JMCM Journal of Managed Care A Peer-Reviewed Publication

The Official Journal of the NATIONAL ASSOCIATION OF MANAGED CARE AMERICAN ASSOCIATION OF INTEGRATED HEALTHCARE DELIVERY SYSTEMS AMERICAN COLLEGE OF MANAGED CARE MEDICINE AMERICAN ASSOCIATION OF MANAGED CARE NURSES

Vol. 9, No. 2

® Impact of a Web-Based Diabetes Program and Personal Health Record on Diabetes Quality of Care

® Evolving Treatments for Cardiometabolic Syndrome

® Management of Non-ST Segment Elevation Acute Coronary Syndrome: The Managed Care Perspective

® PLUS: Spring Managed Care Forum Program Guide

Special Section

® Biotechnology Faces Cost Challenges in Consumer-Driven Healthcare Environment

® Human Genome Project: Implications for Healthcare

JMCM Journal of

JOURNAL Managed Care Medicine OF MANAGED CARE MEDICINE The Official Journal of the 4435 Waterfront Drive, Suite 101 NATIONAL ASSOCIATION OF MANAGED CARE PHYSICIANS Glen Allen, VA 23060 AMERICAN ASSOCIATION OF INTEGRATED HEALTHCARE DELIVERY SYSTEMS (804) 527-1905 AMERICAN COLLEGE OF MANAGED CARE MEDICINE fax (804) 747-5316 AMERICAN ASSOCIATION OF MANAGED CARE NURSES

A Peer-Reviewed Publication Vol. 9, No. 2 EDITOR-IN-CHIEF J. Ronald Hunt, MD PUBLISHER TABLE OF CONTENTS Jack F. Klose

ADVERTISING COORDINATOR Publisher’s Desk ...... 6 Will Williams Impact of a Web-Based Diabetes Program and Personal Health Record JOURNAL MANAGEMENT on Diabetes Quality of Care Douglas Murphy Jay A. Johnson, MD, FACC, and Rahul Singal, MD ...... 12 Communications Inc. 8730 Stony Point Parkway, Suite 250 Richmond, VA 23235 Evolving Treatments for Cardiometabolic Syndrome (804) 272-9100 Stephen Davis, MD, FRCP ...... 17 fax (804) 272-1694 MANAGING EDITOR Management of Non-ST Segment Elevation Acute Coronary Syndrome: Virginia Sowers The Managed Care Perspective [email protected] Jay Johnson, MD, FACC ...... 22 ART DIRECTOR David Balch SPECIAL SECTION: GENOMICS BIOTECH INSTITUTE

DESIGN ASSOCIATE Biotechnology Faces Cost Challenges in Consumer-Driven Paul Lacy Healthcare Environment Tom Morrow, MD ...... 27 ADVERTISING MANAGEMENT Jack F. Klose 804 Broadway Human Genome Project: Implications for Healthcare W. Long Branch, NJ 07764 Eric Green, MD ...... 31 (732) 229-8845 fax (856) 582-9596 SPRING MANAGED CARE FORUM PROGRAM GUIDE ...... 34 [email protected]

The Journal of Managed Care Medicine is pub- lished by Association Services Inc. Corporate and Circulation offices: 4435 Waterfront Drive, Suite Journal of Managed Care Medicine Instructions for Authors 101, Glen Allen, VA 23060; Tel (804) 527-1905; Fax The Journal of Managed Care Medicine is a peer-reviewed national publication. Original articles (804) 747-5316. Editorial and Production offices: 8730 Stony Point Parkway, Suite 250, Richmond, VA dealing with the business or clinical side of managed care are welcome. Manuscript length gen- 23235; Tel (804) 272-9100; Fax (804) 272-1694. Advertising offices: Jack Klose, 804 Broadway, W. erally should range between 10 to 15 typed pages, including a summary with key points, exhibits, Long Branch, NJ 07764; Tel (732) 229-8845; Fax and references. All submissions should include the following elements: (856) 582-9596. Subscription Rates: one year $95 in the ; one year $105 in Canada; one • One printed copy of the manuscript, including illustrations/figures/tables year $120 international. Back issues are available • Contact numbers (phone and fax), complete mailing address, and e-mail address for designated for $15 each. All rights reserved. No part of this publication may be reproduced or transmitted in corresponding author any form or by any means, electronic or mechanical, • Electronic version on CD or via e-mail in Microsoft Word including photocopy, recording, or any information storage or retrieval system, without written con- • Bibliography/References, following the format of the AMA Manual of Style, 9th Ed. sent from the publisher. The publisher does not guarantee, either expressly or by implication, the • Brief biography of author(s) < 50 words and including academic/corporate affiliations factual accuracy of the articles and descriptions • Copyright transfer letter herein, nor does the publisher guarantee the accuracy of any views or opinions offered by the authors of said articles or descriptions. For a complete copy of authors’ guidelines, POSTMASTER: Send address changes to THE contact JMCM’s Managing Editor,Virginia Sowers, (804) 272-9100 (ext. 110). JOURNAL OF MANAGED CARE MEDICINE, 4435 Journal of Managed Care Medicine Waterfront Drive, Suite 101, Glen Allen, VA 23060. Forward submissions to 8730 Stony Point Parkway, Suite 250 • Richmond,VA 23235

Journal of Managed Care Medicine Vol. 9, No. 2 5 Publisher’s Desk

Keeping Members Up to Date

This issue of the JMCM opinions regarding the value of Diabetes Patient Report Card includes the program guide for a patient survey. and the Diabetes Audit our Spring Managed Care In managed healthcare, we all Tool to assist patients with com- Forum, May 4-5 in San Diego at know the importance of preventing pliance and empowerment and to the Lowes Coronado Bay Resort. and detecting disease early. Our help physicians audit the diabetic It promises to be an exciting con- organization has developed a patients in their practices. We ference, as we have great speakers number of tools for patients and offer additional tools for patients and topics lined up for you. and physicians addressing As always, our mission is other diseases. Contact us if to keep you up to date with you are interested in using current information on We have had many new them in your healthcare managed healthcare issues, delivery systems. and also provide you with As you will note in this opportunities to earn con- issues to deal with issue, we now regularly tinuing education credits. devote part of JMCM to the We have had many new in managed healthcare Genomics Biotech Institute issues to deal with in man- via our GBI Reports section. aged healthcare including including Part D, Genomics and biotechnology Medicare Part D,pay for per- will revolutionize the prac- formance, consumer-driven tice of medicine as we move health plans, and myriad pay for performance, forward in managed health- other concerns that are care. We want you to stay changing the landscape for consumer-driven health informed on these issues. all of us working in managed Finally, we hope that you care. Our spring conference plans, and myriad other receive our weekly Managed addresses these topics and Care eNews and GBI eNews more, as we strive to anticipate to keep you up to date on and respond to issues that concerns that are issues in managed health- affect all healthcare delivery care that address your spe- systems. changing the landscape cific responsibilities as pur- Maintaining a healthy chasers, plans, and providers population and keeping the for all of us working in including CMS, new drug patient at the focal point of therapy, and genomics and healthcare is of paramount biotechnology. importance. We can do a managed care. We exist to be patient better job of asking patients advocates and to help develop about issues they encounter a healthcare delivery system within the healthcare delivery that makes sense for everyone systems. Continuously changing physicians to use to address the involved in the continuum. We rules often leads to patient con- issues of education, empowerment, hope that you enjoy the confer- fusion. Perhaps it’s time for our and compliance. One tool is the ence. And remember to let us managed care associations to Preventive Maintenance Report hear from you regarding your conduct a patient survey to get Card, which helps patients keep interest in a patient survey. direct feedback on their experi- track of the appropriate checkups ences with healthcare delivery. recommended by the U.S. Bill Williams, MD After all, we exist to meet their Preventive Task Force under CMS. 804-527-1905 needs. We’d like to hear your We have also developed the [email protected]

6 Journal of Managed Care Medicine Vol. 9, No. 2

Impact of a Web-Based Diabetes Program and Personal Health Record on Diabetes Quality of Care

Jay A. Johnson, MD, FACC, and Rahul Singal, MD

Summary Diabetes mellitus is a chronic disease that affects approximately 6.2 percent of the adult U.S. population. Improvement in diabetic, glycemic control, and risk-factor modification has been shown to reduce complications of the disease and can result in reduced healthcare expenditures. The objective of this study was to evaluate the impact of a web-based education program and personal electronic health record (EHR) on glycemic control and risk-factor modification in patients with diabetes in a large employer group. Patients with the diagnosis of diabetes mellitus were identified and given a $15 incentive to participate. The tools provided feedback on goals for glycemic control (hemoglobin A1C), and risk-factor modification (cholesterol, blood pressure control). Participants’ data (total and LDL-cholesterol, HbA1c, and blood pressure) were imported into the EHR, used in the web-based educational tools, and transmitted electronically to the treating physician. Data were collected at baseline and six months after the program onset.

Key Results • After six months, participants had a significant reduction in HbA1C from 8.0 percent to 7.3 percent (p = 0.039), whereas the control group had no change (7.7 percent to 7.7 percent; p = 0.49). • Total cholesterol also fell during study period in the participant group (187 to 171 mg/dl; p = 0.024) but increased in the control group (188 to 198 mg/dl, p = <0.01). • Similar results occurred with LDL-cholesterol. • These data suggest that a web-based diabetes education program with feedback on laboratory data and recommended treatment goals can significantly improve glycemic control and cholesterol measurements in an employee-based population of patients with diabetes. The magnitude of improvement seen would be expected to result in a healthier population and reduced healthcare expenditures.

TYPE 2 DIABETES MELLITUS is a serious keep up with evidence-based practice guidelines.6 medical condition with potentially devastating Preventive care and screening practices also lag complications. In the past two decades, the number of behind. In 2003, more than 30 percent of U.S. Americans diagnosed with diabetes has more than adults with diabetes did not receive an annual foot doubled.1,2 Currently there are an estimated 18.2 or eye examination.7 million people in the United States with diabetes.The Patient self-management education is an integral part direct and indirect cost of diabetes care in 2005 is of the treatment plan for diabetes, according to estimated at more than $132 billion.1 Appropriate accepted national standards.8,9 Involving patients in management of diabetes and associated risk factors has their care improves diabetes management,adherence to been shown to reduce the incidence of cardiovascular treatment and screening recommendations, glycemic disease3 and many other the devastating complications,4 control,10 and outcomes.11 Patients with diabetes have and lower healthcare costs.5 Currently, however, the an added burden over those with other chronic diseases quality of diabetes management in the U.S. does not in that they must understand treatment goals for risk

12 Journal of Managed Care Medicine Vol. 9, No. 2 factors, such as hypertension and high cholesterol, and containing laboratory data accessible through a personal preventive services recommendations in addition to EHR on the quality of diabetes care—in terms of blood glucose management. Several computer-based glycemic control and risk-factor modification. patient education models have been shown to improve diabetes management.12 However, utilization depends Methods on access, ease of use, and readability of the infor- A web-based, consumer-focused, health education mation. Web-based tools are emerging as effective and decision support system (WorldDoc Inc.,Las Vegas), educational programs and provide the opportunity incorporating personal EHR and electronic healthcare to shift the focus of diabetes management toward provider visit (e-visit) technology served as the platform patient self-management13, but little is known about for the study. The system includes a chronic care the impact of using the web in the clinical care of decision-support tool for diabetes that incorporates a patients with chronic disease. diabetes “report card,” which was developed in The merger of personal electronic health records collaboration with the National Association of (EHR) with web-based educational tools offers an Managed Care Physicians (NAMCP,www.namcp.org) opportunity to improve patient self-management of described below. The advisory board of WorldDoc diabetes.14 The Institute of Medicine has identified key Inc. approved the study design, and all participants features of patient-controlled personal health records, gave informed consent and authorization to release which can lead to improved quality of care.15 Electronic personal health information to their providers. health records alone have not been shown to improve the quality of diabetes care.16 Combining patient- Participants controlled EHR with educational support has been A large employer group (Coast Hotels and Casinos proposed as an effective mechanism to improve diabetes Inc., Las Vegas) served as the population base of study care.To date, we are aware of no study examining the participants. Pharmacy claims data (patients receiving impact of combining web-based educational tools with anti-diabetes drugs) were used to identify those with electronic personal health records on the effectiveness of diabetes. All individuals identified as having diabetes diabetes management. This study was designed to were notified by postal mail of the program, were determine the impact of a web-based educational tool offered an incentive of $15 to participate, and asked to

Exhibit 1: Baseline Characteristics of the Study Group

Characteristics Participants (n=91) Control (n=163) P Value

Sex

Male – no. (%) 45 (49%) 93 (57%)

Female – no. (%) 46 (51%) 70 (43%)

Age

Years 54.5 52.6 0.066

Glycosylated hemoglobin

(%) 7.9 7.5 0.195

Systolic blood pressure

(mmHg) 129 133 0.082

Total cholesterol

(mg/dl) 187 183 .453

LDL cholesterol

106 104 .411

Journal of Managed Care Medicine Vol. 9, No. 2 13 complete a survey assessing their current understanding Assessment results are customized based on the of diabetes management. Participation in the program participant’s answers to the questionnaire and treatment was voluntary, and kept confidential, so the employer guidelines published by national organizations was not aware of individual participation. including American Diabetic Association9 (hemoglobin The medical care for this population is provided by a A1C and screening examinations), National Heart, Lung single, large medical group, which allowed a central and Blood Institute, JNC717 (blood pressure), and the source for collecting laboratory and biometric data. Adult Treatment Panel III report18 (cholesterol). Laboratory data (most recent hemoglobin A1C, total The assessment results were stored in the user’s cholesterol, and LDL-cholesterol) and most recent personal EHR and accessible through his/her secure blood pressure were imported into the personal EHR web portal. In addition, the assessment results were for all patients with diabetes in accordance with privacy delivered electronically to the healthcare provider of and security standards. each participant and follow-up with the provider was encouraged. Data were collected from the healthcare Intervention provider via the EHR system. Participation in the program required each person to create a user name and password on the web-based Results health management system (WorldDoc Inc.) and Among a total of 5,545 employees, 319 (5.8 percent) complete a diabetes assessment questionnaire as part of were identified as having diabetes. Laboratory and the chronic care management tool.The tool provides biometric data were available on 254 employees. The participants with an assessment that includes a diabetes average follow-up was six months. Out of the 254 report card displaying user-specific information on patients with diabetes, 91 agreed to participate in the treatment goals, care-gap analysis, risk-factor program, and the remaining 163 nonparticipants served management, and screening tests and examination as a control population.The baseline characteristics were status in an easy-to-understand format. The tool similar in both groups and are shown in Exhibit 1. provided each user with a concise summary of his/her HbA1C data were available for 65 percent of the study results (from the EHR), as compared to the participants and 66 percent of the controls. On average, recommended target or treatment goal for each of the neither group was at the recommended HbA1C goal of following measurements: hemoglobin A1, blood less <7.0 percent, or the LDL cholesterol level of <100 pressure, LDL-cholesterol, body mass index, dietary mg/dl at baseline. intake, fitness level, and smoking status. In addition, a During the six months following web-based summary was provided showing how the user’s prior diabetes education and goal setting, HbA1C fell care compared to recommendations for the timeliness significantly from 8 percent to 7.2 percent (P=0.039) of the following screening examinations and tests:urine in the participants but not in the controls (7.5 percent protein, retinal examination, foot examination, to 7.9 percent, P=0.498). See Exhibit 2. influenza immunization, hemoglobin A1C testing, blood Similarly,total cholesterol and LDL cholesterol were pressure measurement, and lipid profile testing. reduced in the participants (from 187 to 171 mg/dl,

Exhibit 2: Hemoglobin A1C Exhibit 3: Total Cholesterol

8.2% 205 200 8.0% 195 7.8% 190

7.6% 185 180 7.4% 175 7.2% 170 165 7.0% 160 6.8% 155 Baseline 6 Months Baseline 6 Months

Participants Non-participants Participants Non-participants

14 Journal of Managed Care Medicine Vol. 9, No. 2 P=0.024, and from 106 to 94 mg/dl, P=0.054, program used in this study focused on patient respectively) and not in the controls (183 to 202 empowerment and emphasized the importance of mg/dl, p=0.285, and 104 to 115 mg/dl, P=0.335 each patient knowing that the HbA1C target of 7percent respectively). See Exhibits 3 and 4. There was no included feedback of user values, and involved the significant change seen in systolic blood pressure care providers. Other studies have involved more between the two groups, see Exhibit 5. didactic education methods. It is noteworthy that the population was a relatively well-managed group at Discussion baseline. It has been suggested that it is more difficult These results demonstrate the effectiveness of to have a positive impact on the management of a combining a web-based education and decision- well-managed group as compared to a population support tool with a personal EHR in improving quality with a poor quality of care. It would be reasonable to of care management of diabetes.Improvement was seen expect a greater impact of this method on a more in glycemic control and in risk-factor modification— poorly managed population with diabetes. cholesterol reduction. These results were similar in This study was not designed to assess the impact of men and women and are consistent with other studies improved diabetes management on healthcare demonstrating the positive impact of patient education expenditures.Early studies suggested that there is a high programs on glycemic control in patients with diabetes.19 incremental cost in improving glycemic control20 and The magnitude of the improvement in HbA1C in the that it takes a long time for improved glycemic control to treatment group (-0.80 percent) is a clinically result in improved outcome,20 raising economic concerns significant reduction that would be expected to result about the willingness of employers and health insurers in improved clinical outcome.This is a larger reduction to implement such programs. In contrast to this idea, than seen in other studies. In a meta-analysis of 31 more recent studies have shown that quality management studies of self-management education for adults with of patients with diabetes to achieve target levels, after type 2 diabetes, Norris et al. showed an average controlling for confounding factors, can result in a 32 reduction of 0.76 percent initially in the treatment percent reduction in healthcare expenditures over one group as compared to the controls, but only 0.26 year.22 Gilmer et al. support this notion and suggest that 10 percent by six months. The same study demonstrated HbA1C at any one time independently predicts healthcare that a high degree of patient contact was needed for cost over the subsequent three years, and they propose most education programs. The authors estimated 23 that a reduction in HbA1C would be followed by a hours of contact were needed for every 1 percent substantial reduction in costs.23 Therefore, the magnitude absolute reduction in HbA1C.Therefore, a reduction of of impact on diabetes control seen in this study would be 0.8 percent, as seen with this self-guided education expected to significantly reduce healthcare expenditures. tool, compares favorably to other methodologies. Several factors could explain the greater-than- Future Direction expected improvement in glycemic control seen in The rapid growth of information technology and this study.One important factor is that the education its applications to healthcare create many possibilities

Exhibit 4: LDL Cholesterol Exhibit 5: Systolic Blood Pressure

140 140

120 130 120 100 110 80 100 60 90 40 80

20 70

0 60 Baseline 6 Months Baseline 6 Months

Participants Non-participants Participants Non-participants

Journal of Managed Care Medicine Vol. 9, No. 2 15 to expand on the model of patient empowerment population. The improvements were seen in six and more active involvement of patients in the months and with a relatively simple, low-cost delivery of healthcare and management of disease. intervention. JMCM The more ubiquitous use of the Internet, in combination with portable, secure personal health Jay A. Johnson, MD, FACC, is an attending staff physician with Stanford records, offers an opportunity to provide meaningful, University Medical Center and chief medical officer for WorldDoc Inc., an online consumer education and decision-support service based in Las Vegas. personal information and goal-setting on an ongoing Rahul Singal, MD, is CEO for WorldDoc, Inc. in Las Vegas. basis. Engaging providers and health educators in personalized interactions with patients can further References enhance the involvement of patients in their care. 1. Centers for Disease Control, National Center for Chronic Disease Prevention and Health Promotion, Diabetes Public Health Resource, National diabetes fact Studies that include variations of this model are sheet, April 2005 currently under way. Examining the flexibility will 2. Mokdad AH, Bowman BA, Ford ES,Vinicor F,Marks JS, Koplan JP.The continuing epidemics of obesity and diabetes in the United States. JAMA. 2001;286:1195-1200. provide important insights into the applications of this 3. The Diabetes Control and Complications Trial/Epidemiology of Diabetes program to a variety of populations.Adding predictive Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive modeling to stratify the diabetics into appropriately Diabetes Treatment and Cardiovascular Disease in Patients with Type 1 Diabetes. N Engl J Med. 2005;353:2643-2653 targeted programs, excluding physician involvement, 4.The Diabetes Control and Complications Trial Research Group.The effect of intensive and expanding patient contact with outbound treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993; 329:977-986 communications are some of the variations that need 5. Menzin J, Langley-Hawthorne C, Friedman M, Boulanger L, Cavanaugh R. to be investigated. Potential short-term economic benefits of improved glycemic control: a managed care perspective. Diabetes Care. 2001;Jan.24(1):51-5. Advances in methods for collecting and storing data, 6. Grant RW,Buse JB, Meigs JB; University HealthSystem Consortium (UHC) Diabetes such as home monitoring equipment with wireless and Benchmarking Project Team.Quality of diabetes care in U.S. academic medical centers: low rates of medical regimen change. Diabetes Care. 2005;Feb.28(2):337-442. telecommunication capabilities linked to web-based 7. Centers for Disease Control and Prevention. National diabetes fact sheet: general personal electronic health records, will provide an information and national estimates on diabetes in the United States, 2003. Rev ed. Atlanta, Ga.: U.S. Department of Health and Human Services, Centers for Disease opportunity to put patients at the center of their Control and Prevention, 2004. healthcare delivery systems. Additional incentives 8. Mensing C, et al. National standards for diabetes self-management education. Diabetes Care. 2006; Jan. 29 (S1):S78-85. provided by the consumer-driven healthcare models in 9.Standards of medical care in diabetes–2006,American Diabetes Association. Diabetes which patients understand the health and cost Care. 2004;29(S1):S4-S42. 10. Norris SL, Lau J, Smith SJ, Schmid CH, and Engelgau MM. Self-management implications of their choices will impart even more education for adults with type 2 diabetes. Diabetes Care. 2002;25:1159-1171. control on the patient.The healthcare provider and the 11 Goudswaard AN, Stolk RP, Zuithoff NPA, de Valk HW, and Rutten GEHM. patient working as a team, with full transparency of Long-term effects of self-management education for patients with Type 2 diabetes taking maximal oral hypoglycemic therapy: a randomized trial in primary care. Diabet. practice standards, treatment goals, and therapeutic Med. 2004;21:491-496. options, could create a setting for unprecedented 12. Jackson CL, Bolen S, Brancati FL, Batts-Turner ML, Gary TL.A systematic review of interactive computer-assisted technology in diabetes care. Diabetes Care. 2005;20:01-06. quality-of-care improvements. 13. De Leo G, Krishna S, Boren S, Fato M, Porro I, Balas EA.Web and computer telephone-based diabetes education: Lessons learned from the development and use of a call center. Journal of Medical Systems. 29(4):343-355. Limitations 14. Ornstein SM, Jenkins RG, MacFarlane L, Glaser A, Snyder K, Gundrum T. This study has several limitations. It was a small Electronic medical records as tools for quality improvement in ambulatory practice: theory and a case study. Top Health Info Manage. 1998;19:35-43. group in one geographical area. The control 15. Committee on Data Standards for Patient Safety,Board on Services, population was not randomized, but rather self- Institute of Medicine. Key capabilities of an electronic health record system: Letter; Committee on Data Standards for Patient Safety. The National Academies Press, selected as nonparticipants, possibly introducing bias. Washington, D.C.; 2003. Other parameters, such as biometric data—weight, 16. O’Connor PJ, Crain AL, Rush WA, Sperl-Hillen JM, Gutenkauf JJ, Duncan JE. Impact of an electronic medical record on diabetes quality of care. Ann Fam Med. height, waist circumference—and medications were 2005;Jul-Aug3(4):300-6. not measured.The study was not designed to measure 17. National Heart, Lung, and Blood Institute. The seventh report of the Joint the impact on clinical outcomes or healthcare National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7); May 2003. expenditures. A single medical group provided the 18. National Heart, Lung, and Blood Institute. Third Report of the National medical care for this population.This allowed for easy Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III); September 2002. access to pertinent data, but is a situation that is not 19. Norris SL, Engelgau MM, Narayan KM. Effectiveness of self-management training reproducible for many other populations. in type 2 diabetes: a systematic review of randomized controlled trials. Diabetes Care. 2001; 24:561-587. 20. Diabetes Control and Complications Trial Research Group. Resource utilization Conclusion and costs of care in the Diabetes Control and Complications Trial. Diabetes Care.1995;18:1468-1478. A web-based diabetes education and goal-setting 21 Eastman RC, Javitt JC, Herman WH,et al. Model of complications of NIDDM, program, which focused on patient empowerment II: Analysis of the health benefits and cost-effectiveness of treating NIDDM with the goal of normo-glycemia. Diabetes Care. 1997;20:735-744. and included personal electronic health records for 22. Shetty S, Secnik K, Oglesby AK. Relationship of glycemic control to total dia- laboratory data feedback, resulted in a significant betes-related costs for managed care health plan members with type 2 diabetes. J Manag Care Pharm. 2005 Sep;11(7):559-64. improvement of glycemic control and cholesterol 23.Gilmer TP,O’Connor PJ,Manning WG,Rush WA.The cost to health plans of poor reduction compared to a nonparticipant control glycemic control. Diabetes Care.1997;20:1847-1853.

16 Journal of Managed Care Medicine Vol. 9, No. 2 Evolving Treatments for Cardiometabolic Syndrome

Stephen Davis, MD, FRCP

Summary Forty-seven million adult Americans are estimated to have cardiometabolic syndrome. This syndrome greatly increases risk of developing both type 2 diabetes and cardiovascular disease. Current management typically treats each element of the constellation of cardiometabolic risk factors individually. Treatment of this syndrome is evolving to consideration of the patient as a whole and the probable cause—insulin resistance secondary to excess visceral fat.

Key Points • The number of Americans who have metabolic syndrome is much larger than the number who have diabetes. • Cardiometabolic syndrome increases risk of developing type 2 diabetes. • Cardiometabolic syndrome increases cardiovascular morbidity and mortality by three- to fourfold. • Cardiovascular risks factors in the patient with cardiometabolic syndrome should be addressed as a whole entity rather than individually.

AS DEFINED BY THE American Diabetes disease in the U.S. have gone down, deaths in patients Association, a normal fasting glucose is between 70 and with diabetes have increased.4 100 mg/dL.1 A fasting glucose between 100 and 126 mg/dl is impaired fasting glucose, or pre-diabetes.1 Cardiometabolic Risk Factors Forty million Americans have pre-diabetes. A fasting Cardiometabolic syndrome is a clustering of glucose greater than 126 or a random glucose of greater modifiable risk factors predisposing individuals to than 200 mg/dl on two separate occasions is diagnostic cardiovascular and metabolic disease (type 2 for diabetes.1 About 18.2 million people in the U.S. diabetes). These risk factors include elevated blood have diabetes of which 90 to 95 percent is type 2, and pressure, elevated triglycerides, low high-density the other 5 to 10 percent is type 1. People in the U.S. lipoprotein cholesterol (HDL-C),abdominal obesity, are converting from pre-diabetes to diabetes at the rate inflammation, insulin resistance, and elevated blood of 11 percent a year.The fastest growing population of glucose. The criteria for identifying a patient with people with diabetes in this country are children.The metabolic syndrome are given in Exhibit 1.5,6 prevalence of type 2 diabetes in children has gone up Although there is controversy about cardiometabolic approximately a thousandfold over the last 10 years. syndrome, most clinicians find it a useful designation One study demonstrating the important relationship for identifying patients at high risk of cardiovascular between glucose and health found that when disease and type 2 diabetes.7,8 It is important to look hemoglobin A1C (A1C) increases above 5 percent, the at the individual with high blood pressure, risk for cardiovascular disease increases.2 If the risk of dyslipidemia, and raised glucose as an entity, as macrovascular disease really begins when A1C increases opposed to focusing on blood pressure one year at an above 5 percent, then control of cardiovascular risk annual visit, blood glucose the next year, and lipids factors in the past has not been aggressive enough. the year after that. Current treatment guidelines for diabetes suggest a Cardiometabolic syndrome increases cardiovascular target A1C of less than 7 percent, which may not be morbidity, and also mortality, by three- to fourfold fully minimizing risk.3 Over the last two decades, while (see Exhibit 2).9 Approximately 47 million adult deaths secondary to cancer, stroke, and cardiovascular Americans have metabolic syndrome. As the U.S.

Journal of Managed Care Medicine Vol. 9, No. 2 17 population continues to gain weight, the number of Fat in the liver and muscle can also cause metabolic people estimated to have metabolic syndrome is dysfunction. The breakdown of stored triglycerides increasing every year. into its constituent, fatty acids of glycerol leads to The root cause of metabolic syndrome is insulin insulin resistance. Increased free fatty acids reduce resistance, which is most likely secondary to excess insulin signaling, signal transduction in muscle, and abdominal or visceral adipose tissue.Excess visceral fat change the metabolism of glucose. Free fatty acids are is accumulation of visceral adipose tissue defined as the cause of metabolic insulin-resistant muscle,which intra-abdominal fat bounded by parietal peritoneum empowers fat cells to have major effects on muscle. or transversalis fascia. Subcutaneous fat is the other There is a clear, significant increase in cardiovascular major fat in the body. This is superficial to the (CV) death, myocardial infarction, and all-cause deaths, abdominal and back muscles. Visceral fat is more with increasing central adiposity.Waist circumference, metabolically active than subcutaneous fat, has greater as a marker of visceral fat and central adiposity, is endocrine activity,and causes greater adverse effect on directly related to CV death,MI,and type 2 diabetes;all metabolism and cardiovascular risk.10 Visceral fat has a cause mortality. As waist circumference increases, so greater ability to release cytokines and adipokines does the risk of each indicator (see Exhibit 3).11,12 Body than does subcutaneous fat. weight is also a predictor of disease.As body mass index

Exhibit 1: Diagnostic Criteria for Cardiometabolic Syndrome5,6 Presence of any three of five criteria constitute diagnosis of cardiometabolic syndrome

Measure Categorical Cut Points

>35 inches (88 cm) in women (>31 for Asian Americans) Elevated waist circumference >40 inches (102 cm) in men (>35 for Asian Americans)

Elevated triglycerides >150 mg/dl or drug treatment for elevated TG

<40 mg/dl in men, <50 mg/dl in women Reduced HDL-C or drug treatment for reduced HDL-C

>130 mm Hg systolic BP or >85 mm Hg diastolic BP Elevated BP or drug treatment for hypertension

>100 mg/dl Elevated fasting glucose or drug treatment for elevated glucose

Exhibit 2: Metabolic Syndrome Associated With Increased CV Morbidity and Mortality9

25 25 * *P<0.001 *P<0.001 20 20 ) * ) % (

% ( e

15 t 15 e a c R

n * y e l t i a l v 10 * a 10 t e r r o P * M 5 5 No metabolic syndrome

Metabolic syndrome 0 0 CHD MI Stroke All-Cause Cardiovascular Mortality Mortality

*Cardiovascular mortality was defined using ICD-9 (codes 390-459) before 1997 and ICD-10 (codes 100-199) thereafter.

18 Journal of Managed Care Medicine Vol. 9, No. 2 increases in men and women, type 2 diabetes, in bursts of 10 or 15 minutes at multiple times during gallstones, hypertension, and coronary artery disease the day,exercise adds up. Patients can get discouraged incidence increases dramatically.13 when told they need to exercise for long periods of time; breaking this into smaller chunks of time may Treatment of Cardiometabolic Syndrome make fitting exercise into daily life easier. Ultimately, Current therapies for cardiometabolic syndrome patients should get 60 to 120 minutes of physical often address individual cardiovascular disease risk activity five days a week to lose weight. factors instead of the root cause (see Exhibit 4). To Currently available pharmacotherapies for weight effectively manage cardiometabolic syndrome, it’s loss, orlistat (Xenical®) and sibutramine (Meridia®), can important to induce weight loss of between 5 and 10 percent over • Identify at-risk patients two years or more.14-16 However, drug-induced weight • Recommend a weight-loss diet loss with these agents tends to be only 4 to 9 pounds • Design an exercise plan greater than that produced by dietary changes alone.14 • Encourage behavior modification Despite this, in the XENDOS trial, the modest • Explore pharmacotherapy options. weight-loss difference from placebo produced by orlistat (6 pounds) reduced the incidence of diabetes Weight loss through dietary changes is important, by over a third. 17 Adverse effects such as blood pressure but visceral fat loss is also critical. Helping patients increases with sibutramine, and gastrointestinal issues make appropriate lifestyle changes to lose weight is a can complicate therapy in many patients. significant challenge for all of healthcare. An investigational agent being studied for weight Another important aspect of treatment is exercise. loss is rimonabant. This agent blocks the CB1 Whether taken in one 30- or 45- minute session, or receptor of the endocannabinoid system (ECS).The

Exhibit 3: Waist Circumference and CV Events11

1.4 Women <87

k Men <95 s i P=0.050 P=0.026 P=0.005 R

e

v 1.2 i

t Women 87-98 a l Men 95-103 e R

d e

t 1.0

s Women >98 u j Men >105 d A

0.8 CVD Death MI All-Cause Deaths

Exhibit 4: Current Therapies Often Address Individual Risk Factors Instead of a Root Cause

NCEP-ATP III Waist circumference Antiobesity agents definition of the metabolic syndrome Blood pressure Antihypertensives

Blood glucose Oral antidiabetic agents

Triglycerides

HDL-cholesterol Lipid modifiers

LDL-cholesterol

Insulin resistance Insulin sensitizers

Thrombotic risk Antiplatelet agents

Inflammatory markers ?

Journal of Managed Care Medicine Vol. 9, No. 2 19 ECS is a physiologic neuromodulatory signaling occurs when therapy is stopped. The most common system that plays a role in a number of physiologic adverse effect is a transient self-limiting increase in GI processes. Increased ECS activity is associated with side effects, which goes away after two to three weeks. excessive food intake.18 Effective weight loss likely requires combination Four weight-loss trials have been conducted with medication therapy and lifestyle changes, as has proven rimonabant.19-23 Overall,this agent produces a significant the case in successfully treating hypertension or type 2 reduction in waist circumference and weight, and diabetes. It’s unlikely that one drug will result in a 50- significant improvement in metabolic profile (decreased pound weight loss by the patient,but it may well be that triglycerides, increased HDL-C, and improved insulin a combination of two or three will be effective. sensitivity).The trials found significant decreases in the Bariatric surgery, while effective for weight loss and presence of cardiometabolic syndrome in patients altering metabolic risk factors, has typically been treated with rimonabant (see Exhibit 5). Efficacy has utilized as a last-resort option.This is primarily because been maintained in the trials for up to two years of of the expense, potential for significant adverse effects, therapy. Like all weight-loss medications, weight regain and limitations on third-party coverage.

Exhibit 5: Reduction in Metabolic Syndrome

ITT population RIO North America RIO Europe RIO Lipids RIO North America (2 Years) 0 ) % (

e -10 m o

r -8% -8% d n

y -20 s

c i l -21% -21% o

b -30 a t e m

n -40

i -35%

n -39% P < 0.001 o i t P < 0.001 c -50 u d

e -51% R -60 -53% P < 0.001 P < 0.001 Placebo Rimonabant 20 mg

Exhibit 6: Emerging Paradigms in Type 2 Diabetes Prevention in the DPP Study24

40 Overall Risk Reduction: Placebo • 58% Lifestyle 11% per year ) • 31% Metformin %

( Metformin 30 e

c 7.8% per year* n e d i Lifestyle c n

I 20 4.8% per year*

e v i t a l u

m 10 u C *P<0.001 vs. placebo 0 0 1 234

Years from Randomization

20 Journal of Managed Care Medicine Vol. 9, No. 2 Preventing Conversion From risk factors found in the patient with cardiometabolic Pre-Diabetes to Diabetes syndrome, better patient outcomes will result. JMCM Research from multiple prevention studies of type 2 diabetes has been published in recent years. An Stephen Davis, MD, FRCP, is chief of the Division of Diabetes, important point to note about earlier studies is that they Endocrinology and Metabolism at Vanderbilt University in Nashville, and have not focused on prevention but on delaying disease is the associate director of two NIH-funded programs at Vanderbilt: the Diabetes Research and Training Center and the General Clinical Research development. Within the next five years, many of the Center. He also serves as the Rudolph Kampmeir Professor of Medicine medications currently used to treat type 2 diabetes and and Professor of Molecular Physiology and Biophysics at the University various cardiovascular risks (i.e., angiotensin converting School of Medicine. enzyme inhibitors) likely will show indications for pre- diabetes treatment as well. References 1.American Diabetes Association. Diagnosis and Classification of Diabetes Mellitus. One of the largest trials was the Diabetes Prevention Diabetes Care. 2005;28:S37-42. Program (DPP) conducted by the National Institutes 2. Khaw KT,Wareham N, Luben R, Bingham S, Oakes S,Welch A, Day N. Glycated 24 hemoglobin,diabetes,and mortality in men in Norfolk cohort of European prospective of Health. This study enrolled individuals with investigation of cancer and nutrition (EPIC-Norfolk). BMJ. 2001;322:15-1 8. impaired glucose tolerance and randomized them to 3. American Diabetes Association. Standards of Medical Care in Diabetes. Diabetes Care. 2005; 28:S4-36. lifestyle modifications or metformin. With dietary 4. McKinlay J, Marceau L. US public health and the 21st century: Diabetes mellitus. changes and exercise for 30 minutes per day for five Lancet. 2000;356:757-761. 5. Grundy SM et al.American Heart Association; National Heart, Lung, and Blood days per week, the subjects in the lifestyle modification Institute. Diagnosis and management of the metabolic syndrome. An American group lost an average of 7 percent of their starting Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. weight. 24 With lifestyle changes, the progression from Executive Summary. Circulation. 2005;112:2735-2752. 6. Third report of the National Cholesterol Education Program (NCEP) Expert pre-diabetes to diabetes was reduced by 58 percent (see Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults Exhibit 6). Metformin reduced the progression from (Adult Treatment Panel III). Final report. Circulation. 2002;106:3143-3421. 7. Kahn R, Buse J, Ferrannin E, Stern M.The metabolic syndrome:Time for a critical pre-diabetes to diabetes by about one-third. appraisal. Diabetes Care. 2005:28:2289-2304. Exenatide (Byetta®), a new antidiabetic agent, is a 8. Zimmet PZ,Alberti G.The metabolic syndrome: Perhaps an etiologic mystery but far from a myth—where does the International Diabetes Federation stand? Medscape glucagon-like peptide 1 (GLP-1) analogue that is 53 Diabetes & Endocrinology 2005:7.Available at www.medscape.com. percent analogous with human GLP-1. GLP-1 slows 9.Isomaa B et al. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care. 2001;24:683-689. down gastric emptying. It antagonizes the effect of 10.Wajchenberg BL. Subcutaneous and visceral adipose tissue: their relation to the glucagon on glucose production.Thus, it lowers glucose metabolic syndrome. Endocr Rev. 2000;21:697-738. production, decreases appetite and, in animal models, 11.Dagenais GR,Yi Q, Mann JF, Bosch J, Pogue J,Yusuf S. Prognostic impact of body weight and abdominal obesity in women and men with cardiovascular disease. 25 increases pancreatic beta cells. Exenatide is injected Am Heart J. 2005;149:54-60. twice a day. Many patients experience a profound 12. Carey VJ et al.Body fat distribution and risk of non-insulin-dependent diabetes 26 ® mellitus in women.The Nurses’ Health Study. Am J Epidemiol. 1997;145:614-619. weight loss of 13 to 26 lbs. Pramlintide (Smylin ) is 13.Willett WC, Dietz WH, Colditz GA. Guidelines for healthy weight. N Engl J another new antidiabetic agent that is an amylin analog. Med. 1999;341:427-34. 14. Halford JC. Pharmacotherapy for obesity. Appetite. 2006;46:6-10. Amylin is co-secreted with insulin. When a patient is 15. Sibutramine (Meridia®) package insert.Abbott Pharmaceuticals. North Chicago, insulin deficient, amylin goes down. Pramlintide is Ill.,August 2005. 16. Orlistat (Xenical®) package insert. Roche. Nutley,N.J., January 2005. similar to exenatide in that it slows gastric emptying and 17. Torgerson JS, Hauptman J, Boldrin MN, and Sjostrom L. Xenical in the decreases appetite. It does not have any effect on beta prevention of diabetes in obese subjects (XENDOS) study:A randomized study of cells nor does it produce as much weight loss as orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diabetes Care. 2004;27:155-161. exenatide. Patients can lose 4 to 7 pounds when treated 18. Pagotto U, Vicennati V, Pasquali R. The endocannabinoid system and the with pramlintide.27 Exenatide and pramlintide, like treatment of obesity. Ann Med. 2005;37:270-275. 19.Van Gaal LF,Rissanen AM, Scheen AJ, Zeigler O, Rossner S, RIO-Europe Study other antidiabetic agents, may have a role in preventing Group.Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction the conversion from pre-diabetes to diabetes mellitus. and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet. 2005;365:1389-1397. 20.Van Gaal LF.Metabolic effects of rimonabant in overweight/obese patients:2-year Conclusion data from RIO-Europe. Late-breaking Clinical Trials II, American College of Cardiology 54th Annual Scientific Session, March 5-9, 2005, Orlando Fla. Despite extensive advances in cardiovascular risk 21. Pi-Sunyer FX. Effect of rimonabant on weight reduction and weight maintenance: management,patients are still experiencing cardiovascular RIO-North America (RIO-NA) trial. Late-breaking Clinical Trials III, American events and developing type 2 diabetes.Cardiometabolic Heart Association Scientific Sessions 2004, Nov. 7-12, 2004, New Orleans, La. 22. Scheen A. Late-breaking abstracts. Program and abstracts of the 65th Scientific syndrome is a significant problem that increases risk of Sessions of the American Diabetes Association, June 10-14, 2005; San Diego, Calif. cardiovascular events and type 2 diabetes. Current 23. Despres JP,Golay A, Sjostrom L, Rimonabant in Obesity-Lipids Study Group. Effects of rimonabant on metabolic risk factors in overweight patients with treatment paradigms tend to treat only a single dyslipidemia. N Engl J Med. 2005:353:2121-2134. element of the constellation of cardiometabolic 24. Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. NEJM. 2002;346:393-403. syndrome risk factors. New therapeutic advances 25. Exenatide (Byetta®) package insert. Amylin Pharmaceuticals Inc. San Diego, combined with lifestyle changes reduce Calif.,April 2005. 26. Keating GM. Exenatide. Drugs. 2005;65:1681-1692. cardiometabolic risk factors and offer sustained 27. Pramlintide (Symlin®) package insert.Amylin Pharmaceuticals Inc. San Diego, health benefits. By reducing all of the cardiovascular Calif.,April 2005.

Journal of Managed Care Medicine Vol. 9, No. 2 21 Management of Non-ST Segment Elevation Acute Coronary Syndrome: The Managed Care Perspective

Jay Johnson, MD, FACC A CME version of this article is available at www.namcp.org/cmeonline.htm.

Summary Issues in managing Non-ST Segment Elevation Acute Coronary Syndrome (NSTE-ACS) were discussed at the NAMCP Fall Managed Care Forum in 2005. Central to this discussion were the American Heart Association/American College of Cardiology (AHA/ACC) treatment guidelines.

Key Points • ACS is common and costly to the healthcare system. • The ACC/AHA guidelines can help steer appropriate treatment and cost-effec- tive management. • Managed care has significant opportunities to have an impact on the care of ACS patients by ensuring physician compliance with treatment guidelines, and by ensuring appropriate patient management and education to prevent or reduce morbidity and mortality.

ATHEROTHROMBOSIS, defined as ischemic was $393.5 billion (see Exhibit 3).1 Approximately $249 heart disease and cerebrovascular disease, is the leading billion of direct costs are attributable to hospitalization, cause of death worldwide, exceeding deaths from health professionals, medication, nursing homes, etc. AIDS, cancer, or infectious disease (see Exhibit 1). Indirect costs of CHD are estimated at $144.5 billion. More than 500,000 deaths related to cardiovascular disease occur annually in the United States,1 Educational Issues accounting for one of every 2.6 deaths. About 1.1 Healthcare providers stand to benefit from additional million Americans will have a new or recurrent education on ACS and its appropriate treatment. Many coronary event each year, and about 45 percent will are not aware of the seriousness and risks of ACS. In die. Approximately 2.2 million hospitalizations for addition to a high rate of in- ischemic episodes ACS occur every year in the U.S. (see Exhibit 2).1 and in-hospital MI or recurrent MI, patients with ACS Acute coronary syndrome includes stable angina, have a high long-term mortality rate.Events such as MI unstable angina, non-ST elevation myocardial and death occur most often during the first year after an infarction (NSTEMI),and ST elevation MI (STEMI).2 episode of ACS.2 Managed care has an opportunity to The prevalence of individuals living with a history increase awareness of the significance of ACS. of MI, angina, or both, is skyrocketing, partly due to Atherosclerosis and its consequences is also a significant successful treatment. As the healthcare profession preventive health issue. Lifestyle changes and various effectively treats cardiovascular disease, extending medications can reduce the long-term consequences lives and getting people through the acute phase of a of atherosclerosis. Physicians and providers can heart attack, the prevalence rises correspondingly. encourage patients to seek additional education and In addition to causing significant morbidity and offer assistance with complying with prevention rec- mortality,the economic impact of coronary heart disease ommendations such as smoking cessation, antiplatelet is equally staggering. In 2005, the estimated total cost therapy, dietary changes, and exercise.

22 Journal of Managed Care Medicine Vol. 9, No. 2 Exhibit 1: Atherothrombosis* Is the Leading Cause of Death Wordwide1

Pulmonary Disease 6.3

Injuries 9

AIDS 9.7

Cancer 12.6

Infectious Disease 19.3

Atherothrombosis* 22.3

0 5 10 15 20 25 30

Causes of Mortality (%)

*Atherothrombosis defined as ischemic heart disease and cerebrovascular disease. 1 The World Health Report 2001. Geneva: WHO:2001. Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org.

Exhibit 2: Hospitalizations in the U.S. Due to Atherosclerotic Disease

Vascular Disease

3.2 Million Hospital Admissions

Acute Myocardial Other Ischemic Cerebrovascular Disease Coronary Atherosclerosis Infarction Heart Disease

961,000 Admissions 1,153,000 Admissions 829,000 Admissions 280,000 Admissions

From Popovic JR, Mall MJ. Advance Data. 2001;319:1-20. Slide produced with permission from Cannon CP. Atherothrombosis slide compendium.

Exhibit 3: Coronary Heart Disease Economic Impact in the U.S.

2005 Estimated Total Cost = $393.5 billion

Direct Cost Indirect Cost • Hospital/nursing home $249 billion • Loss of productivity • Medication • Home health/other $144.5 billion medical durables • Physicians/other professionals

American Heart Association. 2005 Heart and Stroke Statistical Update.

Journal of Managed Care Medicine Vol. 9, No. 2 23 Treatment Guidelines for NTSE-ACS procedure.2 At least two studies, TIMI 11b and The ACC and AHA have developed guidelines ESSENCE, have shown enoxaparin, a LMWH, to for treatment and appropriate disease management reduce adverse cardiovascular events more than of various cardiovascular diseases. The guidelines UFH.2 A major advantage of LMWHs is that they are regularly updated and are evidence-based. do not usually require the same laboratory Recommendations are divided into the customary monitoring of activity required when UFH is used. ACC/AHA classifications of I, II, and III evidence. Combination antiplatelet therapy with aspirin Class I recommendations have the most consistent and clopidogrel (Plavix®) is recommended for nine evidence supporting their use. The most recent months after NTSE ACS. Aspirin, if tolerated, version of each guideline is available at www.acc.org. should be continued indefinitely after the end of The prevalence of ACS ensures that many nine months. Clopidogrel is an alternative for healthcare providers who are not cardiovascular long-term treatment in cases of aspirin intolerance specialists will encounter patients with NSTE-MI or resistance. in the course of the treatment of other diseases. 2 It is estimated that 40 percent of patients are aspirin This is especially true in outpatient and emergency nonresponders. Identifying these nonresponders who department settings. possibly should be on more expensive antiplatelet The optimal management of NSTE-ACS has twin therapy, primarily clopidogrel, is not currently goals of immediate relief of ischemia and the standardized. Tests to assess platelet function and prevention of serious adverse outcomes (i.e., death or effectiveness of antiplatelet agents are not widely MI).2 This is best accomplished with a combination used. In clinical practice, many times patients having of anti-ischemic therapy, antiplatelet and a repeat angioplasty or repeat acute coronary antithrombotic therapy, ongoing risk stratification, syndrome who are already on aspirin and other and the use of invasive procedures such as appropriate therapies such as beta blockers and percutaneous coronary intervention (PCI) and angiotensin converting enzyme inhibitors are coronary artery bypass graft (CABG).2 The medical considered aspirin failures and are placed on management recommendations for NTSE-ACS are clopidogrel therapy. summarized in Exhibit 4. Evidence for clopidogrel effectiveness in NSTE Antithrombotic therapy is essential to modify the ACS comes from the CURE trial (see Exhibit 5). ACS disease process and its progression to death, This study compared aspirin plus placebo versus MI, or recurrent MI. A combination of aspirin, aspirin plus clopidogrel up to 12 months after an unfractionated heparin (UFH) or low molecular ACS event. Cardiovascular death, MI, or stroke weight heparin (LMWH), and a platelet GP IIb/IIIa occurred in 11.5 percent of patients assigned to receptor antagonist represents the most effective aspirin plus placebo, and 9.3 percent assigned to therapy.2 The intensity of treatment is tailored to aspirin plus clopidogrel.3 In addition, clopidogrel use individual risk. For example, triple antithrombotic was associated with significant reduction in the rate treatment is used in patients with continuing of in-hospital severe ischemia and revascularization, ischemia or with other high-risk features and in as well as the need for thrombolytic therapy or patients who will be undergoing an early invasive intravenous GP IIb/IIIa receptor antagonists.

Exhibit 4: ACC/AHA Recommendations for In-Hospital Treatment of Patients With NSTE-ACS2

General Management Anti-ischemic Therapy Antiplatelet Therapy Antithrombin Therapy

• Bed rest • Nitroglycerin • Aspirin • Subcutaneous LMWH • Continuous ECG • Beta-blockers • Clopidogrel (Plavix®) or IV UFH monitoring • GP IIb/IIIa inhibitor • Supplemental oxygen [abciximab (ReoPro), ® • IV morphine as needed eptifibatide (Integrilin ), ® for pain, anxiety, tirofiban (Aggrastat )] and/or HF • ACEI for persistent hypertension with LV systolic dysfunction or HF

ECG (electrocardiogram); HF (heart failure); ACEI (angiotensin converting enzyme inhibitor); LV (left ventricular); LMWH (low molecular weight heparin); UFH (unfractioned heparin)

24 Journal of Managed Care Medicine Vol. 9, No. 2 Exhibit 5: The Primary Composite End Point in the CURE Trial

14 20% RRR 12 Placebo + Aspirin P < 0.00009 10 t n

e Clopidogrel + Aspirin v 8 E

h t i 6 W

% 4

2

0 036912 Follow-up (months)

Reproduced with permission from Yusef S, Zhao F, Mehta SR et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N. Engl J Med. 2001;345:494-502. Copyright© 2001. Massachusetts Medical Society. All rights reserved.

Exhibit 6: ACC/AHA Recommendations for Long-Term Medical Therapy in Patients With NSTE-ACS2

• Instructions on smoking cessation, weight, * Combined aspirin + clopidogrel for nine months after NSTE-ACS then, diet, and exercise aspirin or clopidogrel when aspirin is not tolerated.

• Antiplatelet therapy* NSTE-ACS (non-ST segment elevation acute coronary syndrome) • Beta blockers, unless contraindicated LDL-C (low-density lipoprotein cholesterol) HDL-C (high density lipoprotein cholesterol) • Lipid-lowering agents and diet if LDL-C >100 mg/dL ACEI (angiotensin converting enzyme inhibitor) • Niacin or fibrate if HDL-C <40 mg/dl HF (heart failure) LV (left ventricular) • Blood pressure <130/85 mm Hg EF (ejection fraction) • ACEI for patients with HF, LV dysfunction (EF <40%), TG (triglycerides) hypertension, or diabetes • Tight glycemic control in diabetics

Managed Care Opportunities ABCDE (aspirin and antianginals, beta-blockers and Because of the significant morbidity, mortality, and blood pressure, cholesterol and cigarettes, diet and dia- costs of ACS, the treatment guidelines provide a frame- betes, and education and exercise) helps clinicians work for many managed care interventions.Those may remember all of the issues that should be addressed.2 include drug utilization reviews or provider profiling. Overall,ACS results in significant costs to the health- An example intervention might entail identifying care system and takes patients’ lives. Managed care has patients who are frequently hospitalized for ACS and significant opportunities to impact the care of ACS placing them within a disease management program patients.The possible managed care strategies to prevent that includes education, interventions to maximize or reduce morbidity and mortality are numerous. JMCM appropriate therapy to prevent subsequent hospitalizations, and patient and provider support. Jay A. Johnson, MD, FACC, is an attending staff physician with Stanford Another example may be examining cost-effective use University Medical Center and chief medical officer for WorldDoc Inc., an of antiplatelet therapy. Ensuring patients receive appro- online consumer education and decision-support service based in Las Vegas. priate length of combination antiplatelet therapy after an episode of NTSE ACS could be another intervention. References 1. American Heart Association. 2005 Heart and Stroke Statistical Update. Dallas, To prevent re-hospitalization, death, and MI, the Texas: American Heart Association. 2005. Available at www.americanheart.org. ACC/AHA guidelines provide some recommenda- Accessed Dec. 5, 2005. 2.Braunwald et al.ACC/AHA 2002 Guideline Update for the Management of Patients tions for hospital discharge therapeutic strategies (see With Unstable Angina and Non-ST-Segment Elevation Myocardial Infarction.Available Exhibit 6).2 The selection of a medical regimen is indi- at www.acc.org/clinical/guidelines/unstable/update_index.htm.Accessed Dec.5,2005. 3.Yusuf S, Zhao F,Mehta SR et al. Effects of clopidogrel in addition to aspirin in vidualized to the specific needs of the patients based on patients with acute coronary syndromes without ST-segment elevation. N Engl J in-hospital issues and procedures. The mnemonic Med 2001;345:494-502.

Journal of Managed Care Medicine Vol. 9, No. 2 25 ( %,0).' 0 %/0,% , )6% 7)4( . %52/,/')#!, $ )3%!3%3

!T 4EVA .EUROSCIENCE OUR INSPIRATION TO ACHIEVE COMES FROM KNOWING WE HELP PEOPLE WHO LIVE WITH NEUROLOGICAL DISEASES 7E FIRST MADE THAT HAPPEN IN MULTIPLE SCLEROSIS -3 AND TODAY WE ARE EXPANDING OUR REACH WITH A VISION TO BE THE .ORTH !MERICAN LEADER IN NEUROLOGY THROUGH THE QUALITY OF OUR PEOPLE OUR PRODUCTS AND OUR FOCUS ON THE PATIENT %ACH HAS A CRITICAL ROLE BUT THE PATIENT IS AT THE CENTER OF EVERYTHING WE DO 7E ARE COMMITTED n THROUGH OUR OWN RESEARCH AND BY SUPPORTING OTHER ORGANIZATIONS n TO CONTINUETOIMPROVE TREATMENT FOR -3 AND OTHER NEUROLOGICAL DISEASES WITH THE ULTIMATE GOAL OF FINDING A CURE

        WWWSHAREDSOLUTIONSCOM WWWPARKINSONSHEALTHCOM WWWTEVANEUROSCIENCECOM Biotechnology Faces Cost Challenges in Consumer-Driven Healthcare Environment

Tom Morrow, MD

Summary The biggest threat to biotechnology is not competition, but rather benefit design and managed care processes. Particularly for costly medications, the health industry is rapidly shifting costs to individual consumers. Consumer- driven healthcare has many potential advantages and disadvantages. Given the issues seen with consumer-driven retirement savings, the success or failure of having the inexperienced individual determine where to spend healthcare dollars cannot be predicted. Consumer-driven healthcare is an experiment that is going to create a tremendous change in the environment for biotechnology-derived products, in particular because of their incredible cost, but also for all of medicine.

Key Points • Consumer-driven healthcare is going to radically affect the biotechnology industry and dramatically change the face of the healthcare insurance industry. • Consumers, not the employer or insurance provider, will determine how and where to spend their healthcare allotments. • Healthcare value has a different definition for consumers and payers. • Education of consumers on how to make appropriate choices in both choosing a plan and spending their healthcare dollars is lacking.

ONE OF THE BIGGEST challenges to the U.S. Project has identified the 3.1 billion bases of human healthcare system, and especially the biotechnology DNA, and in a matter of decades healthcare and the industry, in the next few years will be the dramatic healthcare insurance industry will be utterly change in the way healthcare benefits are designed. transformed.The history books will mark 2000 as the The biggest threat to this industry is not ceremonial start of the Genomic Era. competition—it is benefit design. Managed care processes are going to be put into place that may Changing Costs of Therapy change the availability of incredible advances in Currently, there are medications that routinely cost therapies and diagnostics to the end user. Actual use $20,000 to $30,000 annually.Diseases, such as psoriasis, of major scientific advances may be limited by a that previously were treated with a $500-per-year benefit design that is being thrown into place because medication, are now treated with a $20,000-per-year managed care cannot identify any other way to deal biotechnology-derived medication. Basic therapies for with the costs related to the issue of biotechnology. common chronic diseases, such as osteoporosis, are After more than a decade, the Human Genome costing nearly as much as what some people pay for

Journal of Managed Care Medicine Vol. 9, No. 2 27 monthly rent ($500 or more).These overall increases directly affects the patient, but the patient has no in the costs of therapy are driving a cost shift to influence in the decision. With the rise of consumers by payers. consumerism,that decision is soon going to be made at the patient level. If decision-makers for payers need a Trends in Healthcare Delivery large amount of information and science to determine Some of the major trends within the healthcare value and coverage, the patient is going to require delivery systems that are going to affect the significant education to make an informed decision. biotechnology industry are listed in Exhibit 1. A degree of conservatism exists among payers when Supply creates its own demand with technology it comes to approving new technologies.For example, advances. When a new medical device, medication, even when potential value can be demonstrated, a biotechnology product, surgical therapy, or test payer may choose not to pay for a new advance such enters the market, there is an immediate demand by as a genetic test because the payer fears opening the the public for more information, access, and, door to paying for additional costly tests. ultimately, payment for these services.Technology is Currently, the trend among healthcare payers is to breeding a tremendous demand. shift increases in cost onto the consumer.Very soon, the When the economics of a new technology are consumer will be the first insurer.The consumer as first examined, the value equation for consumers is equal to insurer is most evident in the “doughnut hole” or gap whatever they define as quality. Quality could be in coverage that rapidly increases in size under the new something they saw in an ad, something their physician Medicare Modernization Act. Employed members of told them about, or something they hope will yield a the general public are increasingly becoming the first positive outcome. But that’s only part of the formula for insurer, and that changes everything. For the practicing the typical consumer who has insurance and is paying a physician, it changes the way a consumer or a patient is $10 or $20 co-pay. The value equation is a different approached with the choice of a test or a therapy.Drug equation for the purchaser.The purchaser’s equation is manufacturers no longer will be negotiating contracts quality divided by cost.The cost then becomes the main to get on a formulary. Instead, they will be evaluating factor in the equation (see Exhibit 2). whether the consumer is willing to pay the price of the Currently, biotechnology companies seeking to get product. Consumers will have increased say in how new products (whether a medication or test) used and their disease or condition is treated.The consumer also reimbursed is to contract with payers, demonstrating will have to evaluate whether to use scarce resources the value equation and the scientific data. The payer (i.e., out-of-pocket costs) for a treatment or test. makes the decision whether to cover a service that Consumers will be deciding which is most important: therapy or some other need in their lives.This will be a tremendous realignment of the economic incentives Exhibit 1: Healthcare 2006—The Issues from the payer and provider to the consumer. • Aging of America • Supply creates demand Consumer-Driven Healthcare • Quality-improvement principles Spiraling healthcare costs and consumer demand for • Cost greater flexibility are the reasons why many employers • Financing structure and payers are moving to consumer-driven healthcare, • 80:20 rule which is defined as a system where consumers, not the • Consumerism company or insurance provider, determine how and • Outcomes where to spend their healthcare allotments.1 The basic • Technology premise of consumer-driven healthcare is that if users • Shift to employers of the healthcare benefit see the true costs of a service, and they are given an incentive to help control these costs, overall healthcare costs will decline while quality Exhibit 2: What Is Value? care is maintained. Whether these outcomes will be achieved is not known. For Consumers: There are four main types of plans being used in Value = Quality (Perceived Outcomes) consumer-driven healthcare: • Fully Defined Contribution: The employee is For Purchasers: responsible for finding and purchasing individual Value = Quality (Outcomes) medical coverage. The employer provides funding Cost through either direct compensation or a voucher. • Tiered Networks:The employer offers employees a

28 Journal of Managed Care Medicine Vol. 9, No. 2 choice of medical plans,which include medical systems Unfortunately, 47 million uninsured Americans don’t of varying costs. have the opportunity to even participate in such plans • Menu-driven: Employers provide online unless they purchase coverage themselves. HSAs are a information to help employees customize their own hope for people, or a promise, but the reality is that benefit plan by selecting co-pays, deductibles, etc. consumer behavior does not necessarily follow what • Managed Competition:The employer provides a program designers plan. Retirement savings plans such subsidized basic medical plan with buy-up options. as IRA and 401K plans are a prime example. Plans can be from the same or multiple insurers. Consumer-driven health plans do have some • Health Savings Accounts (HSA):Current options advantages. They eliminate the automatic “no” to include medical savings accounts, flexible spending coverage that many insurers use as a standard answer. accounts, and health reimbursement arrangements. Consumer-driven plans allow choice, but at a cost. It Other options are still under Congressional is first-dollar coverage,but only if the dollars are in the consideration.1,2 bank.The U.S. experience with the retirement crisis, In mid-2005, 50,000 new HSAs were being opened where people have not saved sufficiently for their monthly. By the end of 2006, 73 percent of U.S. latter years, has shown that Americans are unlikely to employers are likely to offer HSAs.This does not mean save for their healthcare either. Consumer-driven that the majority of employees are going to be in healthcare forces consumers to budget, a requirement them, but the system will reach a point where they are that people with have not had to deal being offered by three-fourths of employers. At that with in the past.This tough reality may especially be point, the 80-20 rule will begin to take over.The 80 an issue for the currently healthy individual. Statistics percent of the people who are healthy and have fewer already show that consumer-driven plans initially than five or 10 claims per year are going to see these as attract the healthier, wealthier members who see this an advantage.The U.S. group insurance model where opportunity as money in the bank. the sick (20 percent) are paid for by the well (80 Over the years, managed care organizations (MCOs) percent) will start to dissolve. have adopted various strategies for dealing with rising Consumers who are already using HSAs are starting healthcare costs (see Exhibit 3). MCOs have years of to deposit tremendous sums in these accounts, but these experience with actuarial data to predict what will deposits are not necessarily by people who are going to happen to their premiums, but they do not have years need them on an immediate basis. The sums that are of experience to predict what is going to happen with going into these accounts will not even come close to consumer behavior under a consumer-driven plan. paying for some of the biologics, once deductibles and Managing biopharmaceuticals by MCOs will occur, co-pays start to rise. Just like the situation seen with the but it’s likely to take directions that no one expects. Medicare Part D coverage gap, out-of-pocket costs will Planning is essential—healthcare needs to create the increase for people with consumer-driven coverage. future in order to predict it. More and more insurers are getting into this arena Consumer-driven healthcare is an experiment that is because they see consumer flexibility as a trend that is going to create a tremendous change in the environment not going away. Health savings accounts have a lot of for biotechnology medications in particular, because promise because they do realign some of the incentives. of their incredible cost, but also for all of medicine.

Exhibit 3: MCO Strategies to Cope With Rising Healthcare Costs

Late 1990s 1970s Future Quality Management Programs • Educate PCP on appropriate • Disease management • Genetic testing referral patterns • Demand management • Then what? • et al. • Preventive health initiatives • Unpathed territory

PUNISH FACILITATE PREVENT SELF-ACCOUNTABLE

Case Management to • Benefit design Expedite D/C Hospitalizations • Consumerism • HSA 1990s 2002

Journal of Managed Care Medicine Vol. 9, No. 2 29 Market-based Approach to Payment Since the medical insurance industry began, Exhibit 4: Web Site Resources healthcare has been in a market-distorting payment • National Center for Policy Analysis system that has never actually used a market-based Consumer-Driven Health Care approach for medical care.That dynamic is changing http://cdhc.ncpa.org rapidly with the rise in consumer-driven healthcare. So far, there has not been a massive shift in the volume • Princeton Consultants white paper on but rather a massive shift in the number of payers consumer-driven healthcare and pharmacy benefits offering consumer-driven plans. As the next phase of www.princeton.com/pbm/pdfs/ medical payment for the non-Medicare age groups princetonCDHwhitepaper.pdf evolves, a market-based approach where the value equation is equal to some quality determination • National Health Information–Consumer Driven divided by cost will be seen.That is going to affect the Health Care newsletter ($329/year) biotechnology industry as well as the rest of medicine www.nhionline.net/products/cdh.htm for many years to come. Exhibit 4 lists resources for additional information. science of biotechnology will not be available to those Consumer Education people who may need it the most.The question for Under consumer-driven healthcare plans, the both the biotechnology industry and all other aspects consumer will be the king.The only problem is the of healthcare is how is consumer-driven healthcare average consumer is not informed regarding medical going to mesh with new technologies such as genetic care. There is nothing like Consumer Reports for testing and biotechnology medications? This is the healthcare decision-making. At this time, no major great unanswered question. JMCM payer (i.e., insurance companies, employers, or the government) is offering educational opportunities to Tom Morrow, MD, is president of the National Association of Managed help the consumer make informed healthcare Care Physicians and has more than 20 years’ experience as a managed care executive. He also has served as an NCQA surveyor overseeing decisions. Consumers, unfortunately, are left to fend disease management programs such as inflammatory arthritis, depression, for themselves. chronic pain syndrome, and multiple sclerosis, as well as common chronic diseases. Conclusion Trends in healthcare insurance, primarily propelled References by consumer-driven healthcare, are going to have a 1. Consumer Driven Health Care:The Changing Role Of The Patient. National Center for Policy Analysis publication.Available at http://cdhc.ncpa.org. huge impact on the biotechnology industry. A fear 2. Henley E. Consumer-directed health care: One step forward, two steps back? among many in healthcare is that the marvelous J Fam Pract. 2005;54(3):212-5.

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30 Journal of Managed Care Medicine Vol. 9, No. 2 Human Genome Project: Implications for Healthcare

Eric Green, MD

Summary The human genome project successfully identified the composition of human and some other species’ DNA. The next phase of genomics research is to begin identifying which DNA sequences are functional and what precisely the sequences code. The future of genomics is personalized medicine with improved diagnostics and treatment based on an individual’s genetic makeup.

Key Points • The Human Genome Project succeeded in decoding the human genome in April 2003. • A complete working knowledge of our genetic instruction book provides unprecedented information and opportunities for knowing the intricacies of human physiology, thereby advancing our understanding of human health and disease. • Now that the human genome has been sequenced, personalized diagnostics, preventive strategies, and medications are on the horizon.

THE 1990s WAS THE DECADE of genomic pivotal, time in the history of bio-medical research, revolution, with the centerpiece being a large with the completion of the human genome sequence international effort aimed at mapping and sequencing and the official end of the Human Genome Project. the human genome.1 Known as the Human Genome Project, this effort began in the fall of 1990 and was The Next Step in Genomics regarded by many as the Lewis and Clark expedition of The next great frontier in fundamental genomics is the 21st century. At its core, the Human Genome actually interpreting the human genome sequence.The Project sought to characterize, in essence, to de-code challenge is being able to determine the subset of bases the human body’s genome. The rationale for the that are active because not all base sequences are project was that a complete working knowledge of our functionally important. This work is being done by own genetic instruction book would provide comparative sequence analysis, which is based on unprecedented information and opportunities to know knowledge that sequences known to be common the intricacies of human physiology and also advance among species that are separated over very large our understanding of human health and disease. evolutionary distances are more likely to be functionally The project’s name was a misnomer, however, important; otherwise evolution would have changed because it was not limited to the study of human them. In essence, scientists are reviewing evolutionary DNA. It included unicellular organisms, such as changes for clues as to how the human genome actually common yeast, a fly, a nematode worm, and a functions. This process involves extracting sequencing mouse. A key goal of the Human Genome Project from human, mouse, and dog genomes and making was to characterize the genomes of these organisms comparisons via computer modeling. in order to provide detailed views of their genetic Genome comparisons have shown that humans and blueprints, and fundamental insights into unicellular, chimpanzees are 98 percent identical.The baboon and multi-cellular, mammalian, and human biology. human genome are less related.In comparing the human In April 2003, two years ahead of schedule, the genome to mouse, rat, cat, and dog genomes, some parts human genome was completely deduced. That date are very similar and other parts are not similar at all.The will forever be regarded as a monumental, perhaps opossum, duck-billed platypus, chicken, and fish

Journal of Managed Care Medicine Vol. 9, No. 2 31 genomes are far removed from the human genome.The eases have a genetic component (see Exhibit 2). Cystic similarities that do exist between the human genome fibrosis, for example, is a genetic disease with a small and the genomes of birds and fish, are found in exxons, environmental component. Even in diseases such as which are the part of the gene that code for protein. AIDS, in which environment is the predominant cause, By having all of these different species sequences there are relevant genetic underpinnings,especially with together for comparison,scientists can start to develop respect to morbidity and mortality. experimental and computational models that allow The purpose of the genome project was to give identification of functionally important sections of tools, technologies, and information so that geneticists, DNA (e.g., the section that turns on the cystic fibrosis clinicians, and biologists can begin to untangle the gene). Sequences that match among different species genetic components of a range of diseases.The genome are called multi-species conserved sequences, which project has delivered on that promise when it comes to are preserved during evolution. Researchers are rare genetic diseases. Individual single genes of rare looking for the 5 percent most conserved sequences diseases often are much easier to find than the multiple because only about 5 percent of our genome is small genetic defects that individually may not cause a thought to be functionally important (see Exhibit 1). disease but are a contributing factor. Obviously, it is These conserved sequences will then be characterized more difficult to determine which subtle genetic in the laboratory to determine their function. defects in which combinations cause disease.The major The National Institutes of Health has invested in contributing genes for many of the most common sequencing various animal genomes in order to diseases will be identified in the next five to 15 years gather additional clues as to how the human (see Exhibit 3).Whole genome association studies are a genome functions. NIH anticipates that a broader strategy that is being used to tease out the genetic understanding of how the human genome functions contributions of complex diseases. In the last couple of will ultimately shed light on human health and how years, a number of significant studies have begun gene alterations can actually lead to disease. identifying the genetic lesions that are associated with The Human Genome Project was originally con- complex diseases such as Crohn’s. ceived as a means of improving human health. A key part of this vision is being able to make the connections The Future of Genomics that are most relevant to humans. Buried in human Identifying the genetic cause of human disease is not genomes are outright alterations that lead to disease or the endpoint,but a new beginning.New tools and better at least predispose the body to disease.Virtually all dis- diagnostics will emerge so that preventive strategies can be implemented as well as better therapeutic strategies, be they gene therapy or personalized medication (see Exhibit 1: The Human Genome…by the Numbers Exhibit 4). New technologies in the clinical setting will ~5% of the Human Genome Is Functionally Important allow determination of DNA sequence data from • 5% of 3B bases = ~150M bases individual patients. In turn, clinicians will be better • Do not yet know the position of these ~150M equipped to predict susceptibility to certain diseases and functional bases determine medications that will work best for the ~1.5% Encodes for Protein (Genes) individual patient. In the future, genomic technologies • Corresponds to ~20-25K genes will be applied to perplexing problems in clinical • Many more than 25K different proteins medicine, and human genome will become increasingly ~3.5% Functional But Non-Coding relevant to practicing physicians. • Gene regulatory elements Pharmacogenomics is the idea of being able to • Chromosomal functional elements stratify individuals based on their genetic background • Undiscovered functional elements (not yet in textbooks) and thus being able to predict whether they’ll be good or bad responders to a particular medication. A recent

Exhibit 2: Virtually All Diseases Have a Genetic Component

Cystic Fibrosis Diabetes AIDS Environmental Contribution

Genetic Contribution

32 Journal of Managed Care Medicine Vol. 9, No. 2 article in the New England Journal of Medicine clearly Human Genome Project and ongoing studies, showed specific genetic alterations predicted exactly consult www.genome.gov. what the response was going to be to the drug warfarin.2 In thinking broadly about this particular area Conclusion of genomics and its relationship to health, science will The year 2003 will stand in history as a pivotal time by go from the most basic DNA sequence to predicting scientists and all of healthcare. Many aspects of medicine what are the best medications for individuals based on will change over the next decade and beyond.Advances their genetic profile, and also designing better in genomics are opening new opportunities for applying medications based on the intricacies of genetics. genetic information to diagnostics, risk prevention, and pharmacotherapy,thus ensuring better health outcomes, Other Issues drug efficacy,and safety in clinical practice. JMCM From its outset, the genome project invested 5 percent of its total budget in studying the ethical, Eric Green, MD, is scientific director of the National Human Genome legal, and social implications of genetic research. Research Institute (NHGRI) at the National Institutes of Health (NIH) in There are many issues in genomics that have to be Bethesda, Md. In addition, he serves as chief of the NHGRI’s Genome grappled with, including genetic discrimination. Technology Branch and director of the NIH Intramural Sequencing Center. Although there is much excitement that could be References capitalized on, the scientific community needs to 1. National Institutes of Health. National Human Genome Research Institute. be careful to properly utilize information gained Available at: www.genome.gov. 2. Rieder MJ, Reiner AP, Gage BF, Nickerson DA, Eby CS, McLeod HL, Blough from the project and to make sure that harm does DK, Thummel KE, Veenstra DL, Rettie AE. Effect of VKORC1 haplotypes on not occur. For additional information on the transcriptional regulation and warfarin dose. N Eng J Med. 2005;352:2285-93.

Exhibit 3: Top Ten Leading Causes of Mortality

3% Pneumonia 2% 3% Kidney 4% Alzheimer's 5% Diabetes 2% Injury Septicemia 6% Chronic Lower Respiratory 37% 9% Heart Disease Cerebrovascular

29% Cancer

The major contributing genes for many common diseases will be identified within the next five to 10 years.

Exhibit 4: The Start of Personalized Medicine

Diagnostics Accelerated by Human Genome Project • Gene Therapy • Drug Therapy Disease With Genetic Identify Gene • Pharmacogenetics Component

Therapeutic Preventive Developments Medicine

Time

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GILCO-149_Corp_Ad_SMCF.indd 1 3/21/06 2:45:36 PM TheWEDNESDAY, Changed Nature MAY of Physician/Hospital 3 Relationships (B2) 2:302:00 pm - 2:303:00 pmpm Herbert Mathewson, MD, Medical Director, Cape Cod Healthcare VNA Break and Networking with Exhibitors 5:30 pm - 7:00 pm Break Examine current conflicts in physician/hospital relationships with an Registration Information Desk Open 3:00 pm - 4:00 pm emphasis on the “businessification” of medicine and how physicians 2:30 pm - 3:30 pm perceive their “social” contracts with . ClinicalNew Trends Integration: in Health Step-by-Step Plan Medical (B) Management THURSDAY, MAY 4 JohnHow Harris,is medical MBA, management Director, DGA changing? Partners How will this affect you, your New7:00 Treatmentam - 4:30 in pm Bladder Control (C) Clinicalorganization integration and your can patients? propel your A must IPA/PHO attend! to a leading role in your MichaelRegistration Kennelly, Information MD, McKay Desk Open Urology and Ken Schaecher, MD, Medical market, but it’s not easy to achieve. Accordingly, this “how to” session Director, Intermountain Healthcare willContinuing focus on theEducation specific steps involved in developing a program that A7:00 survey am found- 8:00 that am one-third of Americans between the ages of 30 and withstandsThe Spring FTCManaged scrutiny. Care Forum has been planned and implemented 70Continental have experienced Breakfast some degree of bladder control loss. This presen- in accordance with the Essential Areas and Policies of the Accreditation tation will provide you with new treatments in bladder control. CouncilManaged for Care’s Continuing Concern Medicalwith the TreatmentEducation of (ACCME) Multiple Sclerosisthrough (C)the joint 8:00 am - 8:15 am 10:00 am - 10:30 am Tomsponsorship Morrow, of MD, the President,NAMCP, AAIHDS NAMCP and AAMCN. NAMCP is accred- Opening Remarks and Welcome Break and Networking with Exhibitors Inited continuing by the ACCME with the to presentationsponsor continuing on MS frommedical the educationFall Managed for Carephy- Doug Chaet, FACHE, Chairman, AAIHDS, Vice President, Managed Care, Forum,sicians. NAMCPthis will bedesignates a discussion this continuingon MS’s burden medical on educationmanaged care.activity 10:30Shands am Healthcare - 11:30 am for a maximum of 12.5 AMA PRA Category 1 Credits™. Physicians Provider Contracting and Conflict Theory (B1) should3:30 pm claim - 4:30 credit pm commensurate with the extent of their participa- MeritKeynote Smith, Address VP, Health Care Practice, Robert E. Nolan Company tionLegal in Issues the activity. Affecting Managed Care (B) John Marren, Managing Partner, Hogan Marren, Ltd. This8:15 provocativeam - 9:30 am presentation examines provider contracting and ap- The American Association of Managed Care Nurses (AAMCN) has been A timely update on hot topics such as messenger model limitations, pliesThe Future two strategic of Managed concepts Care and- asymmetrical Healthcare Delivery conflicts and decision loops. approved as a provider of continuing education by the Virginia Nurses physician incentive plans, antitrust concerns, “gain-sharing” legislation, APeter must Kongstvedt, attend presentation MD, Partner, for Healthall contract & Life negotiators. Sciences, Accenture Association (VNA) for the period of 1/31/04 to 12/31/06. VNA is ac- HIPAA implementation and the enforcement of prompt pay provisions. CreatingAn overview the Value of what You theNeed future to Succeed holds Withfrom aone Hospitalist of the nation’s Program leading (B2) credited as an approver of continuing education in nursing by the Tobyhealthcare Thomas, consultants. Chief Financial This presentationOfficer, Cogent will Healthcare, examine lessons Inc. learned, AmericanChanging Treatment Nurses Credentialing Paradigms: CardioCenter’s Metabolic Commission Risk Factors on Accreditation. (C) Hospitalistscurrent market can trends, play a andkey roleaddress in an opportunities integrated delivery for success. system. Ac- 15.0Current contact treatment hours paradigms will be awarded for obesity to nurses and cardiometabolic who complete syndromethis activ- cordingly, this presentation will focus on the proven elements of a ity. 9:30 am - 10:00 am treat each single element separately. This presentation will provide the successful hospitalist program, ways to measure performance and the Break and Networking with Exhibitors Thismost activityup to datehas beentreatment approved options by andthe Americandiscuss how Board to treat of Managed concur- key action steps involved. Carerently Nursingto improve for outcomes.15.0 contact hours towards CMCN recertification requirements. HypertensionGeneral Sessions and Dyslipidemia Risk Factors for Cardiovascular Disease (C) 4:30 pm - 5:30 pm 11:3010:00 am - 11:0012:30 ampm ParticipantsReception and of Networking this program with Exhibitorswishing to have the American College of ChronicProvider Inflammatory Preparation forDisease Pay for (C) Performance Healthcare Executives (ACHE) consider this program for Category II WithNeil Pressman, Rheumatoid MBA, Arthritis FACHE, as President, the example, Presscott this Associates presentation will ad- (non-ACHE)FRIDAY, MAY continuing 5 education credit should list their attendance An overview of operational implications for Pay for Performance pro- when applying for advancement or recertification in ACHE. dress the evolution of the inflammation process and how it originates to 7:00 am - 4:00 pm grams. Topics to be addressed include contract negotiation issues and cause a disease. Discussion will include what factors are present in the ABQAURPRegistration Informationdiplomates Deskcan Opennow use their non ABQAURP continuing suggested strategies for success in this new era. body and cells that lead to inflammation, the evolution over time, the education credits for their recertification. Please go to the website conditions11:00 am -as 12:00 we knownoon it, the abnormalities in the body needed to www.abqaurp.org7:00 am - 8:00 am and the application can be downloaded and printed arrestManaged and Medicare cure the 2006: disease Implications state, and forwhat Providers drugs are available in the fromContinental the home Breakfast page. marketplace. Participants will learn what parameters, allopathic and Patricia Smith, Director of Medicare Advantage Group, CMS AAMCN has applied for credits for recertification requirements of CPHQ, non allopathic, are necessary to effectively manage the patient to main- A comprehensive overview of what providers can expect from CMS CPURKeynote and AddressCPUM. tainover functionalitythe coming year.and productivity Topics to be and addressed the implications include Medicarein a managed Ad- 8:00 am - 9:00 am carevantage setting. Plans, Additionally, the Center’s we organizational will address what goals, other initiatives disease affecting states have pro- TheManaged Spring Care Managed and Disease Care Management:Forum has been Challenges approved and by Opportunities the Commis- this common path of inflammation, such as Crohns and ulcerative sion for Case Management Certification for 12.25 clock hours towards vider reimbursement and pertinent upcoming demonstration projects. Tom Morrow, MD, President, NAMCP colitis. CCM recertification. 12:00 noon - 1:00 pm A timely presentation/panel discussion addressing the relationship 12:30Lunch and pm Networking - 1:30 pm with Exhibitors between managed care and disease management (DM). Topics to be Lunch and Networking with Exhibitors addressed include the success and failure of DM programs to date, Concurrent Track Sessions (Business Track B/Clinical Track C) opportunities for success and the potential role of DM in an era of General1:00 pm - Sessions2:00 pm consumer-drivenhealthcare. 1:30Advanced pm -Managed 2:30 pm Care Contracting (B) CurrentJohn (Jack) Issues Wolf, in HIV CPA, Treatment FHFMA, and Vice the President Implications Strategic for Managed Planning, Care HCA (C) Concurrent Track Sessions (Business Track B/Clinical Track C) TrevorHealthcare-Eastern Hawkins, MD, Group Associate Clinical Professor, UNM, Medical Direc- 9:00 am - 10:00 am tor,Learn Southwest about strategies CARE Center for success from a seasoned healthcare executive Clinical Integration Panel Discussion (B1) Inwith the an United extensive States background alone, more in thanmanaged 1.1 million care contracting, people are infectedand the Mike Bond, MBA, CEO, PrimeCare and Sylvia Kundig, Attorney, Federal withcreation HIV. of Approximately realistic expectations 25% of thesefor all individualsparties involved. are unaware of their Trade Commission, Marty Thompson, JD, Attorney, Mannatt, Phelps & infection. We will discuss the current diagnosis, treatment and manage- Phillips Post MI Left Ventricle Disorder (C) ment of HIV and how to positively impact your patients and your An interactive panel discussion featuring FTC and IPA representatives Heart failure can lead to left ventricle disorder. This session will discuss organization. who have experience in the clinical integration arena. The panel’s post MI left ventricle disorder and the treatment of this progressive dis- emphasis will be on potentials pitfalls and lessons learned. ease. 12242_RlPhly_8125x10875_M1.qxp 3/24/06 1:24 PM Page 1

The immune system has many secrets. But not for long.

Centocor is a biomedicines company dedicated to unlocking the secrets of the immune system…whenever, wherever. With each secret solved, new therapies emerge that revolutionize the way we treat disease…and help give people back their lives. As long as there is disease, we will be pursuing cures. That’s why we are the Immunology Pioneers. www.centocor.com

© 2006, Centocor, Inc. GUIDE TO CONFERENCE SUPPORTERS

A&S Financial Services, Inc. cancer and gastrointestinal disorders, in Hoveround Corp. Since 1983, A&S Financial Services, Inc. addition to the areas of anesthesia, pain Hoveround Corp. is a manufacturer, dis- has been a leader in providing healthcare management, cardiovascular disease, tributor, and retailer of mobility products cost- containment services. A&S has respiratory, and central nervous system in the United States. Hoveround’s product developed a comprehensive national disorders. line includes power and custom power database that allows substantial savings wheelchairs and scooters. Services include on out-of-network physician and hospital CareAssist client assessment and evaluations of claims. A&S also specializes in fee CareAssist is a specialty focused NIC care mobility needs, product demonstrations, negotiation, bill audits, PBM audits, and consulting firm that specializes in neonatal delivery, set-up, and client education in database management, allowing care management, forensic audit, and their home environment of prescribed complete flexibility to meet all healthcare claims negotiation services. CareAssist and/or ordered mobility equipment. payer clients’ needs. believes that managing a neonatal case Hoveround offers direct, in-home cus- through collaborative, proactive care tomer service for all products provided. Access MediQuip management, and retrospective financial Founded in 1997, Access MediQuip is not management of claims results in optimal KCI only the first but also the leading national outcomes and significant cost containment. Kinetic Concepts, Inc. is a global medical provider of outsourced medical device technology company with leadership management to the healthcare industry. Centocor positions in advanced wound care and With expertise in pre-certification, delivery, Centocor is harnessing the power of world- therapeutic surfaces. We design, manu- and the claims process, Access functions as leading research and biomanufacturing to facture, market, and service a wide range a Device Benefit Manager™, providing deliver innovative biomedicines that of proprietary products, which includes value-added expertise and services. transform patients’ lives. The world leader in V.A.C.® technology, that can improve monoclonal antibody production and clinical outcomes while helping to reduce Allergan, Inc. technology, Centocor, Inc. is a wholly owned the overall cost of patient care. Allergan, Inc., with headquarters in subsidiary of Johnson & Johnson, a Irvine, Calif., is a global specialty phar- worldwide manufacturer of healthcare Maxim Healthcare Services maceutical company that develops and products. Maxim Intermittent Homecare is nationally commercializes innovative products for recognized as a leading provider of the eye care, neuromodulator, skin care, Considine & Associates homecare services. Our goal is to provide and other specialty markets. In addition Considine & Associates provides medical compassionate care that preserves to its discovery-to-development research review services to health, life, and disability patient dignity while helping to achieve programs, Allergan has global marketing insurers. Its primary focus is review of the highest degree of recovery, comfort, and sales capabilities in more than 100 medical claims for group health entities. A and independence. We specialize in pro- countries that deliver value to our cus- national panel of specialist physicians, viding continuous and intermittent skilled tomers, satisfy unmet medical needs, and encompassing more than 120 specialties, nursing services to both adult and pediatric improve people’s lives. reviews complex medical issues. Outpatient patients. To ensure effective clinical out- Driven by technology and innovation, facility bill review, hospital bill line-by-line comes, our staff works with the physician Allergan addresses the needs of consumers repricing, and physician bill review audit and the patient’s family to implement a around the world with more 5,000 are key areas. plan of care that promotes optimal support employees worldwide, four world-class and independence. research and development facilities, and Gilead Sciences, Inc. three state-of-the-art manufacturing plants. Gilead Sciences is a biopharmaceutical Medtronic Diabetes company that discovers, develops, and Medtronic Diabetes, a division of Ancillary Care Management commercializes innovative therapeutics in Medtronic, Inc., is a world leader in Ancillary Care Management markets a areas of unmet medical need. The insulin pump therapy and continuous complete solution linking participants in company’s mission is to advance the care glucose sensing. Diabetes management the ancillary benefits environment through of patients suffering from life-threatening technologies has been our sole pursuit a suite of web-based tools, accessible diseases worldwide. Headquartered in for more than 25 years in an effort to through www.ACMcentral.com. ACM Foster City, Calif., Gilead has operations in improve the lives of people with dia- covers 35+ million lives for the nation’s North America, Europe, and Australia. betes. Medtronic strives to contribute to largest payers, delivering the only human welfare by the application of comprehensive approach to managing GlaxoSmithKline biomedical engineering in the research, specialty pharmaceutical utilization, drug GlaxoSmithKline, one of the world’s design, manufacture, and sale of instru- therapy spend, and related patient care. leading research-based pharmaceutical ments and appliances that alleviate pain, companies, is committed to improving restore health, and extend life. AstraZeneca the quality of human life by enabling AstraZeneca produces a wide range of people to do more, feel better, and live MultiPlan products that make significant longer. To learn more about GSK, contact MultiPlan offers a broad range of solutions contributions to treatment options and your GSK account manager, visit us that help healthcare payers and providers patient care. The company has one of online at www.gsk.com, or call toll-free at partner together to combat rising health- the world’s leading portfolios to treat 888-825-5249. care costs. Founded in 1970, the company has a 35-year history of delivering medicines for humans and animals and Haemophilus influenzae type b, influenza, provider network and related cost-man- many of the world’s best-known consumer rabies, Japanese/encephalitis, typhoid agement solutions to the nation’s top brands. Our innovative, value-added fever, yellow fever, and meningococcal dis- insured and self-funded health plans. Our products improve the quality of life for ease. To learn more about our products, solutions help a conservatively estimated people around the world and help them visit our exhibit. 27 million Americans receive quality enjoy longer, healthier, and more productive healthcare, and equip both providers and lives. The company has three business Sepracor, Inc. payers with strategies for managing the segments: healthcare, animal health, and Sepracor, Inc. is a research-based pharma- financial risks associated with healthcare consumer healthcare. Our products are ceutical company dedicated to treating claims. MultiPlan serves a client roster of available in more than 150 countries. and preventing human disease through more than 2,000 healthcare payers repre- the discovery, development, and com- senting more than 30,000 groups, and a Purdue Pharma, L.P. mercialization of innovative phar- provider network of nearly 550,000 orga- As a privately held pharmaceutical com- maceutical products that are directed nizations. For additional information, visit pany founded by physicians, Purdue is toward serving unmet medical needs. www.multiplan.com. focused on the needs of patients. We are Sepracor’s drug development program dedicated to finding, developing, and has yielded an extensive portfolio of National Diabetic Pharmacies bringing to market new medicines and pharmaceutical compounds, including National Diabetic Pharmacies is dedicated related products that promote health candidates for the treatment of respiratory to delivering cost-effective programs that and healing. and central nervous system disorders. offer innovative solutions to healthcare Sepracor’s corporate headquarters is organizations, employer groups, and RCM Health Care Services located in Marlborough, Mass. unions, while empowering members to RCM Health Care Services offers outstand- improve their quality of life. National ing service and reliability with more than Teva Neurocience Diabetic Pharmacies’ programs are based 30 years of healthcare staffing experience. At Teva Neuroscience, our inspiration to on the promotion and support of opti- With offices nationwide, RCM specializes achieve comes from knowing we help mum self-care principles. The foundation in long-term and short-term staffing as well people who live with neurological diseases. on which these programs are built include as executive search and placement for the We first made that happen in multiple ongoing education, patient intervention, following fields: managed care, nursing, sclerosis (MS), and today we are expanding monitoring, and outstanding customer rehabilitation (PT, OT, and SLP), physicians, our reach with a vision to be the North responsiveness. allied healthcare, healthcare management, American leader in neurology through and medical office support. RCM has a the quality of our people, our products, On Assignment state-of-the-art computerized recruitment and our focus on the patient. Each has a On Assignment Healthcare Staffing is the system with a database of more than critical role, but the patient is at the center premier provider of nursing, allied, clinical 200,000 healthcare professionals to meet of everything we do. We are committed— lab, and administrative/clerical temporary all of its clients’ staffing needs. In addition, through our own research and by sup- professional employees. We provide the RCM is the proven national leader in for- porting other organizations—to continue highest quality healthcare professionals eign nurse and rehabilitation recruitment. to improve treatment for MS and other available. RCM has an extensive foreign talent bank neurological diseases with the ultimate compiled from its foreign recruitment goal of finding a cure. Otsuka America Pharmaceutical, Inc. offices in New York, New Jersey, Manila, Otsuka America Pharmaceutical, Inc. (OAPI) Jakarta, Korea, and Saudi Arabia. Wheelchair Professionals is a successful, innovative, fast-growing Wheelchair Professionals is one of the healthcare company that commercializes Sanofi-Aventis largest providers of basic mobility and Otsuka-discovered and other product The sanofi-aventis Group is the world’s custom rehab equipment in the country. opportunities in North America, with a third-largest pharmaceutical company, With more than 150 locations nationwide, strong focus on and commitment to neuro- ranking number one in Europe. Backed by our certified seating specialists help manage science, cardiovascular, and gastrointestinal a world-class R&D organization, sanofi- your cost-of-care through a unique, therapeutic treatments. OAPI is dedicated aventis is developing leading positions in formulary approach to product fulfill- to improving patients’ health and the quali- seven major therapeutic areas: cardiovas- ment. Our delivery model ensures that ty of human life. The company is part of the cular disease, thrombosis, oncology, your members receive medically appro- Otsuka Pharmaceutical Group, which is metabolic disorders, central nervous sys- priate, high-quality equipment in a rapid comprised of 81 companies and approxi- tem, internal medicine, and vaccines. The timeframe. Please stop by our booth to mately 26,000 people around the world. sanofi-aventis Group is listed on the stock learn how Wheelchair Professionals can With 39 consolidated subsidiaries, Otsuka exchanges in Paris (EURONEXT: SAN) and custom tailor a mobility benefits program earned US$6.2 billion in consolidated annu- New York (NYSE: SNY). to your organization. al revenues in fiscal 2004. For additional information, visit www.otsuka.com. Sanofi Pasteur Inc. Sanofi Pasteur Inc., the vaccines business of Pfizer Inc. sanofi aventis Group, provides pediatric, Pfizer Inc. discovers, develops, manufac- adult, and travel vaccines for diseases such tures, and markets leading prescription as diphtheria, tetanus, pertussis, polio,