression of IGT and impaired fasting glucose (IFG)9 to diabetes, although to a lesser degree than diet and exercise. The ADA endorses lifestyle modifications as the initial treatment for prediabetes. If pharmacologic intervention is required, metformin is the only drug that is recommended in conjunction with diet and exercise in high-risk patients (those with both IGT and IFG).9

Glycemic Control Glycemic goals as recommended by the ADA and AACE are summarized in Table 3. At an HbA1C level of <7%, long-term microvascular and macrovascular risks from hyperglycemia are minimized. Recognizing that there is no threshold to the benefits of lowering HbA1C, experts now stress that HbA1C be reduced to the lowest possible level at which frequent hypoglycemic episodes do not occur. Every 1% reduction in HbA1C is associated with a 40% reduction in microvascular complications.9 Methods to achieve glycemic goals are lifestyle modifications and pharmacologic treatments. Although lifestyle modifications (ie, diet, exercise, and/or behavioral interventions) remain the best and first-line treatment, most patients will not be able to follow a rigid diet and exercise regimen and will eventually require the use of antihyperglycemic medications. Treatment Options The ADA and the European Association for the Study of Diabetes have copublished an algorithm to guide practitioners in the use of oral and/or parenteral antihyperglycemic agents available for the treatment of type 2 diabetes (Figure). A “road map to achieve glycemic goals” has also been developed by the AACE and the American College of Endocrinology and was revised in April 2008.21 Oral Antihyperglycemic Agents Six major classes of oral drugs are currently available for management of type 2 diabetes in the United States (Table 4). These medications can be divided into 4 broad categories based on their mechanisms of action—secretagogues, sensitizers, carbohydrate absorption inhibitors, and dipeptidyl peptidase-4 (DPP-4) inhibitors. These drugs are indicated in patients who do not respond to 3 months of lifestyle modifications. Biguanides (sensitizers). Metformin is the only biguanide available in the United States. Its main

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Table 2 Risk Factors for Type 2 Diabetes First-degree relative with diabetes High-density lipoprotein cholesterol )35 mg/dL and/or triglyceride *250 mg/dL History of gestational diabetes or delivery of a baby weighing >9 lb History of vascular disease Hypertension (*140/90 mm Hg in adults) IGT or IFG on previous testing Member of a high-risk ethnic group (ie, African American, Native American, Hispanic, Asian American, Pacific Islander) Obesity (body mass index >25 kg/m2) Physical inactivity Women with polycystic ovarian syndrome IGT indicates impaired glucose tolerance; IFG, impaired fasting glucose. Source: Executive summary: standards of medical care in diabetes—2008. Diabetes Care. 2008;31(suppl 1):S5-S54.

Table 3 Targets for Glycemic Control Targets Hemoglobin A1C Preprandial glucose Postprandial glucose

ADA

AACE

<7% 70-130 mg/dL <180 mg/dL (peak)

<6.5% <110 mg/dL <140 mg/dL at 2 h from start of meal

ADA indicates American Diabetes Association; AACE, American Association of Clinical Endocrinologists. Sources: Executive summary: standards of medical care in diabetes—2008. Diabetes Care. 2008;31(suppl 1):S5-S54; American Association of Clinical Endocrinologists. Medical guidelines for clinical practice for the management of diabetes mellitus. Endocr Pract. 2007;13(suppl 1):1-68.

action is to decrease hepatic glucose production and enhance insulin sensitivity. As monotherapy, metformin is very effective in decreasing plasma glucose level, reducing HbA1C by approximately 1% to 2% compared with diet or placebo.22 Aside from its glycemic effect, metformin also lowers triglycerides and low-density lipoprotein cholesterol.23 By itself, it does not cause weight gain nor hypoglycemia.24 Gastrointestinal (GI) discomfort, which usually resolves over time with continuation of the medication or dose reduction, is the most common side effect of metformin. To minimize the risk of lactic acidosis, metformin should not be given to patients with renal dysfunction (serum creatinine *1.5 mg/dL in men, *1.4 mg/dL in women). Because of its cost and benign side-effect profile, metformin is considered a first-line drug in the treatment of diabetes. It can be used concurrently with lifestyle modifications at the

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Figure Algorithm for the Metabolic Management of Type 2 Diabetes Diagnosis

Lifestyle intervention + metformin

HbA1C e 7%

Add basal insulin –Most effective No

HbA1C e7%

Add sulfonylurea –Least expensive Yes*

Intensify insulin

Yes*

HbA1C e7%

Add glitazone

†

Yes*

Add glitazone –No hypoglycemia Yes*

Add sulfonylurea†

Add basal insulin No

Yes*

HbA1C e7%

Yes*

Add basal or intensify insulin

† Intensive insulin + metformin + − glitazone

Reinforce lifestyle intervention at every visit. *Check HbA1C every 3 months until <7% and then at least every 6 months. †Although 3 oral agents can be used, initiation and intensification of insulin therapy is preferred based on effectiveness and expense. Hb indicates hemoglobin. Reprinted with permission from Nathan DM, Buse JB, Davidson MB, et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. Diabetes Care. 2006;29:1963-1972.

time of diagnosis or even for diabetes prophylaxis.9,22 To date, it remains 1 of only 2 oral antihyperglycemic medications that have been shown to reduce macrovascular complications.23 Sulfonylureas (secretagogues). Sulfonylureas are the oldest class of antihyperglycemic agents, first introduced to the US market in 1946. Their primary action is to promote insulin secretion from the pancreas. Similar to metformin, sulfonylureas are effective at decreasing plasma glucose level, reducing HbA1C by approximately 1% to 2%.22 Hypoglycemia and weight gain are the 2 major side effects of this class. Because they are the least expensive of all antihyperglycemic medications, sulfonylureas—which are second-line agents after lifestyle modifications and metformin—are the drugs of choice for patients with financial considerations. Nonsulfonylurea secretagogues (secretagogues). Repaglinide (a meglitinide) and nateglinide (a phenylalanine) function in the same manner as sulfonylureas,

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by increasing insulin secretion from the pancreas, and they reduce HbA1C at the same level (–1.5%).22 They are structurally different from the sulfonylureas and have a faster onset of action; thus, they should be taken at mealtime to reduce the risk of hypoglycemia.23 Because these agents are metabolized exclusively by the liver, they can be used in patients with renal insufficiency.25 In head-to-head trials against sulfonylureas, meglitinides and phenylalanines have not been found to be superior in terms of improving postprandial control.26,27 At a cost of 3 to 4 times more than sulfonylureas,23 it is unlikely that these drugs will be widely used. Alpha-glucosidase inhibitors (carbohydrate absorption inhibitors). Alpha-glucosidase inhibitors delay carbohydrate absorption in the small intestine, thereby lowering postprandial blood glucose without causing hypoglycemia.28 They do not cause weight gain but are associated with significant GI side effects (ie, diarrhea,

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Table 4 Oral Antihyperglycemic Agents Mechanism Drug of action Alpha-glucosidase inhibitors Acarbose Delay complex (Precose) carbohydrate absorption Miglitol (Glyset) Biguanides Metformin Decrease (Glucophage) hepatic glucose output; increase peripheral glucose uptake Dipeptidyl peptidase-4 inhibitors Sitagliptin Slow (Januvia) inactivation of incretin hormones Nonsulfonylurea secretagogues Nateglinide Stimulate (Starlix) insulin secretion from the pancreas Repaglinide (Prandin) Sulfonylureas

Second-generation

First-generation

Chlorpropamide

(Diabinese)

Hemoglobin A1C reduction, % 0.5-0.8

Dose range 25-100 mg tid w/meals 25-100 mg tid w/meals

1-2

0.5-0.8

1-1.5

Stimulate 1-2 insulin secretion from the pancreas

Tolazamide (Tolinase)

Titrate slowly to minimize GI effects

25-100 mg/d

Not clinically significant

Renal dose: 50 mg/d for CrCl *30 to <50 mL/min; 25 mg/d for CrCl <30 mL/min

Hypoglycemia, weight gain

Take w/meals due to rapid onset

60-120 mg tid 0.5-4 mg tid to qid

100-750 mg/d

1-8 mg/d

Hypoglycemia, weight gain

4-8 mg/d as a single dose or divided bid

IR: $24.99-$77.99 ER: $6.33-$25.32

$45.27$181.09

$154.11-$164.85

Use of these agents has declined due to side effects and unpredictable results

$8.62-$31.49

$12-$69.98 $5-$59.97 Hypoglycemia, weight gain

IR: 2.5-40 mg/d as a single dose or divided bid ER: 2.5-20 mg/d 1.25-20 mg/d as a single dose or divided bid (Glynase: 0.7512 mg/d as a single dose or divided bid if dose >6 mg/d)

15-45 mg/d

$73.79-$80.99

$164.82-$396.08

100-1000 mg/d given as a single dose or divided bid if dose is >500 mg/d

Glimepiride (Amaryl) Glipizide (Glucotrol)

Cost for 30-day supply (range)*

$79.99-$99.99

Nausea, vomiting, Take w/meals; diarrhea, avoid use in patients flatulence w/renal or hepatic impairment or CHF due to increased risk of lactic acidosis

250-3000 mg/d in divided doses

Thiazolidinediones Pioglitazone (Actos) Increase 0.5-1.4 peripheral tissue Rosiglitazone insulin (Avandia) sensitivity

Flatulence, diarrhea, abdominal pain

Comments

IR: 1000-2550 mg/d divided bid or tid ER: 500-2000 mg/d

Tolbutamide (Orinase)

Glyburide (Micronase, Diabeta, Glynase)

Adverse events

$12.99-$29.98 IR: $3-$25.99 ER: $18.99$39.98 $12.99-$47.96 (Glynase: $4.33$109.42)

Edema, weight gain

Black box warning: these agents can cause $134.07-$195.99 or exacerbate CHF; contraindicated in patients with NYHA class III or $120.10-$223.49 IV heart failure

*Cost calculated from generic, if available, and lowest bottle size available. GI indicates gastrointestinal; IR, immediate release; ER, extended release; CHF, congestive heart failure; CrCl, creatinine clearance; NYHA, New York Heart Association. Sources: Lacy CF, Armstrong LL, Goldman MP, Lance LL, eds. Drug Information Handbook. 17th ed. Hudson, OH: Lexi-Comp; 2008. McEvoy GK, ed. AHFS Drug Information. Bethesda, MD: American Society of Health-System Pharmacists; 2008. Cost: www.drugstore.com.

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Table 5 Insulin Preparations Drug

Onset

Peak

Duration

Comments

Cost (10-mL vial)

Insulin Aspart (NovoLog)

10-20 min

1-3 h

3-5 h

Administer within 15 min before or immediately after meals

$94.25

Insulin Glulisine (Apidra) Insulin Lispro (Humalog)

25 min

45-48 min

4-5 h

$90.68

15-30 min

0.5-2.5 h

3-6.5 h

$89.99

30-60 min

1-5 h

6-10 h

Administer 30 min before meals

$45.99-$49.99

1-2 h

6-14 h

16-24+ h

Cloudy appearance

$46.99-$49.99

Insulin Detemir (Levemir)

1.1-2 h

3.2-9.3 h

Don’t mix with other insulins

$95.30

Insulin Glargine (Lantus)

1.1 h

None

5.7-24 h (dosedependent) 24 h

70% Insulin Aspart Protamine/30% Insulin Aspart (NovoLog Mix 70/30)

10-20 min

1-4 h

24 h

75% Insulin Lispro Protamine/25% Insulin Lispro Protamine (Humalog Mix 75/25) 50% Insulin Lispro Protamine/50% Insulin Lispro Protamine (Humalog Mix 50/50)

15-30 min

22 h

70% Insulin NPH/30% Insulin Regular (Humulin 70/30, Novolin 70/30) 50% Insulin NPH/50% Insulin Regular (Humulin 50/50)

30 min

Rapid-acting

Short-acting

Insulin Regular (Novolin R, Humulin R) Intermediate-acting

Insulin NPH (Novolin N, Humulin N) Long-acting

$97.73

Premixed

$95.03

Cloudy appearance; administer within 15 min before meals

$96.89

Not available

30-60 min

1.5-12 h

1.5-4.5 h

24 h

7.5-24 h

$46.26-$49.99 Cloudy appearance; administer within 30 min before meals

$49.99

Sources: Lacy CF, Armstrong LL, Goldman MP, Lance LL, eds. Drug Information Handbook. 17th ed. Hudson, OH: Lexi-Comp; 2008. McEvoy GK, ed. AHFS Drug Information. Bethesda, MD: American Society of Health-System Pharmacists; 2008. Cost: www.drugstore.com.

abdominal pain, flatulence)24; thus, long-term compliance is a significant issue with these drugs. Unlike the biguanides, alpha-glucosidase inhibitors are not considered first-line therapy because of their minimal glycemic control (HbA1C –0.5%)22 and higher costs.23 Thiazolidinediones (sensitizers). Thiazolidinediones (TZDs; rosiglitazone and pioglitazone) reduce insulin resistance by binding to peroxisome proliferator–

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activated receptors-γ (PPAR-γ) in the peripheral muscles, liver, and adipose tissues. This, in turn, alters the transcription of genes that positively regulate glucose uptake. As monotherapy, they lower HbA1C by 0.5% to 1.4%.22 Their onset of action is slower than that of the sulfonylureas, but they do not cause hypoglycemia.28 In addition to lowering blood glucose, these agents exert beneficial effects on lipid metabolism, as

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Table 6 Noninsulin Injectable Antihyperglycemic Agents Drug Amylin analog Pramlintide (Symlin)

Incretin mimetic Exenatide (Byetta)

Mechanism of action

Hemoglobin A1C reduction, %

Dose range

Adverse events

Comments

Cost for 30-day * supply (range)

Acts in 0.5-1 conjunction with insulin to prolong gastric emptying, reduce postprandial glucose secretion, and promote appetite suppression

Type 1 DM: Nausea, 15-60 µg SC vomiting immediately before each meal Type 2 DM: 60-120 µg SC immediately before each meal

Black box warning: coadministration w/ insulin may induce severe hypoglycemia

$127.58/ 5-mL vial

Stimulates 0.5-1 insulin secretion; slows gastric emptying, suppresses glucagon release, induces satiety

5-10 µg SC bid within 60 min before morning and evening meals

Acute pancreatitis has been reported during postmarketing experience

$213.03 (5-µg cartridge)$229.27 (10-µg cartridge)

Nausea, vomiting, diarrhea

*Cost calculated from generic, if available, and lowest bottle size available. DM indicates diabetes mellitus; SC, subcutaneous. Sources: Lacy CF, Armstrong LL, Goldman MP, Lance LL, eds. Drug Information Handbook.17th ed. Hudson, OH: Lexi-Comp; 2008. McEvoy GK, ed. AHFS Drug Information. Bethesda, MD: American Society of Health-System Pharmacists; 2008. Cost: www.drugstore.com.

well as improve surrogate markers for pancreatic betacell regeneration and vascular inflammation.15,28 A recent meta-analysis has raised the possibility that rosiglitazone may increase the risk of myocardial infarction (not seen with pioglitazone).29 Because of the methodological limitations of this analysis, numerous studies, including one from the US Food and Drug Administration (FDA),30 were subsequently initiated to reevaluate these findings. Results from these studies were mixed and inconclusive,30-32 prompting the FDA to recommend caution in the use of TZDs and to mandate the inclusion of a black box warning in the package inserts of TZDs relaying the 2-fold increased risk of fluid retention and heart failure with this class.33 The future of TZDs remains strong. But at a cost of 2 to 3 times more than the cost of metformin, TZDs should only be considered after failure of lifestyle modifications and metformin.9 DPP-4 inhibitors. These medications represent the newest class of oral antihyperglycemic medications, introduced to the US market in 2006. This class inhibits the breakdown of endogenous glucagon-like peptide 1 (GLP-1),15 a compound that can control or even reverse some of the metabolic derangements seen in type 2 diabetes. Sitagliptin, the only FDA-approved drug in this class to date, has been shown to lower

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HbA1C by 0.5% to 0.8%.22 One advantage of this DPP4 is that it only works when blood glucose is elevated; thus, the risk for hypoglycemia is minimal. Other advantages include once-daily administration, oral availability, and, more important, weight neutrality.34 Sitagliptin is effective and safe in patients with renal insufficiency, including those on hemodialysis; however, dose adjustments will be necessary based on the severity of renal impairment.35 Although the appropriate role of DPP-4 inhibitors is still unclear, sitagliptin’s efficacy and safety profile suggests that this class is a reasonable treatment option for type 2 diabetes.

Parenteral Antihyperglycemic Agents The 3 parenteral antihyperglycemic classes currently available in the United States are insulins (Table 5), and amylin analogs and incretin mimetics (Table 6). Insulins. Insulin is the best agent for reducing blood glucose concentrations. It is mandatory in patients with type 1 diabetes but is a second-line therapy for patients with type 2 diabetes who have failed lifestyle modifications with or without oral antihyperglycemic therapy.22 Patients receiving insulin therapy are more likely to develop hypoglycemia and weight gain than patients taking oral medications.36 However, the recent advent of rapid-acting as well as long-acting insulins

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Table 7 In the Pipeline: Selected Emerging Antihyperglycemic Compounds Drug category Glucokinase activators

Mechanism of action Activate key enzymes to increase hepatic glucose metabolism

Comments Several drugs are currently in phase 2 clinical trials

Sodium-glucose cotransporter 2 inhibitors

Inhibit reabsorption of glucose at the proximal tubule of the kidney, thereby decreasing systemic hyperglycemia

Low potential for hypoglycemia

11β-hydroxysteroid dehydrogenase 1 Inhibit an enzyme responsible for (11β-HSD 1) inhibitors activating cortisone to cortisol, thus minimizing antiglycemic effects of cortisol

Low potential for hypoglycemia, may have beneficial effects on metabolic syndrome

Glucagon receptor antagonists

Block glucagon from binding to hepatic receptors, thereby decreasing gluconeogenesis

Low potential for hypoglycemia

Cannabinoid-1 (CB-1) receptor antagonists

Block CB-1 receptors systemically

Marketed as an obesity drug, may cause psychiatric symptoms

Source: Inzucchi SE, McGuire DK. New drugs for the treatment of diabetes mellitus: part II: incretin-based therapy and beyond. Circulation. 2008;117:574-584.

has significantly reduced these risks.24 Insulin detemir, the newest long-acting insulin analog in the United States, has consistently shown in clinical trials to be very effective in reducing blood glucose levels with less weight gain than other basal insulins.37 Incretin mimetics. Incretins are hormones that are secreted by cells in the small intestine during an oral nutrient load. GLP-1 is one incretin that has antihyperglycemic effects. In the presence of hyperglycemia, GLP-1 causes the release of insulin from the pancreas, shuts down glucagon secretion, slows down gastric emptying, and acts on the hypothalamus to increase satiety.38 Exenatide is the first synthetic GLP-1 to be introduced in the United States. Possessing many of the properties of endogenous GLP-1, exenatide can lower HbA1C by 0.5% to 1%.22 Aside from its antiglycemic effect, exenatide can also induce weight loss. Patients who were treated with exenatide for 30 weeks had an average weight loss of 4.4 kg,39 which was maintained when the study was extended for another 22 weeks using a longer-acting version of exenatide.40 Nausea is the most common side effect of exenatide, which usually subsides with continuation of this medication.38 The FDA has recently alerted physicians to 6 cases of necrotizing pancreatitis thought to be related to exenatide use41; this is in addition to the 30 cases of nonnecrotizing pancreatitis reported by the FDA in October 2007. Although the exact relationship be-

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tween pancreatitis and the drug is still unknown, it is recommended that patients receiving exenatide and presenting with abdominal pain be evaluated promptly. Amylin analogs. Amylin is a neuropeptide that is cosecreted with insulin by pancreatic beta-cells in response to food intake. Amylin complements insulin’s action by suppressing glucagon release, slowing gastric emptying, and inducing satiety.15,42 Pramlintide is the only amylin analog currently available in the United States. Approved as an adjunctive treatment for patients with type 1 or type 2 diabetes who are not optimally controlled with short-acting insulin (mealtime insulin), pramlintide can lower HbA1C by 0.5% to 1%.22 To lower the risk of hypoglycemia, the dose of premeal insulin should be reduced by 50% when pramlintide is initiated. In clinical trials, the use of pramlintide has been associated with modest weight loss.42 The most common side effect is nausea, which usually subsides with continuation of treatment. The availability of a pen formulation has made pramlintide more user-friendly; however, the future of this drug class is still uncertain because of its cost, need for multiple injections, and relatively modest therapeutic profile.

In the Pipeline A multitude of new compounds with very distinct mechanisms of action are being developed in the United States to be added to the clinician’s armamen-

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tarium for the treatment of diabetes. A selected number of these emerging compounds are outlined in Table 7.

Conclusions Lifestyle modification is recognized as the mainstay of therapy for diabetes. Metformin is considered the first-line oral antihyperglycemic drug. If immediate lowering of blood glucose level is required, insulin should be used. Exenatide and DPP-4 inhibitors are 2 new classes with favorable weight profiles. Optimal management should focus not only on glycemic control but also on comorbid conditions that often accompany this potentially life-threatening condition, including hypertension, dyslipidemia, and obesity. ■ Disclosure Statement Dr Felicetta is on the Speaker’s Bureau of Merck and sanofi-aventis. Drs Nguyen and Nguyen have no potential or apparent conflict of interest to report. References 1. Centers for Disease Control and Prevention. National diabetes fact sheet: general information and national estimates on diabetes in the United States, 2007. US Department of Health and Human Services, Centers for Disease Control and Prevention; 2008. http://www.cdc.gov/ diabetes/pubs/pdf/ndfs_2007.pdf. Accessed August 16, 2008. 2. Wild S, Roglic G, Green A, et al. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care. 2004;27:1047-1053. 3. Franco OH, Steyerberg EW, Mackenbach J, et al. Association of diabetes mellitus with total life expectancy and life expectancy with and without cardiovascular disease. Arch Intern Med. 2007;167:1145-1151. 4. Narayan KM, Boyle JP, Thompson TJ, et al. Lifetime risk for diabetes mellitus in the United States. JAMA. 2003;920:1884-1890. 5. Intensive blood-glucose control with sulfonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-853. 6. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993;329:977-986. 7. Ohkubo Y, Kishikawa H, Araki E, et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract. 1995;28:103-117. 8. Saydah SH, Fradkin J, Cowie CC. Poor control of risk factors for vascular disease among adults with previously diagnosed diabetes. JAMA. 2004;291:335-342. 9. Executive summary: standards of medical care in diabetes—2008. Diabetes Care. 2008;31(suppl 1):S5-S54. 10. Selvin E, Crainiceanu CM, Brancati FL, et al. Short-term variability in measures of glycemia and implications for the classification of diabetes. Arch Intern Med. 2007;167:1545-1551. 11. Bennett CM, Guo M, Dharmage SC. HbA1c as a screening tool for detection of type 2 diabetes: Diabet Med. 2007;24:333-343. 12. Saudek CD, Herman WH, Sacks DB, et al. A new look at screening and diagnosing diabetes mellitus. J Clin Endocrinol Metab. 2008;93: 2447-2453. 13. Hu FB, Stampfer MJ, Haffner SM, et al. Elevated risk of cardiovascular disease prior to clinical diagnosis of type 2 diabetes. Diabetes Care. 2002;25:1129-1134.

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14. Pearson TA, Blair SN, Daniels SR. AHA guidelines for primary prevention of cardiovascular disease and stroke: 2002 update: consensus panel guide to comprehensive risk reduction for adult patients without coronary or other atherosclerotic vascular diseases. Circulation. 2002;106:388. 15. American Association of Clinical Endocrinologists. Medical guidelines for clinical practice for the management of diabetes mellitus. Endocr Pract. 2007;13(suppl 1):1-68. 16. US Preventive Services Task Force. Screening for type 2 diabetes mellitus in adults: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. 2008;148:846-855. 17. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403. 18. Torgerson JS, Hauptman J, Boldrin MN, Sjöström L. XENical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diabetes Care. 2004;27:155-161. 19. Chiasson JL, Josse RG, Gomis R, et al. Acarbose for the prevention of type 2 diabetes, hypertension and cardiovascular disease in subjects with impaired glucose tolerance: facts and interpretations concerning the critical analysis of the STOP-NIDDM trial data. Diabetologia. 2004;47:969-975. 20. Buchanan TA, Xiang AH, Peters RK, et al. Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk Hispanic women. Diabetes. 2002;51:2796-2803. 21. Jellingere PS, Davidson JA, Blonde L, et al, for the ACE/ACCE Diabetes Road Map Task Force. Road Map to Achieve Glycemic Control: Naïve to Therapy (Type 2). Revision April 2008. http://www.aace. com/meetings/consensus/odimplementation/roadmap.pdf. Accessed September 20, 2008. 22. Nathan D, Buse JB, Davidson MB, et al. Management of hyperglycemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy. Update regarding the thiazolidinediones. Diabetologia. 2008;51:8-11. 23. DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med. 1999;131:281-303. 24. Fonseca V. Drug Therapy. In: Cefalu WT, Gerich JE, LeRoith D, eds. The CADRE Handbook of Diabetes Management. 1st ed. New York, NY: Medical Information Press; 2004. 25. Sheehan MT. Current therapeutic options in type 2 diabetes mellitus: a practical approach. Clin Med Res. 2003;1:189-200. 26. Carroll MF, Izard A, Riboni K, et al. Control of postprandial hyperglycemia: optimal use of short-acting insulin secretagogues. Diabetes Care. 2002;25:2147-2152. 27. Cozma LS, Luzio SD, Dunseath GJ, et al. Comparison of the effects of three insulinotropic drugs on plasma insulin levels after a standard meal. Diabetes Care. 2002;25:1271-1276. 28. Nathan DM, Buse JB, Davidson MB, et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2006;29:1963-1972. 29. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356:2457-2471. 30. US Food and Drug Administration. FDA briefing document. http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4308b1-02-fdabackgrounder.pdf. Accessed August 20, 2008. 31. Singh S, Loke YK, Furberg CD. Long-term risk of cardiovascular events with rosiglitazone: a meta-analysis. JAMA. 2007;298:1189-1195. 32. Home PD, Jones NP, Pocock SJ, et al. Rosiglitazone RECORD study: glucose control outcomes at 18 months. Diabet Med. 2007;24:626-634. 33. Lago RM, Singh PP, Nesto RW. Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: Lancet. 2007;370:1129-1136. 34. Amori RE, Lau J, Pittas AG. Efficacy and safety of incretin therapy in type 2 diabetes: JAMA. 2007;298:194-206. 35. Bergman AJ, Cote J, Yi B, et al. Effect of renal insufficiency on the

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CLINICAL

pharmacokinetics of sitagliptin, a dipeptidylpeptidase-4 inhibitor. Diabetes Care. 2007;30:1862-1864. 36. Barnett AH, Bowen JD, Burden AC, et al. Multicentre study to assess quality of life and glycaemic control of type 2 diabetic patients treated with insulin compared with oral hypoglycemic agents. Pract Diabetes Int. 1996;13:179-183. 37. Fritsche A, Häring H. At last, a weight neutral insulin? Int J Obes Metab Disord. 2004;28(suppl 2):S41-S46. 38. Exenatide (Byetta) for type 2 diabetes. Med Lett Drug Ther. 2005; 47:45-46. 39. DeFronzo RA, Ratner RE, Han J, et al. Effects of exenatide (exendin4) on glycemic control and weight over 30 weeks in metformin-treated

patients with type 2 diabetes. Diabetes Care. 2005;28:1092-1100. 40. Buse JB. Late-breaking clinical trial: exenatide once weekly elicits sustained glycemic control and weight loss over 52 weeks. Presented at the American Diabetes Association 68th Scientific Sessions June 9, 2008 San Francisco, CA. 41. US Food and Drug Administration. Information for health care professionals: exenatide. http://www.fda.gov/cder/drug/InfoSheets/HCP/ exenatide2008HCP.htm. Accessed August 20, 2008. 42. Whitehouse F, Kruger DF, Fineman M, et al. A randomized study and open-label extension evaluating the long-term efficacy of pramlintide as an adjunct to insulin therapy in type 1 diabetes. Diabetes Care. 2002; 25:724-730.

Stakeholder Perspective Evidence-Based Diabetes Management PAYERS: At a time when the future of the US healthcare system is the subject of a great deal of debate, this excellent review of the current evidence guiding the screening, diagnosis, and treatment of diabetes is indeed timely. Diabetes is one of the key disease states associated with controllable health impact in terms of future patient disability and system cost. Diabetes illustrates how over time we have been able to identify an etiology and understand the disease process and how it can be slowed, thereby mitigating its long-term effects, albeit without a “cure.” By achieving “adequate control” of glucose, longterm microvascular complications may be delayed or prevented, resulting in a reduction in retinal and renal pathology, cardiac disease, and stroke. These negative end points are devastating in terms of patient disability and catastrophic in term of total downstream costs. Yet despite a robust treatment armamentarium, we fail to achieve adequate control in too many patients. Through education and promotion of healthy lifestyle (ie, appropriate diet and exercise) we must slow the epidemic of obesity that will swell the future ranks of diabetic patients. We must be vigilant in screening and monitoring at-risk populations to ensure that secondary prevention and early treat-

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October 2008

ment are initiated in a timely manner. Patients must understand their disease and the steps they can take to participate in their care to reduce the likelihood of complications. We must strive to achieve adequate glucose control and blood pressure while monitoring for early signs of renal, retinal, and neuropathic impact. Because the disease onset and the eventual development of complications may be separated by years if not by decades, physicians and payers involved in early treatment may not benefit from the reductions in complications and may not be responsible for the consequences of poor control. Therefore, through monitoring “process indicators,” all payers and providers must be held responsible (using quality control and health plan monitoring measures) for achieving the best possible results to reduce longterm complications. We must allow neither the fractured system nor the misaligned incentives to serve as barriers to achieving the best short- and long-term outcomes for every diabetic patient. Thomas McCarter, MD, FACP Chief Clinical Officer Executive Health Resources West Chester, PA

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4th Law of Healthonomics:

Investing to keep employees working and healthy beats paying for them when they’re out and sick.

More employers are rethinking their responses to escalating healthcare costs. Why? They recognize chronic diseases are the root problem. Example: An employee managing his diabetes might cost $5,000 per year.1 An employee not managing his diabetes could cost up to $45,000.1 The win-win here is that by providing employees incentives to lead healthier lives and helping them manage their chronic diseases, you reduce your healthcare costs. And you’ll have healthier employees. Sure beats the alternative.

Learn about lowering costs now at www.CenterVBHM.com

Reference: 1. Health Partners. Beyond Beneﬁts. January 2006. http://www.healthpartners.com:747/media/beyondbeneﬁts/BB0106_ br.htm. Last accessed 8/3/07.

EXECUTIVE SUMMARIES

Cutting Through the Politics: Presidential Candidates’ Healthcare Platforms and Impact on Health Benefits By Peyton Howell, MHA

The closer we get to the elections, the less clear the future of the US healthcare appears. The 2 presidential candidates have proposed policy changes that could introduce the most sweeping revisions to the US healthcare since the inception of Medicare in the 1960s. Despite the many recent articles on the future of the US healthcare comparing the 2 candidates’ proposals, many decision makers believe, as reflected in this article, that any change to our healthcare system will be incremental at best and will combine a plethora of proposals issued by many organizations rather than the platform of the president-elect alone. The balance of

power within Congress will have a key impact on healthcare reform, Ms Howell observes. Despite the significant differences in their health plan proposals, the candidates agree on 3 issues: (1) transparency and price reporting, (2) the role of comparative effectiveness in drug decision-making, and (3) health information technology as a key to transforming the system and improving patient outcomes. Any change in the healthcare system will require significant stakeholder collaboration that will involve payers, purchasers, employers, physicians, patient advocacy groups, and regulatory bodies.

Evaluation and Management of Diabetes Mellitus By Quang Nguyen, DO; Loida Nguyen, PharmD; James Felicetta, MD

Approximately 24 million Americans have diabetes, an increase of 3 million over the past 2 years. In addition, 57 million have prediabetes, which could be claimed to be reaching epidemic proportions. This prevalence trend is not expected to be reversed in the near future, making diabetes a top priority for physicians, payers, patients, and drug companies. The cost of diabetes to the US economy is staggering. In 2007, diabetes costs were estimated at $174 billion. Recent studies have consistently shown that early, aggressive glycemic interventions can reduce progression to the many serious, life-threatening sequelae of this disease, including retinopathy, nephropathy, and neuropathy. Although lifestyle modifications are recommended and

remain the best treatment for type 2 diabetes, it is clear that most patients are not able to follow a rigid diet and exercise regimen and will therefore eventually require drug therapy in addition to lifestyle modifications. Several medications have been shown to successfully reduce the progression of impaired glucose tolerance and impaired fasting glucose to diabetes, although to a lesser degree than diet and exercise. A slew of oral and insulin therapies are available. The treatment algorithm offers direction for medication selection. Yet despite the abundance of therapeutic options, most Americans with diabetes are not reaching treatment goals, which should sound an alarm not only for patients and physicians but also for payers and other healthcare stakeholders.

MTM Goes Hi-Tech: Implementing Automated Software Improves Pharmacy Efficiency By Adrienne Giordano, PharmD; Carrie Holden, PharmD; Cathrine Misquitta, PharmD, BCPS

With the recent mandate to health plans to provide medication therapy management (MTM) programs to Medicare Part D beneficiaries, pharmacists faced new challenges of collecting important patient-specific drug information using old, inefficient, and costly systems. Mired in manual procedures, pharmacists at one specif-

ic plan—Health Net—completed about 200 monthly drug therapy reviews of members joining the program, although they had an average of 1500 potential members becoming eligible each month. This article outlines the steps of implementing a new, automated software system for their MTM program, which resulted Continued

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October 2008

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EXECUTIVE SUMMARIES

in increased pharmacy efficiency, as well as improved patient outcomes; drug regimen reviews and drug problems identified increased by 300% with switching to the new program. Plan pharmacists now review 50 member profiles daily compared with 50 weekly reviews

with the old software system. The authors suggest that other Part D sponsors would benefit from customizing their MTM programs to cover the large spectrum of eligibility criteria, enrollment methods, and interventions.

Cost-Effectiveness of Second-Generation Antihistamines and Montelukast in Relieving Allergic Rhinitis Nasal Symptoms By Michael J. Goodman, PhD; Mehul Jhaveri, PharmD; Kim Saverno, RPh; Kellie Meyer, PharmD; Brian Nightengale, PhD

Allergic rhinitis affects about 20% of the US population, resulting in a significant economic burden to the healthcare system; the direct costs are estimated at $1.4 billion to $6 billion annually. In 2004, allergies were estimated to represent the fifth most expensive condition for employers when considering presenteeism, absenteeism, and direct medical costs. Finding therapies that can successfully relieve symptoms and improve employeesâ&#x20AC;&#x2122; productivity could alleviate some of the economic burden to health plans and employers. The goal of this study was to inform US formulary and benefit design decision makers about the relative cost-effectiveness of available treatments for allergic rhinitis.

Antihistamines have long been a mainstay of this condition; the second-generation antihistamines are some of the most widely prescribed medications in the United States and cause fewer adverse events than the first-generation agents. This study represents the first cost-effective comparison of the various second-generation antihistamines and the leukotriene-receptor antagonist montelukast. This analysis shows that levocetirizine had the lowest average cost per clinically significant improvement in nasal symptom score, followed by generic fexofenadine. These findings can assist benefit design decision makers in determining the most cost-effective treatment options for allergic rhinitis. â&#x2013;

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October 2008

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

over six months and more than 1300 for over one year. Adverse experiences have generally been mild and transient in nature and have only infrequently required discontinuation of therapy. In placebo-controlled trials involving 1041 patients treated with various doses of telmisartan (20-160mg) monotherapy for up to 12 weeks, an overall incidence of adverse events similar to that of placebo was observed. Adverse events occurring at an incidence of 1% or more in patients treated with telmisartan and at a greater rate than in patients treated with placebo, irrespective of their causal association, are presented as follows: The most common adverse events occurring with MICARDIS Tablets monotherapy at a rate of e1% and greater than placebo, respectively, were: upper respiratory tract infection (URTI) (7%, 6%), back pain (3%, 1%), sinusitis (3%, 2%), diarrhea (3%, 2%), and pharyngitis (1%, 0%). In addition to the adverse events, the following events occurred at a rate of 1% but were at least as frequent in the placebo group: influenza-like symptoms, dyspepsia, myalgia, urinary tract infection, abdominal pain, headache, dizziness, pain, fatigue, coughing, hypertension, chest pain, nausea and peripheral edema. Discontinuation of therapy due to adverse events was required in 2.8% of 1455 patients treated with MICARDIS tablets and 6.1% of 380 placebo patients in placebo-controlled clinical trials. The incidence of adverse events was not dose-related and did not correlate with gender, age, or race of patients. The incidence of cough occurring with telmisartan in six placebo-controlled trials was identical to that noted for placebo-treated patients (1.6%). In addition to those listed above, adverse events that occurred in more than 0.3% of 3500 patients treated with MICARDIS monotherapy in controlled or open trials are listed below. It cannot be determined whether these events were causally related to MICARDIS tablets: Autonomic Nervous System: impotence, increased sweating, flushing; Body as a Whole: allergy, fever, leg pain, malaise; Cardiovascular: palpitation, dependent edema, angina pectoris, tachycardia, leg edema, abnormal ECG; CNS: insomnia, somnolence, migraine, vertigo, paresthesia, involuntary muscle contractions, hypoaesthesia; Gastrointestinal: flatulence, constipation, gastritis, vomiting, dry mouth, hemorrhoids, gastroenteritis, enteritis, gastroesophageal reflux, toothache, non-specific gastrointestinal disorders; Metabolic: gout, hypercholesterolemia, diabetes mellitus; Musculoskeletal: arthritis, arthralgia, leg cramps; Psychiatric: anxiety, depression, nervousness; Resistance Mechanism: infection, fungal infection, abscess, otitis media; Respiratory: asthma, bronchitis, rhinitis, dyspnea, epistaxis; Skin: dermatitis, rash, eczema, pruritus; Urinary: micturition frequency, cystitis; Vascular: cerebrovascular disorder; and Special Senses: abnormal vision, conjunctivitis, tinnitus, earache. During initial clinical studies, a single case of angioedema was reported (among a total of 3781 patients treated with telmisartan). Clinical Laboratory Findings In placebo-controlled clinical trials, clinically relevant changes in standard laboratory test parameters were rarely associated with administration of MICARDIS tablets. Hemoglobin: A greater than 2 g/dL decrease in hemoglobin was observed in 0.8% telmisartan patients compared with 0.3% placebo patients. No patients discontinued therapy due to anemia. Creatinine: A 0.5 mg/dL rise or greater in creatinine was observed in 0.4% telmisartan patients compared with 0.3% placebo patients. One telmisartan-treated patient discontinued therapy due to increases in creatinine and blood urea nitrogen. Liver Enzymes: Occasional elevations of liver chemistries occurred in patients treated with telmisartan; all marked elevations occurred at a higher frequency with placebo. No telmisartan-treated patients discontinued therapy due to abnormal hepatic function. Post-Marketing Experience The following adverse reactions have been identified during post-approval use of MICARDIS tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to MICARDIS tablets. The most frequently spontaneously reported events include: headache, dizziness, asthenia, coughing, nausea, fatigue, weakness, edema, face edema, lower limb edema, angioneurotic edema, urticaria, hypersensitivity, sweating increased, erythema, chest pain, atrial fibrillation, congestive heart failure, myocardial infarction, blood pressure increased, hypertension aggravated, hypotension (including postural hypotension), hyperkalemia, syncope, dyspepsia, diarrhea, pain, urinary tract infection, erectile dysfunction, back pain, abdominal pain, muscle cramps (including leg cramps), myalgia, bradycardia, eosinophilia, thrombocytopenia, uric acid increased, abnormal hepatic function/liver disorder, renal impairment including acute renal failure, anemia, and increased CPK. Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers, including MICARDIS. OVERDOSAGE Limited data are available with regard to overdosage in humans. The most likely manifestation of overdosage with MICARDIS (telmisartan) tablets would be hypotension, dizziness and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, supportive treatment should be instituted. Telmisartan is not removed by hemodialysis. DOSAGE AND ADMINISTRATION Dosage must be individualized.The usual starting dose of MICARDIS (telmisartan) tablets is 40 mg once a day. Blood pressure response is dose related over the range of 20-80 mg. Special Populations: Patients with depletion of intravascular volume should have the condition corrected or MICARDIS tablets should be initiated under close medical supervision (see WARNINGS, Hypotension in Volume-Depleted Patients). Patients with biliary obstructive disorders or hepatic insufficiency should have treatment started under close medical supervision (see PRECAUTIONS, General, Impaired Hepatic Function, and Impaired Renal Function). Most of the antihypertensive effect is apparent within two weeks and maximal reduction is generally attained after four weeks. When additional blood pressure reduction beyond that achieved with 80 mg MICARDIS is required, a diuretic may be added. No initial dosing adjustment is necessary for elderly patients or patients with mild-to-moderate renal impairment, including those on hemodialysis. Patients on dialysis may develop orthostatic hypotension; their blood pressure should be closely monitored. MICARDIS tablets may be administered with other antihypertensive agents. MICARDIS tablets may be administered with or without food. Rx only MC-BS (03/07)

Printed in U.S.A.

(10/07)

MC48827

Get patients with difﬁcult-to-control hypertension to goal1

MICARDIS. More than POWER…

BP PROTECTION in the early morning2

USE IN PREGNANCY When used in pregnancy during the second and third trimesters, drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus. When pregnancy is detected, MICARDIS Tablets should be discontinued as soon as possible (see WARNINGS, Fetal/Neonatal Morbidity and Mortality). MICARDIS is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents. MICARDIS is contraindicated in patients who are hypersensitive to any component of this product. The most common adverse events occurring with MICARDIS Tablets monotherapy at a rate of e1% and greater than placebo, respectively, were: upper respiratory tract infection (URTI) (7%, 6%), back pain (3%, 1%), sinusitis (3%, 2%), diarrhea (3%, 2%), and pharyngitis (1%, 0%). Please see Brief Summary of Product Information on adjacent page.

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

Printed in U.S.A.

(10/07)

MC48828