Vol.15, No.4, 2012
Journal of Managed Care Medicine
CHIP Lifestyle Program at Vanderbilt University Demonstrates an Early ROI for a Diabetic Cohort in a Workplace Setting: A Case Study Updates in the Guidelines and Treatment of Hepatitis C Emerging Challenges on the Therapeutic Landscape of Multiple Sclerosis: The Managed Care Physician’s Perspective and Medical Director’s Perspective Clinical and Efficiency Benefits of New Oral Anticoagulants after THR/TKR Surgery Telehealth Program for Medicaid Patients with Type 2 Diabetes Lowers Hemoglobin A1c Multiple Myeloma: An Update on Current and Emerging Treatment Options New Developments in the Treatment of Castrate-Resistant Prostate Cancer Recent Breakthroughs in the Treatment of Metastatic Melanoma: Novel Immunologics Preventing Chemotherapy-Induced Nausea and Vomiting and Improving Quality of Life in Cancer Patients Impact on Health Plan Cancer Drug Costs in Different Delivery Models PLUS: Fall Managed Care Forum Program Guide
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JMCM Journal of Managed care medicine 4435 Waterfront Drive, Suite 101 Glen Allen, VA 23060 (804) 527-1905 fax (804) 747-5316
Editor-In-Chief
Journal of Managed Care Medicine The Official Journal of the National Association of Managed Care Physicians American Association of Integrated HealthCare Delivery Systems American College of Managed Care Medicine American Association of Managed Care Nurses A Peer-Reviewed Publication
Vol. 15, No. 4, 2012
J. Ronald Hunt, MD
publisher
TABLE OF CONTENTS
Katie Eads
director of communications Jeremy Williams
Journal management Douglas Murphy Communications Inc. P.O. Box 71895 Richmond, VA 23255-1895 (804) 658-4253 fax (703) 997-5842
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ISSN: 1094-1525. The Journal of Managed Care Medicine is published by Association Services Inc. Corporate and Circulation offices: 4435 Waterfront Drive, Suite 101, Glen Allen, VA 23060; Tel (804) 5271905; Fax (804) 747-5316. Editorial and Production offices: P.O. Box 71895, Richmond, VA 23255-1895; Tel (804) 387-7580; Fax (703) 997-5842. Advertising offices: Sloane Reed, 4435 Waterfront Drive Ste 101, Glen Allen, VA 23060 Tel (804) 527-1905, Fax (804) 747-5316. All rights reserved. Copyright 2012. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage or retrieval system, without written consent from the publisher. The publisher does not guarantee, either expressly or by implication, the factual accuracy of the articles and descriptions herein, nor does the publisher guarantee the accuracy of any views or opinions offered by the authors of said articles or descriptions. POSTMASTER: Send address changes to The Journal of Managed Care Medicine, 4435 Waterfront Drive, Suite 101, Glen Allen, VA 23060.
CHIP Lifestyle Program at Vanderbilt University Demonstrates an Early ROI for a Diabetic Cohort in a Workplace Setting: A Case Study Dexter Shurney MD, MBA, MPH; Sandra Hyde, MSPS; Kristina Hulsey, MSPS; Roy Elam, MD; Abby Cooper, MHIM; Jay Groves, EdD, MMHC. . . . . . . . . . . . 5 Updates in the Guidelines and Treatment of Hepatitis C David H. Winston, MD, FACP, AGAF. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 Emerging Challenges on the Therapeutic Landscape of Multiple Sclerosis: The Managed Care Physician’s Perspective and Medical Director’s Perspective Brian A. Cree, MD, PhD, MCR and Brian Steingo, MD. . . . . . . . . . . . . . . . . . . 22 Clinical and Efficiency Benefits of New Oral Anticoagulants after THR/TKR Surgery Louis M. Kwong, MD, FACS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 Telehealth Program for Medicaid Patients with Type 2 Diabetes Lowers Hemoglobin A1c Kelley D. Stamp, PhD, ANP-C; Nancy A. Allen, PhD, ANP-BC; Susan Lehrer, RN, BSN, CDE; Sofija E. Zagarins, PhD; Garry Welch, PhD . . . . . . . . . . . . . . . 39 Multiple Myeloma: An Update on Current and Emerging Treatment Options Ravi Vij, MD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 New Developments in the Treatment of Castrate-Resistant Prostate Cancer Pamela Ellsworth, MD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53 Recent Breakthroughs in the Treatment of Metastatic Melanoma: Novel Immunologics Adil Daud, MD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60 Preventing Chemotherapy-Induced Nausea and Vomiting and Improving Quality of Life in Cancer Patients Susan Urba, MD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 Impact on Health Plan Cancer Drug Costs in Different Delivery Models Dawn G. Holcombe, FACMPE, MBA, ACHE; Rex W. Force, Pharm D, BCPS, FCCP; Kerry Bradley, Joe Conoshenti, R.Ph., BSPharm, MBA, Keith Huff, R.Ph., PharmD, MS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69 PLUS: Fall Managed Care Forum Program Guide. . . . . . . . . . . . . . . . . . . . . 83
BPA Audited Publication
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Editorial Review Board Alan Adler, MD, MS Medical Director Independence Blue Cross Madeleine Biondolillo, MD Director, Healthcare Safety and Quality Massachusetts Department of Public Health Paul Bluestein, MD Chief Medical Officer Connecticare Anthony Bonagura, MD Medical Director Aetna Inc. Philip M. Bonaparte, MD Chief Medical Officer Horizon NJ Health D. Kete Cockrell, MD Medical Director International Medical Group Pat Deverka, MD, MS, MBE Senior Research Director Center for Medical Technology Policy Stan N. Finkelstein, MD Co-Director, Program on the Pharmaceutical Industry Director, Harvard-MIT Division of Health Sciences & Technology Massachusetts Institute of Technology Howard Garber, MD, MPH Medical Director Johns Hopkins Health Care Mary Parish Gavinski, MD Chief Medical Officer Community Care Annetine Gelijns, PhD Co-Director International Center for Health Outcomes and Innovation Research (InCHOIR) Columbia University Uwe G. Goehlert, MD, MSC, MPH, MBA, FAAFP Staff Physician Northwestern Medical Center Department of Emergency Medicine Steven E. Goldberg, MD, MBA VP and Chief of Medical Affairs Express Scripts Atul Grover, MD, PhD Associate Director Association of American Medical Colleges Humberto Guerra-Garcia, MD, MPH, FACP Chief Medical Officer United Healthcare Community PlanDelaware
Leo M. Hartz, MD, MHM VP Clinical Advocacy/Chief Medical Officer Blue Cross of Northeast PA
Gary R. Proctor, MD Chief Medical Officer, Federal Division ValueOptions Inc.
Barry K. Herman, MD, MMM Executive Medical Director Clinical Research and Medical Affairs Sunovion Pharmaceuticals, Inc.
John W. Richards Jr., MD, MMM, CPE President/CEO Innovative Health Strategies
Kathy Hudson, PhD Director, Genetics and Public Policy Center Johns Hopkins University Thomas Kaye, RPh, MBA, FASHP Senior Pharmacy Director Passport Health Plan Stephen Keir, DrPH Co-Director Center for Quality of Life/Supportive Care Research Robert Preston Tisch Brain Tumor Center Duke University Medical Center Fernando C. Larach, MD, FACR, MBA President A-Bay Area Medical Clinics, PA Catherine Marino, MD Chief Medical Officer MagnaCare Jeff Martin, PharmD Clinical Account Director Innoviant Inc. Peter W. McCauley Sr., MD, CPE Medical Director Gottlieb/West Towns PHO Inc. Wesley Mizutani, MD Talbert Medical Group Thomas Morrow, MD Director Genentech Lawrence Mullany, MD, MBA Medical Director United Healthcare Ray Mummery, MD, CMCE Chief Medical Officer, Dimension Health Denis O’Connell, MD Regional Medical Director Blue Cross Blue Shield of NC A. Mark Parker, MD, MBA Medical Director Quality Assessment Systems Inc.
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Kevin Roache, MD, MMM, CPE, FACPE Vice President Medical Affairs Peoples Health, Inc. Aran Ron, MD, MBA, MPH President and Chief Operating Officer Group Health Inc. Mark R. Rosenberg, MD, PhD President/CEO BHM Healthcare Solutions Jay Schechtman, MD, MBA Senior VP, Chief Medical Officer Healthfirst Nancy Single, PhD Assistant Director for Strategic Planning and Program The Ohio State University Comprehensive Cancer Center Robert H. Small, MD Behavioral Health Medical Director TriWest Healthcare Alliance Jacque J. Sokolov, MD Chairman SSB Solutions Scott Spradlin, DO, FACPF, ACOI VP Medical Affairs/Chief Medical Officer Group Health Plan Bruce Steffens, MD Market Medical Director Iowa– Central Illinois United Healthcare William D. Strampel, DO, FACOI Dean, Michigan State University College of Osteopathic Medicine Jeff Taylor, RPh, MS Pharmacy Director Aetna Prentiss Taylor Jr., MD Regional Medical Center Director Advocate Health Care Pam Thomas, MD, MPH, FACOEM Consulting Medical Director Wellness, Health and Productivity Management Strategies
CHIP Lifestyle Program at Vanderbilt University Demonstrates an Early ROI for a Diabetic Cohort in a Workplace Setting: A Case Study Dexter Shurney, MD, MBA, MPH; Sandra Hyde, MSPS; Kristina Hulsey, MSPS; Roy Elam, MD; Abby Cooper, MHIM; Jay Groves, EdD, MMHC
Summary Several studies have found a strong dose-response relationship between most chronic diseases and lifestyle-related risk factors. This study examined the feasibility of a comprehensive, workplace-based, intensive lifestyle training program, to help type 2 diabetics alter the course of their disease within relatively short (6, 12 and 24-month) measurement windows. An additional purpose of this study was to determine whether health care cost savings could be achieved for the lifestyle group when compared to non-intervened type 2 diabetics within the same employer-sponsored health plan. The Vanderbilt CHIP study measured participants’ pre- and post-intervention health care costs (total medical and prescription drug) and health services utilization on a year-over-year (YOY) basis, and compared them with the costs and utilization of the other (non-intervened) diabetics of the plan. Biometric and lab data were collected at the beginning and end of the program and six months after the study’s conclusion to document immediate and long-term changes in health outcomes and health risk behaviors. Our six-month findings provide evidence that educating a member population about the benefits of a plant-based, whole-foods diet is feasible and can reduce associated health care costs. Key Points • Intensive lifestyle education and training is feasible in a workplace setting. • Positive changes were seen among study participants in HBA1C and cholesterol results as well as positive changes in self-reported physical health and well-being. • Health care costs were substantially reduced for study participants compared to the non-participant group. • Approximately 23.8 percent of study participants have been able to eliminate one or more of their medications.
Introduction
Chronic illnesses have consistently been the largest determinant to rising health care expenditures in the United States and many other industrialized countries. A wealth of empirical evidence further suggests that 70 to 90 percent of such chronic illnesses as diabetes, cancer, cardiovascular disease, and stroke, and certainly death, from these common conditions are preventable and caused by poor lifestyle choices.1,2,3 In 2001, the Harvard Nurses’ Health Study concluded that 90 percent
of type 2 diabetes was preventable and attributable to habits and behaviors not found in the low-risk pattern group.4 Moreover, studies have also found a strong dose-response relationship between most chronic diseases and lifestyle-related risk factors such as poor nutrition and sedentary living.5, 6, 7 Unfortunately, less than 2 percent of Americans meet all seven of the recommended Heart Health Goals: 1) Not smoking, 2) Being physically active, 3) Having a normal blood pressure, 4) Fasting blood-glucose levels below 100, 5) Total cholesterol levels below
www.namcp.org | Vol. 15, No. 4 | Journal of Managed Care Medicine 5
Exhibit 1: Salary Band Data Breakdown
VHP Members Ages 35 - 65 < $50K
Patients by Salary Band
> $50K and > $100K and <$100K < $150K
> $150K and < $200K
> $200K
Chip Participants
60.0%
32.0%
4.0%
4.0% 0.0%
Non-CHIP Diabetes
57.6%
33.5%
4.8%
1.8% 2.3%
All Non-CHIP VHP Members
44.1%
37.8%
7.7%
4.0%
6.3%
Exhibit 2: Aggregate Costs for CHIP Participants Average Cost & Utilization Avg. Net Payment per Member Avg. Copay per Member Avg. Office Visits per Member (Plan-paid Medical & Rx and Copays) (Medical + Rx) (Medical + Rx) (Medical)
Q1 2010 Q1 2011 $2,040
Total
(ages 35 to 65)
% -34.9%
Non-Chip Type 2 VHP Diabetics (ages 35 to 65)
Total
All Non-Chip VHP Members (ages 35 to 65)
Total
$2,258
%
$2,415
$1,733
$1,060
Q1 2010 Q1 2011 $ 255
$2,876
$ 190
17.9%
$1,054
-0.6%
$1,212
$ 208
Q2 2010 Q2 2011 $1,070 $1,065
Q1 2010 Q1 2011 3.25
-30.1% -18.3% -0.5%
$2,440
6.9%
$1,066
%
$1,328
Q2 2010 Q2 2011
Chip Participants
$1,169
200, 6) Maintaining a healthy BMI, and 7) Eating a healthy diet.8 The United States National Institutes of Health recognizes lower cancer rates, lower risk of death from certain heart diseases, and lower LDL cholesterol levels in individuals with plant-based diets and regular physical activity.9 An ongoing NIH study on the link between diet and disease is finding that the closer an individual’s diet is to vegetarian, the lower his or her risk in the aforementioned health concerns.9 The most frequently used lifestyle modifications include improvement to nutrition, tobacco cessation, and increased physical activity. Few studies have tested the overall effectiveness that comprehensive lifestyle programs may offer patients. However, those that have employed a more comprehensive approach have generally yielded positive results. Examples include: PREMIER and DASH programs demonstrated reductions in obesity, blood pressure, and blood lipid levels, all of which are cardiovascular risk factors.10
$ 185
-0.4%
$ 83
10.9%
$ 189
$ 81
$ 80
3.60
2.68
3.16
3.18
3.25
1.0% 2.2%
2.94
-3.3%
Q2 2010 Q2 2011
-11.4% -25.6%
3.13
2.5%
$ 83
-3.1%
$ 189
2.88
2.93
2.91
2.91
-0.3% 0.0%
The Diabetes Prevention Program (DPP) found a higher percentage reduction in diabetes in the lifestyle intervention group over the metformin group. In the long term analysis, “cumulative incidence of diabetes remained lowest in the lifestyle group.”11 ISAIAH in the UK, a “lifestyle-change intervention for pre-diabetic patients,” observed a statistically significant difference between control and intervention groups in three markers for risk of progression to diabetes- weight, BMI, and waist circumference.12 The Look AHEAD Trial, a four-year lifestyle intervention program, produced short-term improvements in glycemic control and CVD risk factors in individuals with type 2 diabetes, as well as longterm improvement in weight, fitness, HbA1c, SBP, and HDL-C.13 The Prevention Plan “revealed that prevention programs based on the clinical practice of preventive medicine are able to achieve measurable health risk reduction in just one year.”14 In spite of the substantial evidence supporting the
6 Journal of Managed Care Medicine | Vol. 15, No. 4 | www.namcp.org
Exhibit 3: Breakdown of Total Claims Costs
Average Cost Detail Avg. Net Payment per Member Avg. Net Payment per Member (Medical & Rx) (Medical) (Rx)
Chip Participants (Ages 35 to 65) Non-CHIP Type 2 VHP Diabetics (ages 35 to 65)
Total
Q1 2010
Q1 2011
$1,337
$ 729
% Total
All Non-Chip VHP Members (ages 35 to 65)
Total
%
1,068
-45.5%
$1,693
%
Q2 2010 Q2 2011
$1,785
$ 848
$ 828
$2,235
$ 933
Q2 2010 Q2 2011
$ 599
$ 666
$ 630
$ 233
$ 641
7.6%
$ 225
6.8%
$ 573
-13.8%
$ 596
11.5%
$ 218
12.6%
Q1 2011
-14.7%
$ 565
21.2%
$ 829
-2.5%
$ 702
-40.3%
$1,843
5.4%
Q1 2010
$ 638
$ 235
4.7%
Exhibit 4: OP Medical Visits Avg. Office Visits per Member Average Medical Utilization
Q1 2010 Q1 2011
Q2 2010 Q2 2011
Chip Participants (ages 35 to 65)
Total 3.25 2.88 3.60 2.68 % -11.4% -25.6%
Non-CHIP Type 2 VHP
Total
Diabetics (ages 35 to 65) All Non-Chip VHP Members (ages 35 to 65)
3.13
% Total
3.18
1.0%
2.94
%
3.16
2.93
2.2%
2.91
-0.3%
3.25
2.91
0.0%
efficacy of comprehensive lifestyle programs to control, and at times reverse, many common chronic conditions,15,16 very few patients in usual primary care settings are offered the opportunity to participate in such programs.
medicine as it demonstrates the point that chronic diseases can be turned around through responsible lifestyle changes. The Vanderbilt application of CHIP emphasizes a whole-food, plant-based diet.
Definition of Lifestyle Medicine
The purpose of the present case study was twofold. We sought to examine the feasibility of conducting a comprehensive, population-based, lifestyle program, such as CHIP (Complete Health Improvement Program)17,18 in our workplace setting. Additionally, we sought to measure its impact in helping individuals with a lifestyle-related chronic illness (in this case type 2 diabetes) alter the course of their disease and reduce their health care costs within defined six-, 12- and 24-month measurement windows. This report presents the outcome of short-term results at two and six months.
Purpose
According to published statements by the American College of Lifestyle Medicine, “Lifestyle Medicine” is the use of lifestyle interventions in the treatment and management of disease. Such interventions include diet (nutrition), exercise, stress management, smoking cessation, and a variety of other non-drug modalities. Definition of CHIP
The Complete Health Improvement project, (formerly known as the Coronary Health Improvement Project), CHIP, was founded by Dr. Hans Diehl and is a “lifestyle enrichment program designed to reduce disease risk factors through the adoption of better health habits and appropriate lifestyle modifications.”21 It serves as a reproducible model for lifestyle
Background
The prevalence of diabetes has been increasing and rose from 6.5 percent in 1999 to 7.8 percent in 2006.19 With this rise in disease burden, health care
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Exhibit 5: Average Prescription Medicine Utilization
Average Prescription Medicine Utilization Chip Participants
Total
(ages 35 to 65)
Avg. Scripts per Patient Rx Q1 2010 Q1 2011 7.92
%
Non-CHIP Type 2 VHP
Total
Diabetics (ages 35 to 65) All Non-Chip VHP
Total
7.14
-3.0%
8.65
%
Members (ages 35 to 65)
7.68
Q2 2010
9.02
5.27
%
5.39
8.99
5.1%
5.27
2.1%
6.92
-3.1%
8.55
4.3%
Q2 2011
5.35
1.5%
Exhibit 6: Therapeutic Class Therapeutic Class
Members
Off Off Medications Medications Q2 2011 Q1 & Q2 2011
Adrenals & Comb, NEC
1
Antidiabetic Agents
2
1
Antihyperlipidemic Drugs, NEC
3
1
Antiinflam Agents EENT, NEC
1
ASH, Benzodiazepines
1
Cardiac, ACE Inhibitors
1
Cardiac, Beta Blockers
1
Cardiac, Calcium Channel
2
Diuretics, Thiazides & Related
2
Gastrointestinal Drug Misc, NEC Psychotherapy, Antidepressants
1
1
2
Vitamin D, NEC
2
Members + Medications
15
7
Unique Members represented:
10
5
expenses are destined to escalate. It is projected that the percentage of national health care expenditure of people with type 2 diabetes mellitis (T2DM) will increase from 10 percent in 2011 to 15 percent in 2031.20 The Vanderbilt University and Medical Center Health Plan (VHP) in Nashville, Tennessee, averages 47,000 covered lives. The paid claims for T2DM are three-and-a-half times higher, per patient, than the claims costs for non-diabetic members. The annual VHP claims expense per T2DM has been increasing an average of 11 percent annually during
the past four years. Methods Design Overview
The voluntary-participation study was free of charge and emphasized the participantsâ&#x20AC;&#x2122; roles in controlling health status through structured discussions / lectures, lifestyle and nutritional videos, and cooking demonstrations. The study measured participantsâ&#x20AC;&#x2122; pre- and post- intervention health care costs (total medical and prescription drug) and health services utilization on a year-over-year (YOY) basis, and it compared them
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Exhibit 7: Participant Improvements Baseline +8 Weeks Group Improvements HBA1C (Changes, ) (Reduction)
Baseline +26 Weeks
Total Total Cholesterol LDL HDL Triglycerides HBA1C Cholesterol LDL HDL (Reduction) (Reduction) (Increase) (Reduction) (Reduction) (Reduction) (Reduction) (Increase)
Triglycerides (Reduction)
N
12
15
14
4
11
13
13
8
6
11
Mean
0.9
28.2
20.9
3.0
36.8
0.5
30.0
30.6
5.7
54.0
p-value
0.01
0.07
0.17
0.02
0.36
0.06
0.08
0.04
0.02
0.07
Minimum
0.1
1.0
2.0
1.0
1.0
0.0
2.0
7.0
3.0
4.0
Maximum
3.2
96.0
70.0
6.0
114.0
1.2
123.0
104.0
9.0
144.0
Median
0.8
20.0
15.0
2.5
22.0
0.4
23.0
18.5
6.0
57.0
Mode
0.7
-
5.0
-
-
0.2
-
13.0
6.0
-
53.5
55.4
55.4
54.8
55.0
54.7
53.6
53.8
58.7
53.5
Average Age Males
2
2
2
0
3
3
3
1
1
3
Females
10
13
12
4
8
10
10
7
5
8
57.1%
71.4%
66.7%
19.0%
52.4%
61.9%
61.9%
38.1%
28.6%
52.4%
% Members with Improvements
Exhibit 8: Average Changes in Individual Responses Timeline, t (weeks)
0
Mean Individual Responses
8
Variable Name Mean Median Mean Median Score Score Score Score
26
Mean % p- Mean Median to t=0 Values Score Score
Mean % to t=0
pValues
Life Evaluation
73.0
75.0
76.0
78.0
4.1%
0.03
80.0
80.0
9.6%
0.07
Physical Health
55.0
50.0
63.0
75.0
14.5%
0.01
75.0
75.0
36.4%
0.00
Emotional Health
58.0
60.0
74.0
80.0
27.6%
0.02
80.0
80.0
37.9%
0.11
Healthy Behaviors
69.0
67.0
69.0
83.0
0.0%
0.67
67.0
67.0
-2.9%
0.91
Work Environment
67.0
75.0
66.0
75.0
-1.5%
0.39
75.0
75.0
11.9%
0.15
Basic Access
92.0
100.0
91.0
100.0
-1.1%
0.44
95.0
100.0
3.3%
0.81
Well Being Index
68.0
67.0
73.0
77.0
7.4%
0.01
79.0
79.0
16.2%
0.01
with the costs and utilization of the other (non-intervened) diabetics in the plan. In addition, biometric and lab data were collected at the beginning and end of the program as well as at six months after the studyâ&#x20AC;&#x2122;s conclusion to document immediate and longterm changes in health risk behavior. Setting and Participants
Although the CHIP model could be applied in a lay or community setting, we focus on its application in the workplace. This study presents an application of CHIP initiated by the VHP in conjunction with Vanderbiltâ&#x20AC;&#x2122;s Center for Integrative Health and The
Dayani Center to Vanderbilt employees. Approximately 5 percent of VHP members have T2DM. During the past four years for which comprehensive claims data are available, an average of 400 VHP members are newly diagnosed with T2DM each year, and approximately 2 percent of the remaining VHP members have conditions that put them at risk for developing T2DM. We chose T2DM for this study for a number of reasons beyond the inherent costs associated with this population. First, there is a strong relationship to lifestyle and T2DM which makes it an ideal condition to analyze with respect to the intervention. Finally,
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it is a rather straightforward condition to identify and track within medical and pharmacy claims data. We chose the employee worksite as the location of this activity as a measure for evaluating the feasibility of program implementation within the workplace. The study recruited adult employees of Vanderbilt University and/or Medical Center on a voluntary and first-to-enroll basis who responded to a general campus communication for the study. Eligibility requirements were clinical diagnoses of T2DM while having at least two consecutive years of coverage under the Plan. Additionally, participants were asked to commit to attend a minimum of 11 of 14 training sessions (80 percent). There were, originally, 30 people in the pilot. Two withdrew prior to the conclusion of the CHIP program due to changes in employment status that resulted in the loss of VHP coverage. The age range of the pilot participants was 35 to 65, and the majority of participants were female. While the socioeconomic status of the participants was not recorded directly, the best estimable measure of this dimension comes from the salary-banding data tracked within the health claims database. The breakdown of the salary band data is shown in Exhibit 1.
the education and training was not specific to diabetes education. Main Outcome Measures
To determine if comprehensive changes to lifestyle for a cohort with a chronic-disease condition, in this case T2DM, could result in cost savings for an employer-sponsored health plan, prescription drug and medical claims cost data were collected and analyzed at pre-CHIP (Baseline, t =0), post-CHIP (Baseline + eight weeks, t=8), and CHIP follow-up (Baseline +26 weeks, t=26). In order to provide a better level of understanding regarding changes in costs, biometric and lab data, were collected and documented at the same time intervals as claims data. Copies of the biometric lab data were submitted by the participants for evaluation. These measures included body weight, HBA1C, LDL, HDL, total cholesterol, and triglycerides. It is noted, however, as the lab data submission was voluntary, for a total of eight participants, some element of the biometric data was missing at either the t=0 or the t=8 time frames. Well-being assessment data were collected at the same time intervals as claims data. Statistical Analysis
Intervention- Group sessions
The primary intervention used in this study was CHIP, shortened from the usual three-month program duration to two months, during which participants met regularly in an onsite classroom setting for educational, instructional, and experiential health training sessions. During an eight-week period, Vanderbilt CHIP participants met for two-hour sessions twice weekly. To meet the needs of working families, meals were prepared for the participants by Vanderbilt Dining Services using recipes from The Optimal Diet: The Official CHIP Cookbook. Participants also received copies of the cookbook for use at home in their personal meal preparations. While eating healthy foods, participants watched program videos pertaining to lifestyle behaviors, which presented a variety of healthy learning objectives such as how to read food labels, and the importance of getting enough sleep, physical activity, and fiber on a daily basis. Participants were encouraged, as well as equipped, with practical “how-to” knowledge for incorporating healthy habits into their daily routines. Participants received instruction in wholefood, plant-based nutrition, exercise, and engaged in health discussions related to disease causation and the benefits of a healthy lifestyle as the basis of overall health and well-being. It should be noted that although the study cohort was comprised entirely of type 2 diabetics, most of
To the extent possible, data for the total group was analyzed. Individuals who were lost to follow-up were excluded in the following well-being summary data but are still being followed in their healthclaims data as long as they remain Vanderbilt employees. Numeric values have been rounded to the nearest whole number. P-values for statistical analyses were calculated on a two-sample, two-tailed ttest for unequal variances with the alternative hypothesis of μ1 ≠ μ2 (α = 0.05). The prescription drug and medical cost analyses were performed using actual VHP medical and prescription claims data. As claims data tend to be cyclical, identical time frames from 2010 were compared to the study period in 2011 for CHIP participants using all Non-CHIP members, as well as all Non-CHIP diabetics, as natural control groups. To provide a basis to assess health status, and to corroborate the claims findings, laboratory and biometric data were collected. Changes in biometric data were evaluated at each of the three evaluation periods. Missing data were not imputed. The Gallup-Healthways Well-Being Index ® survey was administered at each of the three time frames (t=0, +8, +26) and changes in scores between time frames 0 and +8; 0 and +26 were calculated to assess the participants’ changes in well-being. The WellBeing Assessment included self-scoring in seven (continued on page 13)
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ORENCIA® (abatacept) for injection for intravenous use injection, for subcutaneous use Brief Summary of Prescribing Information. For complete prescribing information, please consult official package insert. INDICATIONS AND USAGE Adult Rheumatoid Arthritis (RA) - ORENCIA® (abatacept) is indicated for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active rheumatoid arthritis. ORENCIA may be used as monotherapy or concomitantly with diseasemodifying antirheumatic drugs (DMARDs) other than tumor necrosis factor (TNF) antagonists. Juvenile Idiopathic Arthritis - ORENCIA is indicated for reducing signs and symptoms in pediatric patients 6 years of age and older with moderately to severely active polyarticular juvenile idiopathic arthritis. ORENCIA may be used as monotherapy or concomitantly with methotrexate (MTX). Important Limitations of Use - ORENCIA should not be administered concomitantly with TNF antagonists. ORENCIA is not recommended for use concomitantly with other biologic rheumatoid arthritis (RA) therapy, such as anakinra. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Concomitant Use with TNF Antagonists - In controlled clinical trials in patients with adult RA, patients receiving concomitant intravenous ORENCIA and TNF antagonist therapy experienced more infections (63%) and serious infections (4.4%) compared to patients treated with only TNF antagonists (43% and 0.8%, respectively) [see Adverse Reactions]. These trials failed to demonstrate an important enhancement of efficacy with concomitant administration of ORENCIA with TNF antagonist; therefore, concurrent therapy with ORENCIA and a TNF antagonist is not recommended. While transitioning from TNF antagonist therapy to ORENCIA therapy, patients should be monitored for signs of infection. Hypersensitivity - Of 2688 patients with adult RA treated with ORENCIA intravenously in clinical trials, there were two cases of anaphylaxis or anaphylactoid reactions. Other events potentially associated with drug hypersensitivity, such as hypotension, urticaria, and dyspnea, each occurred in less than 0.9% of ORENCIA-treated patients. Of the 190 patients with juvenile idiopathic arthritis treated with ORENCIA in clinical trials, there was one case of a hypersensitivity reaction (0.5%). Appropriate medical support measures for the treatment of hypersensitivity reactions should be available for immediate use in the event of a reaction [see Adverse Reactions]. Infections - Serious infections, including sepsis and pneumonia, have been reported in patients receiving ORENCIA. Some of these infections have been fatal. Many of the serious infections have occurred in patients on concomitant immunosuppressive therapy which in addition to their underlying disease, could further predispose them to infection. Physicians should exercise caution when considering the use of ORENCIA in patients with a history of recurrent infections, underlying conditions which may predispose them to infections, or chronic, latent, or localized infections. Patients who develop a new infection while undergoing treatment with ORENCIA should be monitored closely. Administration of ORENCIA should be discontinued if a patient develops a serious infection [see Adverse Reactions]. A higher rate of serious infections has been observed in adult RA patients treated with concurrent TNF antagonists and ORENCIA [see Warnings and Precautions]. Prior to initiating immunomodulatory therapies, including ORENCIA, patients should be screened for latent tuberculosis infection with a tuberculin skin test. ORENCIA has not been studied in patients with a positive tuberculosis screen, and the safety of ORENCIA in individuals with latent tuberculosis infection is unknown. Patients testing positive in tuberculosis screening should be treated by standard medical practice prior to therapy with ORENCIA. Antirheumatic therapies have been associated with hepatitis B reactivation. Therefore, screening for viral hepatitis should be performed in accordance with published guidelines before starting therapy with ORENCIA. In clinical studies with ORENCIA, patients who screened positive for hepatitis were excluded from study. Immunizations - Live vaccines should not be given concurrently with ORENCIA or within 3 months of its discontinuation. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving ORENCIA. The efficacy of vaccination in patients receiving ORENCIA is not
known. Based on its mechanism of action, ORENCIA (abatacept) may blunt the effectiveness of some immunizations. It is recommended that patients with juvenile idiopathic arthritis be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating ORENCIA therapy. Use in Patients with Chronic Obstructive Pulmonary Disease (COPD) - Adult COPD patients treated with ORENCIA developed adverse events more frequently than those treated with placebo, including COPD exacerbations, cough, rhonchi, and dyspnea. Use of ORENCIA in patients with RA and COPD should be undertaken with caution and such patients should be monitored for worsening of their respiratory status [see Adverse Reactions]. Immunosuppression - The possibility exists for drugs inhibiting T cell activation, including ORENCIA, to affect host defenses against infections and malignancies since T cells mediate cellular immune responses. The impact of treatment with ORENCIA on the development and course of malignancies is not fully understood [see Adverse Reactions]. In clinical trials in patients with adult RA, a higher rate of infections was seen in ORENCIA-treated patients compared to placebo [see Adverse Reactions]. ADVERSE REACTIONS Clinical Studies Experience in Adult RA Patients Treated with Intravenous ORENCIA - Because clinical trials are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not predict the rates observed in a broader patient population in clinical practice. The data described herein reflect exposure to ORENCIA administered intravenously in patients with active RA in placebocontrolled studies (1955 patients with ORENCIA, 989 with placebo). The studies had either a double-blind, placebocontrolled period of 6 months (258 patients with ORENCIA, 133 with placebo) or 1 year (1697 patients with ORENCIA, 856 with placebo). A subset of these patients received concomitant biologic DMARD therapy, such as a TNF blocking agent (204 patients with ORENCIA, 134 with placebo). The majority of patients in RA clinical studies received one or more of the following concomitant medications with ORENCIA: MTX, nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, TNF blocking agents, azathioprine, chloroquine, gold, hydroxychloroquine, leflunomide, sulfasalazine, and anakinra. The most serious adverse reactions were serious infections and malignancies. The most commonly reported adverse events (occurring in ≥10% of patients treated with ORENCIA) were headache, upper respiratory tract infection, nasopharyngitis, and nausea. The adverse events most frequently resulting in clinical intervention (interruption or discontinuation of ORENCIA) were due to infection. The most frequently reported infections resulting in dose interruption were upper respiratory tract infection (1.0%), bronchitis (0.7%), and herpes zoster (0.7%). The most frequent infections resulting in discontinuation were pneumonia (0.2%), localized infection (0.2%), and bronchitis (0.1%). Infections - In the placebo-controlled trials, infections were reported in 54% of ORENCIA-treated patients and 48% of placebo-treated patients. The most commonly reported infections (reported in 5-13% of patients) were upper respiratory tract infection, nasopharyngitis, sinusitis, urinary tract infection, influenza, and bronchitis. Other infections reported in fewer than 5% of patients at a higher frequency (>0.5%) with ORENCIA compared to placebo, were rhinitis, herpes simplex, and pneumonia [see Warnings and Precautions]. Serious infections were reported in 3.0% of patients treated with ORENCIA and 1.9% of patients treated with placebo. The most common (0.2-0.5%) serious infections reported with ORENCIA were pneumonia, cellulitis, urinary tract infection, bronchitis, diverticulitis, and acute pyelonephritis [see Warnings and Precautions]. Malignancies - In the placebo-controlled portions of the clinical trials (1955 patients treated with ORENCIA for a median of 12 months), the overall frequencies of malignancies were similar in the ORENCIA- and placebo-treated patients (1.3% and 1.1%, respectively). However, more cases of lung cancer were observed in ORENCIA-treated patients (4, 0.2%) than placebotreated patients (0). In the cumulative ORENCIA clinical trials (placebo-controlled and uncontrolled, open-label) a total of 8 cases of lung cancer (0.21 cases per 100 patient-years) and 4 lymphomas (0.10 cases per 100 patient-years) were observed in 2688 patients (3827 patient-years). The rate observed for lymphoma is approximately 3.5-fold higher than expected in an age- and gender-matched general population based on the National Cancer Institute’s Surveillance, Epidemiology, and End
Results Database. Patients with RA, particularly those with highly active disease, are at a higher risk for the development of lymphoma. Other malignancies included skin, breast, bile duct, bladder, cervical, endometrial, lymphoma, melanoma, myelodysplastic syndrome, ovarian, prostate, renal, thyroid, and uterine cancers [see Warnings and Precautions]. The potential role of ORENCIA (abatacept) in the development of malignancies in humans is unknown. Infusion-Related Reactions and Hypersensitivity Reactions Acute infusion-related events (adverse reactions occurring within 1 hour of the start of the infusion) in Studies III, IV, and V [see Clinical Studies (14.1) in Full Prescribing Information] were more common in the ORENCIA-treated patients than the placebo patients (9% for ORENCIA, 6% for placebo). The most frequently reported events (1-2%) were dizziness, headache, and hypertension. Acute infusion-related events that were reported in >0.1% and ≤1% of patients treated with ORENCIA included cardiopulmonary symptoms, such as hypotension, increased blood pressure, and dyspnea; other symptoms included nausea, flushing, urticaria, cough, hypersensitivity, pruritus, rash, and wheezing. Most of these reactions were mild (68%) to moderate (28%). Fewer than 1% of ORENCIA-treated patients discontinued due to an acute infusion-related event. In controlled trials, 6 ORENCIA-treated patients compared to 2 placebo-treated patients discontinued study treatment due to acute infusion-related events. Of 2688 patients treated with ORENCIA in clinical trials, there were two cases of anaphylaxis or anaphylactoid reactions. Other events potentially associated with drug hypersensitivity, such as hypotension, urticaria, and dyspnea, each occurred in less than 0.9% of ORENCIA-treated patients and generally occurred within 24 hours of ORENCIA infusion. Appropriate medical support measures for the treatment of hypersensitivity reactions should be available for immediate use in the event of a reaction [see Warnings and Precautions]. Adverse Reactions in Patients with COPD - In Study V [see Clinical Studies (14.1) in Full Prescribing Information], there were 37 patients with chronic obstructive pulmonary disease (COPD) who were treated with ORENCIA and 17 COPD patients who were treated with placebo. The COPD patients treated with ORENCIA developed adverse events more frequently than those treated with placebo (97% vs 88%, respectively). Respiratory disorders occurred more frequently in ORENCIA-treated patients compared to placebo-treated patients (43% vs 24%, respectively) including COPD exacerbation, cough, rhonchi, and dyspnea. A greater percentage of ORENCIA-treated patients developed a serious adverse event compared to placebo-treated patients (27% vs 6%), including COPD exacerbation (3 of 37 patients [8%]) and pneumonia (1 of 37 patients [3%]) [see Warnings and Precautions]. Other Adverse Reactions - Adverse events occurring in 3% or more of patients and at least 1% more frequently in ORENCIAtreated patients (n=1955) versus placebo (n=989) during placebo-controlled RA studies were: Headache (18%, 13%); Nasopharyngitis (12%, 9%); Dizziness (9%, 7%); Cough (8%, 7%); Back pain (7%, 6%); Hypertension (7%, 4%); Dyspepsia (6%, 4%); Urinary tract infection (6%, 5%); Rash (4%, 3%); Pain in extremity (3%, 2%), respectively. The ORENCIA group included 204 patients on concomitant biologic DMARDs (adalimumab, anakinra, etanercept, or infliximab). The placebo group included 134 patients on concomitant biologic DMARDs (adalimumab, anakinra, etanercept, or infliximab). Immunogenicity - Antibodies directed against the entire abatacept molecule or to the CTLA-4 portion of abatacept were assessed by ELISA assays in RA patients for up to 2 years following repeated treatment with ORENCIA. Thirty-four of 1993 (1.7%) patients developed binding antibodies to the entire abatacept molecule or to the CTLA-4 portion of abatacept. Because trough levels of abatacept can interfere with assay results, a subset analysis was performed. In this analysis it was observed that 9 of 154 (5.8%) patients that had discontinued treatment with ORENCIA for over 56 days developed antibodies. Samples with confirmed binding activity to CTLA-4 were assessed for the presence of neutralizing antibodies in a cellbased luciferase reporter assay. Six of 9 (67%) evaluable patients were shown to possess neutralizing antibodies. However, the development of neutralizing antibodies may be underreported due to lack of assay sensitivity. No correlation of antibody development to clinical response or adverse events was observed. The data reflect the percentage of patients whose test results were positive for antibodies to abatacept in specific assays. The observed incidence of antibody (including neutralizing antibody) positivity in an assay is highly dependent on several factors, including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons,
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comparison of the incidence of antibodies to abatacept with the incidence of antibodies to other products may be misleading. Clinical Experience in MTX-Naive Patients - Study VI was an active-controlled clinical trial in MTX-naive patients [see Clinical Studies (14.1) in Full Prescribing Information]. The safety experience in these patients was consistent with Studies I-V. Clinical Experience in Adult RA Patients Treated with Subcutaneous ORENCIA (abatacept) - Because clinical trials are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not predict the rates observed in a broader patient population in clinical practice. Study SC-I was a randomized, double-blind, double-dummy, non-inferiority study that compared the efficacy and safety of abatacept administered subcutaneously (SC) and intravenously (IV) in 1457 subjects with rheumatoid arthritis, receiving background MTX, and experiencing an inadequate response to MTX (MTX-IR) [see Clinical Studies (14.1) in Full Prescribing Information]. The safety experience and immunogenicity for ORENCIA administered subcutaneously was consistent with intravenous Studies I-VI. Due to the route of administration, injection site reactions and immunogenicity were evaluated in Study SC-I and two other smaller studies discussed in the sections below. Injection Site Reactions in Adult RA Patients Treated with Subcutaneous ORENCIA - Study SC-I compared the safety of abatacept including injection site reactions following subcutaneous or intravenous administration. The overall frequency of injection site reactions was 2.6% (19/736) and 2.5% (18/721) for the subcutaneous abatacept group and the intravenous abatacept group (subcutaneous placebo), respectively. All these injection site reactions (including hematoma, pruritus, and erythema) were mild (83%) to moderate (17%) in severity, and none necessitated drug discontinuation. Immunogenicity in Adult RA Patients Treated with Subcutaneous ORENCIA - Study SC-I compared the immunogenicity to abatacept following subcutaneous or intravenous administration. The overall immunogenicity frequency to abatacept was 1.1% (8/725) and 2.3% (16/710) for the subcutaneous and intravenous groups, respectively. The rate is consistent with previous experience, and there was no correlation of immunogenicity with effects on pharmacokinetics, safety, or efficacy. Immunogenicity and Safety of Subcutaneous ORENCIA Administration as Monotherapy without an Intravenous Loading Dose - Study SC-II was conducted to determine the effect of monotherapy use of ORENCIA on immunogenicity following subcutaneous administration without an intravenous load in 100 RA patients, who had not previously received abatacept or other CTLA4Ig, who received either subcutaneous ORENCIA plus MTX (n=51) or subcutaneous ORENCIA monotherapy (n=49). No patients in either group developed antiproduct antibodies after 4 months of treatment. The safety observed in this study was consistent with that observed in the other subcutaneous studies. Immunogenicity and Safety of Subcutaneous ORENCIA upon Withdrawal (Three Months) and Restart of Treatment - Study SC-III in the subcutaneous program was conducted to investigate the effect of withdrawal (three months) and restart of ORENCIA subcutaneous treatment on immunogenicity in RA patients treated concomitantly with MTX. One hundred sixtyseven patients were enrolled in the first 3-month treatment period and responders (n=120) were randomized to either subcutaneous ORENCIA or placebo for the second 3-month period (withdrawal period). Patients from this period then received open-label ORENCIA treatment in the final 3-month period of the study (period 3). At the end of the withdrawal period, 0/38 patients who continued to receive subcutaneous ORENCIA developed anti-product antibodies compared to 7/73 (9.6%) of patients who had subcutaneous ORENCIA withdrawn during this period. Half of the patients receiving subcutaneous placebo during the withdrawal period received a single intravenous infusion of ORENCIA at the start of period 3 and half received intravenous placebo. At the end of period 3, when all patients again received subcutaneous ORENCIA, the immunogenicity rates were 1/38 (2.6%) in the group receiving subcutaneous ORENCIA throughout, and 2/73 (2.7%) in the group that had received placebo during the withdrawal period. Upon reinitiating therapy, there were no injection reactions and no differences in response to therapy in patients who were withdrawn from subcutaneous therapy for up to 3 months relative to those who remained on subcutaneous therapy, whether therapy was reintroduced with or without an intravenous loading dose. The safety observed in this study was consistent with that observed in the other studies.
Clinical Studies Experience in Juvenile Idiopathic Arthritis In general, the adverse events in pediatric patients were similar in frequency and type to those seen in adult patients [see Warnings and Precautions, Adverse Reactions]. ORENCIA (abatacept) has been studied in 190 pediatric patients, 6 to 17 years of age, with polyarticular juvenile idiopathic arthritis. Overall frequency of adverse events in the 4-month, lead-in, open-label period of the study was 70%; infections occurred at a frequency of 36% [see Clinical Studies (14.2) in Full Prescribing Information]. The most common infections were upper respiratory tract infection and nasopharyngitis. The infections resolved without sequelae, and the types of infections were consistent with those commonly seen in outpatient pediatric populations. Other events that occurred at a prevalence of at least 5% were headache, nausea, diarrhea, cough, pyrexia, and abdominal pain. A total of 6 serious adverse events (acute lymphocytic leukemia, ovarian cyst, varicella infection, disease flare [2], and joint wear) were reported during the initial 4 months of treatment with ORENCIA. Of the 190 patients with juvenile idiopathic arthritis treated with ORENCIA in clinical trials, there was one case of a hypersensitivity reaction (0.5%). During Periods A, B, and C, acute infusion-related reactions occurred at a frequency of 4%, 2%, and 3%, respectively, and were consistent with the types of events reported in adults. Upon continued treatment in the open-label extension period, the types of adverse events were similar in frequency and type to those seen in adult patients, except for a single patient diagnosed with multiple sclerosis while on open-label treatment. Immunogenicity - Antibodies directed against the entire abatacept molecule or to the CTLA-4 portion of abatacept were assessed by ELISA assays in patients with juvenile idiopathic arthritis following repeated treatment with ORENCIA throughout the open-label period. For patients who were withdrawn from therapy for up to 6 months during the double-blind period, the rate of antibody formation to the CTLA-4 portion of the molecule was 41% (22/54), while for those who remained on therapy the rate was 13% (7/54). Twenty of these patients had samples that could be tested for antibodies with neutralizing activity; of these, 8 (40%) patients were shown to possess neutralizing antibodies. The presence of antibodies was generally transient and titers were low. The presence of antibodies was not associated with adverse events, changes in efficacy, or an effect on serum concentrations of abatacept. For patients who were withdrawn from ORENCIA during the double-blind period for up to 6 months, no serious acute infusion-related events were observed upon re-initiation of ORENCIA therapy. Postmarketing Experience - Adverse reactions have been reported during the postapproval use of ORENCIA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to ORENCIA. Based on the postmarketing experience in adult RA patients, the following adverse reaction has been identified during postapproval use with ORENCIA. â&#x20AC;˘ Vasculitis (including cutaneous vasculitis and leukocytoclastic vasculitis) DRUG INTERACTIONS TNF Antagonists - Concurrent administration of a TNF antagonist with ORENCIA has been associated with an increased risk of serious infections and no significant additional efficacy over use of the TNF antagonists alone. Concurrent therapy with ORENCIA and TNF antagonists is not recommended [see Warnings and Precautions]. Other Biologic RA Therapy - There is insufficient experience to assess the safety and efficacy of ORENCIA administered concurrently with other biologic RA therapy, such as anakinra, and therefore such use is not recommended. Blood Glucose Testing - Parenteral drug products containing maltose can interfere with the readings of blood glucose monitors that use test strips with glucose dehydrogenase pyrroloquinolinequinone (GDH-PQQ). The GDH-PQQ based glucose monitoring systems may react with the maltose present in ORENCIA for intravenous administration, resulting in falsely elevated blood glucose readings on the day of infusion. When receiving ORENCIA through intravenous administration, patients that require blood glucose monitoring should be advised to consider methods that do not react with maltose, such as those based on glucose dehydrogenase nicotine adenine dinucleotide (GDH-NAD), glucose oxidase, or glucose hexokinase test methods. ORENCIA for subcutaneous administration does not contain maltose; therefore, patients do not need to alter their glucose monitoring.
USE IN SPECIFIC POPULATIONS Pregnancy - Pregnancy Category C: There are no adequate and well-controlled studies of ORENCIA (abatacept) use in pregnant women. Abatacept has been shown to cross the placenta in animals, and in animal reproduction studies alterations in immune function occurred. ORENCIA should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Abatacept was not teratogenic when administered to pregnant mice at doses up to 300 mg/kg and in pregnant rats and rabbits at doses up to 200 mg/kg daily representing approximately 29 times the exposure associated with the maximum recommended human dose (MRHD) of 10 mg/kg based on AUC (area under the time-concentration curve). Abatacept administered to female rats every three days during early gestation and throughout the lactation period, produced no adverse effects in offspring at doses up to 45 mg/kg, representing 3 times the exposure associated with the MRHD of 10 mg/kg based on AUC. However, at 200 mg/kg, 11 times the MRHD exposure, alterations in immune function were observed consisting of a 9-fold increase in T-cell dependent antibody response in female pups and thyroid inflammation in one female pup. It is not known whether these findings indicate a risk for development of autoimmune diseases in humans exposed in utero to abatacept. However, exposure to abatacept in the juvenile rat, which may be more representative of the fetal immune system state in the human, resulted in immune system abnormalities including inflammation of the thyroid and pancreas [see Nonclinical Toxicology (13.2) in Full Prescribing Information]. Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to ORENCIA, a pregnancy registry has been established. Healthcare professionals are encouraged to register patients and pregnant women are encouraged to enroll themselves by calling 1-877-311-8972. Nursing Mothers - It is not known whether ORENCIA is excreted into human milk or absorbed systemically after ingestion by a nursing infant. However, abatacept was excreted in rat milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ORENCIA, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use - ORENCIA is indicated for reducing signs and symptoms in pediatric patients with moderately to severely active polyarticular juvenile idiopathic arthritis ages 6 years and older. ORENCIA may be used as monotherapy or concomitantly with MTX. Studies in juvenile rats exposed to ORENCIA prior to immune system maturity have shown immune system abnormalities including an increase in the incidence of infections leading to death as well as inflammation of the thyroid and pancreas [see Nonclinical Toxicology (13.2) in Full Prescribing Information]. Studies in adult mice and monkeys have not demonstrated similar findings. As the immune system of the rat is undeveloped in the first few weeks after birth, the relevance of these results to humans greater than 6 years of age (where the immune system is largely developed) is unknown. ORENCIA is not recommended for use in patients below the age of 6 years. The safety and effectiveness of ORENCIA in pediatric patients below 6 years of age have not been established. The safety and efficacy of ORENCIA in pediatric patients for uses other than juvenile idiopathic arthritis have not been established. Geriatric Use - A total of 323 patients 65 years of age and older, including 53 patients 75 years and older, received ORENCIA in clinical studies. No overall differences in safety or effectiveness were observed between these patients and younger patients, but these numbers are too low to rule out differences. The frequency of serious infection and malignancy among ORENCIA-treated patients over age 65 was higher than for those under age 65. Because there is a higher incidence of infections and malignancies in the elderly population in general, caution should be used when treating the elderly. OVERDOSAGE Doses up to 50 mg/kg have been administered intravenously without apparent toxic effect. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment instituted.
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analysis categories. The changes in survey scores for each participant were evaluated, and the average, between-member scores were calculated. Results
At the six-month time frame, a total of eight participants were lost to follow-up. The data presented pertains to the 21 remaining participants (18 females and three males, ranging in age from 36 to 63 for the females and from 56 to 64 for the males).
from medications since the baseline period in the therapeutic classes indicated (Q1 represents a 90day period that encompasses the baseline and eightweek time frames. Q2 represents a 90-day period that encompasses the 26-week time frame). At this point in time, approximately 23.8 percent of CHIP participants have been able to eliminate one or more of their medications since the start of the program intervention. Laboratory Results
Costs
A health care cost analysis was conducted on the accumulated VHP medical and prescription drug paid-claims data. The costs reflected in Exhibits 2 and 3 are average costs per member per quarter for all CHIP participants still employed and covered by the VHP, non-CHIP diabetic VHP members, and all non-CHIP VHP members in the same age range as the CHIP participants. The “All non-CHIP members” category includes all non-CHIP diabetics. Since VHP-paid claims can vary based upon the amount of copays that must be met, the data for copays has been included. Medical-claims costs include both in-patient (IP) and out-patient (OP) utilization as well as OP medications. Prescription drug claims (Rx) represent all self-administered prescription drugs obtained either through retail pharmacies or through a mail-order service. Exhibit 2 provides a presentation of the aggregate costs (medical and pharmaceutical) for all the participants in the study. For the CHIP participants, cost reductions occurred in both the first and second quarters following the program. Savings were realized yearover-year within the study group as well as when compared to non-CHIP diabetics and plan members as a whole. Exhibit 3 provides a breakdown of the total claims costs in the categories of medical costs and pharmaceutical costs (Rx). In an effort to understand where the cost reductions occurred, the utilization of services was measured in terms of OP medical visits (Exhibit 4), and prescription medications (Exhibit 5). Utilization reduction in prescription medication was measured by evaluating the changes in the average number of prescriptions filled per patient as well as an attempt to evaluate where, by medication therapeutic classification, the changes occurred (Exhibits 5 and 6). In Exhibit 6, the first column shows members that were identified during the second quarter that had ceased taking their medications for 90 days. The second column represents participating members who have accumulated a six-month period of time free
Changes in HBA1C, Total Cholesterol, LDL, HDL, and Triglyceride values were determined at t=0, t=8, and t=26. In Exhibits 7 and 8, with the exception of HDL, a positive number indicates a drop (or positive outcome) and a negative number indicates an increase in these values (or negative outcome). For HDL, since an increase is considered favorable, a reduction in this value indicates a negative outcome and an increased a positive outcome. To determine if the changes could be sustained, the same lab parameters were measured six months after the start of the program. Exhibit 7 presents the improvements that occurred among the study participants and the percentage making those improvements at the indicated time periods: Well-Being
In order to measure the immediate and longer term effects that a comprehensive lifestyle program might have on well-being, a validated and complete wellbeing assessment (WBA) was administered at baseline, eight weeks, and 26 weeks. Survey evaluation and scoring was conducted by Healthways™ both at the group level and at individual levels. The WBA included self-scoring in the following categories utilizing the Gallup-Healthways Well-Being Index Assessment Survey ®: Life Evaluation Physical Health Emotional Health Healthy Behaviors Work Environment Basic Access Overall Well-Being Index® The average changes in each individual’s response were evaluated, comparing the results after eight and 26 weeks to baseline measures.(Exhibit 8) Discussion
Although there are multiple factors that contribute to the success of a program, a fundamental requirement of any program that seeks to change behavior is engagement. There was a high degree of skepticism at the planning stage of this study that active
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engagement could be realized in a sizable portion of the study group around a lifestyle program that had as its main tenets exercise and a plant-based diet. These findings suggest that this may be less of an issue than originally believed. Nearly two-thirds (54 percent) of our participants were engaged in the program at a level to effect a change in their labs or biometric measures. Data depicting lab values at two-months and six-months after baseline and comprehensive well-being assessments further support this statement on engagement. It is believed that this greater than expected acceptance, hence engagement, was due, in part, to the fact that the plantbased aspect of the program was never presented as a hard sell. As a part of the biometric analysis, weight loss for participants was evaluated from zero to +six months. 54.17 percent of the members have lost an average of 9.4 pounds (median = 7 lbs). 37.5 percent of the members have gained an average of 13.7 pounds (median = 9.4 lbs). The changes to lab values reflect the effect of eight weeks of intensive CHIP training on diabetic individuals. Significant change was observed in two measurements: Reduction in variation of the HBA1C values of the group (p=0.01) and reduction in mean LDL of the improvement group (p=0.01). This is noteworthy because reductions in HBA1C values are indicative of long-term blood glucose control, and reductions in LDL indicate dietary improvements that can lead to reductions in risk for coronary artery disease which is the number one killer among type 2 diabetics. The same lab values were again assessed at 26 weeks following the baseline measurements. An improvement in the biometric lab results were seen in all areas except HBA1C at the 26-week mark. This suggests that ongoing group activity, or rigorous lifestyle coaching may be necessary in order to sustain the behavioral changes in lifestyle that were seen at the onset of the program. Weight loss, or gain, was not statistically significant. However, a slightly higher proportion of participants lost weight than gained weight. The health care cost analysis, which compared identical time frames from 2010 to the CHIP study period in 2011 for all CHIP participants, all nonCHIP T2DM VHP members, and all non-CHIP members between the ages of 35 and 65, found savings across each comparison group. Total VHP-paid claims per member for the CHIP participants decreased against each comparative time frame, while the costs for the non-CHIP diabetics increased across both comparative time frames. The overall costs for all non-CHIP members decreased in the
first quarter but increased in the second. Comparing Quarter one (Q1) of 2010 to Quarter one (Q1) of 2011, average copays per member decreased across all groups. However, the decrease for the CHIP participants was higher than the other two comparison groups. A slight decrease was noted for all CHIP participants and all non-CHIP members for the Quarter two comparisons. Against this same time, the non-CHIP diabetics had higher out-ofpocket expenses. Drug utilization changes were evaluated based on days’ supply, product name (NDC), and therapeutic class. Our results showed favorable changes in prescription drug utilization: The length of time without possession of medication, in conjunction with discussions held with the participants, indicate that the gaps in possession were intentional and not due to participant negligence. However, it is too early to reliably know if the changes will be sustainable over a longer period of time. The data suggest that during the “engagement period,” or shortly after the intervention, some members may be less likely to sustain the lifestyle habits that allow them to reduce or stop taking their medications. For that reason, the change we see over the time-interval covered in this six-month report will need to be followed and reassessed at the post-26-week time period. Nevertheless, the current findings seem quite promising with 23.4 percent of our study population able to eliminate one, or more, of their medications within a six-month period. The therapeutic categories that demonstrated the most change in drug utilization were in the antidiabetic, anti-hyperlipidemia, cardiac, and gastrointestinal drug categories. As highly-processed, highfat foods in the diet are replaced with high-nutrient and high-fiber foods, and as exercise is introduced into the lifestyle, it appears that individuals can rely less on insulin, cholesterol medications, and GERDreducing agents to treat their conditions. The bulk of the cost reduction changes came from lower utilization which resulted in lower medical expenses and drug costs( 32.7% reduction, on average, across both quarters). Had the CHIP cohort experienced a trend similar to the non-CHIP group, the expected health care cost (medical + prescription) for the participants in CHIP is estimated to have been 45.3% higher. The end result is an estimated 1.38:1 return-on-investment within a six-month period. Comprehensive well-being assessments were conducted and scores were calculated by Healthways. The overall measure of well-being, via the WBA, improved over the baseline measure for both postbaseline time periods. At the individual levels, work environment and
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basic access scores decreased at the eight-week mark. However, the decreases were not statistically significant, and at the 26-week mark, the changes were positive compared to baseline. There was no change across the healthy behaviors category. All other categories reflected positive changes to the well-being scores at the eight-week mark, with statisticallysignificant changes occurring in the life evaluation scores, physical health, emotional health, and the overall Well-Being index. After 26 weeks, all categories, with the exception of healthy behaviors, had positive changes compared to the baseline wellbeing scores. Statistically-significant changes were noted at the 26-week mark in physical health and well-being index. The fact that responses for wellness in Healthy Behaviors decreased from the baseline to the 26-week mark may suggest that these participants have a better understanding of what healthy behaviors truly are, as a consequence of the educational training associated with the program. The statistically-significant changes in the Well-Being Index suggest that even small changes in lifestyle can improve one’s overall outlook on life. Conclusion
The evidence that diet and exercise affect health and well-being is irrefutable. While findings are consistent with previous community-based research in this area, this study provides new evidence, from an employer perspective. This study demonstrates that educating a member population about the benefits of a plant-based, whole-foods diet is feasible, and can improve health outcomes and well-being for individuals suffering from a chronic condition like type 2 diabetes. The study was also intended to evaluate implementation and successful engagement among employees. Within alternative community settings, participants often receive peer support from family members and friends that can bolster engagement. There was uncertainty at the program onset surrounding the ability to actively engage employees in a work setting among workplace peers. Findings of this study suggest that it is possible to achieve engagement around changing lifestyle behaviors in an employee population in a workplace setting. And, that an intensive, comprehensive lifestyle program is capable of generating measurable savings with a meaningful return-on-investment (ROI) within a relatively short period of time. Dexter Shurney, MD, MBA, MPH is an Assistant Professor at Vanderbilt University School of Medicine and is the Chief Medical Director, Employee Health Plan Vanderbilt University Medical Center. Sandra Hyde, MSPS is a data Analyst and Biostatistician II, HR Benefits Employee Health Plan at Vanderbilt University Medical Center, she is an Adjunct Professor of Mathematics at Belmont University.
Kristina Hulsey, MSPS is a Core Research Assistant II, DNA Resources Core at Vanderbilt University Medical Center. Roy Elam, MD, Medical Director, Center for Integrative Health, Vanderbilt University Medical Center Abby Cooper, MHIM, Activities Coordinator and Nutrition Educator, Center for Integrative Health, Vanderbilt University Medical Center Jay Groves, EdD, MMHC, Administrative Director, Dayani Center for Health and Wellness, Vanderbilt University Medical Center
References 1. Yusuf S, Hawken S, Ounpuu S et al. Interheart Study Investigators. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case control study. Lancet 2004; 364(9438): 937-52. 2. Hozawa A, Folsom AR, Sharrett AR, Chambless LE. Absolute and attributable risks of cardiovascular disease incidence in relation to optimal and borderline risk factors: comparison of African American with white subjects: Atherosclerosis Risk in Communities Study. Arch Intern Med. 2007;167:573–579. 3. Stamler J, Stamler R, Neaton JD, Wentworth D, Daviglus ML, Garside D, Dyer AR, Liu K, Greenland P. Low risk-factor profile and long-term cardiovascular and noncardiovascular mortality and life expectancy: findings for 5 large cohorts of young adult and middle-aged men and women. JAMA. 1999;282:2012–2018. 4. Stampfer MJ, Hu FB, Manson JE, Rimm EB, Willett WC. Primary prevention of coronary heart disease in women through diet and lifestyle. N Engl J Med. 2000;343:16 –22. 5. Joshipura, Kaumudi. The Effect of Fruit and Vegetable Intake on Risk for Coronary Heart Disease. Ann Intern Med. 19 June 2001;134(12):1106-1114 6. BMJ 2002;324:1570 7. Lancet 1998: 352: 1801-7 8. Yang Q et al. Trends in cardiovascular health metrics and associations with all-cause and CVD mortality among US adults. JAMA 2012 Mar 28; 307:1273. 9. Digging a Vegetarian Diet. NIH News in Health. July 2012. Contributions by Vicki Contie, Alan Defibaugh (illustrations), Bonnie Tabasko and Harrison Wein. Available at: http://newsinhealth.nih.gov.issue/jul2012/feature1 accessed July 2012). 10. Dietary Approaches to Stop Hypertension (DASH). October 1999. Available at: http://clinicaltrials.gov/ct2/show/record/NCT00000544?term=NCT 00000544&rank=(assessed July 2012). 11. Knowler W, Fowler S, Hamman R, et al. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet 2009; 374(9702): 1677-1686. Doi:10.1016/S0140-6736(09)61457-4 12. Barclay C, Proctor K, Glendenning R, Marsh P, Freeman J, Mathers N. Can type 2 diabetes be prevented in UK general practice?: A lifestyle-change feasibility study (ISAIAH)” British Journal of General Practice 2008; 541-547. 13. Wing R, Bahnson J, Bray G. Long term effects of a lifestyle intervention on weight and cardiovascular risk factors in individuals with type 2 diabetes: Four year results of the Look AHEAD Trial. Arch Intern Med. 2010; 170(17): 15661575. Doi: 10.1001/archinternmed.2010.334. 14. Ben was right: New study proves prevention is the cure. US Preventative Medicine. 2011. Available at: http://www.uspreventivemedicine.com/Wellness/Research.aspx (accessed July 2012). 15. Ornish D, et al. Can lifestyle changes reverse coronary heart disease? The Lifestyle Heart Trial. Lancet 1990 Jul 21;336(8708):129-33. 16. Ornish D, et al. Intensive lifestyle changes for reversal of coronary heart disease. JAMA 1998 Dec 16;280(23):2001-7. 17. Complete Health Improvement Program /CHIP Health: www.chiphealth.com 18. The CHIP Prescription For Health / Absolute Advantage: www.welcoa. org/pdf/CHIP_Prescription_for_Health.pdf 19. Cheung, M.M. et al, Diabetes prevalence and therapeutic target achievement in the United States, 1999 to 2006. Am J Med, 2009. 122 (5): p.443-53. 20. Fitch K. Pyenson B., Iwasaki K., Improved Management Can Help Reduce the Economic Burden of Type 2 Diabetes: A 20-Year Actuarial Projection, Milliman Client Report, 2010. 21. Complete Health Improvement Program sponsored by Lifestyle Medicine Institute LLC. http://www.chiphealth.com/about_chip/index.php��������
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Updates in the Guidelines and Treatment of Hepatitis C David H. Winston, MD, FACP, AGAF For a CME/CEU version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.
Summary Because curative treatments exist, the health care system needs to ensure people with risk factors for hepatitis C get screened and, if positive, get appropriate treatment. Treating infected individuals reduces the long-term consequences of the infection. Cure does require several medications which can be difficult for people to adhere with. Key Points • HCV infection is a major cause of chronic liver disease, cirrhosis and hepatocellular carcinoma, but treatment reduces these consequences. • The majority of infected Americans have genotype 1 virus. • Seventy-five percent of the infected people in the U.S. have not been diagnosed. • Of those diagnosed, the majority are NOT treated. • HCV infection should be suspected based on risk factors, not symptoms or lab tests. • Primary care providers need to screen all patients with HCV risk factors. • All patients with chronic HCV infection should be referred for treatment. • Early diagnosis and treatment will result in improved survival, improved quality of life, and reduced economic burden of HCV. • Triple therapy is currently the best way of achieving SVR in genotype 1 patients and reducing the risk for resistant virus.
Hepatitis C virus (HCV) is a singlestranded RNA virus and is the only member of genus Hepacivirus in the Flaviviridae family. Humans are the only known natural host for this virus. Unlike the DNA viruses HIV and Hepatitis B, cure of HCV infection is possible. With HCV, the viral RNA is in the cytoplasma of the cell and medications can enter the cell and kill the virus. There are six genotypes of the HCV. Treatment choices and duration of therapy depends on the viral genotype. The most common genotypes in the U.S. are 1, 2, and 3.1 Approximately 75 percent of infected Americans have genotype.1.2,3 The World Health Organization has estimated that 200 million people have been infected with HCV worldwide and 170 million have chronic disease worldwide.4 The highest prevalence is in the Far East and Southeast Asia. The Centers for Disease Control estimate that 4.1 million Americans have been infected with HCV.5 Based on a study pub-
lished in 2011, this estimate appears to be low and is likely closer to 5.2 million.6 Over three million (and possibly as many as four million) Americans have chronic disease.6 The prevalence is highest in African Americans and males.6 The majority of infected people are baby boomers – born between 1945 and 1965. As outlined in Exhibit 1, the majority of patients who contract an acute HCV infection will go on to develop chronic infection.7 The major consequences of HCV infection are cirrhosis, hepatocellular carcinoma (HCC), and death. Unfortunately, 75 percent of the infected people in the U.S. have not been diagnosed.8 Additionally, the majority of patients who are diagnosed are not treated. Given that a possible four million Americans are chronically infected with HCV, without treatment over the next 20 years, approximately 780,000 people can be expected to develop cirrhosis. Of these cirrhotic people, approximately 30,000 will develop
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Exhibit 1: Hepatitis C: Natural History7
Acute HCV Infection 15%
85%
Recovery
Chronic HCV Infection
80%
20%
Stable
Cirrhosis
25% Decompensation
75%
Stable
4% Hepatocellular CA
Death or Liver Transplantation
HCC. HCV is the most common cause of HCC in the U.S., accounting for 60 percent of cases. HCV increases the risk for HCC probably by promoting fibrosis and cirrhosis. The number of acute HCV infections peaked between 1970 and 1990. After 1990, acute infections were lowered with screening of blood for transfusions and increased safe sex practices. The peak of chronic HCV prevalence was 2001. Because it takes an average of 20 years to develop cirrhosis after acute infection, the highest prevalence of cirrhosis is projected to be between 2010 and 2030.9 It takes almost 30 years after infection to develop liver cancer thus the incidence of HCC is projected to peak in 2020. There are several factors which increase the risk of disease progression to cirrhosis and cancer with chronic HCV. These include alcohol consumption greater than 30 g/day in males and 20 g/day in females, HCV acquisition at greater than 40 years, male gender, HIV or HBV co-infection, hepatic steatosis, and daily cannabis use.10-12 Thirty grams/ day of alcohol is approximately equal to two drinks per day. It is especially important to get patients who are infected with HCV to stop drinking all forms of alcohol. Patients who are initially exposed to HCV when they are older than 40 years of age generally have a higher degree of fibrosis regardless of how long they have had the disease, compared with individuals who are infected at a younger age.12 Additionally, obesity-related insulin resistance can lead to fatty liver and nonalcoholic steatohepatitis (NASH) and accelerate the development of fibrosis in HCV.13
Several factors have been found to not influence progression of disease. These include transaminase level (ALT), viral load, mode of transmission, and genotype.11 In order to treat and cure the patient infected with HCV, they must first be found. The primary care provider (PCP) has a unique window of opportunity to make a diagnosis of HCV and refer the patient for treatment prior to the development of cirrhosis and its complications. Early diagnosis and treatment will result in improved survival, improved quality of life, and reduced economic burden of HCV. Screening barriers have lead to the high number of undiagnosed patients. Patients are usually asymptomatic so they are not going to seek screening. In the 37 percent who are symptomatic, the main symptom is fatigue, which is very nonspecific. Many persons infected with HCV are unaware of the risk factors for HCV so they do not know they should be screened.14 PCPs are another barrier. Routine HCV risk factor assessment is not current primary care practice. Elevated liver function tests, not risk factors, is the trigger for PCPs to order a liver panel.15 PCPs need to identify and screen all their patients with risk factors for HCV including those with a normal ALT, but this will mean changing practice. HCV risk screening can be done at the same time as alcohol and tobacco use screening. The majority of patients with HCV infection do not have persistently elevated ALT. Most will have intermittent elevations (55 percent) or persistently
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Exhibit 2: Treatment is Associated with Lower Incidence of ESLD, HCC and Death18 25 20
ESLD HCC Liver death or transplant Death
20.7 15.9
15
13.9 9.1
10 6.5 6.5 5 1.4 1.4 1.4
5.2 5.2
2.9
0 SVR Relapse
Non-response
SVR, sustained viral response; ESLD, end stage liver disease; HCC, hepatocellular carcinoma
normal ALT values (30 percent).16 Greater than 75 percent of patients with persistently normal ALT have some degree of liver damage on liver biopsy.16 Thus, ALT levels are an insensitive way of determining disease severity and indication for treatment. Normal ALT HCV infected patients should be evaluated and treated the same as those with increased ALTs. Only 28 percent of PCPs said they would refer an HCV patient with normal ALTs for treatment.17 HCV is spread through contact with infected blood. Intravenous drug use now accounts for twothirds of HCV infection in the U.S. Other bloodrelated risk factors include receiving blood or blood products or a solid organ transplant before 1992, needle sticks, and hemodialysis. Some additional blood-related risk factors for HCV inventions are intranasal cocaine with shared implements, body piercing with contaminated needles, and tattooing with contaminated needles or ink. There are a few less common ways of contracting HCV through infected blood, including the sharing of household items that could carry infected blood such as razors, toothbrushes, and manicure implements; traumatic contact with blood through cuts or nose-bleeds; and perinatal transmission. Perinatal transmission occurs in about 5 percent of deliveries from HCV positive mothers. Sexual transmission accounts for less than 5 percent of all cases. This mode of transmission is seen in people with high-risk sexual behavior such as multiple sex partners, prostitutes, man-to-man sex where there is trauma to the mucosa. The risk in
Exhibit 3: Absolute Contraindications to Peginterferon/ribavirin • Women who are pregnant and men whose female partners are pregnant • Patients and their partners who are unwilling or unable to practice contraception • Poorly controlled psychiatric disease • Poorly controlled or symptomatic coronary artery disease • End-stage renal disease • Kidney and heart transplants
Relative Contraindications to Peginterferon/ribavirin • History of/or ongoing depression • Decompensated cirrhosis • Autoimmune disease • History of coronary heart disease • Active substance abuse • Hemoglobinopathies, preexisting anemia, neutropenia, and thrombocytopenia
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Exhibit 4: Algorithm for Genotype 1: NaĂŻve and Prior Relapsers21 Start Triple Therapy
End of Week 4
End of Week 12 Telaprevir Complete
T+P+R
Undetectable RNA Continue T + P + R
Undetectable RNA Continue P + R (eRVR)
End of Week 24
Test RNA Stop
Detectable RNA
RNA <1000 IU/ml Continue P + R
Undetectable RNA Continue P + R
Stop
Stop
RNA >1000 IU/ml
Detectable
RNA < 1000 IU/ml Continue P+R
Undetectable RNA Continue P + R
Early responder
CIRRHOSIS: Treat 48 weeks
Test RNA @ week 72 Stop
Late responder
T, telaprevir; P, pegylated interferon; R, ribavirin
End of Week 48
RNA <1000 IU/ml Continue T + P + R
Test RNA @ week 72 Stop
Stop
Stop
Stop
RNA >1000 IU/ml
RNA >1000 IU/ml
Detectable
monogamous partners is extremely low. Patients with risk factors or elevated LFTâ&#x20AC;&#x2122;s should be screened with an enzyme immunoassay antiHCV test. This test has greater than 99 percent sensitivity. A positive anti-HCV is confirmed with quantitative HCV ribonucleic acid polymerase chain reaction (RNA PCR). This test will be positive within one to three weeks after exposure. A positive HCV RNA PCR denotes active disease and infectivity. The HCV genotype is also identified since this has treatment implications. Patients who are HCV positive need certain vaccinations and counseling on preventing disease progression. They should be immunized against hepatitis A and B so they do not contract an additional hepatitis virus. Infected individuals should be advised to avoid all alcohol consumption. All current medications, including vitamins, along with over the counter and herbal medications need to be reviewed for potential liver toxins. Infected individuals should consult a health care provider before beginning any new medications. Infected individuals also need to understand that they should not donate blood, sperm, or organs. They need to understand how to prevent transmission to other people, including avoiding sharing personal items and covering open wounds. If they
are using illicit drugs, they need to stop; this will likely require referral to a treatment program. If they continue to use drugs, they should not reuse or share needles. For those people who are not treatment candidates and who have multiple sexual partners or short-term sexual relationships, latex condoms are recommended. No condom use is recommended for long-term monogamous couples who have a low risk of transmission. For those who are treated and are fertile with a fertile partner, two non-hormonal forms of birth control should be used so pregnancy does not result. With the currently available therapies which can cure patients, PCPs can be found negligent if not properly caring for patients with HCV. PCPs need to avoid failure-to-diagnose claims and failure-totreat claims. They should be investigating persistent elevations of ALT. All infected patients, regardless of their insurance status or socioeconomic class, need to be informed that medications do exist to treat HCV. If the PCP prefers not to manage these patients, they should be referred to an HCV specialist. The primary goal in treating HCV infection is the permanent eradication of virus from serum. This is achieved with a sustained viral response (SVR) which is undetectable HCV RNA six months after completion of treatment. A SVR is synonymous
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with “cure”. SVR leads to improved liver histology and improved clinical outcomes (Exhibit 2).18 Therapy of HCV infection has improved since the introduction of interferon in 1991. Interferon only resulted in a 6 percent response rate. The current recommended triple regimen (protease inhibitor, pegylated interferon, and ribavirin) results in 70 to 75 percent SVR. Interferon (IFN) has a large number of biological actions; most of these actions involve the immune system. The primary action against HCV is an antiviral effect. IFNs can inhibit viral replication at one of several sites and by one of several mechanisms, including at entry and/or uncoating, during replication, by influencing RNA stability, during the initiation of translation, or at maturation, assembly, or release. Interferon does not need to have direct contact with HCV to elicit antiviral effect. It induces antiviral protein production in hepatocytes and immunoregulatory protein production in hepatic immune cells. Pegylated interferon has a long duration of activity allowing once weekly injection compared with three times weekly with the nonpegylated form. Pegylated interferon also results in a better response rate than non-pegylated interferon. Ribovirin is a synthetic nucleoside analogue. As monotherapy, it has no antiviral effect against HCV (i.e., does not reduce HCV RNA levels). In combination with interferon, the response rate to interferon is dramatically increased. The mechanism for this increase in response is unknown; it may upregulate interferon. Therapy using pegylated interferon combined with ribavirin leads to SVR in 40 to 52 percent of patients infected with HCV genotype 1.19 For patients with HCV genotype 2 or 3 infection, SVR rates are 76 to 93 percent. Because of the lower response rate with genotype 1, researchers searched for better medications. A breakthrough occurred when the life cycle of HCV was uncovered. This understanding of the life cycle of HCV allowed for the identification of targets for antivirals that directly interrupt HCV replication direct acting antivirals (DAAs). The first approved DAAs have been 2 protease inhibitors - telaprevir (Incivek®) and boceprevir (Victrelis®). These agents target NS3/4A serine protease, the “master switch” for HCV RNA replication and virion assembly. Switching off the protease prevents cleavage of the new viral RNA chain halting viral replication. There are about 50 medications in development for HCV targeting different parts of the life cycle.20 Telaprevir and boceprevir markedly increase the SVR rates for genotype 1 treatment-naïve and treatment-experienced patients and were approved
in 2011 for treatment of genotype 1 but not genotypes 2 and 3.21 Limited data show telaprevir has activity against genotype 2 but not genotype 3 and boceprevir has activity against genotype 2 and 3. Pilot studies are ongoing looking at using DAAs to treat genotype 2 and 3. Because of the risk for resistant virus, neither protease inhibitor can be used alone. At this time, they are not FDA approved for use in post-transplant recurrent HCV, coinfected HIV or HBV, or in children. Both telaprevir and boceprevir are inhibitors of CYP3A liver metabolism causing significant drugdrug interactions. If affected medications cannot be stopped or substituted for the duration of treatment, protease inhibitors cannot be used. A very important interaction with protease inhibitors is with estrogen-based birth control. Estrogen levels are significantly decreased by the protease inhibitors, thus pregnancy may occur. Patients receiving protease inhibitors or ribavirin, which is teratogenic, must use two forms of effective nonhormonal contraception (patient or female partner of male patient). The two forms of birth control need to be continued for six months after the last ribavirin dose. Telaprevir needs to be carefully taken twice a day but separated by seven to nine hours to prevent the development of resistance. It also has to be taken with 20 grams of fat to improve absorption. Boceprevir is given somewhat differently. All patients are first treated with peginterferon and ribavirin as lead-in therapy for four weeks followed by the addition of boceprevir to the regimen. This agent is also given twice a day with seven to nine hours between doses. The dosing requirements can make these medications difficult to comply with. The current standard of care for genotype 1 is triple therapy with peginterferon, ribavirin, and telaprevir or boceprevir. Like HIV, multiple medications need to be used to prevent the emergence of resistant virus. Genotypes 2 and 3 are treated with peginterferon and ribavirin.22 All HCV infected patients with compensated liver disease without contraindications are potential candidates for treatment. There are several absolute and relative contraindications to therapy (Exhibit 3). Response-guided therapy (RGT) is treatment tailored based upon virologic response. With RGT, treatment duration is determined by viral response during the course of therapy. Not all patients with the same genotype respond to treatment in the same way. In those who obtain an extended rapid viral response (eRVR), RGT permits a shorter duration of treatment without jeopardizing the SVR rate which results in substantial cost savings. An eRVR is de-
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fined as virus RNA negative at both eight and 24 weeks if boceprevir is part of the regimen or at four and 12 weeks if telaprevir is used. Exhibit 4 provides an algorithm for the management of genotype 1 in na誰ve and prior relapsers using triple therapy with telaprevir.21 Guidelines for treating prior partial and null responders with genotype 1, for use of boceprevir, and for treatment of genotypes 2 and 3 are available at the American Association for the Study of Liver Disease website (www.aasld.org). Patients who can achieve an eEVR have a better likelihood of having an SVR. There are several other predictors of SVR including race, baseline viral RNA levels, age, body mass index (BMI), and liver fibrosis stage. African Americans have lower SVR than Caucasians. Patients with lower RNA at baseline have a slightly higher SVR. Patients who are less than 40 at the time of treatment have slightly higher SVR. Patients with a higher BMI are less likely to respond. Patients with mild or moderate fibrosis have a higher SVR than those with cirrhosis. The agents used to treat HCV can cause significant adverse effects. The major adverse effects with interferon include psychiatric symptoms, hematologic side effects, flu-like symptoms, gastrointestinal symptoms, retinopathy, and thyroid toxicity. Hemolytic anemia, cough, dyspnea, anorexia, rash, and pruritis are the most common adverse effects with ribavirin. As noted previously, this agent is teratogenic. Telaprevir causes rash, anemia, and anorectal discomfort while boceprevir causes anemia, neutropenia, and dysgeusia. It is important that the dose of the two protease inhibitors not be reduced in an attempt to reduce side effects. Efficacy is lost with any dose reduction.
1999;341;556-62. 3. Blatt LM, Mutchnick MG, Tong MJ, et al. Assessment of hepatitis C virus RNA and genotype from 6807 patients with chronic hepatitis C in the United States. J Viral Hepat. 2000;7:196-202. 4. World Health Organization. Hepatitis C Fact Sheet. Available at www.who. int/mediacentre/factsheets/fs164/en/. 5. Armstrong GL, Wasley A, Simard EP, et al. The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med. 2006;144:705-14. 6. Chak E, Talal AH, Sherman KE, et al. Hepatitis C virus infection in USA: an estimate of true prevalence. Liver Int. 2011;31:1090-101. 7. Hoofnagle JH. Hepatitis C: the clinical spectrum of disease. Hepatology. 1997;26(suppl 1):15S-20S. 8. CDC. Hepatitis C fact sheet. Available at www.cdc.gov. 9. Davis G, Alter MJ, El-Serag H, et al. Aging of hepatitis C virus (HCV)-infected persons in the United States: a multiple cohort model of HCV prevalence and disease progression. Gastroenterology. 2010;138:513-521. 10. Ishida JH, Peters MG, Jin C, et al. Influence of cannabis use on severity of hepatitis C disease. Clin Gastroenterol Hepatol. 2008;6:69-75. 11. Patton HM, Patel K, Behling C, et al. The impact of steatosis on disease progression and early and sustained treatment response in chronic hepatitis C patients. J Hepatol. 2004;40:484-90. 12. Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet. 1997;349:825-32. 13. Clouston AD, Jonsson JR, Powell EE. Steatosis as a cofactor in other liver diseases: hepatitis C virus, alcohol, hemochromatosis, and others. Clin Liver Dis. 2007;11:173-189. 14. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. Centers for Disease Control and Prevention. MMWR Recomm Rep. 1998;47(RR-19):1-39. 15. Institute of Medicine. Hepatitis and liver cancer: a national strategy for prevention and control of hepatitis B and C. Washington, D.C. 2010. 16. Shiffman ML, Stewart CA, Hofmann CM, et al. Chronic infection with hepatitis C virus in patients with elevated or persistently normal serum alanine aminotransferase levels: comparison of hepatic histology and response to interferon therapy. J Infect Dis. 2000;182:1595-601.
Conclusion
17. Bacon BR. Chronic hepatitis C and normal ALT: considerations for treat-
HCV infection is a major cause of chronic liver disease, cirrhosis and hepatocellular carcinoma. Primary care providers need to screen for HCV infections, diagnose appropriately, and refer these mostly asymptomatic patients for treatment. HCV infection should be suspected based on risk factors, not symptoms or lab tests. Triple therapy is currently the best way of achieving SVR in genotype 1 patients.
ment. Am J Gastroenterl. 2004;99:1706-7. 18. Morgan TR, Ghany MG, Kim HY, et al. Outcome of sustained virological responders with histologically advanced chronic hepatitis C. Hepatology. 2010;52:833-44. 19. Hadziyannis SJ, Sette H Jr, Morgan TR, et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med. 2004;140:346-55. 20. Kronenberger B, Welsch C, Forestier N, et al. Novel hepatitis C drugs in current trials. Clin Liver Dis. 2008;12(3):529-55.
David H. Winston, MD, FACP, AGAF is Section Head, Gastroenterol-
21. AASLD Practice Guideline on Treatment of Genotype 1 Chronic Hepatitis
ogy and Hepatology for CIGNA HealthCare of Arizona.
C. Hepatology. 2011;54:1433-1444
References 1. Simmonds P. Variability of the hepatitis C virus genome. Curr Stud Hematol Blood Transfus. 1998;62:38-63. 2. Alter MJ, Kruszon-Moran D, Nainan OV, et al. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med
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Emerging Challenges on the Therapeutic Landscape of Multiple Sclerosis: The Managed Care Physician’s Perspective and Medical Director’s Perspective Bruce A. Cree, MD, PhD, MCR and Brian Steingo, MD For a CME/CEU version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.
Summary The treatment paradigm for multiple sclerosis (MS) is evolving from one focused on peripheral inflammation and relapse rates to consideration of all the possible factors which lead to disability from this disease. The methods for measuring disability over time are continuing to evolve to measure more than just relapse rates. Long-term data are now showing that disease-modifying therapy begun early and continued over time has an impact on disability development and mortality. Key Points • MS is a chronic, debilitating, and progressive disease. • Economic implications are significant and appear directly correlated with disease severity. • Long-term data and expert consensus support the primary role of disease-modifying therapy in managing disease progression and impacting long-term disability development and mortality. • Relapses are only the tip of the iceberg in what leads to disability with this disease. • There is an ongoing paradigm shift in MS treatment toward measuring more relevant outcomes for long-term disability than just annual relapse rates. • The generally accepted sustained change in expanded disability status scale (EDSS) scores at three or six months is not a reliable marker of long-term disability. • Categorical change in EDSS scores correlate with long-term disability much better than sustained change measures. • Optimal therapeutic benefit with DMT requires starting therapy as early as possible and keeping patients on therapy for as long as possible.
Multiple sclerosis (MS) is the most common chronic disease affecting the central nervous system in young adults. It strikes individuals between the ages 20 to 50, normally a time of peak productivity. There are approximately 400,000 cases in the United States with estimates ranging from 250,000 to 500,000 cases. The chance of developing MS is 1:1000 in the general population with the highest incidence in Caucasians and women.1 MS initially presents as clinically isolated syndrome (CIS), a first neurologic episode that lasts at least 24 hours, and is caused by inflammation and demyelination in one or more sites in the central nervous system (CNS).2 Individuals who experience a CIS may or may not go on to develop multiple
sclerosis. The challenge for the physician is to determine the likelihood that a person experiencing this type of demyelinating event is going to experience a second event in the future, thereby meeting the criteria for a definite diagnosis of MS. People with MS can typically experience one of four disease courses, each of which might be mild, moderate, or severe.3 With relapsing-remitting MS (RRMS) there are clearly defined attacks of worsening neurologic function followed by partial or complete recovery periods (remissions), during which no disease progression occurs. Approximately 85 percent of people are initially diagnosed with relapsingremitting MS. Primary-progressive MS (PPMS) is characterized by slowly worsening neurologic func-
22 Journal of Managed Care Medicine | Vol. 15, No. 4 | www.namcp.org
Exhibit 1: The Evolving Landscape of MS Therapy Disability
Brain Atrophy Multiple End Points Predict Core Health Outcomes and Disease Progression for RRMS
TREATMENT PARADIGM SHIFT
Relapse Rates
Relapse Rates
tion from the beginning—with no distinct relapses or remissions. The rate of progression may vary over time, with occasional plateaus and temporary minor improvements. Approximately 10 percent of people are diagnosed with primary-progressive MS. Following an initial period of RRMS, many people develop secondary-progressive MS (SPMS) in which the disease worsens more steadily, with or without occasional flare-ups, minor remissions, or plateaus. Before the disease-modifying medications became available, approximately 50 percent of people with relapsing-remitting MS developed this form of the disease within 10 years. Long-term data are not yet available to determine if treatment significantly delays this transition. Progressive-relapsing MS (PRMS) is a relatively rare course of MS (5 percent) with steadily worsening disease from the beginning, but with clear attacks of worsening neurologic function along the way. Individuals with this form of MS may or may not experience some recovery following these relapses, but the disease continues to progress without remissions. Relapses are the most obvious evidence of inflammatory disease activity in RRMS. From natural history studies, it is known that patients who have frequent relapses are at high risk for long-term disability. Although many patients recover from relapses, about 30 percent of patients will have a sustained decline in function as measured by the Expanded Disability Status Scale (EDSS) by 1 point and 46 percent will have a half point worsening.4 The lower the relapse rate early in the course, the less disability a patient will have over time. Although relapses early in the disease course correlate with late disability, relapses occurring greater than five years after onset have a diminished effect. Many RRMS patients eventually develop secondary-progressive disease. Once the progressive phase of MS is reached, relapses seem to have little impact on major disability milestones. For example, once an EDSS of 4 is reached, patients progress to an EDSS of 6 at the same rate independent of relapse
Axonal Preservation
occurrence. Thus, relapses may be only the “tip of the iceberg” as an indicator of disease severity but not the primary cause of disability.5 It is estimated that for every attack symptomatic enough for a patient to seek care, there are perhaps 10 attacks that can be documented on MRI scans; thus sub-clinical damage is ongoing. The latter phase of MS is characterized by increasing disability (as measured by the EDSS) as the process of irreversible nerve damage continues. As neurodegeneration progresses, the disease becomes increasingly more difficult to treat. As MS progresses and the level of disability increases, both the direct and indirect costs of care increase. The objective of early treatment is to lessen the development of long-term disability, and thereby reduce the overall cost of care. Currently, there is a basic paradigm shift in MS treatment ongoing (Exhibit 1). In the past, there was a great deal of focus on the neuroinflammatory component of the disease, the contrast enhancing lesions, and measuring annual relapse rates to judge medication efficacy. The treatment paradigm is now shifting from only measuring relapse rates to including long-term measures for disability such as sustained changes in the EDSS score and brain volume loss. Rather than showing a one point change in the EDDS or a decrease in the annualized relapse rate, other outcomes need to be tracked including patient reported outcomes. The goals of treatment are reducing frequency of relapse, slowing progression of disability, reducing MRI disease activity, preventing morbidity from symptoms, maintaining medication adherence, and providing long-term efficacy and safety. Obtaining long-term efficacy and safety data is difficult in this disease because it evolves over a long period of time which makes conducting a randomized trial difficult. A number of landmark disease-modifying therapies (DMT) have been introduced since 2005 and many more are under study (Exhibit 2). Exhibit 3 illustrates the effect on annualized relapse rate
www.namcp.org | Vol. 15, No. 4 | Journal of Managed Care Medicine 23
Exhibit 2: Existing and Emerging MS Therapies Tysabri® (natalizumab)
Betaseron® (IFNß-1b)
Daclizumab Extavia® (IFNß-1b)
Avonex® (IFNß-1a) Copaxone® (glatiramer acetate)
Campath® (alemtuzumab) Laquinimod
Gilenya® (Fingolimod)
Novantrone® (mitoxantrone)
Fumarate (BG-12) Teriflunomide
Rebif ® (IFNß-1a) 1995
2000
2005
2009
2010
2011
2012
Approval date Approval therapies
of the currently approved front-line therapies for RRMS.6-12 It is important to note that this exhibit shows cross-trial results. The agents have not been compared head-to-head and the placebo groups from the trials were very different. Additionally, the most recent clinical trials have recruited patients who are younger and have less active disease. This is especially evident with the trials for fingolimid where only 50 percent of patients had a relapse during the trial and only 24 percent experienced an increase in EDSS. It is becoming harder to show an impact in modern clinical trials. Most clinical trials define disease progression by demonstrating a one point change in the EDSS, and then confirming the change at three or six months. There is still debate whether a sustained change in EDSS for three or six months represents true longterm disability. Fifty percent of patients with a one point change, confirmed at three months, will improve to a lower EDSS by the end of a two-year trial.13 Thirty-three percent of patients with a one point change, confirmed at six months, will improve to a lower EDSS. More stringent measures of change are harder to demonstrate in two-year trials because relatively few MS patients will progress. Six month sustained EDSS change is more rigorous than a three-month sustained change, but neither is a good predictor of long term disability.13 In addition to reducing the annualized relapse rate, interferon beta-1a, glatiramer acetate and fingolimod have statistically significant impacts on the mean change in EDSS over three to six months (Exhibit 4).6-12 Data from long-term follow-up of clinical trials
In Phase III
can help demonstrate true changes in disability over time with treatment. More MS clinical trails are now incorporating a long-term follow-up in which patients are contacted and re-assessed several years after the trial ended. The patients would have been under routine care in the intervening years and the patient may or may not still be on the original investigational agents. Long-term follow-up studies have shown several key findings. The most important is that categorical change in EDSS scores correlate with long-term disability much better than sustained change measures. Patients with mild disability at study entry are more likely to do better long term than patients with more disability. Long-term follow-up has also shown that new brain MRI lesions and clinical relapses while on treatment predict more serious long-term disability. This finding should lead to changes in the recommended treatment algorithms; medication changes should be made when new lesions are seen on MRI or a relapse occurs. Additionally, the duration of exposure to treatment influences long-term disability. Lastly, early initiation of treatment reduces MS mortality.14,15 The National MS Society Expert Consensus Statement recommends initiating therapy as soon as possible following diagnosis of active-relapsing disease with interferon beta agent or glatiramer acetate.16 Drug therapy should also be considered in patients with CIS at high risk of MS. This statement recommends that access to medications not be limited by age, level of disability, or frequency of relapses. Additionally, it recommends continuing treatment indefinitely unless lack of benefit, intolerant adverse
24 Journal of Managed Care Medicine | Vol. 15, No. 4 | www.namcp.org
Exhibit 3: Annualized Relapse Rates with Current Therapies: Phase III Trials6-12
% Reduction in relapse rates
70
54%
60
P<.0001
50 40 30
31% P=.0001
20
18%
P<.001
32% P<.0001
29% P=.055
P=.04
10 0
29%
250 μg qod 30 μg qw 22 μg tiw 44 μg tiw IFN ß-1b IFN ß-1a IFN ß-1a IFN ß-1a
20 mg qd glatiramer acetate
0.5 mg qd fingolimod
Important Note: Results are from separate clinical trials
Exhibit 4: Effect on Sustained Disability*: Phase III Trials 6-12 40 Reduction in sustained disability progression (%)
35 30 25 20
37% 6 mon
37% 29% P=NS
P=.02
30% 22%
P=.02
P<.05
P<.05
15
12%
10
P=NS
5 0 250 μg qod 30 μg qw 22 μg tiw 44 μg tiw IFN ß-1b IFN ß-1a IFN ß-1a IFN ß-1a
20 mg qd glatiramer acetate
0.5 mg qd fingolimod
*>1 EDSS point sustained for 3 months in IFN ß-1b, IFN ß-1a tiw, GA trials and fingolimod phase III trials. >1 EDSS point sustainedt for 6 months in IFN ß-a qw and fingolimod phase III trials.
effects, or better treatment becomes available. MS is a costly disease to manage with total costs estimated to exceed $14 billion annually. Direct correlation between cost (direct and indirect) and severity of disease has been well-established.17 DMT has been shown to result in economic benefits by delaying progression.18-20 Early use of DMTs in patients with CIS that delayed conversion to active MS provided a positive incremental cost-effectiveness ratio per patient-year compared with no treatment.21,22 As noted previously, there are many agents under study for MS. Alemtuzumab is one that is close to market. It is given as a once yearly infusion. In early trials, this agent had a significant effect on relapse rate but not on disability. Laquinimod is an investigational oral agent with significant anti-inflammatory effects. It resulted in
approximately a 22 percent reduction in annualized relapse rate, 36 percent reduction in three month EDSS progression, fewer MRI lesions, and less decrease in brain volume.23 It resulted in less disability and brain loss compared with interferon. MS has been traditionally viewed as an autoimmune inflammatory disease mediated by peripheral immune responses. Studies are now showing that axonal and neuronal degeneration occurs at least partly independent of inflammation. Cortical lesions and ongoing local inflammation may represent “unseen” pathology mediated by the local immune cells of the CNS. In the past 10 years, a renewed focus on innate immune responses and the role of glial cells in MS pathology has occurred. In 2011, alone, there have been over 25 publications investigating the role of glial cells in MS pathology. Microglia
www.namcp.org | Vol. 15, No. 4 | Journal of Managed Care Medicine 25
and astrocytes can create an environment that promotes ongoing damage to oligodendrocytes and inhibits repair processes. Unseen gray matter lesions, mediated by local innate immune responses, may explain why patients continue to progress in spite of anti-inflammatory treatments. BG-12, an oral formulation of dimethylfumarate, is under investigation for treating MS and is showing some neuroprotective effects in the brain. It has some potential neuroprotective effects by inducing antioxidant enzyme production, protecting oligodendrocytes against free-radical induced cytotoxicity, increasing neuronal survival and protecting astrocytes against oxidative stress in vitro, and preserves myelin, axons, and neurons in animal models.24 Conclusion
MS is a chronic, debilitating, and progressive disease. Economic implications are significant and appear directly correlated with disease severity. Although costly, long-term data and expert consensus support the primary role of DMT in managing disease progression and impacting long-term disability development and mortality. Optimal therapeutic benefit with DMT requires starting therapy as early as possible and keeping patients on therapy for as long as possible. Relapse reduction has been a common therapeutic target, but biologic mechanisms leading to acute attacks may differ from those responsible for disability. Relapses early in the disease process have limited effect on permanent disability in the later stages of the disease. It remains to be determined if inflammation is primary or secondary to a degenerative process in the brain. Brian A. Cree, MD, PhD, MCR is an Assistant Professor of Neurology in the Department of Neurology at the University of California, San Francisco Multiple Sclerosis Center in San Francisco, CA.
for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Ann Neurol. 1996;39:285-94. 7. The IFNB Multiple Sclerosis Study Group.Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology. 1993;43:655-61. 8. IFNB MS Study Group and University of British Columbia MS/MRI Analysis Group. Interferon beta-1b in the treatment of multiple sclerosis: final outcome of the randomized controlled trial. Neurology. 1995;45:1277-85. 9. Johnson KP, Brooks BR, Cohen JA, et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology. 1995;45:1268-76. 10. Johnson KP, Brooks BR, Cohen JA, et al Extended use of glatiramer acetate (Copaxone) is well tolerated and maintains its clinical effect on multiple sclerosis relapse rate and degree of disability. Copolymer 1 Multiple Sclerosis Study Group. Neurology. 1998;50:701-8. 11.PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group. Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. Lancet. 1998;352:1498-504. 12. Doggrell SA. Oral fingolimod for relapsing-remitting multiple sclerosis Evaluation of: Kappos L, Radue E-M, O’Connor P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 2010;362:387-401; and Cohen JA, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 2010;362:402-15. Expert Opin Pharmacother. 2010;11(10):1777-81. 13. Liu C, Blumhardt LD. Disability outcome measures in therapeutic trials of relapsing-remitting multiple sclerosis: effects of heterogeneity of disease course in placebo cohorts. J Neurol Neurosurg Psychiatry. 2000;68:450-7. 14. Ford C, Goodman AD, Johnson K, et al. Continuous long term immunomodulatory therapy in relapsing multiple sclerosis: results from the 15-year analysis of the US prospective open-label study of glatiramer acetate. Mult Scler. 2010;16:342-50. 15. Bermel RA, Cohen JA. Multiple sclerosis: advances in understanding pathogenesis and emergence of oral treatment options. Lancet Neurol. 2011;10:4-5. 16. National Clinical Advisory Board of the National MS Society. MS Disease Management Consensus Statement. 2007. Available at www.nationalmssociety.org. 17. Kobelt G, Berg J, Atherly D, Hadjimichael O. Costs and quality of life in multiple sclerosis: a cross-sectional study in the United States. Neurology. 2006;66:1696-702. 18. Pope GC, Urato CJ, Kulas ED, et al. Prevalence, expenditures, utilization, and payment for persons with MS in insured populations. Neurology. 2002;58:37-
Brian Steingo, MD is Medical Director at Multiple Sclerosis Research
43.
Associates’ Fort Lauderdale MS Center in Pompano Beach, FL.
19. Patwardhan MB, Matchar DB, Samsa GP, et al. Cost of multiple sclerosis by level of disability: a review of literature. Mult Scler. 2005;11:232-9.
References
20. Kobelt G, Berg J, Lindgren P, et al. Costs and quality of life of patients with
1. National Multiple Sclerosis Society. Who gets MS? Available at www.nation-
multiple sclerosis in Europe. J Neurosurg Psychiatry. 2006;77:918-26.
almssociety.org/about-multiple-sclerosis/what-we-know-about-ms/who-
21. Birnbaum HG, Ivanova JI, Samuels S, et al. Economic impact of multiple
gets-ms/index.aspx.
sclerosis disease-modifying drugs in an employed population: direct and indi-
2. National Multiple Sclerosis Society. Clinically Isolated Syndrome. Available
rect costs. Curr Med Res Opin. 2009;25:869-77.
at www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-about-
22. Lazzaro C, Bianchi C, Peracino L, et al. Economic evaluation of treating
ms/diagnosing-ms/cis/index.aspx.
clinically isolated syndrome and subsequent multiple sclerosis with interferon
3. National Multiple Sclerosis Society. What is MS? Available at www.nation-
beta-1b. Neurol Sci. 2009;30:21-31.
almssociety.org/about-multiple-sclerosis/what-we-know-about-ms/what-is-
23. Brück W, Zamvil SS. Laquinimod, a once-daily oral drug in development
ms/index.aspx.
for the treatment of relapsing-remitting multiple sclerosis. Expert Rev Clin Phar-
4. Lublin FD, Baier M, Cutter G. Effect of relapses on development of residual
macol. 2012;5:245-56.
deficit in multiple sclerosis. Neurology. 2003;61:1528-32.
24. Linker RA, Lee DH, Ryan S, et al. Fumaric acid esters exert neuroprotec-
5. Tremlett H, Yousefi M, Devonshire V. Impact of multiple sclerosis relapses on
tive effects in neuroinflammation via activation of the Nrf2 antioxidant path-
progression diminishes with time. Neurology. 2009;17:1616-23.
way. Brain. 2011;134(Pt 3):678-92.
6. Jacobs LD, Cookfair DL, Rudick RA, et al. Intramuscular interferon beta-1a
26 Journal of Managed Care Medicine | Vol. 15, No. 4 | www.namcp.org
Introducing Prevnar 13
®
The firsT and only pneumococcal conjugaTe vaccine for adulTs 50+ prevnar 13® may help prevent pneumococcal pneumonia and invasive disease
INDICATIONs • Prevnar 13® is a vaccine indicated for active immunization for the prevention of disease caused by Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F • In adults 50 years and older for pneumococcal pneumonia and invasive disease. Indication is based on immune responses • In children 6 weeks through 5 years for invasive pneumococcal disease and otitis media (caused by 7 of the 13 serotypes only [4, 6B, 9V, 14, 18C, 19F, and 23F]) Limitations of Use and Effectiveness • Prevnar 13® will only help protect against S pneumoniae serotypes in the vaccine • Effectiveness when administered <5 years after pneumococcal polysaccharide vaccine is not known ImpOrTANT sAfETy INfOrmATION • Severe allergic reaction (eg, anaphylaxis) to any component of Prevnar 13® or any diphtheria toxoid–containing vaccine is a contraindication • Immunocompromised individuals or individuals with impaired immune responsiveness due to the use of immunosuppressive therapy may have reduced antibody response • In adults, antibody responses to Prevnar 13® were diminished when given with inactivated Influenza Virus Vaccine • In adults, the commonly reported solicited adverse reactions were pain, redness, and swelling at the injection site, limitation of arm movement, fatigue, headache, muscle or joint pain, decreased appetite, chills, or rash
• Apnea following intramuscular vaccination has been observed in some infants born prematurely. Vaccination of premature infants should be based on the infant’s medical status, and the potential benefits and risks • In infants and toddlers, the most commonly reported serious adverse events were bronchiolitis (0.9%), gastroenteritis (0.9%), and pneumonia (0.9%) • In infants and toddlers, the most commonly reported solicited adverse reactions were injection site tenderness, redness, or swelling, irritability, decreased appetite, decreased or increased sleep, and fever
please see Brief summary of full prescribing Information on adjacent page. scan here or enter www.prevnar13adulthcp.com into your browser to learn more.
PREVNAR 13 is a registered trademark of Wyeth LLC. Manufactured by Wyeth Pharmaceuticals Inc. PSA283798-03
© 2012 Pfizer Inc.
Marketed by Pfizer Inc. All rights reserved.
April 2012
BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION
This brief summary does not include all of the information needed to use Prevnar 13® safely and effectively. Before prescribing, please consult the full Prescribing Information for Prevnar 13®. DOSAGE FORMS AND STRENGTHS Prevnar 13® is a suspension for intramuscular injection available in 0.5 mL single-dose prefilled syringes. CONTRAINDICATIONS Severe allergic reaction (eg, anaphylaxis) to any component of Prevnar 13® or any diphtheria toxoid– containing vaccine. WARNINGS AND PRECAUTIONS Management of Allergic Reactions Epinephrine and other appropriate agents used to manage immediate allergic reactions must be immediately available should an acute anaphylactic reaction occur following administration of Prevnar 13®. Altered Immunocompetence Data on the safety and effectiveness of Prevnar 13® when administered to immunocompromised individuals including those at higher risk for invasive pneumococcal disease (eg, individuals with congenital or acquired splenic dysfunction, HIV infection, malignancy, hematopoietic stem cell transplant, nephrotic syndrome) are not available. Individuals in these groups may have reduced antibody response to active immunization due to impaired immune responsiveness. Apnea in Premature Infants Apnea following intramuscular vaccination has been observed in some infants born prematurely. Decisions about when to administer an intramuscular vaccine, including Prevnar 13®, to infants born prematurely should be based on consideration of the individual infant’s medical status and the potential benefits and possible risks of vaccination. ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse-reaction rates observed in the clinical trials of a vaccine cannot be directly compared to rates in the clinical trials of another vaccine and may not reflect the rates observed in practice. As with any vaccine, there is the possibility that broad use of Prevnar 13® could reveal adverse reactions not observed in clinical trials. Clinical Trials Experience With Prevnar 13® in Infants and Toddlers The safety of Prevnar 13® was evaluated in 13 clinical trials in which 4729 infants and toddlers received at least 1 dose of Prevnar 13® and 2760 infants and toddlers received at least 1 dose of Prevnar® active control. Overall, the safety data show a similar proportion of Prevnar 13® and Prevnar® subjects reporting serious adverse events. Among US study subjects, a similar proportion of Prevnar 13® and Prevnar® recipients reported solicited local and systemic adverse reactions as well as unsolicited adverse events. Serious Adverse Events in All Infant and Toddler Clinical Studies Serious adverse events were collected throughout the study period for all 13 clinical trials. This reporting period is longer than the 30-day post-vaccination period used in some vaccine trials. The longer reporting may have resulted in serious adverse events being reported in a higher percentage of subjects than for other vaccines. Serious adverse events reported following vaccination in infants and toddlers occurred in 8.2% among Prevnar 13® recipients and 7.2% among Prevnar® recipients. Serious adverse events observed during different study periods for Prevnar 13® and Prevnar®, respectively, were: 1) 3.7% and 3.5% from dose 1 to the bleed approximately 1 month after the infant series; 2) 3.6% and 2.7% from the bleed after the infant series to the toddler dose; 3) 0.9% and 0.8% from the toddler dose to the bleed approximately 1 month after the toddler dose; and 4) 2.5% and 2.8% during the 6-month follow-up period after the last dose. The most commonly reported serious adverse events were in the “Infections and infestations” system organ class, including bronchiolitis (0.9%, 1.1%), gastroenteritis (0.9%, 0.9%), and pneumonia (0.9%, 0.5%) for Prevnar 13® and Prevnar®, respectively. There were 3 (0.063%) deaths among Prevnar 13® recipients and 1 (0.036%) death among Prevnar® recipients, all as a result of sudden infant death syndrome (SIDS). These SIDS rates are consistent with published age-specific background rates of SIDS from the year 2000. Among 6839 subjects who received at least 1 dose of Prevnar 13® in clinical trials conducted globally, there was 1 hypotonic-hyporesponsive episode adverse reaction reported (0.015%). Among 4204 subjects who received at least 1 dose of Prevnar® in clinical trials conducted globally, there were 3 hypotonichyporesponsive episode adverse reactions reported (0.071%). All 4 events occurred in a single clinical trial in Brazil in which subjects received whole cell pertussis vaccine at the same time as Prevnar 13® or Prevnar®. Solicited Adverse Reactions in the 3 US Infant and Toddler Studies A total of 1907 subjects received at least 1 dose of Prevnar 13® and 701 subjects received at least 1 dose of Prevnar® in the 3 US studies. Solicited adverse reactions that occurred within 7 days following each dose of Prevnar 13® or Prevnar® administered to US infants and toddlers were: in infants and toddlers vaccinated at 2, 4, 6, and 12-15 months of age in US clinical trials, the most commonly reported solicited adverse reactions were irritability (>70%), injection site tenderness (>50%), decreased appetite (>40%), decreased sleep (>40%), increased sleep (>40%), fever (>20%), injection site redness (>20%), and injection site swelling (>20%). Unsolicited Adverse Reactions in the 3 US Infant and Toddler Safety Studies The following were determined to be adverse drug reactions based on experience with Prevnar 13® in clinical trials: reactions occurring in greater than 1% of infants and toddlers: diarrhea, vomiting, and rash; and reactions occurring in less than 1% of infants and toddlers: crying, hypersensitivity reaction (including face edema, dyspnea, and bronchospasm), seizures (including febrile seizures), and urticaria or urticaria-like rash. Clinical Trials Experience With Prevnar 13® in Adults Aged ≥50 Years The safety of Prevnar 13® was assessed in 6 clinical studies conducted in the United States and Europe, which included 6198 adults (5667 received Prevnar 13®) ranging in age from 50 through 95 years. Serious Adverse Events in Adult Clinical Studies Across the 6 studies, serious adverse events within 1 month of vaccination were reported after an initial study dose in 0.2%-1.4% of 5055 persons vaccinated with Prevnar 13® and in 0.4%-1.7% of 1124 persons vaccinated after an initial study dose of the 23-valent pneumococcal polysaccharide vaccine (PPSV23). From 1 month to 6 months after an initial study dose, serious adverse events were reported in 1.2%-5.8% of persons vaccinated during the studies with Prevnar 13® and in 2.4%-5.5% of persons vaccinated with PPSV23. One case of erythema multiforme occurred 34 days after receipt of a second dose of Prevnar 13®. Twelve of 5667 (0.21%) Prevnar 13® recipients and 4 of 1391=0.28% PPSV23 recipients died. Deaths occurred between day 3 and day 309 after study vaccination with Prevnar 13® or PPSV23. Two of 12 deaths occurred within 30 days of vaccination with Prevnar 13® and both deaths were in subjects >65 years of age. One death due to cardiac failure occurred 3 days after receiving Prevnar 13® administered with trivalent inactivated influenza vaccine (TIV) and the other death was due to peritonitis 20 days after receiving Prevnar 13®. The reported causes of the 10 remaining deaths occurring greater than 30 days after receiving Prevnar 13® were cardiac disorders (4), neoplasms (4), Mycobacterium avium complex pulmonary infection (1), and septic shock (1). Solicited Adverse Reactions in Adult Clinical Studies In adults aged 50 years and older, the commonly reported solicited adverse reactions were pain at the injection site (>50%), fatigue (>30%), headache (>20%), muscle pain (>20%), joint pain (>10%), decreased appetite (>10%), injection site redness (>10%), injection site swelling (>10%), limitation of arm movement (>10%), chills (>5%), or rash (>5%). Solicited Adverse Reactions in Adult Clinical Studies of Concomitant Administration of Prevnar 13® and TIV (Fluarix) The safety of concomitant administration of Prevnar 13® with TIV was assessed in 2 studies in PPSV23 unvaccinated adults aged 50 through 59 years and aged ≥65 years.
Frequencies of local reactions within 14 days post-vaccination in adults aged 50 through 59 years and in adults aged ≥65 years were similar after Prevnar 13® was administered with TIV compared to Prevnar 13® administered alone, with the exception of mild redness at the injection site, which was increased when Prevnar 13® was administered concomitantly with TIV. An increase in some solicited systemic reactions within 14 days post-vaccination was noted when Prevnar 13® was administered concomitantly with TIV compared with TIV given alone (headache, chills, rash, decreased appetite, muscle and joint pain) or with Prevnar 13® given alone (fatigue, headache, chills, decreased appetite, and joint pain). Clinical Trials Experience With Prevnar® in Infants and Toddlers The safety experience with Prevnar® is relevant to Prevnar 13® because the 2 vaccines share common components. Generally, the adverse reactions reported in clinical trials with Prevnar 13® were also reported in clinical trials with Prevnar®. Overall, the safety of Prevnar® was evaluated in a total of 5 clinical studies in the United States in which 18,168 infants and children received a total of 58,699 doses of vaccine at 2, 4, 6, and 12-15 months of age. Adverse events reported in clinical trials with Prevnar® that occurred within 3 days of vaccination in infants and toddlers and resulted in emergency room visits or hospitalizations, but were not presented in Section 6.1 as adverse reactions for Prevnar 13®, are listed below: Bronchiolitis, UTI, acute gastroenteritis, asthma, aspiration, breath holding, influenza, inguinal hernia repair, viral syndrome, URI, croup, thrush, wheezing, choking, conjunctivitis, pharyngitis, colic, colitis, congestive heart failure, roseola, and sepsis. Post-marketing Experience With Prevnar® in Infants and Toddlers The following adverse events have been reported through passive surveillance since market introduction of Prevnar® and, therefore, are considered adverse events for Prevnar 13® as well. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to the vaccine. Administration site conditions: Injection site dermatitis, injection site pruritus, injection site urticaria Blood and lymphatic system disorders: Lymphadenopathy localized to the region of the injection site Immune system disorders: Anaphylactic/anaphylactoid reaction including shock Skin and subcutaneous tissue disorders: Angioneurotic edema, erythema multiforme Respiratory: Apnea DRUG INTERACTIONS Concomitant Immunizations In clinical trials with infants and toddlers, Prevnar 13® was administered concomitantly with the following US licensed vaccines: Pediarix [Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, Hepatitis B (Recombinant) and Inactivated Poliovirus Vaccine Combined] (DTaP-HBV-IPV) and ActHIB [Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate)] (PRP-T) for the first 3 doses and with PedvaxHIB [Haemophilus b Conjugate Vaccine (Meningococcal Protein Conjugate)] (PRP-OMP), M-M-R II [Measles, Mumps, Rubella Virus Vaccine Live] (MMR) and Varivax [Varicella Virus Vaccine Live], or ProQuad [Measles, Mumps, Rubella, and Varicella Virus Vaccine Live] (MMRV) and VAQTA [Hepatitis A Vaccine, Inactivated] (HepA) for dose 4. In adults, Prevnar 13® was administered concomitantly with US licensed Fluarix (TIV) for the 2007/2008 influenza season. There are no data on the concomitant administration of Prevnar 13® with diphtheria toxoid–containing vaccines and other vaccines licensed for use in adults 50 years of age and older. When Prevnar 13® is administered at the same time as another injectable vaccine(s), the vaccines should always be administered with different syringes and given at different injection sites. Do not mix Prevnar 13® with other vaccines/products in the same syringe. Immunosuppressive Therapies Individuals with impaired immune responsiveness due to the use of immunosuppressive therapy (including irradiation, corticosteroids, antimetabolites, alkylating agents, and cytotoxic agents) may not respond optimally to active immunization. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B A developmental and reproductive toxicity study has been performed in female rabbits at a dose approximately 20 times the human dose (on mg/kg basis) and revealed no evidence of impaired female fertility or harm to the fetus due to Prevnar 13®. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this vaccine should be used during pregnancy only if clearly needed. Nursing Mothers It is not known whether this vaccine is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Prevnar 13® is administered to a nursing woman. Pediatric Use Safety and effectiveness of Prevnar 13® in children below the age of 6 weeks or on or after the 6th birthday have not been established. Immune responses elicited by Prevnar 13® among infants born prematurely have not been specifically studied. Geriatric Use Of the total number of Prevnar 13® recipients (N=5667), 3051/5667 or 53.8% were 65 years and older and 1266/5667 or 22.3% were 75 years and older. Antibody responses to Prevnar 13® were lower in persons >65 years of age compared to antibody responses in persons 50 through 59 years of age. No overall differences in safety outcomes were observed in persons aged ≥65 years as compared to persons 50 through 59 years of age. PATIENT COUNSELING INFORMATION Potential Benefits and Risks Prior to administration of this vaccine, the health care professional should inform the individual, parent, guardian, or other responsible adult of the potential benefits and risks to the patient [see Warnings and Precautions (5) and Adverse Reactions (6)]. Parents, guardians, or other responsible adults should be informed of the importance of completing the immunization series for their child(ren) unless contraindicated. Vaccine Information Statements are available free of charge at the Centers for Disease Control and Prevention (CDC) Web site (www.cdc.gov/vaccines). Adverse Reactions Instruct the individuals, parents, guardians, or other responsible adults to report any suspected adverse reactions to their health care professional. This product’s label may have been updated. For current Prescribing Information and further product information, please visit www.pfizerpro.com/products or call Pfizer Medical Information toll-free at 1-800-438-1985. Manufactured by
Wyeth Pharmaceuticals Inc. A subsidiary of Pfizer Inc, Philadelphia, PA 19101
US Govt. License No. 3 LAB-0469-4.0 CPT Code 90670 United States Patent Number: 5,614,382.
Cosmos Communications
1
Q1
Q2
Clinical and Efficiency Benefits of New Oral Anticoagulants after THR/TKR Surgery Louis M. Kwong, MD, FACS
Summary Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is a frequently occurring disorder with an annual incidence of at least one case per 1000 persons. Patients undergoing total hip replacement (THR) or total knee replacement (TKR) surgery are among the groups of patients with the highest risk for developing post-operative VTE. In the absence of appropriate prophylaxis, VTE, as detected venographically, occurs in 40 to 60 percent of patients undergoing major orthopaedic surgery, including 42 to 57 percent and 41 to 87 percent of patients undergoing THR and TKR, respectively. Emerging new oral anticoagulants have the potential to simplify in-hospital and post-discharge VTE prophylaxis and may help to improve adherence to the recommended guidelines due to their oral route of administration and lack of any need for routine monitoring. This may lead to potentially lower rates of recurrent VTE and its associated complications. By increasing compliance and reducing VTE risk, these agents may reduce the financial costs associated with VTE treatment and complications. Key points • Low-molecular weight heparins (LMWH) and unfractionated heparin (UFH) are effective anticoagulants, but limited by their route of administration. • Vitamin K antagonists (VKAs) are effective anticoagulants but are limited by the requirement for routine clinical monitoring, the need for individualized dose adjustment, and the potential for drug-based and diet-based interactions. • Direct Factor Xa and thrombin inhibitors have more ideal characteristics that have made them promising alternatives for thromboprophylaxis. • The financial burden of VTE events due to lack of thromboprophylaxis is high, but the emergence of the new anticoagulants with simpler administration and dosing may help to increase the rates of thromboprophylaxis, thereby reducing VTErelated costs.
Introduction
Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is a frequently occurring disorder with an annual incidence of at least one case per 1000 persons.1,2 Although major surgery is the primary risk factor for VTE, patients who experience trauma, cancer, increasing age, pregnancy, obesity, acute medical illness, central venous catheterization, and myeloproliferative disorders are also at an increased risk.3 Data from over seven million patients discharged from approximately 1000 hospitals in the United States (U.S.) demonstrated that VTE was the second most common complication following surgery and the third most common reason for health
care expenses and mortality.3 Patients undergoing total hip replacement (THR) or total knee replacement (TKR) surgery are among those at highest risk for developing VTE.3 In the absence of appropriate prophylaxis, VTE, as detected venographically, occurs in 40 to 60 percent of patients undergoing major orthopaedic surgery.3,4 Despite its prevalence among patients following surgical procedures, VTE has been designated as a nonpayable provider preventable condition by the Centers for Medicare and Medicaid Services (CMS).5 Pathophysiology of VTE
Asymptomatic DVT is common and, in the absence of thromboprophylaxis, affects at least half of
www.namcp.org | Vol. 15, No. 4 | Journal of Managed Care Medicine 29
Exhibit 1 The coagulation cascade and the specific factors targeted by traditional and newer anticoagulants. Vitamin K antagonists (VKAs) such as warfarin inhibit the vitamin K窶電ependent synthesis of biologically active forms of the calcium-dependent clotting factors prothrombin and Factors VII, IX, and X. The Factor Xa inhibitors, rivaroxaban and apixaban, directly inhibit Factor Xa and subsequent thrombin formation, whereas fondaparinux indirectly inhibits Factor Xa via selective binding to antithrombin, potentiating its inhibition of Factor Xa and thrombin. The direct thrombin inhibitor, dabigatran etexilate, abrogates the conversion of fibrinogen into fibrin by directly inhibiting the action of free and fibrin-bound thrombin. Extrinsic pathway
Intrinsic pathway
Tenase Complex FVIIa
Tenase Complex FIXa
FX
VKAs
Rivaroxaban Apixaban
Dabigatran
Fondaparinux
FXa FVa Prothrombinase Complex
FV
Antithrombin Prothrombin
Thrombin
Fibrinogen
all patients undergoing major orthopedic surgery.3 Hemodynamic disturbances associated with major orthopaedic surgery promote the activation of the coagulation pathway and fibrinolytic shut-down, resulting in increased risk for VTE.6 Long-term complications of VTE include recurrent VTE, postthrombotic syndrome, and chronic thromboembolic pulmonary hypertension.7 Prophylaxis of VTE in THR/TKR
Historically, anticoagulation therapy for the prevention of VTE has been a necessary but challenging process due to difficulties in ensuring therapeutic drug levels and patient adherence, while minimizing the risk of serious adverse effects such as major bleeding events. Appropriate use of thromboprophylaxis significantly reduces the risk of postoperative VTE, and the most recent guidelines of the American College of Chest Physicians (ACCP) recommend routine anticoagulation in patients undergoing THR or TKR.3 The most commonly used agents include low-molecular-weight heparin (LMWH), fondaparinux, and adjusted dose vitamin K antagonists (VKAs).3 Current and established anticoagulants
Currently available anticoagulants include both par-
Fibrinunstable
Fibrinstable
enteral and oral agents. LMWH and the synthetic pentasaccharide fondaparinux are parenteral anticoagulants that have been proven effective in reducing the risk of VTE after major orthopaedic surgery.8-11 These agents are administered subcutaneously and exert their anticoagulant effects via inhibition of thrombin and thrombin-activating factors that catalyze the conversion of fibrinogen to fibrin at various stages of the coagulation cascade. LMWH is composed of short chains of polysaccharide that bind to antithrombin via a unique pentasaccharide sequence and catalyze the inactivation of thrombin and the prothrombinase activating factor, Factor Xa LMWHs have a predictable PK and PD profile, relatively long half-life, and low risk of adverse side effects such as heparin-induced thrombocytopenia (HIT).11 The most widely studied LMWH for thromboprophylaxis, enoxaparin, is administered once or twice daily as a subcutaneous (s.c.) injection.12 VKAs, such as warfarin, have been the mainstay of oral anticoagulant therapy for more than 60 years, and their efficacy in VTE prevention has been established in numerous clinical trials for the primary and secondary prevention of VTE.13 However, similar to parenteral agents, VKAs are associated with a number of practical limitations. Patients treated with VKAs must be monitored routinely to main-
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Exhibit 2. Comparison of primary efficacy and safety endpoints in the RECORD trials Results of RECORD studies % Primary Efficacy Endpoint % Relative Risk Primary Safety Patient (composite of any DVT, non-fatal Reduction (P- Endpoint: Group (n) PE, and all-cause mortality) value) Major Study Bleeding RECORD 121 Extended prophylaxis with oral rivaroxaban vs extended s.c. enoxaparin
THR (4541)
Rivaroxaban (10 mg once daily) Enoxaparin (40 mg once daily) RECORD 222 Extended prophylaxis with oral rivaroxaban vs short-term s.c. enoxaparin
2.0 (17/864) 79 (P<.001) 9.3 (81/869)
<0.1 (1/1228) <0.1 (1/1229)
9.6 (79/824) 49 (P<.001) 18.9 (166/878)
0.6 (7/1220) 0.5 (6/1239)
6.9 (97/965) 31 (P=.012) 10.1 (97/959)
0.7 (10/1526) 0.3 (4/1508)
TKR (2531)
Rivaroxaban (10 mg once daily) Enoxaparin (40 mg once daily) RECORD 424 Throboprophylaxis with oral rivaroxaban versus s.c. enoxaparin
0.3 (6/2209) 0.1 (2/2224)
THR (2509)
Rivaroxaban (10 mg once daily) Enoxaparin (40 mg once daily) RECORD 323 Throboprophylaxis with oral rivaroxaban versus s.c. enoxaparin
1.1 (18/1595) 70 (P<.001) 3.7 (58/1558)
TKR (3148)
Rivaroxaban (10 mg once daily) Enoxaparin (30 mg twice daily)
DVT, deep vein thrombosis; PE, pulmonary embolism; s.c., subcutaneous; THR, total hip replacement; TKR, total knee replacement
tain levels of coagulation in accordance with the international normalized ratio (INR), a measure of anticoagulation. In addition, VKAs have a narrow therapeutic window within which they are optimally effective, and frequent dose adjustments must be made to maintain adequate levels of anticoagulation and minimize the risk of serious bleeding events. VKAs are also associated with multiple drug- and diet-based interactions, resulting in an increased burden on the caregiver, and the potential for serious adverse events.4,8,12 Patient-related factors, such as discomfort and the inconvenience of frequent monitoring, may also result in suboptimal anticoagulation control and reduced patient compliance.14 Although effective, parenteral and oral agents all have signif icant limitations. LMWHs, and fondaparinux require daily s.c. administration, making them inconvenient for long-term use. In addition, patients taking LMWH are at increased risk for HIT, necessitating routine platelet count monitoring. 8 VKAs also prove challenging from a managerial perspective, and their utility is often limited by their pharmacologic shortcomings. The requirement of frequent monitoring, dose adjustments to compensate for a narrow therapeutic window, multiple food and
drug interactions, and variable pharmacology may contribute to frequent underuse and inadequate anticoagulation, especially in elderly patients.15 Therefore, there is a critical unmet need for thromboprophylactic strategies that provide pharmacologic advantages, such as predictable PK and PD prof iles and standard dosing regimens, and obviate the need for extensive monitoring and patient knowledge of drugâ&#x20AC;&#x201C;drug and drugâ&#x20AC;&#x201C;food interactions. Factor Xa inhibitors
The synthetic pentasaccharide, fondaparinux, was the first thromboprophylactic agent developed to selectively target Factor Xa.16 It is administered via once-daily s.c. injection, has excellent bioavailability, and a half-life between 17 and 21 hours.9,17 Fondaparinux indirectly inhibits Factor Xa activity, and subsequent thrombin production, via selective and reversible binding to antithrombin.17 Because fondaparinux binds only to antithrombin and does not interact with platelet factor 4, adverse side effects, such as immune induced HIT, will not occur. Fondaparinux was approved for use in the U.S. in 2001 and has been shown to be safe and effective for the prevention of VTE in patients undergoing
www.namcp.org | Vol. 15, No. 4 | Journal of Managed Care Medicine 31
Exhibit 3. Comparison of primary efficacy and safety endpoints in Phase III apixaban clinical trials
Results of Phase III Apixaban Studies Patient Study Group (n) ADVANCE-129 Throboprophylaxis with oral apixaban versus s.c. enoxaparin
TKR (3195)
Apixaban (2.5 mg twice daily) Enoxaparin (30 mg every 12 hours) ADVANCE-230 Throboprophylaxis with oral apixaban versus s.c. enoxaparin
9.0 (104/1157) P=0.06 8.8 (100/1130)
0.7 (11/1596) 1.4 (22/1588)
15 (147/976) P<0.0001 24 (243/997)
0.6 (9/1501) 0.9 (14/1508)
1.4 (27/1949) P<0.001 3.9 (74/1917)
0.8 (22/2673) 0.7 (15/2659)
TKR (3057)
Apixaban (2.5 mg twice daily) Enoxaparin (40 mg once daily) ADVANCE-331 Extended prophylaxis with oral apixaban versus s.c. enoxaparin
% Primary Efficacy Endpoint P-value for Non- % Primary Safety (composite of total VTE events inferiority vs Endpoint: Adjudicated and all-cause mortality) Enoxaparin Major Bleeding
THR (5407)
Apixaban (2.5 mg twice daily) Enoxaparin (40 mg once daily)
VTE, venous thromboembolism; s.c., subcutaneous; THR, total hip replacement; TKR, total knee replacement
hip surgery, TKR, and major abdominal surgery, as well as for initial treatment of VTE.12 The safety and efficacy of fondaparinux in orthopaedic surgery patients was assessed in a meta-analysis of four multicenter randomized trials: EPHESUS, PENTATHLON 2000, PENTHIFRA, and PENTAMAKS. In all of these trials, fondaparinux was administered s.c. at a dose of 2.5 mg, once daily, starting six hours post-operatively.18 In the PENTATHLON 2000 and PENTAMAKS trials, fondaparinux was compared with the 30 mg twice-daily regimen of enoxaparin (starting 12 to 24 hours post-operatively); and in the other two studies, fondaparinux was compared with the 40 mg once-daily regimen of enoxaparin (starting 12 hours before surgery and followed by a second injection 12 to 24 hours post-operatively). Results of the meta-analysis showed that fondaparinux reduced the incidence of venous thromboembolism by Day 11 from 13.7 percent in the enoxaparin-treated group to 6.8 percent. However, the primary safety outcome of major bleeding was increased in the fondaparinux group (2.7 percent) vs enoxaparin (1.7 percent).18 In addition, fondaparinux demonstrated similar efficacy and safety to LMWH or intravenous UFH as initial therapy for DVT or PE in the MATISSEDVT and MATISSE-PE trials.12
New oral anticoagulants
There is a critical unmet need for novel thromboprophylactic agents that incorporate efficacious anticoagulation with ease of use. The ideal anticoagulant would include characteristics such as an oral route of administration, simple, predictable dosing without the need for routine clinical monitoring, a rapid onset and offset of action, minimal drug–drug and food–drug interactions, a wide therapeutic window to minimize the risk of bleeding events, minimal adverse effects, and cost-effectiveness.17 One novel oral anticoagulant (OAC), the Factor Xa inhibitor rivaroxaban, has been approved for VTE prophylaxis after orthopaedic surgery, and two others, dabigatran etexilate and apixaban, are currently in development. Unlike VKAs, which target multiple stages of the coagulation cascade, these new oral agents focus on the direct inhibition of single coagulation factors, primarily thrombin (dabigatran) and Factor Xa (rivaroxaban and apixaban)— two serine proteases with critical roles in thrombin formation19 (Exhibit 1). Inhibition of Factor Xa prevents the activation of prothrombin—the thrombin precursor responsible for converting fibrinogen to fibrin—thereby preventing the activation of downstream Factors V, VIII, XI, XIII, and subsequent thrombus formation. Direct inhibition of thrombin prevents the activation of Factors V, VIII, XI, and
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Exhibit 4. Comparison of primary efficacy and safety endpoints in Phase III dabigatran etexilate clinical trials Results of Phase III Dabigatran Etexilate Studies Patient Study Group (n) RE-NOVATE33 Extended prophylaxis with oral dabigatran vs extended s.c. enoxaparin
TKR (3494)
Dabigatran (150 mg once daily) Dabigatran (220 mg once daily) Enoxaparin (40 mg once daily) RE-MODEL 34 Short-term prophylaxis with oral dabigatran vs short-term s.c. enoxaparin
8.6 (75/874) P<0.0001 6.0 (53/880) 6.7 (60/897)
1.3 (15/1163) 2 (23/1146) 1.6 (18/1154)
P<0.0003 40.5 (213/526) P<0.0017 36.4 (183/503) 37.7 (193/512)
1.3 (9/703) 1.5 (10/679) 1.3 (9/694)
P =.0009 33.7 (219/649) P =.0234 31.1 (188/604) 25.3 (163/643)
0.6 (5/871) 0.6 (5/857)
TKR (2076)
Dabigatran (150 mg once daily) Dabigatran (220 mg once daily) Enoxaparin (40 mg once daily) RE-MOBILIZE35 Throboprophylaxis with oral dabigatran vs s.c. enoxaparin
% Primary Efficacy Endpoint P -value for Non- % Primary Safety (composite of total VTE events inferiority vs Endpoint: Major and all-cause mortality) Enoxaparin Bleeding
TKHR (1896)
Dabigatran (150 mg once daily) Dabigatran (220 mg once daily) Enoxaparin (30 mg once daily)
VTE, venous thromboembolism; s.c., subcutaneous; TKR, total knee replacement
XIII, as well as fibrin formation.16 There is currently no indication that one of these targets provides a more beneficial effect than another. Rivaroxaban
The direct Factor Xa inhibitor rivaroxaban was approved in July 2011 by the U.S. Food and Drug Administration (FDA) for the prevention of DVT in patients undergoing THR or TKR surgery.20 In the landmark RECORD trials (Regulation of Coagulation in Orthopedic Surgery to Prevent DVT and PE), rivaroxaban was compared with subcutaneously administered enoxaparin for the prevention of VTE after THR or TKR in over 12,500 patients (Exhibit 2). The series of four Phase III trials demonstrated the superiority of rivaroxaban vs enoxaparin in reducing VTE incidence without significantly increasing bleeding risk.21-24 In RECORD1, patients undergoing THR were randomized to receive rivaroxaban (10 mg, once daily) or enoxaparin (40 mg, once daily) for 35 (±4) days.21 In RECORD2, patients were randomized to receive rivaroxaban (10 mg, once daily) for 35 (±4) days or enoxaparin (40 mg, once daily) for 12
(±2) days.22 RECORD3 and 4 were similar in design, with the exception that they were conducted in Europe or North America, respectively, and the administration of rivaroxaban and enoxaparin was in accordance with the standard guidelines of the respective regions.16 Briefly, patients enrolled in RECORD3 and 4 began enoxaparin treatment (40 mg once daily) the evening prior to surgery, or 30 mg every 12 hours beginning 12 to 24 hours postsurgery, respectively.16,23,24 In all RECORD trials, the primary efficacy endpoint was the composite of DVT, non-fatal PE, or all-cause mortality, and the primary safety endpoint was major bleeding. All patients were administered the first dose of rivaroxaban six to eight hours post-surgery.21-24 The outcomes of RECORD1–4 were similar with respect to efficacy and safety. In RECORD1, the primary efficacy endpoint of total number of VTE events was significantly reduced in the rivaroxaban group (1.1 percent) compared vs the enoxaparin group (3.7 percent; P=0.001), with a relative risk reduction (RRR) of 70 percent.21 In RECORD2, the total number of VTE events was also significantly lower in patients who received rivaroxaban (2 percent), compared with
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the enoxaparin group (9.3 percent; P<0.0001), with a RRR of 79 percent.22 In RECORD3, the primary efficacy outcome of total number of VTE events was significantly decreased in patients treated with rivaroxaban (9.6 percent) compared with patients treated with enoxaparin (18.9 percent [RRR=49 percent, 95 percent CI 35 to 61;P<0.001]).23 In RECORD4, the 30 mg dose of rivaroxaban resulted in a lower rate of total VTE events (6.9 percent) vs enoxaparin treatment (10.1 percent), establishing the superiority of rivaroxaban (RRR=31 percent, 95 percent CI 0.71 to 5.67; P=0.0118).24 In all studies, rates of major and clinically relevant non-major bleeding events were similar between rivaroxaban- and enoxaparin-treated patients.21-24 Rivaroxaban is a potent and selective Factor Xa inhibitor with a relatively high bioavailability (~80 percent) and predictable PK/PD profile.20,25 Rivaroxaban is metabolized primarily in the liver via cytochrome P (CYP)450 and 3A4 enzymes, and more than 30 percent of the drug is excreted in the feces unchanged – a phenomenon mediated, at least in part, by P-glycoprotein (P-gp). Therefore, concomitant administration of rivaroxaban with strong CYP3A4 or P-gp inhibitors, such as ritonavir and ketoconazole, significantly interferes with the metabolism of rivaroxaban and should be avoided to prevent increased drug exposure and risk of bleeding events.20,26 Caution should be exercised when prescribing rivaroxaban to patients with moderate to severe renal impairment (creatinine clearance [CrCl] 15 to 30 mL/min) or hepatic impairment (Child–Pugh Class B and C) as the drug is cleared by these organs.20 Administration with food does not significantly alter plasma drug levels.16,26 The mean half-life of rivaroxaban is five to nine hours in healthy individuals, and 11 to 13 hours in the elderly.16 Interestingly, gender and body weight do not appear to alter the PK of rivaroxaban, allowing for simple, fixed dose administration.27,28
or within two days after the last dose of study medication. Patients treated with apixaban experienced a similar rate of the primary efficacy endpoint; however, the apixaban group demonstrated an improved safety profile, with 2.9 percent of patients experiencing major or non-major bleeding vs 4.3 percent of patients treated with enoxaparin (P =0.03).29 In the ADVANCE-2 trial, patients were randomized to receive apixaban 2.5 mg bid for 12 (±2) days or enoxaparin 40 mg once daily administered prior to surgery, in accordance with the European standard of care (Exhibit 3) The rate of the primary efficacy endpoint (similar to ADVANCE-1) was significantly lower in the apixaban arm compared with the enoxaparin arm (15.1 percent vs 24.4 percent, respectively), with a RRR 34 percent. In this trial, there was no significant difference in the rates of major and clinically relevant non-major bleeding between apixaban and enoxaparin treatment.16,30 The ADVANCE-3 trial showed similar superiority of apixaban 2.5 mg bid over enoxaparin 40 mg s.c. once daily (P<0.0001) for the same primary efficacy outcome, without increased bleeding.31 Apixaban is a small-molecule inhibitor that selectively and reversibly targets Factor Xa in both its free and bound states. Apixaban is metabolized by the CYP450 family of enzymes, and has few drug-drug interactions. In addition, administration of apixaban with food does not significantly alter its absorption. The bioavailability of apixaban is approximately 50 percent, with peak plasma levels reached in approximately three hours, resulting in a half-life of 12 hours.16,32
Apixaban
Dabigatran etexilate was compared with enoxaparin for VTE prophylaxis in the randomized, non-inferiority study, Dabigatran Etexilate Versus Enoxaparin for Prevention of Venous Thromboembolism after Total Hip Replacement (RE-NOVATE). In this double-blind study, 3494 patients undergoing THR were randomized to receive dabigatran etexilate 150 mg or 220 mg once daily, beginning with a half-dose one to four hours post-surgery, or enoxaparin 40 mg once daily beginning the evening before surgery (Exhibit 4).33 The primary efficacy endpoint was the composite of venographic and symptomatic VTE and all-cause mortality. The rate of VTE events in patients treated with dabigatran etexilate 150 mg and
Direct thrombin inhibitors
Direct thrombin inhibitors target thrombin directly, both in its soluble and bound states. Because these agents produce a predictable anticoagulant effect and may be administered orally, they represent a convenient option for thromboprophylaxis.17 Dabigatran etexilate
Apixaban has been evaluated for thromboprophylaxis in patients undergoing TKR in the randomized, double-blind Phase III trials, Apixaban Dose Orally Versus Anticoagulant with Enoxaparin (ADVANCE-1 and ADVANCE-2), and in patients undergoing THR in the ADVANCE-3 study. In ADVANCE-1, patients were randomized to receive apixaban 2.5 mg twice daily (bid) or enoxaparin 30 mg bid 12 to 24 hours post-surgery for 12 (±2) days. The primary endpoint was the composite of asymptomatic and symptomatic DVT, fatal and non-fatal PE, and all-cause mortality. The primary safety endpoint was bleeding during the treatment period
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220 mg was 8.6 percent and 6 percent, respectively, compared with 6.7 percent in patients treated with enoxaparin (95 percent CI, 0.6 to 4.4 and 2.9 to 1.6, respectively). In addition, both dabigatran etexilateand enoxaparin-treated groups demonstrated similar rates of major bleeding. The investigators determined that both doses of dabigatran etexilate were non-inferior to enoxaparin in patients undergoing THR surgery, with similar rates of adverse events.33 Similar to the RE-NOVATE study, the Oral Dabigatran Etexilate Versus Subcutaneous Enoxaparin for the Prevention of Venous Thromboembolism after Total Knee Replacement (RE-MODEL) trial compared dabigatran etexilate with enoxaparin in 2076 patients undergoing TKR surgery with the same composite primary efficacy endpoint as RENOVATE (Exhibit 4).34 The primary efficacy outcome was observed in 40.5 percent and 36.4 percent of patients treated with dabigatran etexilate 150 mg or 220 mg, respectively, compared with 37.7 percent (95 percent CI, 3.1 to 8.7 and 7.3 to 4.6, respectively) of the patients treated with enoxaparin. Similar to the RE-NOVATE trial, rates of major bleeding were similar among all treatment groups.34 In the double-blind Oral Thrombin Inhibitor Dabigatran Etexilate vs. the North American Enoxaparin Regimen for the Prevention of Venous Thromboembolism after Knee Arthroplasty Surgery (RE-MOBILIZE) trial, 1896 patients undergoing TKR surgery were randomized to receive dabigatran etexilate 150 mg or 220 mg, or enoxaparin 30 mg bid, according to the North American enoxaparin dosing regimen (Exhibit 3).35 The 30 mg bid dose of enoxaparin was found to be superior to both doses of dabigatran etexilate. Patients treated with dabigatran etexilate 150 mg and 220 mg experienced VTE rates of 34 percent and 31 percent, respectively compared with 25 percent in the enoxaparin group (P<0.001 and P =0.02, respectively). Bleeding rates were similar among all treatment groups.35 The investigators concluded that dabigatran, although effective compared with once-daily enoxaparin, was inferior to the twice-daily North American enoxaparin regimen. Dabigatran etexilate is an oral pro-drug that is converted to the active metabolite, dabigatran.36 In its pro-drug form, dabigatran has poor bioavailability and requires an acidic environment for absorption; therefore, this process is affected by the consumption of food and other medications, including P-gp inhibitors (i.e. cyclosporine, tacrolimus, clarithromycin, and ketoconazole).36 Drug–drug interactions may result in increased bleeding and should be monitored carefully. A single dose of dabigatran has a half-life of eight hours, whereas continuous dosing of dabigatran
results in a 17-hour half-life, allowing for once-daily dosing. The majority of dabigatran is cleared by the kidneys and, therefore, is contraindicated in patients with severe renal impairment.36 Economic burden of VTE and cost-effectiveness of prophylaxis
Several studies have evaluated the financial burden of VTE and associated prophylaxis strategies. A retrospective analysis of medical records from 529 consecutive cancer patients hospitalized for DVT showed that the average duration of hospitalization in the U.S. was 11 days, with a mean cost of $20,065 per episode ($1784 per hospital day) in 2002.37 Another study, by Bullano et al., identified 2147 patients from two major U.S. health care insurance providers who experienced a VTE event between 1998 and 2000. The authors showed that the median cost of a DVT, PE, or recurrent VTE event was $3131, $6424, and $5736, respectively.38 However, the costs obtained from this study are probably much lower than would be incurred today. Finally, a study by Spyropoulos et al. analyzed the costs associated with DVT or PE as the primary or secondary reason for hospital discharge, including both initial and recurrent cases, between 1998 and 2004. Analysis of data obtained from the Integrated Health Care Information Services (IHCIS) National Managed Care Database showed that the mean cost of hospitalization for an initial DVT or PE event was $9805 or $14,146, respectively.39 Similarly, the mean cost of a recurrent PE event was $14,722. However, the cost of readmission for a recurrent DVT event was increased to $11,862.39 VTE events, both initial and recurrent, can result in long-term complications, which are also associated with a financial burden. A 15-year retrospective cohort study of 257 DVT patients showed that the cost of care following a thrombotic event comprised 75 percent of the initial cost. The initial cost for DVT treatment was approximately $6000, and the cost of subsequent DVT-associated complications was $4659.40 A more recent study showed that the discounted lifetime cost—an adjusted amount in which future costs are discounted by a fixed percentage—of DVT-associated complications was about $3069. Consistent among these studies’ findings is the high financial burden associated with initial and recurrent VTE events, as well as associated life-long complications that highlight the need for more costeffective anticoagulation strategies.41 Cost-effectiveness of traditional agents versus new OACs
VKAs require routine clinical monitoring to maintain
www.namcp.org | Vol. 15, No. 4 | Journal of Managed Care Medicine 35
adequate levels of anticoagulation and to minimize major bleeding events. New anticoagulants require less involvement at the clinic, relieving some of the financial burden associated with traditional anticoagulant drugs. Several studies have analyzed the costs associated with use of these new agents. The cost-effectiveness of fondaparinux relative to enoxaparin was evaluated for VTE prophylaxis in patients undergoing hip fracture surgery. Using a decision analysis model to simulate clinical outcomes, Sullivan et al showed that fondaparinux 2.5 mg once daily was estimated to prevent an additional 30 VTE events (per 1000 patients) at three months compared with enoxaparin 3 mg twice daily.42 This translated to a cost savings of $103 at discharge, $291 over one month, $361 over three months, and $466 over five years. Using a similar model, Duran et al compared the cost effectiveness of rivaroxaban compared with enoxaparin based on clinical outcomes from the phase III RECORD trials.43 In patients undergoing THR, treatment with rivaroxaban was associated with cost savings of $511.93 per patient and prevented an average of 14.5 symptomatic VTE events (per 1000 patients) compared with enoxaparin. For TKR patients, 10 to 14 days of rivaroxaban prophylaxis was associated with a cost savings of $465.74 and prevented an average of 19.3 symptomatic VTE events per 1000 patients.43 Conclusions
VTE occurs at high rates among THR/TKR patients in the U.S. and is associated with significant morbidity and mortality, as well as high health care costs. Although consensus guidelines provide clear recommendations for VTE prophylaxis in patients with THR/TKR, and the efficacy of anticoagulation for VTE prevention has been demonstrated in clinical trials, VTE prophylaxis remains underused, and physician adherence to guidelines is suboptimal.44 In addition, because hospital stays for many THR/TKR patients are short, and this population is at increased risk for VTE, there is an unmet need for effective and safe in-hospital and post-discharge VTE prophylactic strategies. Novel and emerging oral anticoagulants have the potential to simplify in-hospital and post-discharge VTE prophylaxis and may help to improve adherence to the recommended guidelines due to their convenient oral route of administration, simple dosing regimens, and lack of need for routine monitoring. This may lead to potentially lower rates of recurrent VTE and associated sequelae. By increasing compliance and reducing VTE risk, these agents have the potential to significantly reduce the financial costs associated with VTE treatment and complications.
Louis M. Kwong, MD, FACS is Professor and Vice Chairman of the Department of Orthopaedic Surgery, Medical Director of the Orthopaedic Clinics, Chief of the Orthopaedic Arthritis Service, and Program Director of Orthopaedic Residency Training at Harbor-UCLA Medical Center. He is also Co-director of the Harbor-UCLA Thrombosis Research Institute at LA BioMed (TRIAL Group). Acknowledgements and disclosures The author would like to acknowledge Lisa Grauer, MSc, who provided editorial support with funding from Janssen Scientific Affairs, LLC.
References 1. White RH. The epidemiology of venous thromboembolism. Circulation. 2003;107:I4-I8. 2. Bauersachs R, Berkowitz SD, Brenner B, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363:2499-2510. 3. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133:381S-453S. 4. Friedman R.J., Gallus AS, Cushner FD, Fitzgerald G, Anderson FA, Jr. Physician compliance with guidelines for deep-vein thrombosis prevention in total hip and knee arthroplasty. Curr Med Res Opin. 2008;24:87-97. 5. Centers for Medicare and Medicaid Services. Web site. https://www.cms. gov/MedicaidRF/03_PPC.asp. Accessed January 20, 2012. 6. Sanford M, Plosker GL. Dabigatran etexilate. Drugs. 2008;68:1699-1709. 7. Fanikos J, Piazza G, Zayaruzny M, Goldhaber SZ. Long-term complications of medical patients with hospital-acquired venous thromboembolism. Thromb Haemost. 2009;102:688-693. 8. Lassen MR, Laux V. Emergence of new oral antithrombotics: a critical appraisal of their clinical potential. Vasc Health Risk Manag. 2008;4:1373-1386. 9. Paolucci F, Clavies MC, Donat F, Necciari J. Fondaparinux sodium mechanism of action: identification of specific binding to purified and human plasmaderived proteins. Clin Pharmacokinet. 2002;41 Suppl 2:11-18. 10. Grouzi E, Kyriakou E, Panagou I, Spiliotopoulou I. Fondaparinux for the treatment of acute heparin-induced thrombocytopenia: a single-center experience. Clin Appl Thromb Hemost. 2010;16:663-667. 11. Tufano A, Coppola A, Cerbone AM, Ruosi C, Franchini M. Preventing postsurgical venous thromboembolism: pharmacological approaches. Semin Thromb Hemost. 2011;37:252-266. 12. Wienbergen H, Zeymer U. Management of acute coronary syndromes with fondaparinux. Vasc Health Risk Manag. 2007;3:321-329. 13. Ansell J, Hirsh J, Hylek E, et al. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133:160S-198S. 14. van Walraven C, Jennings A, Oake N, Fergusson D, Forster AJ. Effect of study setting on anticoagulation control: a systematic review and metaregression. Chest. 2006;129:1155-1166. 15. Ansell J, Hirsh J, Poller L, et al. The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126:204S-233S. 16. Romualdi E, Ageno W. Oral Xa inhibitors. Hematol Oncol Clin North Am. 2010;24:727-7ix. 17. Bereznicki LR, Peterson GM. New antithrombotics for atrial fibrillation. Cardiovasc Ther. 2010;28:278-286. 18. Turpie AG, Eriksson BI, Lassen MR, Bauer KA. A meta-analysis of fondaparinux versus enoxaparin in the prevention of venous thromboembolism after major orthopaedic surgery. J South Orthop Assoc. 2002;11:182-188.
36 Journal of Managed Care Medicine | Vol. 15, No. 4 | www.namcp.org
19. Ansell J. Factor Xa or thrombin: is factor Xa a better target? J Thromb Hae-
parin for prevention of venous thromboembolism after total hip replacement: a
most. 2007;5 Suppl 1:60-64.
randomised, double-blind, non-inferiority trial. Lancet. 2007;370:949-956.
20. Janssen. XARELTO® (Rivaroxaban) prescribing information. 2011.
34. Eriksson BI, Dahl OE, Rosencher N, et al. Oral dabigatran etexilate vs.
21. Eriksson BI, Borris LC, Friedman RJ, et al. Rivaroxaban versus enoxaparin for
subcutaneous enoxaparin for the prevention of venous thromboembolism after
thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008;358:2765-2775.
total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost.
22. Kakkar AK, Brenner B, Dahl OE, et al. Extended duration rivaroxaban
2007;5:2178-2185.
versus short-term enoxaparin for the prevention of venous thromboembolism
35. Ginsberg JS, Davidson BL, Comp PC, et al. Oral thrombin inhibitor dabi-
after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet.
gatran etexilate vs North American enoxaparin regimen for prevention of ve-
2008;372:31-39.
nous thromboembolism after knee arthroplasty surgery. J Arthroplasty.
23. Lassen MR, Ageno W, Borris LC, et al. Rivaroxaban versus enoxaparin for
2009;24:1-9.
thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008;358:2776-2786.
36. Boehringer Ingelheim Pharmaceuticals I. PRADAXA® (dabigatran etexi-
24. Turpie AG, Lassen MR, Davidson BL, et al. Rivaroxaban versus enoxaparin
late mesylate) prescribing information. 2011.
for thromboprophylaxis after total knee arthroplasty (RECORD4): a ran-
37. Elting LS, Escalante CP, Cooksley C, et al. Outcomes and cost of deep venous
domised trial. Lancet. 2009;373:1673-1680.
thrombosis among patients with cancer. Arch Intern Med. 2004;164:1653-1661.
25. Eriksson BI, Quinlan DJ. Oral anticoagulants in development: focus on
38. Bullano MF, Willey V, Hauch O, et al. Longitudinal evaluation of health
thromboprophylaxis in patients undergoing orthopaedic surgery. Drugs.
plan cost per venous thromboembolism or bleed event in patients with a prior
2006;66:1411-1429.
venous thromboembolism event during hospitalization. J Manag Care Pharm.
26. Kubitza D, Becka M, Wensing G, Voith B, Zuehlsdorf M. Safety, pharma-
2005;11:663-673.
codynamics, and pharmacokinetics of BAY 59-7939-an oral, direct Factor Xa
39. Spyropoulos AC, Lin J. Direct medical costs of venous thromboembolism
inhibitor-after multiple dosing in healthy male subjects. Eur J Clin Pharmacol.
and subsequent hospital readmission rates: an administrative claims analysis
2005;61:873-880.
from 30 managed care organizations. J Manag Care Pharm. 2007;13:475-486.
27. Kubitza D, Becka M, Zuehlsdorf M, Mueck W. Effects of single-dose BAY
40. Bergqvist D, Jendteg S, Johansen L, Persson U, Odegaard K. Cost of long-
59-7939 – an oral, direct Factor Xa inhibitor – in subjects with extreme body
term complications of deep venous thrombosis of the lower extremities: an
weight. Presented at: Blood. 2005,106. 11.
analysis of a defined patient population in Sweden. Ann Intern Med.
28. Kubitza D, Becka M, Mueck W, Zuehlsdorf M. The effect of extreme age,
1997;126:454-457.
and gender, on the pharmacology and tolerability of rivaroxaban - an oral, di-
41. Gold MR, Siegel JE, Weinstein MC et al. Cost-Effectiveness in Health and
rect Factor Xa inhibitor. Blood. 2006;108:Abstract 905
Medicine. Oxford University Press; 1996.
29. Lassen MR, Raskob GE, Gallus A, et al. Apixaban or enoxaparin for throm-
42. Sullivan SD, Kwong L, Nutescu E. Cost-effectiveness of fondaparinux com-
boprophylaxis after knee replacement. N Engl J Med. 2009;361:594-604.
pared with enoxaparin as prophylaxis against venous thromboembolism in pa-
30. Lassen MR, Raskob GE, Gallus A, et al. Apixaban versus enoxaparin for
tients undergoing hip fracture surgery. Value Health. 2006;9:68-76.
thromboprophylaxis after knee replacement (ADVANCE-2): a randomised
43. Duran A, Sengupta N, Diamantopoulos A, et al. Cost and outcomes associ-
double-blind trial. Lancet. 2010;375:807-815.
ated with rivaroxaban vs enoxaparin for the prevention of postsurgical venous
31. Lassen MR, Gallus A, Raskob GE, et al. Apixaban versus enoxaparin for
thormboembolism from a US payer’s perspective. J Med Econ. 2011;October 24,
thromboprophylaxis after hip replacement. N Engl J Med. 2010;363:2487-2498.
e-pub ahead of print.
32. Bristol-Myers Squibb, Pfizer EEIG. Eliquis® (Apixaban) summary of prod-
44. Burleigh E, Wang C, Foster D, et al. Thromboprophylaxis in medically ill
uct characteristics. 2011.
patients at risk for venous thromboembolism. Am J Health Syst Pharm.
33. Eriksson BI, Dahl OE, Rosencher N, et al. Dabigatran etexilate versus enoxa-
2006;63:S23-S29.
www.namcp.org | Vol. 15, No. 4 | Journal of Managed Care Medicine 37
Get connected to the perspectives of 100 stakeholders who manage 143 million covered lives Connecting you with relevant information is part of our commitment to you. That’s why Lilly commissioned the publication of a report based on the Managed Care Oncology Index.* This study surveyed managed care executives, practicing oncologists, and oncology practice managers who shared their views on interesting oncology topics such as: • Coverage and reimbursement of oncolytics • Oncology management strategies • Clinical pathways The publication, Trend Report on Oncology Management, is just one example of how Lilly Oncology can connect you with important information to assist your organization in managing members with cancer. To get your copy of the trend report, simply call 1-800-247-7832 and a Lilly Account Manager–Oncology Payer Services will contact you to arrange delivery of your copy and answer any questions you might have about other available services. Visit www.lillyoncology.com.
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Telehealth Program for Medicaid Patients with Type 2 Diabetes Lowers Hemoglobin A1c Kelly D. Stamp, PhD, ANP-C; Nancy A. Allen, PhD, ANP-BC; Susan Lehrer, RN,BSN, CDE; Sofija E. Zagarins, PhD; Gary Welch, PhD
Summary Diabetes telehealth research to date has provided minimal description of its clinical protocols, including strategies used to foster behavior change and procedures to deliver diabetes self-management education (DSME) and medical care. Also, there has been a focus on time-limited research interventions but little on working clinical programs. We describe here an effective diabetes telehealth program (HouseCalls) that serves an urban Medicaid population living with poorly-controlled type 2 diabetes (T2DM). We also discuss barriers to the future scalability and long-term sustainability of such programs that our health care system will need to overcome if we are to provide population-level telehealth solutions for the growing epidemic of T2DM. Key Points • T2DM affects 7.8 percent of the U.S. population, with only 7 percent of these individuals meeting the guidelines for control of hyperglycemia, hypertension, and dyslipidemia. • HouseCalls uses a system of in-home remote monitoring devices- blood glucose (BG) meters and blood pressure (BP) monitors- that upload readings electronically to a secure website. A nurse-led team provides telephone support: rapid feedback regarding the remote monitoring data, self-care advice, education, and timely clinical follow-up. • Data from 330 urban dwelling, T2DM Medicaid patients showed a clinically and statistically significant improvement in mean glycosylated hemoglobin (HbA1c) of -1.8 percent (SD = 2.2). • Despite such positive outcomes, practical barriers exist that threaten the scalability and long-term financial viability of T2DM telehealth. Emerging models, including HouseCalls, provide evidence that telehealth can improve access and quality of care, and reduce health care costs.
Introduction
Landmark studies of T2DM have demonstrated significant clinical benefit from intensive management of elevated BG and BP.1,2 However, there is a significant gap between evidence-based recommendations for T2DM and the medical care currently delivered. Only 7 percent of diabetes patients in the U.S. meet recommended goals: HbA1c less than 7 percent, BP <130/80 mmHg, and LDL <100 mg/dL. The percentage of patients receiving recommended annual screenings for early detection of diabetes-related changes in the eyes, kidneys, and feet remains suboptimal.3 From the patient’s perspective, T2DM is a complex and demanding chronic illness.4,5 Patients must
initiate or modify many daily lifestyle behaviors to benefit from the treatment plan.6 DSME, delivered in individual or group outpatient sessions, is the cornerstone of clinical support for behavior change.6 Telehealth has emerged as a patient-centered strategy for the delivery of DSME that leverages communication and information technologies to provide more timely and convenient support in the patient’s home.7 Remote patient monitoring (RPM) enables patients to monitor and transmit biometric data from home, including BG, BP and body weight. These monitors upload readings to a secure server by landline or cellular modem, and patients cannot alter or delete readings. Patients can answer questions about symptoms and self-care be-
www.namcp.org | Vol. 15, No. 4 | Journal of Managed Care Medicine 39
Exhibit 1: Patient eligibility criteria and final sample size.
402 patients enrolled from January 1, 2008 to December 31, 2009 Excluded 8 patients aged < 21years at enrollment
75 patients dropped out of program
Excluded 64 patients with a baseline A1c < 7.0% 330 patients included in the analysis dataset
1 patient died 41 patients were excluded due to changes in their insurance 35 patients met their goals and graduated out of the program
8 patients were excluded due to care plan change (care managerâ&#x20AC;&#x2122;s decision) 19 patients were excluded when they moved out of the service area
126 patients were still enrolled in the program as of January 31, 2011
25 patients left program due to unresolved technical issues
169 patients did not complete the program
haviors via automated telephony or an LCD screen on the modem. Telehealth nurses typically track trends and outof-range readings using a web-based interface that provides decision support, automated alerts via email for severely out-of-range readings, and communication protocols to coordinate care with the primary care provider (PCP). Telephone support to the patient provides rapid feedback on RPM data patterns, self-care advice, education, and follow-up. The literature documents a growing level of intervention complexity over the past 30 years, from simple BG uploads to more comprehensive monitoring and nurse support programs.8 Patients report high satisfaction levels, but clinical findings are mixed.9-14 Recently, four large, well-designed trials have demonstrated improved outcomes and cost-ef-
fectiveness. The Diabetes Education and Telecare Demonstration project (IdeaTel) showed a reduction in mean HbA1c from 8.4 to 7.4 percent, with improvements in HbA1c, LDL-cholesterol and BP sustained over five years.16 In the VA Care Coordination Home Telehealth program, 445 T2DM veterans had a 50 percent decrease in hospitalizations, an 11 percent decrease in emergency room visits, and a significant improvement in three quality of life dimensions.17 Baker and colleagues later reported cost reductions of 7.7 to 13.3 percent for Medicare patients with T2DM and other chronic conditions, using a telehealth program similar to that used by the VA.17,18 The United Kingdomâ&#x20AC;&#x2122;s Department of Health Whole System Demonstrator program19 is the largest clinical trial of telehealth conducted to date, involving 6,191 patients with diabetes, heart failure, and
40 Journal of Managed Care Medicine | Vol. 15, No. 4 | www.namcp.org
Exhibit 2: Patient characteristics by follow-up status
Duration of Follow Up
Enrollment Status Mean % n Age (SD) Female
Mean Range Base HbA1c (SD) Mean (SD)
Goals met (graduated) Still in program Excluded Dropped out
16.8 (8.6) 25.5 (6.5) 10.1 (6.4) 8.5 (6.4)
35 126 94 75
52.9 (8.3) 55.2 (8.6) 56 (9.5) 52.4 (11.9)
62.9 69.8 67.0 65.3
3.4 - 33.5 13.3 - 36.3 0.3 - 27.4 0.4 - 26.4
9.7 (2.2) 9.8 (1.9) 9.8 (2.1) 10.1 (2.3)
Note: Groups do not differ in terms of age, gender distribution, or baseline HbA1c. Groups did differ significantly in terms of duration of follow up (p<.001)
chronic obstructive pulmonary disease. Outcomes included significant reductions in urgent visits and admissions, elective admissions and bed days, and a 45 percent reduction in mortality. In contrast, the Medicare Health Support Pilot Program (MHSPP) examined eight disease management vendor programs for diabetes and/or heart failure and found only modest improvements in quality-of-care measures and no demonstrable reduction in costs of care.20 Patients received health-coaching calls from nurses every 2.7 months (on average) and were given literature, videos, and Internet resources regarding their conditions. The poor results may reflect a lack of key program ingredients, including a need for frequent contact with patients, integration of disease management programs into the patient’s routine medical care, and use of RPM strategies to activate and engage the patient for self-management behavior change. One important weakness of diabetes telehealth research is the minimal description of the clinical protocols and procedures employed in telehealth interventions, including the behavior change techniques and telehealth protocols used by nurses to deliver DSME and clinical care. Studies to date have typically involved time-limited research-oriented interventions in which clinical care is paid for by research funding. Discussion of program scalability and long-term financial viability is largely absent. This issue is critical, as most public payers and commercial health plans do not currently cover telehealth. 21 Some hospital-based diabetes telehealth programs are partly integrated into local clinical care networks and have service contracts in place with local health plans. Often these programs are not reported in the telehealth literature, but insights obtained from them could inform research in this area. To address this gap, we describe an established diabetes telehealth program that has been in place since 2006, including details of its clinical
procedures and protocols, and we discuss barriers to its scalability and long-term sustainability that must be overcome if our health care system is to provide a realistic solution for the growing T2DM epidemic. Methods Description of HouseCalls, the Diabetes Telehealth Program
New York City Health and Hospitals Corporation (HHC) is one of the largest hospital and health systems in the country, serving 1.3 million people including 400,000 uninsured. The prevalence of diabetes is estimated at 12.5 percent, and of those, 59 percent are African American or Hispanic.22 In 2006, HHC initiated the HouseCalls diabetes telehealth program in collaboration with MetroPlus, HHC’s Medicaid health plan. Patients were referred to the program based on poorly-controlled T2DM (HbA1c > 7 percent in the previous three to six months) and, optionally, a history of diabetes-related emergency department and unscheduled office or clinic visits, hospital or home care admissions, and inconsistent follow-up care. Clinical staff from 17 HHC facilities referred patients to the program. PCPs communicated individualized treatment plans to the telehealth nurses, including high and low BG parameters for RPM alerts. The telehealth nurses provided weekly telephone education and counseling based on the patients prescribed treatment plan. The telehealth nurses had no face-to-face contact with the patients. Patients were given a BG monitor (LifeScan One Touch Ultra®) connected to a landline telemonitoring modem (AMC Health®) to use at home. Patients with hypertension were also given a digital autoinflate BP monitor (A&D Medical 767PC®) for transmission of BP data via the same telemonitoring modem. After taking readings, the patient pressed a button on the modem to transmit the readings to the program’s secure website. In recent years, a cel-
www.namcp.org | Vol. 15, No. 4 | Journal of Managed Care Medicine 41
Mean Change in A1c (%)
Exhibit 3: Mean change in HbA1c by patient follow-up status. *
-3.5 -3.0 -2.5 -2.0 -1.5 -0.5 0
Goals met Still in program Excluded Dropped out (graduated) Follow-up status
* Change (improvement) in HbA1c was significantly larger in those patients who graduated from the program as compared to the other groups (p<0.001).
Number of Readings
Exhibit 4: Mean number of blood pressure and blood glucose readings by month in telehealth program. 50 40 30 20 10 0 1
2
3
4
5
6
7
8
9
10
11
Month of Follow Up Blood Pressure
lular modem was provided if patients did not have a landline telephone. A technician from the RPM vendor installed the modem in the patient’s home, trained the patient to use the equipment, and provided telephone-based or in-home technical support, as needed. Nurses reviewed BG and BP data on the RPM vendor’s secure website. The protocol set a red (high) alert for BG and BP values greater than 20 percent above or below parameters preset by the patient’s PCP. High alerts prompted a nurse response call within two hours of notification between 6 a.m. and 5 p.m. weekdays. Patients were instructed to call 911 emergency services or report to the nearest emergency room for any physical distress, falls, severe dizziness or lightheadedness not relieved by rapid-acting glucose. Nurses reviewed yellow alerts (BG and BP readings above or below the normal range but not in the alert range) with follow-up as needed. Daily reports listed patients who had not
Blood Glucose
transmitted RPM data for 24 hours. Telehealth nurses used the secure HouseCalls website to track and manage patients’ status, document care plans, and record communication with PCPs. DSME support focused on insulin titration, medication adherence, appointment reminders and problem solving skills training. Use of the American Diabetes Educators (AADE-7) behavior change guidelines was enhanced by use of open questions in telephone discussions with reflections and brief summaries to help patients explore barriers to selfcare (BG monitoring, diet, medication adherence and physical activity). Rapport, coaching, and feedback were used to improve patient-provider communication and strengthen patient motivation and engagement with self-management, while the immediate response to patient alerts helped patients make accurate connections between their behaviors and their out-of-range readings. Patients received weekly 10-20-minute phone calls from their nurse,
42 Journal of Managed Care Medicine | Vol. 15, No. 4 | www.namcp.org
with regular motivational discussions of DSME goals and problem solving. Additional calls were made in response to significant hypoglycemia, hyperglycemia, or hypertension. All communications were HIPPAA/HITECH compliant. The patientsâ&#x20AC;&#x2122; PCPs received BG and BP RPM results for the prior 30-60 days via secure email before scheduled appointments. Telehealth nurses provided coordination of care and decision support for PCPs, endocrinologists, nurse practitioners, physician assistants, chronic care coordinators and home health agency clinicians by phone, email and fax. Patients could request discharge from the program at any time and could be discharged: (1) at the request of their PCP; (2) for non-adherence to the program protocol; (3) for loss of home telephone service; (4) for abusive behavior to program staff; (5) for disenrollment from the managed care plan; or (6) because the patient had achieved program goals (i.e., HbA1c less than 7 percent, BP<130/80 mmHg). Discharge from the program for goal achievement was a threestep process, with PCP approval. Step 1 was reached when the BG level was predominantly <135 mg/dL for three months or HbA1c progressively decreased to less than 8 percent for three consecutive readings. At this stage, DSME calls were reduced from weekly (plus as-needed calls) to every two weeks (plus as-needed calls). Step 2 was achieved with HbA1c trending down and with typical BG readings of 80120 mg/dL. Discharge (Step 3) was achieved when HbA1c was below 7 percent for three months. Patients, PCPs, and the managed care company were then notified. The program was reimbursed by the health plan at a negotiated monthly rate of $10 per patient per day.
phone or were otherwise unable to participate in the program, n=94); and(4) Dropouts (patients who voluntarily left the program without reaching goal, n= 75). Analyses were also conducted based on two aggregates in which Graduates and Still Enrolled patients (Successful) were compared to Dropouts and Discharged patients (Unsuccessful). Analysis of variance was used to test for differences in age, duration in program, and baseline HbA1c across these groups, and the chi-square test was used to test for differences in gender. Change in HbA1c was calculated by comparing baseline HbA1c levels to levels obtained at the end of follow-up (i.e., graduation from program, time of discharge/dropout, or most recent value for those still enrolled at the end of follow-up). Paired t-tests were used to test whether changes in HbA1c were significant. Adherence to the program was measured using BG and BP RPM data. Frequency of BG and BP measurements was recorded and averaged by month. Mean BP over time was collected for patients who were hypertensive at baseline and was analyzed for Successful vs. Unsuccessful, using a repeated measures analysis of variance. BMDP program 5V23 was used for the analysis, with month of measurement used as the within (repeated) factor. This allows for an unbalanced design in which each subject is not measured on each occasion. It also allows for various covariance structures.24 Compound symmetry was used as the covariance structure. Linear contrasts determined whether there was a linear change in BP over time. Waldâ&#x20AC;&#x2122;s test was used to test these hypotheses. A maximum likelihood procedure using the Newton-Raphson algorithm was used to obtain estimates of the regression and covariance parameters.25
Data Collection and Statistical Analysis
Data analyses were conducted with SAS 9.2Š (SAS Institute Inc.). Age and gender, as well as repeated measures of systolic and diastolic BP and HbA1c, were collected from patients who were enrolled in HouseCalls from January 1, 2008 through December 31, 2009. Patients were excluded if they were less than 21 years of age at enrollment or had a baseline HbA1c less than 7 percent (Exhibit 1). All data were stripped of patient identifiers and analyzed to identify trends and to test for significant changes among variables. For this analysis, patients were divided into four groups: (1) Still Enrolled (patients still in the program at the end of the follow-up period, n=126;(2) Graduates (patients who were disenrolled after meeting and maintaining program goals, n=35); (3) Discharged (patients who were no longer members of the health plan, no longer had a land-line tele-
Results
Data were available for a total of 330 patients who met the inclusion criteria (Exhibit 1). Mean age (SD) at enrollment was 54.0 (9.7) years and 67 percent of patients were female. Follow-up duration differed significantly among groups (p<0.001): Dropouts and Discharged had the shortest duration (8.5 and 10.1 months, respectively), while patients who successfully completed the program did so in an average of 16.8 months (Exhibit 2). The four groups did not differ at baseline in terms of gender (p=0.83) or mean HbA1c (p=0.68) (Exhibit 2). Groups differed in age (p=0.06) but the differences do not appear to be clinically significant (Exhibit 2). We used an intention-to-treat analysis, and the primary outcome, mean change in HbA1c for the entire population, was -1.8 percent (SD: 2.2),
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(p<0.001) a clinically significant improvement. Graduates had larger reductions in HbA1c than Still Enrolled, Discharged and Dropouts (p < 0.001) (Exhibit 3). In the last three groups, there were no significant differences in change in HbA1c. The Successful patients had a larger reduction in HbA1c than the Unsuccessful patients (-2.2 percent vs. -1.4 percent, respectively; p = 0.002). Enrolled patients were adherent to the program, as demonstrated by their regular measurements of BG and BP. At baseline, the average number of BG readings per month was 38.2 (SD: 27.3), while at 12 months the average was 34.1 (28.0) (Exhibit 4). Among patients with hypertension at baseline (n=253) the average number of BP readings was 32.7 (20.3) at baseline, while at 12 months the average was 20.2 (16.5). Among patients who were hypertensive at baseline, there was a significant reduction in mean systolic BP over time for the first 12 months for all participants combined (Chi-sq=40.2, df=11, p<0.0001). There was no significant difference between groups (Successful vs. Unsuccessful) in terms of trends in systolic BP over time (p=0.88). Results were similar for diastolic BP, such that there was a similar significant reduction in diastolic BP over time for all subjects combined (Chi-sq=67.7, df=11, p<0.001), but there was no difference between groups in terms of reduction in diastolic BP over time. Discussion
The mean change in HbA1c among all patients enrolled in the HouseCalls program was both statistically and clinically significant. Overall, patients enrolled in the program saw a 1.8 percent reduction in HbA1c. To put these clinical findings in perspective, the landmark T2DM United Kingdom Prospective Diabetes Study showed that a 1 percent reduction of HbA1c was associated with a 35 percent reduction in macrovascular endpoints, an 18 percent reduction in myocardial infarction, and a 17 percent reduction in all-cause mortality.2 It was notable that even patients withdrawing early from the program (as a result of loss of phone service or insurance or personal decision not to participate) received 8.5 to 10 months of treatment and achieved significant clinical benefit in BG control (mean change in HbA1c: -1.4 percent). We examined the pattern of patient participation in the program as well as the reasons for discontinuing participation. Patients who were actively engaged demonstrated sustained participation in regular self-management tracking behaviors (i.e., measurement of BG and BP) with an average of 32 to 37 BG measurements per month during their first
year in the program. Patients also consistently took part in weekly nurse-led DSME sessions delivered by phone over a 12-month period. Of the 330 patients included in this analysis, approximately half dropped out or were excluded before meeting the program goals. Patients could drop out actively, or dropout could be inferred through non-compliance (i.e., patient stopped taking RPM readings or responding to telehealth nurses). Reasons for exclusion are detailed in Exhibit 1, and included moving out of the service area, changes in insurance coverage, and unresolved technical issues. Given the impressive improvements in HbA1c observed in this population, future refinements could focus on retention to further improve outcomes for the subset of patients who do not complete the program. For example, cellular RPM technology could be provided for patients who have no landline telephone for data upload. Additionally, voluntary dropouts could trigger an automatic nurse outreach to provide education and feedback to the patient on the value of the program in an attempt to ensure that the patient makes an informed decision. The HouseCalls program is an integral part of the HHC healthcare system and as such, the telehealth team (nurses and physicians) has access to the local clinical informatics network and implements the treatment plan provided and documented in the patientâ&#x20AC;&#x2122;s electronic medical record by the PCP. Disappointing findings from a recent evaluation of commercial disease management telehealth programs suggested that clinical integration and the use of RPM to engage patients and track vital signs, neither of which were part of the programs that were evaluated, may be key ingredients of successful telehealth programs. Further research is needed to examine the effect of these components. The economic sustainability of nurse-led telehealth programs remains a significant challenge as numerous barriers limit their scalability, including technology interoperability, institutional program support, Federal regulations, and low patient and provider awareness.26-28 A further significant barrier concerns the lack of program reimbursement by Medicare, Medicaid and most private insurance companies in the U.S. By contrast, the HouseCalls program has been sustained since 2006 by a local service contract negotiated with HHCâ&#x20AC;&#x2122;s own health plan to provide diabetes care for high-risk members. This contract was instituted as part of a citywide public health initiative targeting T2DM. Given this political context around the birth of the HouseCalls program, the clinical outcomes reported here provide important evidence that the city initiative of providing nurse-led telephone support to
44 Journal of Managed Care Medicine | Vol. 15, No. 4 | www.namcp.org
patients participating in this program has improved care outcomes and that these improvements may be sustainable as a result of cost savings related to preventable emergency room visits and hospital stays. The HouseCalls program costs $300/month, Medicare home health services cost approximately $41/ day over a typical 60 day episode of care, whereas skilled nursing facilities cost $358/day and a hospital stay costs $1805/day. Nationally, the U.S. lacks a coherent public and private telehealth policy, and reimbursement to support telehealth is lacking. 27 Reimbursement reform should provide not only payment for nurseled telephone-based diabetes care that is equivalent to face-to-face visits, but also payment for program development, and the installation and maintenance of RPM systems.27 It is helpful to learn from other systems that have embraced telehealth as part of their chronic care management plan and now provide reimbursement for fast growing telehealth programs as part of broader communication and information health care strategies. For example, the VA managed 31,000 chronically ill patients in 2010 using telehealth applications and plans to have 92,000 patients enrolled by 2012 for programs targeting diabetes, heart failure, and mental health medical conditions. The reimbursement is funded through U.S. Congressional approval of a $163 million VA telehealth budget included within the larger national Department of Defense budget. The UK Department of Health is planning to provide telehealth over the next five years to three million high risk patients with diabetes, heart failure, and pulmonary disease following the success of its recent large clinical trial. 27 While these large scale programs being developed by the U.S. VA and UK Department of Health may provide some impetus for change in the U.S., a more potent influence may be the current U.S. health care reforms, including the introduction of the Patient Centered Medical Home (PCMH) model that links coordinated networks of health care providers, Accountable Care Organizations, (ACOs) that link reimbursement to clinical outcomes, and other emerging models of payment that have financial incentives aligned with better clinical care. Importantly, these changes will support a transition from a volume-based, fee-forservice payment system to a risk-based payment system tied to clinical outcomes and efficiency. 27 One specific recommendation within the PCMH model is the use of telehealth with a provider-led team model that may include greater use of nurses, community health workers (CHWs) and patient caregivers to support patient self-management at
lower cost. Future refinements of the HouseCalls program could include a broadening of the telehealth care team to include trained CHWs and patient family supports that also monitor, educate, and motivate the patient and improve outcomes and quality of life. In summary, the results from the HouseCalls program showed improved patient outcomes, access to care and care quality, while potentially reducing the health care cost for a population of urban dwelling patients with T2DM. The details of clinical protocols and procedures utilized were shared along with identified strategies to improve the program by promoting increased engagement of the participants that dropped out and by exploring the addition of support systems. Although most health care payers in the U.S. have been reluctant to fund programs such as HouseCalls due to skepticism about their effectiveness and a general cutting back of all ‘non-essential’ health care services, PCMHs and ACOs may be a promising new care model that will support telehealth and more patient-centered care while improving access and quality, and reducing costs. Kelly Stamp, PhD, ANP-C is an Assistant Professor at Boston College, School of Nursing and Nurse Scientist at Massachusetts General and Brigham and Women’s Hospitals in Boston, Massachusetts. Dr. Stamp’s research focuses on behavioral interventions that will improve outcomes for individuals with chronic illnesses such as heart failure and diabetes. Nancy A. Allen, PhD, ANP-BC is an Assistant Professor at Boston College, School of Nursing and a Research Assistant Professor at Tufts University School of Medicine in the Department of Psychiatry at Baystate Medical Center in Springfield, MA. Her research focuses on diabetes, obesity, lifestyle changes, and using technology to support and maintain behavioral changes. Susan Lehrer, RN, BSN, CDE is the Associate Executive Director of Care Management Program for the New York City Health and Hospitals Corporation. She is a nurse and Certified Diabetes Educator and together with the administration of Health & Homecare, she designed and implemented the HHC Telehealth program called “House Calls” that provides care to poorly controlled individuals with diabetes and heart failure. Sofija Zagarins, PhD is a Research Assistant Professor at the Tufts University School of Medicine, and is a Senior Clinical Researcher in the Department of Behavioral Medicine Research at Baystate Medical Center in Springfield, MA. Her research focuses on virtual (webbased) support for clinical and surgical weight loss patients, including a focus on remote home monitoring technologies for measuring and supporting physical activity changes and weight loss. Garry Welch, PhD is the Director of Behavioral Medicine Research at Baystate Medical Center and Research Associate Professor in Psychiatry at Tufts University School of Medicine. His research focuses on new patient monitoring technologies and patient-centered clinical programs to support comprehensive care for chronic medical conditions including Type 2 diabetes and obesity surgery. Acknowledgements: The authors offer special thanks to John Holland, Debra Katz-Feigenbaum, MPH, RD and Ann Frisch, RN, MBA for their support in providing access to the data, their insights, and editorial assistance.
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References
15. Shea S, Consortium ID. The Informatics for Diabetes and Education Telemedi-
1. A National Center for Chronic Disease Prevention and Promotion Division
cine (IDEATel) project. Trans. Am. Clin. Climatol. Assoc. 2007;118:289-304.
of Diabetes Translation. National Diabetes Fact Sheet 2011; http://www.cdc.
16. Shea S, Weinstock RS, Teresi JA, et al. A randomized trial comparing tele-
gov/.
medicine case management with usual care in older, ethnically diverse, medi-
2. Anonymous. Effect of intensive blood-glucose control with metformin on
cally underserved patients with diabetes mellitus: 5 year results of the IDEATel
complications in overweight patients with type 2 diabetes (UKPDS 34). UK
study. J. Am. Med. Inform. Assoc. 2009;16(4):446-456.
Prospective Diabetes Study (UKPDS) Group.[Erratum appears in Lancet 1998
17. Chumbler NR, Neugaard, B., Kobb, R., Ryan, P., Qin, H., Yongsung, J.
Nov 7;352(9139):1558]. Lancet. 1998;352(9131):854-865.
Evaluation of a Care Coordination/Home-Telehealth Program for Veterans
3. Bojadzievski T, Gabbay RA. Patient-centered medical home and diabetes.
with Diabetes: Health Services Utilization and Health-Related Quality of Life.
Diabetes Care. 2011;34(4):1047-1053.
Eval. Health Prof. 2005;28(4):464.
4. Anderson R, Funnell MM. The art of empowerment: Stories and strategies for
18. Baker LC, Johnson SJ, Macaulay D, Birnbaum H. Integrated telehealth and
diabetes educators. Alexandria: American Diabetes Association; 2000.
care management program for Medicare beneficiaries with chronic disease
5. Welch G, Weinger, K., Jacobson AM. Textbook of type 2 diabetes. London:
linked to savings. Health Aff. (Millwood). 2011;30(9):1689-1697.
Martin Dunitz Publishers; 2007.
19. Department of Health. National Health System UK. Whole System Demon-
6. American Association of Diabetes Educators. 2011; http://www.diabetesed-
strator Programme. 2011; http://www.dh.gov.uk/health/2011/12/wsd-head-
ucator.org/. Accessed Janurary 6, 2012, 2011.
line-findings/. Accessed January 12, 2011.
7. Tran K. Polisena J CD, Coyle K, Kluge E-H W, Cimon K, McGill S, Noora-
20. McCall N, Cromwell J. Results of the Medicare Health Support disease-
ni H, Palmer K, Scott R. Overview of Home Telehealth for Chronic Disease Man-
management pilot program. N. Engl. J. Med. 2011;365(18):1704-1712.
agement Ottawa: Canadian Agency for Drugs and Technologies in Health;2008.
21. Tynan A, Draper DA. Getting what we pay for: innovations lacking in pro-
8. Oâ&#x20AC;&#x2122;Brien M. Remote telemonitoring. A preliminary review of current evi-
vider payment reform for chronic disease care. Research Briefs. 2008(6):1-8.
dence. European Center for Connected Health 2008; http://www.eu-cch.org/re-
22. Kim M. BD, Matte T. Diabetes in New York City: Public Health Burden and
mote-telemonitoring-a-preliminary-review-of-current-evidence.pdf.
Disparities. New York City: New York City Department of Health and Mental
9. Polisena J, Coyle D, Coyle K, McGill S. Home telehealth for chronic disease
Hygiene;2006.
management: a systematic review and an analysis of economic evaluations. Int.
23. BMDP/Dynamic [computer program]. Version 7th. Los Angeles: BMDP
J. Technol. Assess. Health Care. 2009;25(3):339-349.
Statistical Software; 1993.
10. Boren SA. A review of health literacy and diabetes: opportunities for tech-
24. Jennrich RI, Schluchter MD. Unbalanced Repeated - Measures Models
nology. Journal of Diabetes Science & Technology. 2009;3(1):202-209.
with Structured Covariance Matrices. Biometrics. 1986;42:805-820.
11. Montori VM, Helgemoe PK, Guyatt GH, et al. Telecare for patients with
25. Jennrich RI, Robinson SM. A Newton-Raphson algorithm for maximum
type 1 diabetes and inadequate glycemic control: a randomized controlled trial
likelihood factor analysis. Psychometrika. 1969;34:111-123.
and meta-analysis. Diabetes Care. 2004;27(5):1088-1094.
26. Stachura M KE. Teleheomecare and Remote Monitoring: An Outcomes Over-
12. Blanchet KD. Telehealth and diabetes monitoring. Telemedicine Journal &
view2007.
E-Health. 2008;14(8):744-746.
27. Verhoeven F, Tanja-Dijkstra K, Nijland N, Eysenbach G, van Gemert-Pi-
13. G. P, Moqadem K, Pineau G, St-Hilaire C. Clinical effects of home tele-
jnen L. Asynchronous and synchronous teleconsultation for diabetes care: a sys-
monitoring in the context of diabetes, asthma, heart failure and hypertension: a
tematic literature review. Journal of Diabetes Science & Technology. 2010;4(3):666-
systematic review. Journal of Medical Internet Research. 2010;12(2):e21-e21.
684.
14. Costa BM, Fitzgerald KJ, Jones KM, Dunning Am T. Effectiveness of IT-
28. Lipowicz A. Veterans Affairs Takes a Leap of Faith into Telehealth. Federal
based diabetes management interventions: a review of the literature. BMC Fam-
Computer Week2010.
ily Practice. 2009;10:72.
46 Journal of Managed Care Medicine | Vol. 15, No. 4 | www.namcp.org
Multiple Myeloma: An Update on Current and Emerging Treatment Options Ravi Vij, MD For a CME/CEU version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.
Summary Multiple myeloma is a cancer in which plasma cells are produced in proliferative amounts at the expense of normal blood cells. Typically a disease of older age, multiple myeloma results in significant consequences such as anemia and bone fractures and is expensive to treat. Although treatments including chemotherapy, stem cell transplant, proteasome inhibitors, and immune modulating agents have improved survival, this is not yet a curable disease. Key Points • Monoclonal gammopathy of unknown significance can progress to smoldering multiple myeloma and multiple myeloma. • Multiple myeloma is increasingly recognized as more than one disease, characterized by marked cytogenetic, molecular, and proliferative heterogeneity which all affect prognosis. • Newer treatments have improved survival; however, the disease is not yet curable. • Treatment may include stem cell transplant, chemotherapy, proteasome inhibitors and/or immune modulating agents. • Bisphosphonates are used to reduce skeletal events.
Multiple myeloma (MM) is a plasma cell neoplasm characterized by proliferation in the bone marrow of monoclonal post germinal B cells. Multiple myeloma is increasingly recognized as more than one disease, characterized by marked cytogenetic, molecular, and proliferative heterogeneity. It is characterized by evidence of end-organ damage that can be attributed to the plasma cell proliferative disorder. Hypercalcemia, renal dysfunction, anemia, and lytic bone lesions (CRAB) are the classic end organ damages of MM. MM is the second most common hematologic malignancy in the United States, after non-Hodgkin lymphoma. Each year more than 20,000 new cases of myeloma are reported and 10,650 deaths occur.1 It accounts for 10 percent of all hematologic malignancies, nearly 20 percent of all deaths caused by hematologic malignancies, and 2 percent of all cancer deaths.2,3 This is a disease where plasma cells undergo genetic changes to progress from normal to abnormal (monoclonal gammopathy of unknown significance, MGUS) to premalignant (smoldering myeloma) to malignant (active MM). The genetic events that are responsible for this transition are still being determined. MGUS carries a 1 percent yearly risk of
progressing to MM.4 Ten percent of patients with smoldering myeloma will progress yearly during the first five years of diagnosis, 3 percent will progress yearly in years five to ten of diagnosis, and only 1 percent will progress beyond year 10. Currently, there is no evidence that treating MGUS or smoldering myeloma is of utility. Once MM is diagnosed, it is staged based on ß2-microglobulin and albumin levels into three categories. Higher ß2-microglobulin levels indicate a greater tumor burden and are a marker of poor prognosis. Stage I disease has a 62-month average survival, Stage II- 44 months, and Stage III- 29 months. Although there are many different negative prognostic factors that have been identified, the prognostic impact of the plasma cell chromosomal abnormalities are a major focus (Exhibit 1).5-10 There is now a 70 gene signature test that is Medicare approved for prognostic purposes for patients with MM. Because patients may develop new chromosomal abnormalities as their disease progresses, cytogenetics and/or fluorescence in situ hybridization (FISH) testing is recommended for all patients at diagnosis and at relapse. Some of the newer medications are starting to target the genetic abnormalities of this disease.
48 Journal of Managed Care Medicine | Vol. 15, No. 4 | www.namcp.org
Exhibit 1: Impact of Genetic Abnormalities on Prognosis in MM5-10
Chromosomal abnormality Incidence (%) Prognosis (FISH-based) Hyperdiploidy
39%-45% Favorable
Isolated del 13
–
No significance
t(11;14)
7.8%-21%
No significance
t(14;16)
1.9%-5%
Poor
t(4;14)
6.5%-15%
Poor
del 17p
11%
Poor
8.6% 11.9%
Poor
36% 29.8%
Poor
del 13 with del 17p t(4;14) Chromosome 1 1q gain 1p del FISH, fluorescence in situ hybridization
Treatment of MM has made much advancement since the 1960s when the only treatment was melphalan and prednisone. The next improvement was the advent of combination chemotherapy in 1984, which improved response rates and progression-free survival rates, but overall survival did not change. The late 1990s brought another advance with the use of high- dose chemotherapy with autologous stem cell transplant (ASCT) which is still the standard of care for patients who are transplant eligible. This improved median survival to five to six years. The most recent advance was the introduction of two new classes of medications – proteasome inhibitors [(bortezomib(Velcade®)] and immune modulating agents [thalidomide (Thalomid®), lenalidomide (Revlimid®)] - which have further extended survival by an additional 18 to 24 months. There is now a median survival of seven to eight years. Thalidomide, the infamous sedative associated with teratogenicity in the 1950s, works as an antiangiogenic and immune system modulator in MM. This agent does cause significant adverse effects. Thirty to 40 percent of people discontinue taking thalidomide within six months of starting because of neuropathy. Another significant adverse effect is deep vein thrombosis which must be prevented with anticoagulation. Lenalidomide is an analog of thalidomide, synthesized to increase efficacy and decrease toxicity. In two large Phase III trials, relapsed myeloma was improved with lenalidomide and dexamethasone compared to placebo plus dexamethasone leading to
FDA approval for use in patients who have failed one prior therapy.11 Bortezomib, which inhibits the proteasome, targets the bone marrow microenvironment and is used to prepare patients with MM for stem cell transplant. It may overcome the effect of adverse chromosomal features including chromosome 13 deletion in the MM cells.12 In relapsed or chemotherapy refractory patients, 33 percent responded to bortezomib with an average response lasting a year. This agent does cause significant adverse effects including peripheral neuropathy in up to 45 percent of patients. Although not universally agreed upon, the mSmart (Mayo Stratification for Myeloma And Risk-adapted Therapy) criteria from the Mayo clinic are used by some centers to stratify patients into high, intermediate, and standard risk groups to select optimal therapy (Exhibit 2).13 The complete guidelines can be found at www.msmart.org. Under these guidelines, patients considered high and intermediate risk receive more aggressive treatment. Exhibit 3 outlines the general approach to therapy which considers whether a patient is transplant eligible or not. The primary factor that makes a patient transplant ineligible is poor performance status. Additionally, patients need good social support to be a transplant candidate. They need adequate care givers, require support for transport to and from the transplant center, and they must have the ability to comply with peri-transplant care. Older age per se should not be considered an absolute contraindication for stem cell collection and transplantation. Age can be
www.namcp.org | Vol. 15, No. 4 | Journal of Managed Care Medicine 49
Exhibit 2: mSmart 2.0: Classification of Active MM13 High-Risk Intermediate Risk* Standard Risk*† – FISH – FISH All others including: - Del 17p - t(4;14)‡ - Hyperdiploid - t(14;16) - t(11;14)** - t(14;20) – Cytogenetic - t(6;14) Deletion 13 or – GEP Hypodiploidy - High risk signature PCLI >3% * Note that a subset of patients with these factors will be classified as high-risk by GEP † LDH > ULN and beta-2 M > 5.5 may indicate worse prognosis ‡ Prognosis is worse when associated with high beta-2 M and anemia ** t(11;14) may be associated with plasma cell leukemia
Del, deletion; GEP, gene expression profiling; PCLI, plasma cell labeling index
Exhibit 3: Approach to Treatment of MM
Clearly not a transplant candidate based on age, performance status and comorbidity
Potential transplant candidate
Non-alkylator based induction x 4 cycles Conventional Therapy
Stem cell harvest
a factor for some patients because 78 is the hard cutoff where Medicare will no longer pay for a transplant. Patients with active myeloma are initially treated with induction chemotherapy to reduce tumor burden. For transplant eligible patients, alkylating agents are avoided so stem cells for an autologous transplant can be collected after induction chemotherapy. The mortality with ASCT for MM is less than 1 percent, which is much less than some of the chemotherapy regimens. The mortality is so low because patients typically are only neutropenic for about a week after the high-dose chemotherapy before the transplanted stem cells begin to produce new cells. Since the introduction of active agents for treating MM, an issue of the role of transplant has emerged. There is a diversity of opinion with three main opinions - no role for transplant, offer transplant on relapse after medical treatment, and transplant as initial therapy. The group that advocates no role for transplant is looking for a combination of medica-
tions which will be curative. With three and four drug combinations, the response rate can be as high as 90 percent, but this is only a surrogate for survival, not for cure. Complete responses achieved with high- dose therapy can last two or more years. For the point of view of early transplant, there are questions as to how many cycles of chemotherapy to offer before transplanting. Some sites use three to four cycles and then transplant. There are no data to support giving additional chemotherapy cycles. Delaying transplant until first progression appears to be a valid strategy as long as the transplant is done at first progression rather than later (second or third). A transplant done four to six months after chemotherapy results in approximately two years of disease-free survival; the survival is only 14 months if the transplant is delayed until first progression. Another area of controversy is chemotherapy regimens before transplant. There are ongoing studies examining which chemotherapy regimen before trans-
50 Journal of Managed Care Medicine | Vol. 15, No. 4 | www.namcp.org
plant produces the longest lasting disease free survival. Most centers have moved to three drug regimens. The combination of bortezomib, thalidomide, and dexamethasone produces some of the best induction phase complete responses and improves disease free survival compared with two drug regimens. Overall survival benefits have not yet been demonstrated for a three-drug regimen over two drugs. Using lenalidomide instead of thalidomide in the three-drug regimen is becoming standard in many institutions. Maintenance therapy after transplant or chemotherapy is another area of controversy. Previously, two cycles of chemotherapy would be given after best response and then therapy would be restarted when the cancer recurred. This was primarily done because of the toxicity of the medications. Because the new medications available are less toxic, are oral (thalidomide and lenalidomide), and can be given for years, there is a move to give long-term maintenance therapy. The thought is that by continually suppressing the cancer, remission can be maintained. Although this is a costly approach, it does increase progressionfree survival. There are no data yet to say long term maintenance increases overall survival. One issue with lenalidomide maintenance is secondary malignancies that emerge in patients who have had prior exposure to alkylating agents. At this time, it is believed the benefit of lenalidomide outweighs the small increase in risk of another malignancy. Bortezomib has been studied as maintenance therapy and appears to also improve progression-free survival. Some centers are using it for maintenance especially for patients with high-risk disease. To answer the question of whether to use transplant or the novel agents will require a comparison trial. This will be a difficult trial design because most patient advocates will protest a trial unless it offers transplant at some point. There are several ongoing trials comparing various early versus late transplant and chemotherapy regimens. In addition to treating the disease, therapy to avoid end organ damage will also be needed. ASCO guidelines recommend the use of bisphosphonates for two years after the initial MM diagnosis to prevent skeletal events.14 This can usually be discontinued after the two-year period if the disease is inactive. However, recent data suggest the bisphosphonates have antineoplastic effects. This may lead to longer-term use, but there are adverse effects, such as renal insufficiency, which may occur with the long-term use. More active therapies are needed to treat MM. For patients who fail bortezomib and lenalidomide, the median overall survival is only nine months. One agent very close to FDA approval is carfilzomib. This is another proteasome inhibitor that causes minimal
inhibition of off-target proteases. It overcomes bortizimib resistance in the laboratory setting. Pomalidomide is another immune modulator that is structurally similar to thalidomide and lenalidomide. It is active in cases which have failed the other two agents. A third agent under study is elotuzumab. This is a humanized monoclonal IgG1 targeting CS1, a cell surface glycoprotein specific to plasma cells. CS1 is highly and uniformly expressed on MM cells with little to no expression on normal tissues. It is being studied in relapsed and refractory disease. Like other cancers, it is becoming apparent that it is important to not only treat the MM cancer cells but also the environment surrounding the cancer. This includes the growth factors that keep the myeloma cell alive. There are a host of potential factors in the bone marrow which are under study that may be therapeutic targets. Conclusion
Treatment of MM has come a long way from an era of ineffective therapy to an era of therapy that is prolonging survival. MM is not yet a curable disease, but it is hoped that advances will continue to get closer to that target. Ravi Vij, MD is an Associate Professor in the Section of Bone Marrow Transplantation and Leukemia at Washington University School of Medicine in St. Louis, MO.
References
1. Cancer facts and figures. American Cancer Society Web site. http://www. cancer.org/Research/CancerFactsFigures/CancerFactsFigures/cancer-factsand-figures-2010. 2. Kyle RA, Gertz MA, Witzig TE, et al. Review of 1,027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc. 2003;78:21-33. 3. Kuehl WM, Bergsagel PL. Multiple myeloma: evolving genetic events and host interactions. Nat Rev Cancer. 2002;2:175-87. 4. Rajkumar SV, Dispenzieri A, Kyle RA. Monoclonal gammopathy of undetermined significance, WaldenstrĂśm macroglobulinemia, AL amyloidosis, and related plasma cell disorders: diagnosis and treatment. Mayo Clin Proc. 2006;81:693-703. 5. Palumbo A, Sezer O, Kyle R,et al. International Myeloma Working Group guidelines for the management of multiple myeloma patients ineligible for standard high-dose chemotherapy with autologous stem cell transplantation. Leukemia. 2009;23:1716-30. 6. Fonseca R, Barlogie B, Bataille R, et al. Genetics and cytogenetics of multiple myeloma: a workshop report. Cancer Res. 2004;64:1546-58. 7. Avet-Loiseau H, Attal M, Moreau P, et al. Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe Francophone du MyĂŠlome. Blood. 2007;109:3489-95. 8. Fonseca R, Bergsagel PL, Drach J, et al. International Myeloma Working Group molecular classification of multiple myeloma: spotlight review. Leukemia. 2009;23:2210-21. 9. Dewald GW, Therneau T, Larson D, et al. Relationship of patient survival and chromosome anomalies detected in metaphase and/or interphase cells at diagnosis of myeloma. Blood. 2005;106:3553-8. 10. Walker BA, Leone PE, Chiecchio L, et al. A compendium of myeloma-associated chromosomal copy number abnormalities and their prognostic value. Blood. 2010;116:e56-65. 11. Weber DM, Chen C, Niesvizky R, et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med. 2007;357(21):2133-42. 12. Jagannath S, Richardson PG, Sonneveld P, et al. Bortezomib appears to overcome the poor prognosis conferred by chromosome 13 deletion in phase 2 and 3 trials. Leukemia. 2007;21:151-7. 13. Mayo Stratification for Myeloma And Risk-adapted Therapy Guidelines. Treatment of Newly Diagnosed Myleoma. Available at www.msmart.org. 14. Berenson JR, Hillner BE, Kyle RA, et al. American Society of Clinical Oncology clinical practice guidelines: the role of bisphosphonates in multiple myeloma. J Clin Oncol. 2002;20:3719-36.
www.namcp.org | Vol. 15, No. 4 | Journal of Managed Care Medicine 51
KNOW MORE. SPEND SMARTER. IMPROVE OUTCOMES. At Ethicon Endo-Surgery we are dedicated to transforming patient care by working daily to ensure our medical devices create new and innovative ways to treat patients, leading to more successful outcomes.
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Ethicon Endo-Surgery Reimbursement and Healthcare Economics DSL#10-1155
New Developments in the Treatment of Castrate-Resistant Prostate Cancer Pamela Ellsworth, MD For a CME/CEU version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.
Summary With improved screening, most patients with prostate cancer are diagnosed early and receive definitive treatment. Unfortunately, about 40 percent of these patients will develop a biochemical recurrence. Although there are many treatment options, many patients with advanced prostate cancer will become hormone therapy resistant (i.e., castrate resistant). The management of castrate-resistant prostate cancer continues to evolve with several new agents recently approved. Key Points • Because of improved screening and early diagnosis, biochemical recurrence rather than metastatic disease is the most common form of advanced prostate cancer diagnosed. • Approximately 40 percent of men who originally receive localized treatment will develop a PSA-only recurrence. • Patients with advanced prostate cancer have several treatment options depending on how their cancer was initially treated. • Despite treatment, many patients will develop castrate-resistant prostate cancer. • Sipulecel-T or corticosteroids are options for initial management of castrate-resistant prostate cancer after maximum androgen blockade has failed. • Chemotherapy using docetaxel is an option after initial management. • If the patient fails docetaxel, abiraterone or carbazitaxel are additional treatment options.
Prostate cancer (PC) accounts for 29 percent of all cancers among men and 11 percent of all cancer-related deaths.1 It is the leading cancer in men and second most common cause of cancer related death. Since 1995, the age-adjusted death rate from prostate cancer has declined; thus identification and management has had an impact on mortality. Historically, PC was typically diagnosed in the advanced stage with pelvic lymphadenopathy and/or bone metastases already present. With the advent of prostate specific antigen (PSA) testing, more men are identified with earlier stage disease and undergo definitive therapy. Definitive therapies primarily include radical prostatectomy, external beam radiation therapy, and intersitial radiation seeding. In select cases, cryotherapy may be used as initial primary therapy. The “new” advanced prostate cancer is a biochemical recurrence after definitive treatment for what was originally presumed to be localized disease. Defining a biochemical recurrence depends on what
type of definitive therapy the patient received. After radiation, seeding, or cryotherapy, the prostate is still intact. After these therapies, a biochemical recurrence is defined as a rise of 2 ng/mL or more above the nadir PSA after definitive therapy with or without hormone therapy.2 Many definitions exist for a biochemical recurrence after a radical prostatectomy. After removal of the prostate, the PSA should be undetectable. Stephenson and colleagues have proposed that biochemical recurrence after prostate removal be defined as a PSA of at least 0.4ng/ml followed by another increase.3 Approximately 40 percent of men who originally receive localized treatment will develop a PSA-only recurrence.4,5 For men with a biochemical recurrence, a variety of options are available. Treatment may be dependent on the initial form of treatment. Options include PSA surveillance and institution of hormonal therapy once the PSA reaches a critical level, radiation for post-radical prostatectomy recurrence, cryotherapy or radical prostatectomy for post–exter-
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Exhibit 1: Autologous Cellular Immunotherapy With Sipuleucel-T
Recombinant PAP-GM-CSF antigen combines with resting APC
Antigen is processed and displayed on surface of the APC
APC takes up the antigen
The mature antigenloaded APCs are the active component of sipuleucel-T
INFUSE PATIENT
T-cells proliferate and attack prostate cancer cells
nal beam radiation therapy recurrence, or hormone therapy with gonadotropin-releasing hormone (GnRH) analog/antagonist therapy. The hormonal therapies are not curative but are pallative therapies that slow disease progression. The GnRH agonists and antagonists reduce testosterone and thus reduce prostate tumor growth. With the agonists [leuprolide (Lupron®), goserelin (Zoladex ®)], there is an initial surge in testosterone levels, followed by a decrease. GnRH antagonists do not cause that surge. There is only one FDA approved antagonist – degarelix (Firmagon®). For most patients there is no difference between a GnRH agonist and antagonist. No efficacy differences have been shown between the two classes. In those patients with bone metastases, the use of an antagonist prevents the flare phenomenon seen with agonists. The rise in testosterone causes bone metastases pain. Additionally, patients with metastases in the spine can be at risk for spinal cord compression. If using analog in a patient with bone metastases, pretreatment with an androgen receptor blocker will prevent the flare. Androgen receptor blockers include flutamide (Eulexin®), bicalutamide (Casodex ®), and nilutamide (Nilandron®). The major disadvantage of degerelix is that it requires monthly injections, whereas the other agents can be given on a variety of schedules (i.e., monthly, every three months, every six months, or yearly). There are many side effects with the hormonal therapies from decreasing testosterone including fatigue, decreased bone mass, and decreased muscle mass. Intermittent hormone therapy has been investigated as an option to limit adverse effects. This approach is investigational at present. The potential benefits of intermittent hormone therapy are a delay in emergence of castrate-resistant prostate cancer
Sipuleucel-T activates T-cells in the body
(CRPC), decreased morbidity, improved quality of life, and decreased cost. The delay to emergence of CRPC has only been demonstrated in rats; no human clinical data are available.6 The approach to intermittent therapy is to treat patients with hormone therapy for six to nine months. Men with a rapid and good PSA response without evidence of metastases at start tend to do the best with intermittent therapy. Hormone therapy is stopped and the PSA followed. Hormone therapy is resumed when the PSA goes above 10 ng/mL. This cycling on and off is continued until the disease becomes resistant. Intermittent hormone therapy may be more applicable to select patients such as those men with biochemical recurrence only or older men with increased PSA velocity on watchful waiting. There are some data to support the combination of a GnRH agonist/antagonist and an androgen receptor blocker for maximal androgen blockade. Three large studies suggested that maximum androgen blockade conferred a survival advantage.7-9 Many clinicians start with the agonist/antagonist and add the receptor blocker when the PSA begins to rise. If the patient has an increasing PSA on a GnRH agonist/antagonist, the testosterone level should be checked to make sure they are at a castrate level (< 50ng/dL). If they are non-castrate, the GnRH therapy can be changed or surgical castration can be done. If the testosterone is at a castrate level, an androgen blocker can be added for maximum androgen blockage. Up to 40 percent of dihydrotestoterone is derived from adrenal precursors.10 Castrate-resistant prostate cancer is disease progression despite androgen depletion therapy and may present as either a continuous rise in serum prostate-specific antigen (PSA) levels, the progression of pre-existing disease, and/or the appearance
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Exhibit 2: Overall Survival in ITT Population with Sipuleucel versus Placebo17 P=.032 (Cox model) HR = 0.775 (95% CI, 0.614-0.979)
Percent Survival
100
Median survival benefit = 4.1 months
75
50
Sipuleucel-T (n=341) Median survival: 25.8 mo
25
0 ITT=intent to treat
Placebo (n=171) Median survival: 21.7 mo
0
6
12
18
24
30
36
42
48
54
60
66
Survival (Months)
of new metastases. CRPC is defined as castrate levels of testosterone (< 50ng/dl or < 1.7nmol/l) and three consecutive rises in PSA, one week apart, resulting in two 50 percent increases over the nadir PSA with progression of osseous lesions.11 Antiandrogen therapies should be discontinued to ensure the patient is castrate resistant. Stopping anti-androgen therapy will lead to PSA decreases in about 30 percent of patients for about three months duration. Most guidelines recommend continuing GnRH agonist/ antagonist therapy in CRPC. CRPC is thought to occur by several possible mechanisms. There can be an up regulation of androgen biosynthesis enzymes leading to intratumoral androgen concentration. There may also be overexpression of androgen receptors, androgen-receptor mutations leading to androgen-receptor binding by additional ligands, and/or altered levels of co-factors which may co-activate the androgen receptor.12-14 Options for treatment of CRPC include ketoconazole, corticosteroids, chemotherapy, abiraterone, or immunotherapy with sipuleucel-T. Historically, CRPC was treated with ketoconazole which blocks steroid hormone production in the adrenal glands. Ketoconazole is occasionally still used. Corticosteroids, either low dose prednisione or dexamethasone, may also offer improvements in PSA values and/or palliative outcomes in up to 30 percent of patients in both symptomatic and asymptomatic men. Docetaxel is the first-line chemotherapy of choice for CRPC. Clinical trials have confirmed the efficacy of docetaxel chemotherapy in prolonging survival in CRPC patients.15 There are, of course, significant adverse effects with chemotherapy that have to be balanced against the modest increase in survival two to three months). Abiraterone and sip-
uleucel-T are two new therapies. Abiraterone (Zytiga®) is an oral androgen biosynthesis inhibitor indicated for use in combination with prednisone for patients with metastatic CRPC who have failed docetaxel. Once more studies are done with this agent, it may be indicated for use before chemotherapy. This agent inhibits 17 alpha-hydroxylase/C17,20-lyase (CYP17), which is expressed in testicular, adrenal, and prostatic tumor tissues and is required for androgen biosynthesis. CYP17 catalyzes two sequential reactions essential for the production of testosterone precursors, dehydroepiandrosterone (DHEA) and androstenedione. Changes in serum PSA levels may be observed but have not been shown to correlate with clinical benefit in individual patients. In one study of patients who had failed hormone therapy and chemotherapy, overall survival was longer with abiraterone and prednisone compared with placebo and prednisone (14.8 months versus 10.9 months).16 Secondary end points, including time to PSA progression, progression-free survival and PSA response, rate favored abiraterone. A unique way of targeting CRPC is the use of immunotherapy. Sipuleucel-T (Provenge®) is FDA approved for treatment of asymptomatic or minimally symptomatic metastatic CRPC. This agent has a significant cost of $96,000. It is primarily for use earlier in the course of CRPC – probably after failure of hormone therapy but before chemotherapy. A course of sipuleucel-T treatment consists of three basic steps: 1) a patient’s antigen presenting cells (APCs), also called dendritic cells, are extracted in a leukapheresis procedure, 2) the blood product is sent to the manufacturer’s laboratory and incubated with a fusion protein consisting of two parts - the antigen prostatic acid phosphatase (PAP), which is
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present in 95 percent of prostate cancer cells, and. granulocyte-macrophage colony stimulating factor (GM-CSF) that helps the APCs to mature and 3) the activated blood product is returned from the laboratory to the infusion center and re-infused into the patient to cause an immune response against cancer cells carrying the PAP antigen. A complete sipuleucel-T treatment repeats three courses over the span of a month, with two weeks between successive courses. Essentially this agent upregulates the patientâ&#x20AC;&#x2122;s immune system to fight off the cancer (Exhibit 1). The key clinical trial of this agent was IMPACT, which showed a median survival benefit of 4.1 months (Exhibit 2).17 Patients have to be premedicated with oral acetaminophen and an antihistamine to reduce the risk of infusion reactions. Acute infusion reactions were reported in over 70 percent of clinical trial patients. Cabazitazel, a tubulin-binding taxane, is a new chemotherapy agent FDA approved for docetaxal failures. Cabazitaxel in combination with prednisone resulted in a longer overall survival when compared to mitoxantrone and prednisone (15.1 months versus 12.7 months). There are additional agents under investigation for treating CRPC. As discussed previously, one possible mechanism for CRPC is overexpression of androgen receptors. First generation antiandrogens actually have agonist properties in cells engineered to express higher androgen receptor levels.18 MDV3100 is a second generation antiandrogen that does not have this agonist property. This agent blocks androgen receptors with greater affinity than bicalutamide. Additionally, it impedes movement of the androgen receptor to the nucleus (translocation), inhibits binding to DNA, and induces apoptosis without agonist activity when the androgen receptor is overexpressed.19 Data from the phase one and two trials are promising.20 Many patients had regressions of soft-tissue disease, no progression in bone disease, and prolonged times to PSA and radiographic progression. Management and prevention of skeletal-related events is important in the treatment of advanced prostate cancer. Skeletal-related events including pathologic fractures, need for bone surgery, spinal cord compression, and need for radiation to bone can occur because of bony metastases. Two agents are FDA approved for the prevention of skeletalrelated events in patients with bone metastases from solid tumors zoledronic acid (ZometaÂŽ) and denosumab (XgevaÂŽ). Any patient on hormone therapy is going to have decreased bone mineral density. Men with risk factors for low bone mass should be scanned before hormone therapy. Preventive therapy should be started early rather than waiting until a skeletal event occurs.
Conclusion
Historically, patients with prostate cancer were discovered late in the disease process. Now, patients are diagnosed earlier and receive definitive treatment. Now, biochemical recurrence is the most common form of advanced prostate cancer. The management of castrate- resistant prostate cancer continues to evolve with several new agents recently approved. SipulecelT or corticosteroids are options for initial management of CRPC after maximum androgen blockade has failed. If those fail, docetaxel is considered firstline chemotherapy. If the patient fails docetaxel, abiraterone or carbazitaxel are treatment options. Pamela Ellsworth, MD is an Associate Professor of Urology at the Warren Alpert School of Medicine at Brown University in Providence, RI.
References
1. American Cancer Society. Cancer Facts & Figures. 2012. Available at www. cancer.org. 2. Roach M 3rd, Hanks G, Thames H Jr, et al. Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: recommendations of the RTOG-ASTRO Phoenix Consensus Conference. Int J Radiat Oncol Biol Phys. 2006;65:965-74 3. Stephenson AJ, Kattan MW, Eastham JA, et al. Defining biochemical recurrence of prostate cancer after radical prostatectomy: a proposal for a standardized definition. J Clin Oncol. 2006; 24: 3973-8. 4. Moul JW, Wu H, Sun L, et al. Epidemiology of radical prostatectomy for localized prostate cancer in the era of prostate-specific antigen: an overview of the Department of Defense Center for Prostate Disease Research national database. Surgery. 2002;132:213-19. 5. Moul JW, Wu H, Sun L, McLeod DG, et al. Early versus delayed hormonal therapy for prostate specific antigen only recurrence of prostate cancer after radical prostatectomy. J Urol. 2004;171:1141-7. 6. Sandford NL, Searle JW, Kerr JF. Successive waves of apoptosis in the rat prostate after repeated withdrawal of testosterone stimulation. Pathology. 1984;16:406-10. 7. Denis LJ, Carnelro de Moura JL, Bono A, et al. Goserelin acetate and flutamide versus bilateral orchiectomy: a phase III EORTC trial (30853). Urology. 1993;42:119-29. 8. Janknegt RA, Abbou CC, Bartoletti R, et al. Orchiectomy and nilutamide or placebo as treatment of metastatic prostatic cancer in a multinational doubleblind randomized trial. J Urol. 1993;149:77-82. 9. Crawford ED, Eisenberger MA, McLeod DG, et al. A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Engl J Med. 1989;321:419-24. 10. Geller J, Albert J, Vik A. Advantages of total androgen blockade in the treatment of advanced prostate cancer. Semin Oncol 1988;15(2 suppl 1):S6-S10. 11. Nicolas Mottet, Joaquim Bellmunt, Michel Bolla, et al. EAU guidelines on prostate cancer. Part II: Treatment of advanced, relapsing, and castration-resistant prostate cancer. Eur Urol. 2011;59:572-83. 12. Scher HI, Sawyers CL. Biology of progressive, castration-resistant prostate cancer: directed therapies targeting the androgen-receptor signaling axis. J Clin Oncol. 2005;23:8253-61. 13. Attard G, Cooper CS, de Bono JS. Steroid hormone receptors in prostate cancer: a hard habit to break? Cancer Cell. 2009;16:458-62. 14. Seruga B, Ocana A, Tannock IF. Drug resistance in metastatic castrationresistant prostate cancer. Nat Rev Clin Oncol. 2011;8:12-23. 15. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351:1502-12. 16. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364:1995-2005. 17. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363(5):411-22. 18. Kelly WK, Slovin S, Scher HI. Steroid hormone withdrawal syndromes. Pathophysiology and clinical significance. Urol Clin North Am. 1997;24:421-31. 19. Scher HI, Beer TM, Higano CS, et al. Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study. Lancet. 2010;375:1437-46. 20. Tran C, Ouk S, Clegg NJ, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. 2009;324:787-90.
56 Journal of Managed Care Medicine | Vol. 15, No. 4 | www.namcp.org
The waiting is over
Now Approved:
STRIBILD
(elvitegravir 150mg/cobicistat 150mg/emtricitabine 200mg/ tenofovir disoproxil fumarate 300mg) One tablet contains elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate. Please see Brief Summary of full Prescribing Information for STRIBILD, including BOXED WARNINGS, on the following pages.
Scan the code to go to STRIBILD.com/hcp
A new name to know
Š2012 Gilead Sciences, Inc. All rights reserved. QP14453 09/12
STRIBILD™ (elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) tablets, for oral use Brief summary of full Prescribing Information. See full Prescribing Information. Rx only. WARNING: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir disoproxil fumarate (tenofovir DF), a component of STRIBILD, in combination with other antiretrovirals [See Warnings and Precautions]. STRIBILD is not approved for the treatment of chronic hepatitis B virus (HBV) infection and the safety and efficacy of STRIBILD have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and human immunodeficiency virus-1 (HIV-1) and have discontinued EMTRIVA or VIREAD, which are components of STRIBILD. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue STRIBILD. If appropriate, initiation of anti-hepatitis B therapy may be warranted [See Warnings and Precautions]. INDICATIONS AND USAGE: STRIBILD is indicated as a complete regimen for the treatment of HIV-1 infection in adults who are antiretroviral treatment-naive. DOSAGE AND ADMINISTRATION: The recommended dose is one tablet taken orally once daily with food. Renal Impairment: Do not initiate in patients with estimated creatinine clearance (CrCl) below 70 mL/min. Discontinue if CrCl declines below 50 mL/min during treatment [See Warnings and Precautions, Adverse Reactions, Use in Specific Populations]. Hepatic Impairment: No dose adjustment is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. No pharmacokinetic or safety data are available regarding use in patients with severe hepatic impairment (Child-Pugh Class C). STRIBILD is not recommended for use in patients with severe hepatic impairment [See Use in Specific Populations]. CONTRAINDICATIONS: Coadministration: Do not use with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening adverse events, or with drugs that strongly induce CYP3A as this may decrease STRIBILD plasma concentrations leading to a loss of virologic response and possible resistance [See Drug Interactions]: • Alpha 1-adrenoreceptor antagonists: alfuzosin. Potential for hypotension. • Antimycobacterial: rifampin. May lead to a loss of virologic response and possible resistance to STRIBILD. • Ergot derivatives: dihydroergotamine, ergotamine, methylergonovine. Potential for acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues. • GI motility agents: cisapride. Potential for cardiac arrhythmias. • Herbal products: St. John’s wort (Hypericum perforatum). May lead to a loss of virologic response and possible resistance to STRIBILD. • HMG CoA reductase inhibitors: lovastatin, simvastatin. Potential for myopathy, including rhabdomyolysis. • Neuroleptics: pimozide. Potential for cardiac arrhythmias. • PDE-5 inhibitors: sildenafil when dosed as REVATIO for the treatment of pulmonary arterial hypertension. A safe and effective dose has not been established; the potential for sildenafilassociated adverse events (visual disturbances, hypotension, priapism, and syncope) is increased. • Sedative/hypnotics: orally administered midazolam, triazolam. Potential for prolonged or increased sedation or respiratory depression. WARNINGS AND PRECAUTIONS: Lactic Acidosis/Severe Hepatomegaly with Steatosis: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with nucleoside analogs, including tenofovir DF, a component of STRIBILD, in combination with other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with STRIBILD should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations). Patients Coinfected with HIV-1 and HBV: It is recommended that all patients with HIV-1 be tested for the presence of chronic HBV before initiating antiretroviral therapy. STRIBILD is not approved for the treatment of chronic HBV infection and the safety and efficacy of STRIBILD have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued emtricitabine or tenofovir DF, two of the components of STRIBILD. In some patients infected with HBV and treated with EMTRIVA, the exacerbations of hepatitis B were associated with liver decompensation and liver failure. Patients who are coinfected with HIV-1 and HBV should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment with STRIBILD. If appropriate, initiation of anti-hepatitis B therapy may be warranted. New Onset or Worsening Renal Impairment: Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with tenofovir DF and with STRIBILD [See Adverse Reactions]. In clinical trials of STRIBILD over 48 weeks (N=701), 8 (1.1%) subjects in the STRIBILD group and 1 (0.1%) subject in the combined comparator groups discontinued study drug due to a renal adverse event. Four (0.6%) of the subjects who received STRIBILD developed laboratory findings consistent with proximal renal tubular dysfunction leading to discontinuation of STRIBILD compared to none in the comparator groups. Two of these 4 subjects had renal impairment (CrCl less than 70 mL/min) at baseline. The laboratory findings in these 4 subjects improved but did not completely resolve in all subjects upon discontinuation. Renal replacement therapy was not required. STRIBILD should be avoided with concurrent or recent use of a nephrotoxic agent. Monitoring: CrCl, urine glucose and urine protein should be documented in all patients prior to initiating therapy. STRIBILD should not be initiated in patients with CrCl below 70 mL/min. Routine monitoring of CrCl, urine glucose, and urine protein
should be performed during STRIBILD therapy in all patients. Additionally, serum phosphorus should be measured in patients at risk for renal impairment. Although cobicistat may cause modest increases in serum creatinine and modest declines in CrCl without affecting renal glomerular function [See Adverse Reactions], patients who experience a confirmed increase in serum creatinine of greater than 0.4 mg/dL from baseline should be closely monitored for renal safety. STRIBILD should be discontinued if CrCl declines below 50 mL/min. Use with Other Antiretroviral Products: STRIBILD is a complete regimen for the treatment of HIV-1 infection and should not be coadministered with other antiretroviral products. STRIBILD should not be coadministered with products containing any of the same active components (ATRIPLA, COMPLERA, EMTRIVA, TRUVADA, VIREAD); or with products containing lamivudine (COMBIVIR, EPIVIR, EPIVIR-HBV, EPZICOM, TRIZIVIR). STRIBILD should not be administered with adefovir dipivoxil (HEPSERA). Decreases in Bone Mineral Density (BMD): In previous clinical trials, tenofovir DF has been associated with decreases in BMD and increases in biochemical markers of bone metabolism (serum bone-specific alkaline phosphatase, serum osteocalcin, serum C telopeptide, and urinary N telopeptide), suggesting increased bone turnover. Serum parathyroid hormone levels and 1.25 Vitamin D levels were also higher in subjects receiving VIREAD. The effects of tenofovir DF-associated changes in BMD on future fracture risk are unknown. For additional information, please consult the VIREAD prescribing information. Cases of osteomalacia (associated with proximal renal tubulopathy and which may contribute to fractures) have been reported in association with tenofovir DF [See Adverse Reactions]. In Study 103, BMD was assessed by DEXA in a non-random subset of 120 subjects. Mean percentage decreases in BMD from baseline to Week 48 in the STRIBILD group (N=54) were comparable to the atazanavir + ritonavir + emtricitabine/tenofovir DF group (N=66) at the lumbar spine (-2.6% versus -3.3%, respectively) and at the hip (-3.1% versus -3.9%, respectively). In Studies 102 and 103, bone fractures occurred in 9 subjects (1.3%) in the STRIBILD group, 6 subjects (1.7%) in the efavirenz/emtricitabine/tenofovir DF group, and 6 subjects (1.7%) in the atazanavir + ritonavir + emtricitabine/tenofovir DF group. These findings were consistent with data from an earlier 144-week trial of treatment-naive subjects receiving tenofovir DF + lamivudine + efavirenz. Assessment of BMD should be considered for patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial in all patients. If bone abnormalities are suspected appropriate consultation should be obtained. Fat Redistribution: Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. Immune Reconstitution Syndrome (IRS): IRS has been reported in patients treated with combination antiretroviral therapy, including STRIBILD. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections [such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis], which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barre syndrome) have been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment. ADVERSE REACTIONS: See BOXED WARNINGS and WARNINGS AND PRECAUTIONS sections for additional serious adverse reactions. Adverse Reactions from Clinical Trials Experience: The safety assessment of STRIBILD is based on pooled data from 1408 subjects in two Phase 3 trials, Study 102 and Study 103, in antiretroviral treatment-naive HIV-1 infected adult subjects. A total of 701 subjects received STRIBILD once daily for at least 48 weeks. The proportion of subjects who discontinued treatment with STRIBILD due to adverse events, regardless of severity, was 3.7%. Treatment Emergent Adverse Drug Reactions: Treatment emergent adverse drug reactions (all grades) reported in ≥5% of subjects receiving STRIBILD (N=701) in Studies 102 and 103 (Week 48 analysis) were: nausea (16%); diarrhea (12%); abnormal dreams (9%); headache (7%); and fatigue (5%). Frequencies of adverse reactions are based on all treatment emergent adverse events, attributed to study drugs. See WARNINGS AND PRECAUTIONS for a discussion of renal adverse events from clinical trials experiencewith STRIBILD. Laboratory Abnormalities: Treatment emergent laboratory abnormalities (Grades 3-4) occurring in ≥2% of subjects receiving STRIBILD (N=701) in Studies 102 and 103 (Week 48 analysis) were: creatine kinase (≥10.0 x ULN), 5%; urine RBC (hematuria) (>75 RBC/HPF), 3%; AST (>5.0 x ULN), 2%; and amylase (>2.0 x ULN), 2%. For subjects with serum amylase >1.5 x ULN, lipase test was also performed. The frequency of increased lipase (Grades 3-4) occurring in STRIBILD (N=58) was 12%. Proteinuria (all grades) occurred in 39% of subjects receiving STRIBILD. Cobicistat has been shown to decrease CrCl due to inhibition of tubular secretion of creatinine without affecting renal glomerular function. In Studies 102 and 103, decreases in CrCl occurred early in treatment with STRIBILD, after which they stabilized. Mean ± SD changes after 48 weeks of treatment were 0.14 ± 0.13 mg/dL for serum creatinine and -13.9 ± 14.9 mL/min for estimated glomerular filtration rate (eGFR) by Cockcroft-Gault method. Elevation in serum creatinine (all grades) occurred in 7% of subjects. Serum Lipids: In the clinical trials of STRIBILD, 11% of subjects were on lipid lowering agents at baseline. While receiving study drug through Week 48, an additional 4% of subjects were started on lipid lowering agents. Through 48 weeks, 1% or fewer subjects in any treatment arm experienced Grades 3-4 elevations in fasting cholesterol (greater than 300 mg/dL) or fasting triglycerides (greater than 750 mg/dL). Mean changes from baseline in total cholesterol, HDL-cholesterol, LDLcholesterol, and triglycerides reported in subjects receiving STRIBILD (N=701) in Studies 102 and 103 (Week 48 analysis) were: total cholesterol (fasted): baseline 166 mg/dL (N=675), week 48 change +11 (N=606); HDL-cholesterol (fasted): baseline 43 mg/dL (N=675), week 48 change +6 (N=605); LDL-cholesterol (fasted): baseline 100 .mg/dL (N=675), week 48 change +10 (N=606); triglycerides (fasted): baseline 122 mg/dL (N=675), week 48 change +13 (N=606). The change from baseline is the mean of within-patient changes from baseline for patients with both baseline and Week 48 values. Emtricitabine and Tenofovir DF: Adverse drug reactions: In addition to the adverse drug reactions observed with STRIBILD, the following adverse drug reactions occurred in at least 5% of treatment-experienced or treatment-naive subjects receiving emtricitabine or tenofovir DF with other antiretroviral agents in other clinical trials: depression, abdominal pain, dyspepsia, vomiting, fever, pain, nasopharyngitis, pneumonia, sinusitis, upper respiratory tract infection, arthralgia, back pain, myalgia, paresthesia, peripheral neuropathy (including peripheral neuritis and neuropathy),
anxiety, increased cough, and rhinitis. Skin discoloration has been reported with higher frequency among emtricitabine treated subjects; it was manifested by hyperpigmentation on the palms and/ or soles and was generally mild and asymptomatic. The mechanism and clinical significance are unknown. Laboratory Abnormalities: In addition to the laboratory abnormalities observed with STRIBILD, the following laboratory abnormalities have been previously reported in subjects treated with emtricitabine or tenofovir DF with other antiretroviral agents in other clinical trials: Grades 3-4 laboratory abnormalities of ALT (M: greater than 215 U/L; F: greater than 170 U/L), alkaline phosphatase (greater than 550 U/L), bilirubin (greater than 2.5 x ULN), serum glucose (less than 40 or greater than 250 mg/dL), glycosuria (greater than or equal to 3+), neutrophils (less than 750/mm3), fasting cholesterol (greater than 240 mg/dL), and fasting triglycerides (greater than 750 mg/dL). Postmarketing Events: The following adverse reactions have been identified during post approval use of tenofovir DF: allergic reaction (including angioedema), lactic acidosis, hypokalemia, hypophosphatemia, dyspnea, pancreatitis, increased amylase, abdominal pain, hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT gamma GT), rash, rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathy, acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, polyuria, and asthenia. The following adverse reactions listed above may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, and hypophosphatemia.
• Endothelin Receptor Antagonists: bosentan. Discontinue bosentan at least 36 hours prior to initiating STRIBILD. For patients taking STRIBILD for at least 10 days, start or resume bosentan at 62.5 mg once daily or every other day based on individual tolerability.
DRUG INTERACTIONS: STRIBILD is a complete regimen for the treatment of HIV-1 infection. STRIBILD should not be administered with other antiretroviral medications for treatment of HIV-1 infection. Complete information regarding potential drug-drug interactions with other antiretroviral medications is not provided.
• Phosphodiesterase-5 (PDE5) Inhibitors: sildenafil, tadalafil, vardenafil. Dosage for erectile dysfunction: sildenafil, a single dose not exceeding 25 mg in 48 hours; vardenafil, a single dose not exceeding 2.5 mg in 72 hours; tadalafil, a single dose not exceeding 10 mg in 72 hours; increase monitoring for PDE-5 associated adverse events. Dosage for pulmonary arterial hypertension (PAH): tadalafil: stop tadalafil at least 24 hours prior to initiating STRIBILD; start or resume at 20 mg once daily in patients receiving STRIBILD for at least 1 week and increase to 40 mg once daily based on individual tolerability.
STRIBILD should not be used in conjunction with protease inhibitors or non-nucleoside reverse transcriptase inhibitors due to potential drug interactions including altered and/or suboptimal pharmacokinetics of cobicistat, elvitegravir, and/or the coadministered antiretroviral products. STRIBILD should not be administered concurrently with products containing ritonavir or regimens containing ritonavir due to similar effects of cobicistat and ritonavir on CYP3A.
• Sedative/hypnotics: Benzodiazepines. Parenteral midazolam: coadministration should be done in a setting ensuring close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation; dose reduction should be considered, especially if more than a single dose is administered. Other sedative/hypnotics: dose reduction may be necessary and clinical monitoring recommended.
Potential for STRIBILD to Affect Other Drugs: Cobicistat is an inhibitor of CYP3A and CYP2D6. The transporters that cobicistat inhibits include p-glycoprotein (P-gp), BCRP, OATP1B1 and OATP1B3. Coadministration of STRIBILD with drugs that are primarily metabolized by CYP3A or CYP2D6, or are substrates of P-gp, BCRP, OATP1B1 or OATP1B3 may result in increased plasma concentrations of such drugs. Elvitegravir is a modest inducer of CYP2C9 and may decrease the plasma concentrations of CYP2C9 substrates.
Consult the full PI prior to and during treatment with STRIBILD for potential drug interactions; this list is not all inclusive.
See CONTRAINDICATIONS for additional serious adverse reactions.
Potential for Other Drugs to Affect One or More Components of STRIBILD: Elvitegravir and cobicistat are metabolized by CYP3A. Cobicistat is also metabolized, to a minor extent, by CYP2D6. Drugs that induce CYP3A activity are expected to increase the clearance of elvitegravir and cobicistat, resulting in decreased plasma concentration of cobicistat and elvitegravir, which may lead to loss of therapeutic effect of STRIBILD and development of resistance. Coadministration of STRIBILD with other drugs that inhibit CYP3A may decrease the clearance and increase the plasma concentration of cobicistat. Drugs Affecting Renal Function: Because emtricitabine and tenofovir are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion, coadministration of STRIBILD with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of emtricitabine, tenofovir, and other renally eliminated drugs. Established and Other Potentially Significant Interactions: The drug interactions described are based on studies conducted with either STRIBILD, the components of STRIBILD as individual agents and/or in combination, or are predicted drug interactions that may occur with STRIBILD. The list includes potentially significant interactions but is not all inclusive. An alteration in dose or regimen may be recommended for the following drugs when coadministered with STRIBILD: • Acid Reducing Agents: antacids. Separate STRIBILD and antacid administration by at least 2 hours. • Antiarrhythmics: amiodarone, bepridil, digoxin, disopyramide, flecainide, systemic lidocaine mexiletine, propafenone, quinidine. Caution warranted and therapeutic concentration monitoring recommended. • Antibacterials: clarithromycin, telithromycin. Clarithromycin: no dose adjustment required for patients with CrCl ≥60 ml/min; the dose should be reduced by 50% for patients with CrCl between 50 and 60 mL/min. Telithromycin: concentrations of telithromycin and/or cobicistat may be increased. • Anticoagulants: warfarin. International normalized ratio (INR) monitoring recommended.
• HMG CoA Reductase Inhibitors: atorvastatin. Initiate with the lowest starting dose and titrate carefully while monitoring for safety. • Hormonal Contraceptives: norgestimate/ethinyl estradiol. Coadministration with STRIBILD resulted in decreased plasma concentrations of ethinyl estradiol and an increase in norgestimate. The effects of increased progesterone exposure are not fully known. The potential risks and benefits of coadministration should be considered, particularly in women who have risk factors for progesterone exposure. Alternative (non hormonal) methods of contraception can be considered. • Immunosuppressants: cyclosporine, rapamycin, sirolimus, tacrolimus. Therapeutic monitoring recommended. • Inhaled Beta Agonist: salmeterol. Coadministration not recommended due to the increased risk of salmeterol cardiovascular adverse events, including QT prolongation, palpitations, and sinus tachycardia. • Neuroleptics: perphenazine, risperidone, thioridazine. Decrease in dose of the neuroleptic may be needed.
USE IN SPECIFIC POPULATIONS: Pregnancy: STRIBILD is Pregnancy Category B; however, there are no adequate and well-controlled studies in pregnant women. STRIBILD should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Antiretroviral Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to STRIBILD, an Antiretroviral Pregnancy Registry has been established. Healthcare providers are encouraged to register patients by calling 1-800-258-4263. Nursing Mothers: The Centers for Disease Control and Prevention recommend that HIV infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. Studies in rats have demonstrated that elvitegravir, cobicistat, and tenofovir are secreted in milk. Emtricitabine and tenofovir have been detected in human milk; it is not known if elvitegravir or cobicistat is secreted in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions and/or drug resistance in nursing infants, mothers should be instructed not to breastfeed if they are receiving STRIBILD. Pediatric Use: Safety and effectiveness in children less than 18 years of age have not been established. Geriatric Use: Clinical studies of STRIBILD did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Renal Impairment: STRIBILD should not be initiated in patients with CrCl below 70 mL/min. STRIBILD should be discontinued if CrCl declines below 50 mL/min during treatment with STRIBILD. [See Warnings and Precautions, Adverse Reactions]. Hepatic Impairment: No dose adjustment is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. STRIBILD is not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C) as no pharmacokinetic or safety data are available in these patients [See Dosage and Administration]. OVERDOSAGE: If overdose occurs the patient must be monitored for evidence of toxicity. Treatment consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient.
• Anticonvulsants: carbamazepine, oxcarbazepine phenobarbital, phenytoin, clonazepam, ethosuximide. Phenobarbital, phenytoin, carbamazepine, and oxcarbazepine: may lead to loss of virologic response and possible resistance to STRIBILD. Alternative anticonvulsants should be considered. Clonazepam and ethosuximide: clinical monitoring recommended. • Antidepressants: Selective Serotonin Reuptake Inhibitors (SSRIs), Tricyclic Antidepressants (TCAs), trazodone. Dose titration of the antidepressant and monitoring for antidepressant response recommended. • Antifungals: itraconazole, ketoconazole, voriconazole. Ketoconazole and itraconazole: the maximum daily dose should not exceed 200 mg/day. Voriconazole: an assessment of benefit/ risk ratio is recommended to justify use. • Anti-gout: colchicine. Do not coadminister in patients with renal or hepatic impairment. For other patients, modify the dose and/or regimen as described in the full PI for STRIBILD. • Antimycobacterials: rifabutin, rifapentine. May lead to loss of virologic response and possible resistance to STRIBILD. Coadministration not recommended. • Beta-Blockers: metoprolol, timolol. Clinical monitoring recommended and a dose decrease of the beta blocker may be necessary. • Calcium Channel Blockers: amlodipine, diltiazem, felodipine, nicardipine, nifedipine, verapamil. Caution warranted and clinical monitoring recommended. • Corticosteroids (Systemic): dexamethasone. May lead to loss of virologic response and possible resistance to STRIBILD. • Corticosteroids (Inhaled/Nasal): fluticasone. Alternative corticosteroids should be considered, particularly for long term use.
COMPLERA, EMTRIVA, GILEAD, the GILEAD Logo, HEPSERA, STRIBILD, the STRIBILD Logo, TRUVADA, and VIREAD are trademarks of Gilead Sciences, Inc., or its related companies. ATRIPLA is a trademark of Bristol-Myers Squibb & Gilead Sciences, LLC. All other trademarks referenced herein are the property of their respective owners. 203100-GS-000
August 2012
Recent Breakthroughs in the Treatment of Metastatic Melanoma: Novel Immunologics Adil Daud, MD For a CME/CEU version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.
Summary Unlike many other cancers, the incidence of melanoma has been increasing. Because of a new medication which target cancers with a specific genetic mutation, the treatment of melanoma is being revolutionized. Although this medication can produce dramatic tumor responses in metastatic melanoma, the effect can be short lived and may not significantly prolong survival. Key Points • The incidence of melanoma is increasing, primarily in older Caucasian males. • Even when identified early, deaths can occur from the disease. • The location where a melanoma arises will predict the genetics of the tumor. • New medications targeted at specific genetic mutations are revolutionizing the treatment of metastatic melanoma.
Approximately 60,000 cases of melanoma occur each year. It is the third most common of the major skin cancers (basal cell, squamous, and melanoma) but results in the vast majority of deaths. Melanoma accounts for 72 percent or 8,000 deaths per year. Melanoma is one of the few cancers with increasing incidence; the incidence has been increasing steadily since 1975. The increased incidence is primarily in older Caucasian males. Unlike other cancers where five or 10 years without recurrence is considered cancer free, the mortality curves with melanoma continue (Exhibit 1).1 Even with early stage disease (Stage 1), there are continued deaths over time from the disease. A breakthrough in melanoma occurred when the ability to sequence genomes was developed. In the first work on melanoma cells, it was discovered that a large percentage of these cells had a BRAF mutation. As shown in Exhibit 2, it is now known that not all melanomas are the same.2-4 Depending on the location where the cancer arises, different genetic mutations are likely to be displayed.
About 50 percent of melanomas harbor activating BRAF mutations. BRAF is a human gene that makes the B-Raf protein. The gene is also referred to as proto-oncogene B-Raf and v-Raf murine sarcoma viral oncogene homolog B1, while the protein is more formally known as serine/threonine-protein kinase B-Raf. The B-Raf protein is involved in sending signals inside cells, which are involved in directing cell growth. In 90 percent of the BRAF mutations, thymine is substituted with adenine at nucleotide 1799. This leads to valine (V) being substituted for by glutamate (E) at codon 600 (referred to as V600E). BRAFV600E has been implicated in different mechanisms underlying melanoma, most of which are due to the deregulated activation of the downstream cell growth factors (Exhibit 3).5 In patients who have had a melanoma removed, adjunctive therapy may be used to prevent recurrence. Interferon is the most commonly used agent but is controversial. Interferon does not kill cancer cells but rather activates the immune system to recognize the melanoma as foreign. It is given by injec-
60 Journal of Managed Care Medicine | Vol. 15, No. 4 | www.namcp.org
Exhibit 1: Survival in Melanoma by Stage1
1.0 0.9
Stage I (n=9175)
Proportion Surviving
0.8 0.7 0.6
Stage II (n=5739)
0.5 0.4
Stage III (n=1528)
0.3 0.2 Stage IV (n=1158)
0.1 0
1
2
3
4
5
6
7
8
9
10
11 12 13 14 15
Survival, years
Exhibit 2: Melanoma Genetic Mutations by Site of Origin2-4
GNAQ 32% G11 45%
Eye
Scalp/Face
Trunk/Legs
NRAS 15% BRAF 28%
NRAS 18% BRAF 57%
C-Kit 5% -10% NRAS 25% BRAF 10%
Fingernails and Toenails Genital/rectal mucosa C-Kit 10% -20% NRAS 15%
GNAQ, Guanine nucleotide-binding protein G(q); C-KIT, Mast/stem cell growth factor receptor; NRAS, Neuroblastoma RAS viral oncogene homolog; BRAF, v-Raf murine sarcoma viral oncogene homolog B1
www.namcp.org | Vol. 15, No. 4 | Journal of Managed Care Medicine 61
Exhibit 3: Oncogenic BRAF Signaling5
Oncogenic BRAF signaling
Oncogenic BRAF signaling arrested with BRAF inhibitors
Constitutive activation is independent of extracellular factors and does not respond to biochemical signals that would normally regulate activity BRAFv600
BRAFv600
MEK
MEK
ERK
ERK
cell proliferation and survival
BRAF inhibitors Selective binding of onogenic BRAF kinase by vemurafenib, blocks the constitutively activated pathway and downstream activity
cell proliferation and survival
MEK, mitogen-activated protein kinase; ERK, extracellular-signal-regulated kinases
tion for a year after surgery. In a recent meta-analysis, the use of interferon was shown to reduce the risk of recurrence.6 The controversy with interferon is whether it improves survival. The same metaanalyses found an 11 percent reduction in death. In patients less than 70, without a history of liver dysfunction or depression, interferon will likely prolong survival. But, there are significant adverse effects â&#x20AC;&#x201C; this agent makes patients feel like they have a chronic case of the flu. Pegylated interferon is a long-acting form of interferon that is given by injection once a week compared with daily or thrice weekly with shorter acting forms. It appears to cause fewer adverse effects. The major trial of PEG interferon found that it did increase relapse-free survival but did not change overall survival at six years.7 It appears to be the most benefit in patients with microscopic metastatic disease rather then macroscopic lymph node involvement. Historically, metastatic melanoma, where most of the deaths occur, has been treated with chemotherapy and immunologic therapy (interferon or interleukin 2). Although numerous chemotherapy trials have been conducted in metastatic melanoma with various chemotherapy regimens since the early 2000s, none showed significant benefit for overall survival. The revolution in metastatic melanoma treatment occurred with the approval of vemurafenib (Zelbo-
raf ÂŽ), a BRAF inhibitor which is only effective in V600E mutated disease. BRAF- mutated melanoma primarily occurs in younger patients on the trunk and legs. Studies with vemurafenib showed dramatic improvements in tumor load, even in bone lesions, after just two weeks of therapy. The early trials showed a 48.7 percent overall response rate compared with a 5.5 percent response rate to dacarbazine. A recently published trial found an overall response rate of 53 percent (6 percent with a complete response and 47 percent with a partial response).8 Although long-term survival data are not yet available for vemurafenib treatment, there does appear to be a benefit in progression-free survival and overall survival from the short-term data. Although the vast majority of patients with BRAF-mutated disease respond to vemurafenib, the response may not be very long lasting. The next evolution of therapy is to combine treatments to block two different mechanism of tumor growth â&#x20AC;&#x201C; BRAF and mitogen-activated protein kinase (MEK). Data from Phase 1 trials appear hopeful that this will be a way to treat patients who progress on a BRAF inhibitor. The major adverse effect of BRAF inhibitors is squamous cell skin cancer. About 25 percent of patients on a BRAF inhibitor develop a squamous cell cancer. This adverse effect can occur within a few weeks of starting therapy. While being treated, patients must not experience sun exposure. The com-
62 Journal of Managed Care Medicine | Vol. 15, No. 4 | www.namcp.org
bination of BRAF and MEK inhibitors appears to reduce the risk of squamous cell cancers. Ipilimumab (Yervoy 速) is the next recent advance in melanoma therapy. This agent is immunotherapy that augments T-Cell activation and proliferation. One of the down sides of ipilimumab is a very low tumor response rate. With immunotherapy, it appears tumors are not shrinking, but patients may be living slightly longer. This agent is very costly and overall survival does not appear to be significantly greater when compared to chemotherapy. One trial has examined the combination of ipilimumab and dacarbazine.9 There is a modest improvement in response (~5 percent better) with the combination. The most impressive finding from this study was the duration of response is 19 months with combination therapy versus eight months with chemotherapy alone. The bottom line for this agent is if a patient has a response to ipilimumab, it will likely be long lasting but the chance of having a response is not great. This agent causes significant adverse effects, especially severe diarrhea requiring corticosteroids. Skin rashes and hepatotoxicity are also relatively common. There are numerous immune system factors which are being targeted with investigational agents for melanoma. One is programmed cell death 1 (PD-1). PD-1 is a member of CD28 family involved in T-cell regulation. Anti PD-1 agents are under investigation.
BRAF inhibitor is the first agent available for melanomas with specific BRAF mutations. More BRAF inhibitors and agents targeting other genetic mutations are likely to come to market in the near future. It is yet to be determined which therapy (chemotherapy, immunotherapy, or genetic targeted agents) should be used first and in which sequence in a patient with metastatic melanoma. Adil Daud, MD is a Professor of Clinical Medicine and Director of the Melanoma Program at the University of California, San Francisco.
References 1. Balch CM, Buzaid AC, Soong SJ, et al. Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol. 2001;19:3635-3648. 2. Van Raamsdonk CD, Griewank KG, Crosby MB, et al. Mutations in GNA11 in uveal melanoma. N Engl J Med. 2010;363:2191-9. 3. Curtin JA, Busam K, Pinkel D, Bastian BC. Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol. 2006;24:4340-6. 4. Lee JH, Choi JW, Kim YS. Frequencies of BRAF and NRAS mutations are different in histological types and sites of origin of cutaneous melanoma: a meta-analysis. Br J Dermatol. 2011;164:776-84. . 5. Ascierto PA, Kirkwood JM, Grob JJ, et al. The role of BRAF V600 mutation in melanoma. J Transl Med. 2012;10:85. 6. Mocellin S, Pasquali S, Rossi CR, Nitti D. Interferon alpha adjuvant therapy in patients with high-risk melanoma: a systematic review and meta-analysis. J Natl Cancer Inst. 2010;102:493-501. 7. Patel JN, Walko CM. Sylatron: a pegylated interferon for use in melanoma. Ann Pharmacother. 2012;46:830-8. 8. Sosman JA, Kim KB, Schuchter L, et al. Survival in BRAF V600-mutant
Conclusion
advanced melanoma treated with vemurafenib. N Engl J Med. 2012;366:707-14.
The recognition that all melanomas are not genetically alike is leading to advances in therapy. A
9. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364:2517-26.
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www.namcp.org | Vol. 15, No. 4 | Journal of Managed Care Medicine 63
Preventing Chemotherapy-Induced Nausea and Vomiting and Improving Quality of Life in Cancer Patients Susan Urba, MD For a CME/CEU version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.
Summary Chemotherapy-induced nausea and vomiting (CINV) is a significant fear for patients and is costly to manage, particularly if not controlled. When highly emetogenic chemotherapy is given, good control requires medication combinations which target various neurotransmitters involved in the process. The potential for a given regimen to induce nausea and vomiting and the individual patient’s risk factors must be considered when choosing a regimen. Key Points • CINV is mediated by both central and peripheral mechanisms which overlap and require combination therapy for adequate prevention. • By identifying those at most risk for CINV, medications can be targeted best. • Prevention is the goal and guidelines are available which should be followed. • Risk of CINV lasts for at least four days after highly or moderately emetogenic chemotherapy. • The financial and human costs of uncontrolled CINV are substantial.
Chemotherapy induced nausea and vomiting (CINV) can occur in 70 to 80 percent of patients receiving chemotherapy if they are not given prophylactic therapy. Nausea and vomiting are in the top three adverse effects of chemotherapy that patients dread the most.1 Unfortunately, health care providers can significantly underestimate the risk for CINV, particularly delayed CINV.2 CINV is mediated by two major mechanisms – central and peripheral (Exhibit 1).3-5 When someone gets chemotherapy, enterochromaffin cells in the gastrointestinal tract release serotonin which starts the syndrome of CINV. The serotonin stimulates vagal afferent nerves which communicate with the brain. Through the dorsal vagal complex, the brain communicates back to stomach causing reverse peristalsis which results in nausea and vomiting. In the brainstem, stimulation of the neurokinin 1 (NK1) receptors by substance P can also lead to CINV. In addition to serotonin and substance P, many other neurotransmitters, including gamma aminobutyuric
acid (GABA), dopamine, histamine, acetylcholine, and endorphins, are known to play roles in the emetic response. There are four types of CINV – acute, delayed, anticipatory, and breakthrough – which must be considered when discussing prevention and treatment. Acute CINV is nausea and vomiting that occurs within the first 24 hours after administration of chemotherapy. Delayed CINV starts more than 24 hours after administration of chemotherapy and typically lasts three to four days. Anticipatory CINV is a conditioned response that happens after a negative past experience with chemotherapy. Breakthrough CINV occurs despite prophylaxis and requires rescue medications. The development of acute CINV influences the rate of delayed CINV. Patients who have acute CINV are more likely to have delayed CINV. In one study, 83 percent of those with acute CINV developed delayed CINV compared with 37 percent of those without acute CINV.6 Unfortunately, the
64 Journal of Managed Care Medicine | Vol. 15, No. 4 | www.namcp.org
Exhibit 1: Mechanisms of CINV3-5
Brainstem NK1 receptors Substance P Central Dorsal vagal complex Area postrema Chemotherapy Enterochromaffin cell
Serotonin release
Peripheral
Vagal afferent 5-HT3 receptors
prevention of acute events does not automatically provide complete protection from delayed events but does significantly decrease the rate. Acute CINV is predominately mediated by serotonin-dependent mechanisms, whereas delayed is predominately substance P mediated, but there is some overlap as shown in Exhibit 2.7 The overlap of differential involvement of neurotransmitters supports combination therapy to enhance prevention of emesis. Both acute and delayed mechanisms need to be covered from the beginning (i.e., day chemotherapy is given). Several patient-related risk factors have been shown to influence the development of CINV. These include low alcohol consumption (< 10 drinks/week), younger age (< 50), female gender, history of motion sickness, and poor control with prior chemotherapy. The most important factor for determining whether CINV will occur is the emetogenic potential of the chemotherapy being given. Chemotherapy agents have minimal, low, moderate, or high emetogenic potential. A highly emetic agent causes CINV in greater than 90 percent of patients. Exhibit 3 lists the highly emetogenic intravenous agents. As noted in the exhibit, the dose given can influence
the emetogenicity of an agent. Because combinations of chemotherapy agents are commonly given, the emetogenic potential of all the agents used have to be considered in choosing prophylactic therapy. Additionally, there are now many oral chemotherapy agents which can also cause CINV. Three professional groups produce treatment guidelines for preventing CINV - National Comprehensive Cancer Network (NCCN), American Society of Clinical Oncology (ASCO), and Multinational Association of Supportive Care in Cancer (MASCC).8-10 There is significant overlap among the guidelines. Where the guidelines differ will be discussed as appropriate. The major agents used for highly emetogenic chemotherapy are serotonin antagonists, corticosteroids, and neurokinin 1 (NK1) antagonists. The serotonin antagonists include dolasetron (Anzemet®), granisetron (Kytril®), ondansetron (Zofran®, generic), and palonosetron (Aloxi®). They are given on the same day as highly emetogenic chemotherapy to prevent acute CINV and are available in a variety of dosing forms – intravenous, oral, and transdermal patch – which varies by agent. In the NCCN guidelines, palonesetron intravenous is the preferred
www.namcp.org | Vol. 15, No. 4 | Journal of Managed Care Medicine 65
Exhibit 2: CINV: Differential Involvement of Neurotransmitters Over Time7
Acute (Day 1) Delayed (Days 2-5) Predominantly serotonin- dependent mechanisms (peripheral)
0
8
Predominantly substance P-dependent mechanisms (central)
12
24
120
Hours After Cisplatin
Exhibit 3: Highly Emetogenic Agents
Level Intravenous Agents High Adrimycin/Cytoxan combination (>90% Carmustine > 250 mg/m2 Frequency Cisplatin > 50 mg/m2 of Emesis) Cyclophosphamide > 1,500 mg/m2 Dacarbazine Doxorubicin > 60 mg/m2 Epirubicin > 90 mg/m2 Ifosfamide > 10 g/m2 Mechlorethamine Streptozocin
agent for highly emetogenic chemotherapy.8 Palonosetron does have a longer half-life (40 hours versus four to eight hours for others) and higher receptor binding affinity, which is the likely reason it is listed as preferred in the NCCN guidelines. It has not been shown to be significantly more effective than the other serotonin antagonists.11 The ASCO and MASCC guidelines do not identify a preferred agent. The serotonin antagonist used in most cancer centers is based on the negotiated price with the manufacturer. The average response rate with serotonin antagonists given alone is around 55 percent, thus they need to be combined with corticosteroids. Dexamethasone is the typical corticosteroid used in conjunction with serotonin antagonists. The addition of dexamethasone is important in improving control of CINV. It is given to prevent both acute and delayed CINV on the day of highly emetogenic chemotherapy administration and for three to four days afterwards.8-10
Aprepitant (Emend速) is a selective high-affinity antagonist of NK1 receptors used for delayed CINV. It has little or no affinity for serotonin, dopamine, and corticosteroid receptors. Animal and human PET scan studies show that it crosses the blood brain barrier and occupies brain NK1 receptors. This agent is available as an oral dosage form (aprepitant) or intravenous (fosaprepitant). It is given once on the day of highly emetogenic chemotherapy administration. If the oral form is used, doses need to be given for two to three days after chemotherapy. The intravenous formulation has a long enough duration of action that a single dose covers acute and delayed CINV. Combining the three classes of agents just discussed leads to the best control of both acute and delayed CINV (Exhibit 4).12 For highly emetogenic chemotherapy, a regimen including all three classes is recommended.8-10 For moderately emetogenic chemotherapy, the
66 Journal of Managed Care Medicine | Vol. 15, No. 4 | www.namcp.org
Complete response (%)
Exhibit 4: Aprepitant, Ondansetron, and Dexamathasone versus Ondansetron and Dexamethasone12 100 80 60
73
75 56
52
40 20 0
*P < 0.001
89 78
Overall (days 1-5)* Acute (day 1)* Delayed (days 2-5)* Control
Aprepitant treatment group
recommended regimens are slightly different. On the day of moderately emetogenic chemotherapy administration, both a serotonin antagonist and dexamethasone are recommended. The addition of aprepitant is only recommended by NCCN if certain chemotherapy is given (carboplatin, cisplatin, doxorubicin, epirubicin, ifosfamide, irinotecan, or methotrexate).8 The ASCO guidelines state there is limited evidence supporting aprepitant use for moderately emetogenic chemotherapy but clinicians may opt to add it.9 At least one study found improved complete response rates with palonesetron compared with ondansetron in moderately emetogenic chemotherapy.13 There are three options for therapy beyond Day 1. If palonesetron was used on Day 1 as the serotonin antagonist, no further therapy needs to be given. The NCCN guidelines recommend either steroid monotherapy or a serotonin antagonist (other than palonesetron) be used for subsequent days of therapy.8 ASCO and MASCC recommend dexamethasone monotherapy for several days.9,10 For chemotherapy regimens with low emetic risk, the NCCN guidelines recommend dexamethasone, metoclopromide, or prochlorperazine.8 The ASCO guidelines recommend dexamethasone and the MASCC guidelines recommend no therapy.9,10 For minimal emetogentic potential chemotherapy, all the guidelines agree that no prophylaxis needs to be given. Prophylactic regimens are recommended for moderate or highly emetogenic chemotherapy that is given orally. Because oral chemotherapy is given for a longer duration, only oral agents are recommended. Serotonin antagonists with or without lorazepam and proton pump inhibitors are given. If the regimen has low or minimal emetogenic potential, metoclopramide, prochlorperazine, or haloperidol, as needed, can be used.
Prevention of CINV with optimal antiemetics is the best way to reduce the incidence of anticipatory CINV. If patients develop anticipatory CINV, they can be taught relaxation techniques and can use guided imagery, music therapy, and acupuncture/acupressure to manage symptoms. Antianxiety agents such as alprazolam or lorazepam can be started the night before treatment to lessen this type of CINV. Breakthrough CINV is treated with a class of agent not previously used. There are many different choices including benzodiazepines, cannabinoids, metoclopramide, haloperidol, phenothiazines, and scopolamine. There are many consequences of uncontrolled CINV. It has a significant effect on quality of life.14 The dread of future chemotherapy can lead to anticipatory nausea which requires significant health care provider time to manage. Chemotherapy may have to be stopped or delayed because of uncontrolled CINV. It can also lead to loss of days at work There are major financial costs of uncontrolled CINV, including nursing time, physician time, antiemetic rescue medication, additional office visits, visits to the emergency room, intravenous hydration, and hospital admission. In one study, 25 percent of patients required medical care for uncontrolled CINV.15 Two percent required an emergency room visit. The financial costs for managing uncontrolled CINV were significantly more than those for patients who were controlled ($10,376 without an ER visit and $12,810 with ER visit versus $8,132). Conclusion
The financial and human costs of uncontrolled CINV are substantial. Prevention of CINV is the goal, but current regimens are not perfect, and about 25 percent of patients will still have some nausea and
www.namcp.org | Vol. 15, No. 4 | Journal of Managed Care Medicine 67
vomiting. The available treatment guidelines should be followed for optimal management. It is important to remember that the risk for CINV lasts for several days days after highly or moderately emetogenic chemotherapy. Thus, patients need medications which cover both acute and delayed CINV.
7. Hesketh PJ, Van Belle S, Aapro M, et al. Differential involvement of neurotransmitters through the time course of cisplatin-induced emesis as revealed by therapy with specific receptor antagonists. Eur J Cancer. 2003;39:1074-80. 8. NCCN Clinical Practice Guidelines in Oncology. Antiemesis. Version 1.2012. Available at www.nccn.org. 9. Basch E, Prestrud AA, Hesketh PJ, et al. Antiemetics: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clinl Oncol.
Susan Urba, MD is a Professor of Medicine and is the Medical Director
2011;29:4189-98.
for Symptom Management and Supportive Care at the University of
10. Roila F, Herrstedt J, Aapro M, et al. Guideline update for MASCC and ESMO
Michigan Comprehensive Cancer Center.
in the prevention of chemotherapy and radiotherapy-induced nausea and vomiting: results of the Perugia consensus conference. Ann Oncol. 2010;21(Suppl
References
5):v232-43.
1. de Boer-Dennert M, de Wit R, Schmitz PI, et al. Patient perceptions of the
11. Aapro M, Bertoli L, Lordick P, et al. Palonosetron (PALO) is effective in
side-effects of chemotherapy: the influence of 5HT3 antagonists. Br J Cancer.
preventing chemotherapy-induced nausea and vomiting (CINV) in patients re-
1997;76:1055-61.
ceiving highly emetogenic chemotherapy (HEC): results of a phase III trial
2. Grunberg SM, Hansen M, Deuson R et al. Incidence and impact of nausea/
[abstract A-17]. Support Care Cancer. 2003:11:391.
vomiting with modern antiemetics: perception vs. reality. Proc Am Soc Clin On-
12. Warr D, Gralla RJ, Hesketh PJ, et al. The oral NK1 antagonist aprepitant for
col. 2002:21(part 1);250a. Abstract #996.
the prevention of chemotherapy induced nausea and vomiting: 2 randomized,
3. Diemunsch P, GrĂŠlot L. Potential of substance P antagonists as antiemetics.
double-blind, placebo controlled trials. 39th ASCO Annual Meeting, May 31-
Drugs. 2000:60:533-46.
June 3, 2003, Chicago, Illinois. Abstract #2919.
4. Grunberg SM, Hesketh PJ. Control of chemotherapy-induced emesis. N Engl
13. Aapro M, Selak E, Santini D, et al. Palonosetron is more effective than on-
J Med.1993;329:1790-6.
dansetron in preventing CINV in patients receiving moderately emetogenic
5. Hornby PJ. Receptors and transmission in the brain-gut axis. II. Excitatory
chemotherapy: Results of a phase III trial. Proc Am Soc Clin Oncol. 2003. Ab-
amino acid receptors in the brain-gut axis. Am J Physiol Gastrointestinal Liver
stract 2918.
Physiol. 2001;280:G1055-60.
14. Lindley CM, Hirsch JD, Oâ&#x20AC;&#x2122;Neill CV, et al. Quality of life consequences of
6. Goedhals L, Heron JF, Kleisbauer JP, et al. Control of delayed nausea and
chemotherapy-induced emesis. Qual Life Res. 1992;5:331-340.
vomiting with granisetron plus dexamethasone or dexamethasone alone in pa-
15. Shin YT, Han S, Zao L, et al. Economic burden of uncontrolled chemother-
tients receiving highly emetogenic chemotherapy: a double-blind, placebo-
apy-induced nausea and vomiting among working-age patients. J Clin Oncol.
controlled, comparative study. Ann Oncol.1998;9:661-6.
2005;2(16S):Abstract 5053.
NAMCP Medical Directors Oncology Institute The purpose of the Medical Directors Oncology Institute is to provide updated and pertinent information and resources to Medical Directors from Purchasers, Health Plans and Provider systems in the area of Oncology. The Institute is currently looking for medical directors that are interested in serving on the Oncology Institute Executive Leadership Council (ELC). To learn more about the NAMCP Oncology Institute, or to become involved in the Executive Leadership Council, please contact Katie Eads at 804-527-1905 or keads@namcp.org.
68 Journal of Managed Care Medicine | Vol. 15, No. 4 | www.namcp.org
Impact on Health Plan Cancer Drug Costs in Different Delivery Models Identifying whether cancer drugs costs to health plans are affected by differences between original prescription and drugs actually used for treatment in two different drug acquisition models in practices (Direct Acquisition Model or External Delivered Model) Dawn G. Holcombe, FACMPE, MBA, ACHE; Rex W. Force, PharmD, BCPS, FCCP; Kerry Bradley; Joe Conoshenti, R.Ph., BSPharm, MBA; Keith Huff, R.Ph., PharmD, MS Summary Health plans, specialty pharmacy providers, and cancer providers are engaged in cancer management initiatives, some of which include discussion about whether cancer providers should continue to acquire cancer drugs or whether an external vendor, such as a specialty pharmacy, should deliver cancer drugs to the cancer provider upon receipt of a prescription of the original cancer treatment plan. However, during active treatment, a cancer patient is usually assessed for health status and ability to receive the planned cancer treatment on the day of treatment. If that assessment leads to a change in the treatment prescription, that prescription change could result in a cost to health plans under one of the drug delivery models that does not occur under the other drug delivery model. This study reviewed the incidence of changes in treatment prescription versus actual treatment, as well as the potential cost to health plans of such changes under the Direct Acquisition Model and the External Delivered Model, as identified by ICD-9 coding conventions. Both the changes in treatments delivered and cost implications were found to be significant. The results are likely to change the perspective and strategies of future discussions between health plans, specialty pharmacies and cancer providers regarding drug delivery models. The results may be useful to health plans and physicians in discussing cost efficient methods of getting the right drug to the patient at the time of treatment. Key Points • About one in 10 cancer treatments have variations in treatment between the original planned dosing and the actual day of treatment for the most common cancers: breast, lung, colon and prostate. • Over 90 percent of those variations in treatment result in the planned dose not being given on the day of treatment. • The rest of the variations result from dose increases or dose decreases. • If drugs are pulled on the day of treatment from a general inventory maintained by the cancer provider (Direct Acquisition Model), only those drugs which are actually used are billed to the health plan by the cancer provider, so no waste of drug in comparison to the original prescription occurs. • If drugs are delivered to the cancer practice for administration based upon the original planned prescription by the cancer provider (External Delivered Model), they are billed out to the health plan by the external vendor upon shipment, not upon actual utilization for the patient. • If drugs are delivered from an external vendor to the cancer practice for a specific patient under the planned prescription and are not used for that patient – those drugs cannot be used for another patient, nor returned….they must be handled as “waste” and discarded by the cancer provider, resulting in a cost to both the health plan and the provider, in addition to the cost of the drugs actually used for treatment of the cancer patient. • Based upon the results of this study, on a conservative basis, the cost of such potential “waste” to the health plan (in addition to the drugs actually used for treatment) under a External Delivered Model, could reach about $5,000 per treating physician, and are possibly significantly higher under less conservative assumptions. • There is a potential high impact of “waste” dollars in drug use even resulting from low (under 10 percent) variations resulting from same day treatment changes – for both chemotherapy drugs and ancillary drugs that are delivered to the cancer provider for use, but that “waste” does not occur when cancer drugs are used from within the cancer provider’s own acquired inventory. • Drug shortages are a significant issue in oncology today, and delivery policies that cause large numbers of unused drugs to be destroyed would only exacerbate cancer drug shortages.
Introduction
About 80 percent of cancer care is delivered in community oncology office settings (private or hospital owned). These are predominantly private physician offices, which, as small business-
es, keep a very tight rein over their expensive drug inventories. Patients coming in for treatment have their health status assessed in the physician office immediately prior to receiving any drug treatments, so the assessment of the patient and any decisions
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made about changes in needed drugs for treatment are closely linked, both in terms of staff resources and knowledge of the actual drugs involved and the causes for the change. Drug Delivery Models in Flux: Historically, all drugs have been acquired by the oncology office for cancer treatment, but with the advent of newer oral drugs and increased public and private payer focus on cost management in oncology, there has been some increase in the volume of drugs ordered by physician prescription and shipped to the office from an external pharmacy, usually driven by health plan policy or reimbursement structure. There has also been an increasing interest on the part of health plans and specialty pharmacy organizations in whether more drugs, if not all, should be delivered upon prescription to the oncology office. Physician practices are more closely evaluating individual drugs for both public and private payers, and occasionally making decisions to either send patients to another care system (such as a hospital outpatient center) or to acquire drug through an External Delivered Model if the cost of the drug is significantly higher than the reimbursement rate. Physician practices across the country are struggling financially, and many have recently been acquired by hospitals or merged into large group models. Each of these changes is initially driven by differences between cost and reimbursement policies of both public and private health plans, but as practices merge into larger organizations, can also then have an unintended adverse financial consequence for that same public or private health plan. Hospitals usually have different contract structures and pricing differences. Health plans are now starting to analyze relationships with those private physiciansâ&#x20AC;&#x2122; practices that are still private, and consider what policies might encourage them to remain in practice rather than to seek integration into a more costly hospital setting. In some cases, those policies under review include consideration of the impact on both the health plan and the provider of different drug delivery models. Potential Changing Drug Delivery Models Cost Implications for Payers: The National Association of Managed Care Physicians, facing questions from their membership (medical directors of health plans, employers and larger providers) about the costs and implications of different delivery models for oncology drugs, engaged the services of DGH Consulting, onPoint Oncology, LLC and Improve RX, LLC, to analyze the rate and volume of drug changes for cancer patients during treatment. While there are some variations in payment structure and other drug delivery models in use across the country, the Direct Acquisition Model and External Deliv-
ered Model are by far the most common currently in use. Payers pay for drugs to different entities under these two delivery models currently being employed or under consideration â&#x20AC;&#x201C; and at different times in the treatment process. Those differences could be greatly affected by drug changes during treatment, but are not easily measurable by any current tracking process in either payer or specialty pharmacy systems. Impact is based upon delivery-related costs of drug cost only: It is important to note that many health plans, as well as providers, are engaged in numerous other activities to manage the selection of appropriate treatment for cancer patients and their disease by the physician. While those initiatives can also affect the ultimate cost of treatment by managing drug or regimen choice, they do not affect the types of costs that could be incurred under the situation created by changing drug delivery models. Any changes related to prior authorizations, use of guidelines or pathways, or other oncology management programs would not be affected by the delivery method of the planned treatment. The only costs considered in this study relate to whether or not a planned treatment, once delivered, is actually used, and whether or not the method of delivery might result in a cost of unused product. While it would also be possible to use other price points for the purpose of quantifying the potential impact on a dollar basis, causing the numbers to vary somewhat, the fact that there is a dollar impact related to the potential for unused prescribed drug would not vary. The two most common drug delivery models in use or under consideration for oncology care are described as follows: Direct Acquisition Mode: Most oncology drugs are now acquired by the provider directly from a specialized oncology drug distributor and stored until actually used by a patient, at which point a claim is issued to the payer and submitted for payment. Physicians are paid for Medicare patients at a payment rate of Average Selling Price (ASP) plus 6 percent, which is modified quarterly by the federal government. Private health plans pay physicians on a wide range of payment rates, which can be based upon Average Wholesale Price (AWP) or ASP. ASP plus 10 percent was selected as a fairly common representative comparison for reimbursement rates under the Direct Acquisition Delivery Model for the purposed of this study. External Delivered Model: Under this model, health plans contract with an entity external to the health provider (typically a specialty pharmacy) to acquire and deliver drugs to the health provider. The treating physician is expected to
70 Journal of Managed Care Medicine | Vol. 15, No. 4 | www.namcp.org
Exhibit 1: Patients in Dataset 4/1/11 – 3/31/12, 1,368 total
3-D Extrude & Bevel 53 14 -10
Prostate 119, 9% Breast
Colon 269, 20%
Lung Breast 540, 41%
Perspective: 0
Colon Prostate
Extrude & Bevel: 20 pt. Plastic Shading
Lung 394, 30%
Exhibit 2: Doses in Dataset 4/1/11 – 3/31/12, 25,202 total Prostate 896, 4%
3-D Extrude & Bevel 53 14 -10
Breast
Colon 7,857, 31%
Lung Breast 7,892, 31%
Colon Prostate
Perspective: 0 Extrude & Bevel: 20 pt.
Lung 8,557, 34%
Plastic Shading
send a prescription to that designated specialty pharmacy for the planned cancer treatment and those drugs are then sent to the physician’s office, usually within 24 to 72 hours in advance of the scheduled treatment day. Specialty pharmacies then bill the health plan for the ordered drugs at the time they are shipped from the specialty pharmacy, without the knowledge or ability to reconcile whether or not the drugs were actually used in the office setting. These delivered drugs arrive specifically labeled for the individual patient for whom they were ordered. Safe Handling Guidelines for Chemotherapy Administration
Cancer practices follow well-defined protocols for the safe administration of chemotherapy and supportive care medications, including clinical assessment regarding the appropriateness of the planned treatment on the day of treatment given the patient’s
current health status. These guidelines also provide for the safe documentation of treatment changes on the day of treatment, as deemed necessary. Treating providers will not treat a cancer patient with any drugs without assessing the patient’s health status and assessment of the appropriateness of the planned treatment on the day of treatment. The American Society of Clinical Oncologists (ASCO) and the Oncology Nursing Society (ONS) have published guidelines for the safe handling of chemotherapy which are the national standard for safe practice. These ASCO/ONS Standards for Safe Chemotherapy Administration establish that: 22. On each clinical visit or day of treatment during chemotherapy administration, staff: Assess and document clinical status and/or performance status Document vital signs and weight Verify allergies, previous reactions, and treatmentrelated toxicities
www.namcp.org | Vol. 15, No. 4 | Journal of Managed Care Medicine 71
Exhibit 3 Patients in Dataset (n = 1,368) (Breast/Lung/Colon/Prostate CA) Apr 1, 2011 - Mar 31, 2012
Total Chemo “Waste” $497,024 Ancillary “Waste” $657,280
Breast (n = 540)
Lung (n = 394)
Colon (n = 269)
Prostate (n = 119)
Total Doses = 25,202 Matching Doses = 90.1% No Dose Given = 4.4% Dose Decrease = 2.0% Dose Increase = 3.5%
Patients with One Cancer (n - 1,322)
Total Providers = 237
Providers = 164
Total Doses = 7,892 Matching Doses = 92.0% No Dose Given = 4.7% Dose Decrease = 0.8% Dose Increase = 2.5%
Chemo “Waste” $171,188 Ancillary “Waste” $156,373
Providers = 164
Total Doses = 8,557 Matching Doses = 94.1% No Dose Given = 2.8% Dose Decrease = 0.5% Dose Increase = 2.6%
Chemo “Waste” $76,398 Ancillary “Waste” $160,326
Providers = 151
Total Doses = 7,857 Matching Doses = 83.5% No Dose Given = 5.7% Dose Decrease = 5.0% Dose Increase = 5.8%
Chemo “Waste” $223,426 Ancillary “Waste” $275,610
Providers = 65
Total Doses = 896 Matching Doses = 92.6% No Dose Given = 7.0% Dose Decrease = 0.1% Dose Increase = 0.5%
Chemo “Waste” $26,012 Ancillary “Waste” $64,931
* Based on AWP - 17%
Assess and document psychosocial concerns and need for support; taking action when indicated. This standard applies to all clinical encounters (including each inpatient day, practitioner visits and chemotherapy administration visits, but not laboratory or administrative visits). 23. At each clinical visit or day of treatment during chemotherapy administration, staff review the patient’s current medications including over the counter medications and complementary and alternative therapies. Any changes in the patient’s medications are reviewed and documented by a practitioner during the same visit. This standard applies to all clinical encounters (including each inpatient day practitioner visit and chemotherapy administration visits but not laboratory or administrative visits).1 Regulatory Impact on Drug Management and Costs: Federal and state pharmacy laws dictate whether drug ordered and labeled for a specific patient, if not used for the designated patient, may be returned to the source or re-allocated to another
patient. Federal and state pharmacy regulations, as well as individual manufacturer/distributor policies, also dictate whether or under what conditions a drug may be returned after delivery to the end point pharmacy or physician’s office, with more restrictive policies for refrigerated rather than non-refrigerated drug. Most state pharmacy regulations prohibit any reuse of drugs issued for specific patients, and also preclude dispensing pharmacies from even accepting the return of prescribed drugs, as illustrated in this simple statement from the Missouri Division of Professional Regulation, “Under Missouri law, unused medication cannot be returned to a pharmacy for purposes of disposal/destruction.”2 Most state pharmacy regulations require that a drug, once it leaves the pharmacy labeled for a specific patient based upon a doctor’s prescription, must be destroyed if not used for that specific patient – not returned or reused for other patients. These regulations do cause concern because of the large numbers of drugs already being wasted from unused medications accumulating in individual homes and long-
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Exhibit 4: Percent of Doses That Didn’t Match Original MD Order – Dataset 4/1/11 - 3/31/12 18% 16% 14% 12% 10% 8% 6% 4% 2% 0%
16.50%
9.90% 8%
7.40% 5.90%
Breast Lung
term care nursing facilities. The National Conference of State Legislatures recently reviewed the problem and support efforts on different state levels to provide regulatory guidance for “take back” programs. However, in all circumstances, such take back programs focus on finding ways to accept unused prescribed drugs for controlled distribution to needy individuals, not for resale in the domain of the general public..3 Those take back policies, while useful for uninsured patients who might not otherwise receive medications, do not allow for use of unused medications for commercial or Medicare populations. Methodology
To identify the impact of different drug delivery methods, a data set derived from electronic medical records (OncoEMR,® Altos Solutions, Pleasanton, CA and onPoint Oncology, LLC, Hudson, OH) was queried The data set contained de-identified patient information such as dose, duration, sequence and key patient demographic data including diagnoses. Importantly, the originally ordered treatment plan including the anticipated drug and dose as well as the drug and dose actually administered to the patient on the day of treatment were available. Mismatches between the ordered drug and dose and the administered drug and dose provided the basis for comparisons of the two drug delivery models. The data from the 12-month period of April 1, 2011 through March 31, 2012 were utilized. Patients receiving drug orders and administrations during the study period were divided into one of four cancer groups: breast, prostate, colon, and lung, as identified by conventional ICD-9 coding. Patients with diagnoses of multiple cancers were excluded. The drugs were divided into two groups: 1) chemotherapy/biologics and; 2) ancillary drugs, such as colony stimulating factors , anti-emetics, etc..
Colon
Prostate
Total
Three different scenarios were identified when a mismatch between ordered amount and administered amount occurred: ordered>administered, including situations where administered amount = 0 (ordered dose held); ordered<administered; and ordered=administered. The primary outcome measure was the mean cost difference between ordered drug amounts and administered drug amounts ,when ordered was greater than administered. Under a delivered drugs model, drug is pre-ordered by the physician practice from an external source (i.e., specialty pharmacy) and cannot be returned if unused (ordered>administered). This was considered as potential ‘waste’. Thirty-day per patient drug waste was also calculated based on the observed utilization patterns for both Average Wholesale Price (AWP)-17 percent and Average Selling Price (ASP) + 10 percent and normalized to mean time on drug (in days, first to last). Secondary measures included percent with any waste (ordered ≠ administered), percent where ordered>administered, percent where administered amount = 0 (ordered dose held) and percent ordered<administered; and ordered=administered (matching doses). In addition, All administrations were reviewed by drug to ensure that consistent dosing units were used. Results
Over the 12 months of data aggregated for the study (April 1, 2011 to March 31, 2012) detailed dosing data was collected for 237 physicians practicing in locations across the country. The documented dosing data covered a total of 1,368 patients with diagnoses of either breast, lung, colon or prostate cancer (Exhibit 1 ). Of the total 25,202 number of doses administered and documented during those twelve months, almost two-thirds (63 percent, 15,815) were for che-
www.namcp.org | Vol. 15, No. 4 | Journal of Managed Care Medicine 73
Exhibit 5: Potential Dollars of “Waste” per MD (at AWP - 17% value of doses) due to Unmatched Doses - Dataset 4/1/11 - 3/31/12 $5,000 $4,000 $3,000 $2,000 $1,000 $0 Breast Lung
Total
Colon
Prostate
Total
Chemo Ancillary
“Waste” in AWP - 17% Values
Exhibit 6: Potential Dollars of “waste” due to Unmatched Doses – Dataset 4/1/11 - 3/31/12 $1,400,000 $1,200,000 $1,000,000 $800,000 $600,000 $400,000 $200,000 $0 Total AWP - 17% “Waste”
Breast Lung $327,561
$236,764
Colon $499,036
Prostate $90,943
Total $1,154,304
Chemo AWP - 17% “Waste”
$171,188
$76,398
$223,426
$26,012
$497,024
ANC AWP - 17% “Waste”
$156,373
$160,366
$275,610
$64,931
$657,280
motherapy treatments and the remaining third (37 percent, 9,387) were for ancillary drugs. Most of those doses were evenly distributed between breast (31 percent), lung (34 percent) and colon (31 percent) with another 4 percent being used for prostate cancer. (Exhibit 2) Overall, about one in 10 doses were not administered as originally planned. The doses that did not match the original dose indicated a change from planned treatment: either no dose was given, or the dose was increased or decreased. Colon cancer treatments were the most likely to be changed (16.5 percent), followed by breast (8 percent), prostate (7.4 percent) and lung cancers (5.9 percent). (Exhibit 3), (Exhibit 4) Limitations related to Study: The database
source offers one of the most detailed national records currently available across multiple practices related to the actual utilization of cancer treatment planning versus actual delivery. Health plans only receive claims information from practices related to drugs actually used in treatment. Many physician practice EMRs might track treatments dosed, but not necessarily the original treatment plan if it differed. As detailed as this database was, other variations in treatment were unable to be pulled although they do occur often in actual practice. Such variations uncounted in this study could include: • Complete changes in regimen based upon a reassessment of the patient from one treatment to another, especially when related to a change in disease progression.
74 Journal of Managed Care Medicine | Vol. 15, No. 4 | www.namcp.org
Exhibit 7: Top 10 Chemo Drugs “Waste” – doses valued at AWP-17% Dataset 4/1/11 - 3/31/12 $14,628 $18,656
$12,026
3-D Extrude & Bevel 53 14 -10
Bevacizumab
$9,822
$28,222
Oxaliplatin Trastuzumab
$31,643 $155,150 $31,970
Leuprolide Alemtuzumab Docetaxel
Perspective: 0
Carboplatin
Extrude & Bevel: 20 pt.
Centuximab
$74,539
Rituximab
$79,412
Plastic Shading
Pemetrexed
Exhibit 8: Top 10 Chemo Drugs “Waste” % not matching original dose Dataset 4/1/11 - 3/31/12
32.4% 26.2%
17.9%
Bevacizumab Oxaliplatin
8.8%
Trastuzumab Leuprolide
7.0%
40.3%
9.2%
Alemtuzumab Docetaxel Carboplatin Centuximab
9.8% 13.0%
57.1%
• Undercounting of chemotherapy dosing changes (other reports have suggested higher variation rates – we chose to track only what was documented in this limited data set for these four cancers). Another recent study from ICORE Healthcare found a 20 percent rate of change for shipped cancer drugs – “Moreover, approximately 20 percent of drugs shipped to a provider’s office fail to be used due to, for example, changes in dose, therapy, duration of therapy, benefit, and higher costs, since partial vial use is not possible when billing NDC-11 codes to the pharmacy benefit. • Under-tracking of actual experience due to escalating volume of documentable cases each month from April 1, 2011 to March 31, 2012. Actual total drug administrations in database for all of 2011 were 13,651. In contrast, the actual total drug administrations in the database for just the first four
Rituximab Pemetrexed
months of 2012 (as more practices came online with the EMR and entered data) were 18,495, which if annualized could total 55,485 for 2012. Since the database is in a phase of constant growth, a conservative decision was made to analyze only those administrations that were actually documented for the twelve months of the study period (April 1, 2011 to March 31, 2012 – an actual total of 25, 202.4 Discussion
Oncology patients receiving treatment are evaluated by the treating physician to determine appropriate treatment for the state and stage of the disease. Many, if not most, planned treatments can be a combination of different chemotherapy agents, as well as some combination of ancillary drugs in-
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Exhibit 9: Top 10 Ancillary Drugs “Waste” – doses valued at AWP-17% Dataset 4/1/11 - 3/31/12 $16,265
3-D Extrude & Bevel 53 14 -10
$36,990
$17,022
$11,253 Pegfilgrastim
$4,171 $3,760
$48,962
Palonosetron Darbepoetin
$52,473
Denosumab
Perspective: 0 Extrude & Bevel: 20 pt.
Zoledronic Acid
Filgrastim Gammagard
$65,051
Epoetin Alfa Aprepitant
Plastic Shading
tended to mitigate toxicities and side effects of the chemotherapy agents. Advances in cancer treatment now allow for more aggressive use of chemotherapy agents when accompanied by the ancillary drugs to help manage the side effects of these toxic chemotherapy drugs, but patients continue to fight on a daily basis the impact of the disease and the treatment on their bodies and minds. Cancer patients are thus evaluated at the beginning of each day of treatment to determine the appropriateness of the planned treatment given their daily medical, physical and psychological condition. While there may be a few times when drugs could be retained to be used later for that same patient, the majority of these cases in practice seem to require that substitution/ correction/change/cancellation of drug choice and dosage must occur. Estimated Impact of Cancer Treatment Variation from Original Prescription under the two different drug delivery models: If the planned drug was shipped to the MD office under an “External Delivered Model”, and then not given, or more or less drug was actually administered, the unused drug is paid for by the payer upon shipment and cannot be used for another patient or sent back to the shipping facility. It must be discarded and thus becomes “waste”. This waste does not exist under the physician Direct Acquisition Model (sometimes also referred to as “Buy and Bill”), because only drug actually administered is billed to the payer by the provider. If planned treatment changes occur under the Direct Acquisition Model, the original drug may be left on the shelf or in the refrigerator for the next patient because it is not “issued” to an individual patient until the moment it is actually
$400,481
Oprelvekin
used, and thus remains available for use for the next patient if not needed for the current one. Calculation of Impact: “Potential Waste” This study looked at chemotherapy treatments ordered and administered by hundreds of oncologists over a one-year period, and where sufficient documentation existed, tracked the frequency, volume and value of when a difference occurred between the specific drugs initially ordered and the specific drugs actually administered to the patient in the oncology office on the day of treatment. Managed care organizations pay for drugs in two different ways: 1) upon shipment out of a specialty pharmacy before delivery and actual use for a specific patient (usually at a rate of AWP minus 17 percent), or 2) directly to the physician upon submission of a claim for the exact drugs that were administered to the patient in the course of treatment (at a variable rate but ASP + 10 percent is fairly common). If drugs are shipped out of a specialty pharmacy for treatment, but not actually used in the treatment for the patient, the health plan would incur costs for drugs twice for that patient – both the drugs initially ordered, as well as those ultimately administered. This study quantified those times where differences occurred between the drugs originally ordered and those administered. It then valued those differences at the most common rate at which health plans pay specialty pharmacies for drugs billed out when shipped (AWP minus 17 percent), to create a reasonable estimate of costs that health plans could incur if oncology drugs were provided under an External Delivered Model rather than a Direct Acquisition Model. This data drawn from the emerging resource of
76 Journal of Managed Care Medicine | Vol. 15, No. 4 | www.namcp.org
Figure 10: Top 10 Ancillary Drugs “Waste” % not matching original dose Dataset 4/1/11 - 3/31/12
trude & Bevel 53 14 -10
21.4%
7.6%
Pegfilgrastim
3.7% 18.8% 9.2%
Palonosetron Darbepoetin
Perspective: 0
4.0%
Denosumab Filgrastim
de & Bevel: 20 pt.
Gammagard 16.6%
astic Shading
Zoledronic Acid
Epoetin Alfa Aprepitant
35.7% 5.6%
6.5%
electronic medical records in the treating provider office demonstrated that for the documented breast, lung, colon and prostate cancers (if the planned drugs had been shipped before treatment and billed at a usual specialty pharmacy payment rate of AWP minus 17 percent) a potential drug “waste” of over $1.1 million paid by health plans could have resulted BEFORE payment for the drugs actually used in an individual patient. On a per physician basis, this could amount to close to $5,000 per treating MD. (Exhibit 5) (Exhibit 6) With over 6,000 currently practicing oncologists in the United States, a wholesale conversion of all cancer drugs from the Direct Acquisition Model to the External Delivered Model could potentially result, on a conservative basis, in almost $30 million of shipped and paid for drug becoming “waste” because the patient in whose name those drugs were delivered for some reason was not able to receive the planned treatment on the day of treatment. Study projects Potential “Waste”, if delivery model were to change, not actual current magnitude of “waste”: Since the majority of cancer drugs are not now delivered by specialty pharmacy to cancer practices but are currently acquired under the Direct Acquisition Model, this “waste” does not yet occur in large quantities. In some areas of the country oncology practices do receive delivered drugs from external sources, and do also anecdotally report high rates of unused drug that has been paid for by the payer but cannot be used by the patient, nor returned. In these circumstances, the drug accumulates in the storage areas of the practices until it can be discarded. It was the existence of these needless situations of “waste” that prompted
Oprelvekin
the implementation of this study to ascertain the frequency and potential implications of a shift in drug delivery models on a more widespread basis. It may be useful in another study to assess the degree of current “waste” generated by the few areas where the External Delivered Model does result in shipped drug in advance of the day of treatment. Most of those situations do now involve drugs for Medicaid patients, which are not found in high volumes in private community offices, so the volume and incidence is still fairly low. Variation in treatment for oral chemotherapy drugs and ancillary drugs does also happen and there are a few areas of the country where either state pharmacy policy or private payer oncology policy lead to External Delivered Models for these drugs. Again, this study doesn’t quantify the extent of potential “waste” from those situations, but does recognize that there are several reports of similar unusable “waste” accumulating in those practices, for which health plans have already paid.5 Slight Variations can lead to High “Waste”: Even doses not matching rates of less than 10 percent per drug in a given disease can lead to very high “waste” rates at the drug reimbursement rate for specialty pharmacy of about AWP – 17 percent. While about one in 10 cancer treatments in this 12-month database did show variations in treatment, the majority of those variations (over 90 percent) led to the planned dose not being given at all on the day of treatment. The rest of the variations were from resultant dose increases or decreases. The database was not able to provide the detail of the reason for the variation in treatment for each patient, but oncology practice physicians and nurses have verbal-
www.namcp.org | Vol. 15, No. 4 | Journal of Managed Care Medicine 77
ized that patient health status changes are the most common reason that led to an inability to tolerate the treatment, or the need for postponement or cancellation of treatment. These health status changes can occur rapidly in a fragile cancer patient, so assessment of the patient’s ability to accept the planned treatment needs to occur on the day of treatment, rather than a day or more in advance. Management of costs in cancer is critical to health plans
Pharmaceutical spend in cancer, on a per member per year (PMPY) basis, is higher for cancer than for any other therapy class.6 In the “Distribution of Pharmacy and Medical Specialty Spending, Ranked by Relative Change in Medical Spend, Thomson Reuters MarketScan® Commercial Database, 20062010”, the 2011 Express Scripts Drug Trend Report ranked the top ten therapy classes by per member per year costs for both the medical and pharmacy benefits. Cancer totaled $68.88 per member per year. Even just 10 percent ($6.88 PMPY) of the cancer costs amounted to more than the individual per member per year spend for pulmonary hypertension ($4.03 PMPY), respiratory conditions ($5.95 PMPY), transplant ($6.11 PMPY) or hepatitis C ($2.17 PMPY). All growth deficiency pharmaceutical spend totaled just a little more on a PMPY basis ($7.92) than 10 percent of the cancer spend. A health plan strategic decision regarding selection of an External Delivered Model that could affect additional health plan expenses for up to one in 10 cancer treatments could have financial implications far greater than all monies spent on any one of those therapy classes. Examples of Specific Percentages of Potential “Waste” Doses and Potential Financial Cost of such “Waste”
The top 10 chemotherapy and ancillary drugs, as measured by the potential financial cost of possible “waste” are illustrated in Exhibits 7 and 9. Exhibits 8 and 10 also show the percentage of time the original planned dose did not match the actual dose used on the day of treatment. These analyses illustrate that even small rates of treatment doses not matching planned doses can lead to high potential “waste”, which would be magnified if applied to every cancer patient in the country. (Exhibits 7,8,9 and 10) Ancillary drugs are often considered as manageable (and deliverable) separate from chemotherapy drugs by external vendors and oncology drug managers. These ancillary drugs are often considered as primary candidates for External Delivered Models even when chemotherapy drugs may not be by some
health plans. However, the ancillary drugs play a critical role in the success of chemotherapy, and for most cancers other than breast, showed greater variation and potential “waste” impact than the chemotherapy treatments. In breast cancer, the potential financial impact of both chemotherapy and ancillary “waste” was fairly close. The ancillary drugs manage the symptoms and side effects of the toxic chemotherapy treatments (both oral and infused/ injectable), and as such are sensitive to variations in the patient’s health status on the day of treatment. • Alemtuzumab in over half of the doses in the database (57.1 percent), did not match the original dose, showing variations that could have resulted in over $31,000 in total “waste”. • Leuprolide had a rate of just 13 percent not matching but also demonstrated a total “waste” of over $31,000. • Bevacizumab reflected a better than one in four dose likelihood of not matching prescribed doses (26 percent) , leading to the highest total “waste” of over $155,000. • 40.3 percent of oxaliplatin doses didn’t match the original plan (about a two in five likelihood per dose), for the second highest total “waste” of over $79,000. • The ancillary drug Pegfilgrastim showed a rate of just under one in 10 (less than 8 percent) for not matching the original planned dose, but posted the highest ancillary “waste” total of over $400,000. Summary Observations and Next Steps: It is clear that there are variations on the day of actual treatment that can become significant to health plans and providers (even if the percentage is below 10 percent) between an original prescribed oncology treatment plan and dosing and the final actual given oncology treatment and doses. These variations and changes have now been quantified because of new documentation and tracking options that were not previously available to the oncology community. As electronic medical records are increasingly utilized in oncology practices, and more complete information is entered, additional information should become available not only about the frequency and volume of such variations, but eventually the reasons. If the current dominant Direct Acquisition Model were to be eliminated in favor of the External Delivered Model, the timing of both the pre-treatment drug order and fulfillment as well as the payment by the health plan to the billing entity would change dramatically. This study has illustrated the magnitude of how actual drug utilization can vary from the original drug prescription on the day of treatment. Because the payment under the External Delivered Model goes directly from the health plan to
78 Journal of Managed Care Medicine | Vol. 15, No. 4 | www.namcp.org
the specialty pharmacy upon shipment of the drug, health plans would end up paying for drug that is not actually used in treatment of the patient. Additionally, the drugs shipped to the oncology practice for an individual patient, that are not actually used must be discarded at a management cost to the oncology practice. They cannot be returned nor used for another patient under pharmacy regulations. Specialty pharmacies are usually paid by health plans at a rate of about AWP minus 17 percent, so it was possible for this study to value the potential “waste” that could occur from unused but shipped drug under an External Delivered Model. The study revealed significant potential financial costs that could be incurred by health plans under a shift to a External Delivered Model (on a conservative basis almost $5,000 per treating oncology provider) before the costs of the drugs actually used in treatment for the patients. The study also showed that conservatively, at least one in 10 cancer treatments for the top four cancers are likely to result in the treatment not matching the original plan. Additional notable findings were as follows: • There is potential for a high dollar impact to health plans even if there are fairly low (under 10 percent) variations in drug use resulting from same day patient health status changes. • Many chemotherapy drugs observed in this study do have notable rates of variation from planned doses – most between 10 and 20 percent and some even as high as 100 percent. • In lung, prostate and colon cancers, there is even a higher potential dollar impact on health plans from variations in ancillary drugs used to support high density chemotherapy administration than there is in the chemotherapy drugs used for those cancers. Ancillary and chemotherapy impact is fairly equal for breast cancer treatments; yet, ancillary drugs are more likely to be considered as candidates for movement to Delivered Drug Models through a specialty pharmacy. Implications for the future for health plans and providers: This study has demonstrated and quantified a reality of the complexity of cancer treatment for fragile cancer patients that has previously gone unmeasured or quantified in a formal manner. Health plans, specialty pharmacies and oncology providers are likely to examine the potential logistical and financial implications of a shift from a Direct Acquisition Model to an External Delivered Model carefully in light of these findings. It appears to be essential that if drugs were to be delivered to an oncology practice, it would need to happen in a timely fashion after the patient assessment has occurred, and any subsequent treatment
changes have been made. Logistically, this would be extremely difficult to manage for each cancer treatment site on the same day of treatment, and yet it would not be medically practical to assess the patient on other than the day of treatment. Health plans will not want to pay for drugs that are shipped but not used, and we cannot afford as a society to create a situation that will lead to huge numbers of cancer drugs having to be discarded. There are some External Delivered Models in practice that have demonstrated that timing and assessment hurdles can be surmounted. This study was presented so that the entire community that cares for and pays for cancer treatments can better understand some of the variables that the different models bring, not to suggest that one model is inherently better than the other. As health plans, treating providers and specialty pharmacies continue to address changes in oncology management, an understanding of the complexity of the delivery of cancer treatment to fragile oncology patients will help all entities to make informed decisions. The U.S. Drug Enforcement Administration’s (DEA’s) fifth semiannual National Takeback Day program was held on September 29, 2012. At the previous event, in April 2012, 276 tons of unused, expired, or excess medication was collected, bringing the total for the four previous events held to over 1.5 million pounds (774 tons).7 This medication waste resulted mostly from medications that the general public had taken home but were unable to take as planned. It is not likely that the pharmacy regulations governing the management of medications that have been prescribed for an individual will be significantly changed, but it is possible to consider the implications of oncology drug management policy in light of these new findings on the complexity of cancer patients during treatment. Obtaining the Report
The full report on this Impact on Cancer Drug Costs from Different Delivery Models is available from the National Association of Managed Care Physicians, by contacting Katie Eads at keads@namcp.org or 804-527-1905. In the full report, further details are provided on the analyses and specific variations for each of the four major cancers: breast, lung, colon and prostate. Funding
Funding for the study was provided by SanofiAventis U.S. LLC. The authors retained full editorial control over the content of the manuscript and received no compensation from any party for this work.
www.namcp.org | Vol. 15, No. 4 | Journal of Managed Care Medicine 79
Dawn G. Holcombe, FACMPE, MBA, ACHE is President of DGH Con-
asco.org/ASCOv2/Practice+%26+Guidelines/Quality+Care/Quality+Meas
sulting and has extensive experience in oncology focused strategies
urement+%26+Improvement/ASCO-ONS+Standards+for+Safe+Chemother
and quality programs for both providers and managed care. She is a
apy+Administration+%5B2011%5D, Last Accessed September 13, 2012.
past President for AOHA (the Medical Group Management Associa-
2. “Board of Pharmacy home page: Consumer Information: DISPOSING OF
tions oncology leadership association), is the Editor in Chief for “On-
UNUSED MEDICATIONS heading”, Missouri Division of Professional Reg-
cology Practice Management” and on the Editorial Advisory Board for
ulation, http://pr.mo.gov/pharmacists-consumerinformation.asp, Last Ac-
“Value Based Cancer Care.” Dawn is a Fellow in the American College
cessed September 13, 2012.
of Medical Practice Executives (ACMPE).
3. State Prescription Drug Return, Reuse and Recycling Laws, website for the National Conference of State Legislatures, Updated as of September 2102 ,
Kerry Bradley is a Principal with onPoint Oncology, LLC. onPoint On-
http://www.ncsl.org/issues-research/health/state-prescription-drug-return-
cology is a targeted solutions company for the oncology market, with
reuse-and-recycling.aspx, Last Accessed on September 13, 2012.
a focus on technology, data, reimbursement and market intelligence.
4. “Medical Pharmacy and Oncology Trend Report 2011, ICORE Healthcare, Page 27.
Rex W. Force, PharmD, FCCP, BCPS is a Founder and Partner of
5. “Is Oncology Compatible with Specialty Pharmacy?” By Dawn Holcombe,
improveRX. His expertise is in drug utilization review; pharmacoepi-
Community Oncology, VOLUME 2, NUMBER 2 (March/April 2005) http://
demiology and claims analysis; primary care pharmacotherapy; and
communityoncology.net/journal/articles/0202173.pdf
evidence-based medicine. His academic appointments include As-
6. “Distribution of Pharmacy and Medical Specialty Spending, Ranked by
sociate Dean for Clinical Research, Professor and Director of Research
Relative Change in Medical Spend, Thomson Reuters MarketScan(r) Com-
in the Department of Family Medicine and Professor of Pharmacy
mercial Database, 2006-2010”, 2011 Drug Trend Report, Express Scripts web-
Practice at Idaho State University.
site, http://www.drugtrendreport.com/charts: Exhibit 12, Last Accessed on September 14, 2012.
References
7. “National Takeback Initiative”, Office of Diverson Control, Drug Enforce-
1. “ASCO-ONS Standards for Safe Chemotherapy Administration [Revised
ment Administration website., last accessed September 4, 2012: http://www.
11/15/2011], American Society of Clinical Oncology website, http://www.
deadiversion.usdoj.gov/drug_disposal/takeback/
American Association of Managed Care Nurses (AAMCN) For 18 years, the American Association of Managed Care Nurses has supported nurses working throughout the managed care industry through solution-driven educational initiatives, collaborative activities with affiliate associations, membership connectivity and networking and association-wide dedication to patient advocacy. Join over 2000 dedicated managed care nurses throughout the country and receive many benefits of membership, including: Networking - Twitter, LinkedIn & Facebook - Spring & Fall Managed Care Forums - member discount - Committee involvement & writing articles Education - Complimentary Online CEUs - Spring & Fall Managed Care Forums - member discount - Access to online, disease specific resource centers & tools - Ongoing webinars throughout the year Please contact Jennifer Turner at jturner@aamcn.org or visit www.aamcn.org to learn more about the association and to JOIN AAMCN TODAY!
80 Journal of Managed Care Medicine | Vol. 15, No. 4 | www.namcp.org
Boehringer Ingelheim ranks among the worldâ&#x20AC;&#x2122;s 15 leading pharmaceutical corporations. Our vision drives us forward. It helps us to foster value through innovation in our company and to look to the future with constantly renewed commitment and ambition.
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Delivering on the promise of biotechnology through partnership.
Š 2011 Amgen Inc. All rights reserved. 52817-H 9-11
www.amgenoncology.com
Fall Managed Care Forum: Guide to Conference Supporters Abiomed, Inc. Exhibit Booth 231 Abiomed, Inc., based in Danvers, Massachusetts, is a leading provider of medical devices that provide circulatory support. Our products are designed to enable the heart to rest by improving blood flow and/or performing the pumping of the heart. For additional information, please visit: www.abiomed.com.
Accumetrics Exhibit Booth 410 Accumetrics is committed to advancing medical understanding of platelets and enhancing quality of care for patients who are at risk of cardiovascular disease by providing industry-leading diagnostic tests to assess response to every major type of antiplatelet therapy, including aspirin, P2Y12 inhibitors (Plavix® and Effient®) and GP IIb/IIIa inhibitors (e.g. ReoPro® and Integrilin®). Accumetrics’ family of VerifyNow® tests provides physicians with rapid, easy and valuable tools to help make informed treatment decisions.
Aerocrine Exhibit Booth 404 Aerocrine is a breakthrough medical technology company focused on improved management and care of patients with inflammatory airway diseases. NIOX MINOR enables fast, reliable measurements of airway inflammation and may therefore play a critical role in more effective diagnosis, treatment and follow-up of patients.
information, visit www.alcon.com.
lar volume ($) and units (100 mg equivalents).
Agendia
Amarin Pharma
Ameritox
Exhibit Booth 408
Exhibit Booth 227
Exhibit Booth 323,325
Agendia is an oncology molecular diagnostics com-
Amarin Pharma Inc. is a biopharmaceutical compa-
Ameritox offers the comprehensive solutions pay-
pany based in Irvine, California, focused on sig-
ny focused on the commercialization and develop-
ers and providers need to achieve the best possible
nificantly improving cost effectiveness and breast
ment of therapeutics to improve lipid management.
outcomes for chronic pain patients. From our su-
cancer patient outcomes by reducing healthcare
Amarin’s product development program leverages
perior laboratory services and innovative technolo-
costs as a means of guiding adjuvant chemotherapy
its extensive experience in lipid science. Vascepa™
gies to our exceptional service and clinical support,
use in patients with early stage breast cancer, of-
is Amarin’s first FDA-approved product.
we provide important information for managing chronic pain effectively. Learn how Ameritox Pain
fering significant benefits over existing treatment approaches.
American Regent
Medication Monitoring SolutionsSM can help you
Exhibit Booth 322
lower costs and improve chronic pain outcomes.
Alcon Laboratories
American Regent, Inc. is the manufacturer and dis-
Exhibit Booth 308, 310
tributor of Venofer®, (iron sucrose injection, USP),
Amgen
Alcon, the global leader in eye care, provides in-
the #1 selling IV Iron in the U.S.* Venofer® is avail-
Exhibit Booth 127
novative products that enhance quality of life by
able in 50 mg/2.5 mL, 100 mg/5 mL and 200 mg/10
Amgen, a biotechnology pioneer, discovers, de-
helping people see better. The three Alcon busi-
mL single use vials (preservative free). Visit us at:
velops, and delivers innovative human therapeu-
nesses - Surgical, Pharmaceutical and Vision Care
www.americanregent.com and www.venofer.com
tics. Our medicines help millions of patients in the
- offer the widest spectrum of products addressing
*Based on IMS Health, National Sales Perspec-
fight against cancer, kidney disease, rheumatoid
the world´s most pressing eye care needs. For more
tives™ - (July 2012) 2nd Quarter 2012 Results – dol-
arthritis, bone disease, and other serious illnesses.
www.namcp.org | Vol. 15, No. 4 | Journal of Managed Care Medicine 83
Oncology with soul At Eisai, human health care is our goal. We give our first thoughts to patients and their families, and helping to increase the benefits healthcare provides. Our therapies and diverse oncology pipeline are designed to help make a difference and have an impact on patients’ lives. We are Eisai, where oncology is more than just our business—it’s our passion.
CORP82R1
©2012 Eisai Inc.
All rights reserved.
April 2012
www.eisai.com/us
Fall Managed Care Forum: Guide to Conference Supporters With a deep and broad pipeline of potential new
company, Bayer HealthCare provides products for
We invite you to visit our exhibit and welcome the
medicines, we continue to advance science to serve
General Medicine, Hematology, Neurology, Oncol-
opportunity to meet our representatives to discuss
patients.
ogy and Women’s Healthcare. The company’s aim
the products and services we have to offer.
is to discover and manufacture products that will
Amylin Pharmaceuticals
improve human health worldwide by diagnosing,
Celleration
Exhibit Booth 203
preventing and treating diseases.
Exhibit Booth 123
Amylin Pharmaceuticals is a biopharmaceutical
Celleration® manufactures and distributes MIST®
company dedicated to improving lives of patients
Biogen Idec
through the discovery, development, and commer-
Exhibit Booth 305
cialization of innovative medicines. Amylin is com-
Through
medicine,
duce inflammation, bacteria and biofilm deep be-
mitted to delivering novel therapies that transform
Biogen Idec discovers, develops and delivers to
low the wound bed to accelerate the body’s normal
the way diabetes and other metabolic disorders
patients worldwide innovative therapies for the
healing process. Currently, over 60,000 patients
are treated. Amylin is headquartered in San Diego,
treatment of neurodegenerative diseases, hemo-
have benefited from the accelerated healing of
California. www.amylin.com
philia and autoimmune disorders. Founded in 1978,
MIST Therapy.
cutting-edge
Ultrasound Healing Therapy. The painless, noncontact, low-frequency sound waves of MIST rescience
and
Biogen Idec is the world’s oldest independent bio-
Astellas Pharma US
technology company. Patients worldwide benefit
Dendreon
Exhibit Booth 205
from its leading multiple sclerosis therapies and the
Exhibit Booth 219
Astellas Pharma US, Inc., a subsidiary of Tokyo-
company generates more than $5 billion in annual
Dendreon Corporation is a biotechnology company
based Astellas Pharma, Inc., is a research-based
revenues. For product labeling, press releases and
whose mission is to target cancer and transform
pharmaceutical company dedicated to improving
additional information about the company, please
lives through the discovery, development and com-
the health of people around the world through in-
visit www.biogenidec.com.
mercialization of novel therapeutics. The company
novative pharmaceutical products. Astellas ranks
applies its expertise in antigen identification, engi-
among the top 20 pharmaceutical companies in the
BioRx
neering and cell processing to produce active cel-
world. For more information on Astellas, please go
Exhibit Booth 318
lular immunotherapy product candidates designed
to www.astellas.com/us.
BioRx is a specialized provider of pharmacy and in-
to stimulate an immune response.
fusion services targeted at rare, chronic, costly dis-
first product, PROVENGE® (sipuleucel-T), was
Dendreon’s
Authentidate
eases, including hemophilia, immune deficiencies,
approved by the FDA in April 2010 for the treat-
Exhibit Booth 311
autoimmune disorders, nutrition and digestive dis-
ment of asymptomatic or minimally symptomatic
Authentidate is a provider of telehealth, hospital
orders, alpha-1 antitrypsin deficiency, and heredi-
metastatic, castrate-resistant (hormone-refractory)
discharge, referral, and order management soft-
tary angioedema. An ACHC-accredited provider,
prostate cancer.
ware and products for the healthcare industry.
BioRx delivers savings by providing increased pa-
Our Hospital Discharge software automates and
tient monitoring and clinical assistance. Learn more
Eisai
simplifies the discharge process. Inscrybe Health-
at www.biorx.net.
Exhibit Booth 202
care enables healthcare providers, suppliers, and
Eisai Inc. is the U.S. pharmaceutical operation of
insurers to exchange, update and electronically
Bioventus
Eisai Co., Ltd., a research-based human health care
sign healthcare documents quickly and accurately.
Exhibit Booth 209
(hhc) company that discovers, develops and martered in Woodcliff Lake, New Jersey, the company
hospital readmissions, increase care plan compli-
Boehringer Ingelheim Pharmaceuticals
ance and improve overall outcomes for chronically
Exhibit Booth 402
rology, gastrointestinal disorders and oncology/
ill patients.
Boehringer Ingelheim Pharmaceuticals, Inc., the
critical care. Established in 1995 and ranked among
U.S. subsidiary of Boehringer Ingelheim, headquar-
the top-20 U.S. pharmaceutical companies (based
tered in Germany, operates globally with more than
on retail sales), the company began marketing its
Our telehealth solutions include vital signs monitoring devices and applications that help reduce
kets products throughout the world.
Headquar-
focuses its efforts in three commercial areas: neu-
Bayer HealthCare Pharmaceuticals Inc.
44,000 employees. The company is committed to
first product in the United States in 1997 and has
Exhibit Booth 312
researching, developing, manufacturing and mar-
rapidly grown to become a fully integrated phar-
Bayer HealthCare Pharmaceuticals Inc. is the U.S.-
keting novel products of high therapeutic value
maceutical business. For more information about
based pharmaceuticals business of Bayer Health-
for human and veterinary medicine. Visit http://
Eisai, please visit www.eisai.com/US.
Care LLC, a subsidiary of Bayer AG. Bayer Health-
us.boehringer-ingelheim.com, Follow us on twitter
Care is one of the world’s leading, innovative
at @boehringerus.
Express Scripts Exhibit Booth 324
companies in the healthcare and medical products industry, and combines the activities of the Animal
Bristol-Myers Squibb Company
Express Scripts offers the industry’s most compre-
Health, Consumer Care, Medical Care, and Pharma-
Exhibit Booth 226
hensive range of specialty drug management solu-
ceuticals divisions. As a specialty pharmaceutical
Bristol-Myers Squibb welcomes you to Las Vegas.
tions to improve care for patients and reduce waste
www.namcp.org | Vol. 15, No. 4 | Journal of Managed Care Medicine 85
To us, science is personal. At Genentech, we’re passionate about finding solutions for people facing the world’s most difficult-to-treat conditions. That’s why we use cutting-edge science to create and deliver innovative medicines around the globe. To us, science is personal. Find out more at gene.com
Dan, patient
Visit us at booth 416 at NAMCP
Your Single-Source Laboratory Solution
From routine blood analysis to complex genetic testing and clinical decision support programs, LabCorp, with its Specialty Testing Group, is your single-source laboratory solution.
Oncology
Genetic counseling
Companion diagnostics
Kidney stone prevention
Expert, subspecialized pathologists
Clinical decision support for CVD and CKD
Reproductive genetics
Infectious disease
Women’s health
©2012 Laboratory Corporation of America ® Holdings. All rights reserved. mc-206-v1-1012
Fall Managed Care Forum: Guide to Conference Supporters for plan sponsors. Through the application of be-
sions. The company’s lead product, the Oncotype
Healthpoint Biotherapeutics
havioral science and a specialized clinical approach,
DX® breast cancer test, has been shown to predict
Exhibit Booth 320
we enable both better decisions and healthier
the likelihood of chemotherapy benefit as well as
Healthpoint Biotherapeutics is a commercial-stage
outcomes. To optimize care and maximize savings
recurrence in invasive breast cancer and has been
biopharmaceutical company focused on the devel-
we manage specialty medications across both the
shown to predict the likelihood of recurrence in
opment and commercialization of novel, cost-ef-
pharmacy and medical benefit.
ductal carcinoma in situ (DCIS). In addition to this
fective solutions for tissue repair and healing. The
widely adopted test, Genomic Health provides the
company’s diversified research and development
First Call IV Pharmacy
Oncotype DX colon cancer test, the first multi-gene
strategy is presently centered around therapeutic
Exhibit Booth 224
expression test developed for the assessment of
enzymes, biologics and next-generation cell- and
First Call IV Pharmacy is a leading provider of home
risk of recurrence in patients with stage II disease
cell-matrix based therapies for the prevention
infusion and high-tech specialty pharmacy services
and appropriate stage III patients.
and treatment of acute, chronic and burn-related wounds. Healthpoint Biotherapeutics is a DFB Phar-
throughout America. We are ACHC accredited with a staff of professionals having combined homecare
Gilead Sciences
maceuticals, Inc., affiliate company, and is based in
experience rivaling anyone in the business. Offer-
Exhibit Booth 302
Fort Worth, Texas. For more information, visit the
ing true national coverage and customer service
Gilead Sciences is a biopharmaceutical company
company website at www.Healthpointbio.com.
second to none, we can provide services for your
that discovers, develops and commercializes in-
patients in any location – we specialize in those
novative therapeutics in areas of unmet medical
Hologic
challenging cases in tough to reach rural areas.
need. The company’s mission is to advance the care
Exhibit Booth 412
Additionally, we offer this comprehensive cover-
of patients suffering from life-threatening diseases
Hologic is a leading developer, manufacturer and
age and top-notch service at rates that are cheaper
worldwide. Headquartered in Foster City, Califor-
supplier of premium diagnostic tests, medical im-
than most in-network rates. Should your home in-
nia, Gilead has operations in North America, Eu-
aging systems and surgical products dedicated to
fusion patient require additional nursing or therapy
rope and Asia Pacific.
the healthcare needs of women. We are commit-
services, you can access the wealth of resources
ted to enhancing women’s lives through earlier
provided by our network of over 3,000 full service
Halt Medical
detection, improved diagnosis and less invasive
home health agencies across the country. Make one
Exhibit Booth 327
treatments. Our core business areas focus on mam-
call to our centralized intake center and speak to
Halt Medical has developed an RF system for glob-
mography, breast MRI and breast biopsy, radiation
one of our customer service professionals for help
al fibroid ablation (GFA) to address a major unmet
treatment for early-stage breast cancer, cervical
with your next home infusion case. No matter how
need in women’s health - relief of the debilitating
cancer screening, treatment of fibroids and menor-
challenging the case, we will make the process as
symptoms caused by uterine fibroids. GFA treats
rhagia, osteoporosis assessment, and preterm birth
easy and seamless as possible, getting your patient
fibroids of all sizes, types, and locations. GFA is
screening. Learn more at www.hologic.com.
home quickly with all of their home infusion needs
an outpatient gynecological procedure that targets
met. We are truly your “First Call” for the best in
just the fibroids while preserving normal uterine
Home Instead Senior Care
home infusion services. Remember, regardless of
function and anatomy. Patients go home within
Exhibit Booth 223
location or time, First Call IV Pharmacy is always
hours of the procedure and return to normal activi-
Home Instead Senior Care is the world’s largest
where you need us to be. National Central Intake
ties in a few days. To visit our website, go to: www.
provider of home care services for seniors. With
- (800) 877-5705
HaltMedical.com.
more than 680 offices in North America and 14
Genentech
Hayes, Inc.
20 million hours of service to seniors around the
Exhibit Booth 103
Exhibit Booth 230
world. Our services are designed for any living ar-
Genentech has led the biotechnology industry for
Hayes, Inc., an internationally recognized leader
rangement where an older adult needs assistance
more than 30 years, using human genetic informa-
in health technology research and consulting, is
with activities of daily living that will allow them to
tion to develop medicines for patients with serious
dedicated to the delivery of high-quality health-
remain independent wherever they may call home.
or life-threatening medical conditions. In March
care and improved outcomes through the integra-
2009, the company became a wholly owned mem-
tion of evidence into decision making and policy
Horizon Pharma
ber of the Roche Group, and Genentech now serves
development. The unbiased information and com-
Exhibit Booth 330
as the headquarters for Roche pharmaceutical op-
parative effectiveness analyses we provide enable
We are a biopharmaceutical company that is devel-
erations in the United States.
evidence-based decisions about acquiring, manag-
oping and commercializing innovative medicines
ing, and paying for health technologies. Our world-
to target unmet therapeutic needs in arthritis, pain
Genomic Health, Inc.
wide clients include hospitals, healthcare systems,
and inflammatory diseases. We received FDA ap-
Exhibit Booth 131
government agencies, health plans, and employers.
proval for DUEXIS on April 23, 2011, a novel tablet
Genomic Health, Inc. (NASDAQ: GHDX) is a global
Hayes, Inc. is a certified woman-owned small busi-
formulation containing a fixed-dose combination
health company that provides actionable genomic
ness (WOSB).
of ibuprofen and famotidine in a single pill. We re-
other countries, these franchises provide more than
information to personalize genomic health deci-
ceived FDA approval for RAYOS® on July 26, 2012,
www.namcp.org | Vol. 15, No. 4 | Journal of Managed Care Medicine 89
Personalized LDL Management The NMR LipoProfile® test is more than a cholesterol test . . . It provides a patient’s LDL particle number (LDL-P) for a more complete picture of CVD risk for personalized LDL management.
LDL Particles
More LDL Particles = More Plaque
carry cholesterol in the blood LDL Particle
Cholesterol
The higher the number of LDL particles, the greater the likelihood for them to enter the arterial wall and form atherosclerotic plaque.1
Fewer LDL Particles
More LDL Particles
The NMR LipoProfile test may provide actionable information if your patient has any of these factors that contribute to cardiometabolic risk2 : Diabetes
High blood pressure
Metabolic Syndrome
Low HDL (dyslipidemia)
Previous heart attack or stroke
High triglycerides
Family history of heart disease or diabetes
Knowing a patient’s LDL-P may aid in determining treatment strategies and clinical decision-making for personalized LDL management.
1. Otvos et al. Am J Cardiol. 2002;90(suppl)22i-29i. 2. Brunzell et al. Diabetes Care. 2008:4:811-822. © 9/2012 LipoScience Inc. | 84-300-00
Visit booth #424 at the 2012 Fall Managed Care Forum to learn more and get your complimentary NMR LipoProfile test.
Fall Managed Care Forum: Guide to Conference Supporters a proprietary delayed-release formulation of low-
Long-term acute care hospitals
more information, please contact us at 800-654-
dose prednisone. Our strategy is to commercialize
Nursing and rehabilitation
2422 ext. 6553, marketing@mrioa.com, or check
our products in the U.S., to explore co-promotion
Our rehabilitation services business—RehabCare
them out online at mrioa.com.
opportunities for DUEXIS in the U.S. and to enter
Inpatient rehabilitation facilities
into licensing or additional distribution agreements
Home health care, which offers services provided in
Medtronic
for commercialization of our products outside the
the comfort of home.
Exhibit Booth 109,111
U.S.
Hospice, a family-oriented model of care designed
Medtronic is the world’s largest standalone medical
to meet patients’ end of life needs.
technology company, offering an unprecedented
ImpediMed, Inc.
For more information, go to www.kindredhealth-
breadth and depth of innovative products, thera-
Exhibit Booth 212
care.com.
pies, and services to fulfill our Mission of alleviating pain, restoring health, and extending life. In the
Pre-emptively managing breast cancer patients at high risk of Lymphedema reduces costs while im-
LabCorp
past year, more than 8 million people worldwide re-
proving care. Bioimpedance spectroscopy (BIS or
Exhibit Booth 416
lied on our therapies which treat many conditions,
L-Dex®) quantitates extracellular fluid differences
LabCorp provides leading-edge diagnostic tests
including cardiac and vascular diseases, diabetes,
between the arms.
Compliments NIH paradigm
and services through a national network of pri-
and neurological and spinal conditions.
of prospectively managing Lymphedema and IOM
mary clinical laboratories and specialized Centers
recommendations for monitoring late effects of
of Excellence, including Integrated Genetics and
Merck & Co.
cancer treatment. Aids physician in assessment of
Integrated Oncology.
Exhibit Booth 119
Lymphedema prior to irreversible changes. Earlier
services for specialists in reproductive medicine
Today’s Merck is a global healthcare leader working
detection allows earlier, more cost-effective inter-
include infectious disease donor screening, repro-
to help the world be well. Merck is known as MSD
vention minimizing intensive OT/PT treatment and
ductive endocrinology, coagulation, genetic testing
outside the United States and Canada. Through our
expensive compression pumps. Standardized, ob-
and counseling services, preimplantation genetics,
prescription medicines, vaccines, biologic thera-
jective, and validated.
drugs-of-abuse screening, and routine testing.
pies, and consumer care and animal health prod-
Janseen Pharmaceuticals
LipoScience
than 140 countries to deliver innovative health solu-
Exhibit Booth 313
Exhibit Booth 424,426
tions. We also demonstrate our commitment to in-
Janssen Pharmaceuticals, Inc., a pharmaceutical
The NMR LipoProfile test—The Particle Test—is a
creasing access to healthcare through far-reaching
company of Johnson & Johnson, provides medi-
simple blood test and can be part of your standard
policies, programs and partnerships. For more in-
cines for an array of health concerns in several ther-
blood draw. It gives you and your doctor a direct
formation, visit www.merck.com
apeutic areas, including: ADHD, general medicine
measure of your LDL particle number (LDL-P) along
(acid reflux disease, infectious diseases), mental
with your standard cholesterol results. Knowing
Millennium Laboratories
health (bipolar I disorder, schizophrenia), neurology
your LDL-P gives you a more complete picture of
Exhibit Booth 117
(Alzheimer’s disease, epilepsy, migraine prevention
your heart health. It is important to know that hav-
Millennium Laboratories is the leading research-
and treatment), pain management, cardiovascular,
ing a high number of LDL particles is bad. LDL parti-
based, clinical diagnostic company dedicated to
and women’s health.
cles carry and deposit cholesterol into your arteries
improving the lives of people with chronic pain.
and the cholesterol becomes plaque—called ath-
The company provides healthcare professionals
KCI
erosclerosis or hardening of the arteries. More LDL
with medication monitoring, drug detection and
Exhibit Booth 220
particles (a higher LDL-P) means there is a greater
pharmacogenetic testing services to personalize
KCI is a leading global medical technology com-
likelihood that plaque may develop in your arteries
treatment plans to improve clinical outcomes and
pany devoted to the discovery, development,
increasing your risk for heart disease. If you have a
patient safety.
manufacture and marketing of innovative, high-
high number of LDL particles, you should lower the
technology therapies and products for the wound
number. There are many treatment options avail-
Mission Pharmacal Company
care and therapeutic support system markets. KCI’s
able to lower your LDL particle number.
Exhibit Booth 222
LabCorp’s comprehensive
ucts, we work with customers and operate in more
success can be traced to a history deeply rooted in
Mission Pharmacal Company is a privately held Pharmaceutical company based in San Antonio,
patient outcomes while reducing the overall cost of
Medical Review Institute of America
care for patients around the world.
Exhibit Booth 217
dedicated to identifying unmet health needs in the
Medical Review Institute of America (MRIoA) has
marketplace and developing innovative prescrip-
Kindred Healthcare
been an innovative leader in physician peer re-
tion and over-the-counter products to meet them.
Exhibit Booth 326
view since 1982. MRIoA offers high quality reviews
innovation and a passion for significantly improving
Texas. For sixty-five years, the company has been
Kindred Healthcare is the largest provider of post-
meeting rapid turn-around times through their na-
Myriad Genetic Laboratories
acute care services in the nation. We provide post-
tional network of over 550 active practicing, board
Exhibit Booth 321
acute care through:
certified physicians and other allied specialties. For
Myriad Genetics is a leading molecular diagnostic
www.namcp.org | Vol. 15, No. 4 | Journal of Managed Care Medicine 91
Fall Managed Care Forum: Guide to Conference Supporters company dedicated to making a difference in pa-
prehensive, proven oncology pharmacy solutions to
SI-BONE, Inc.
tient’s lives through the discovery and commercial-
more than 1,800 oncologists, payers, hospitals, and
Exhibit Booth 210
ization of transformative tests to assess a person’s
NCCN Centers of Excellence through a growing na-
SI-BONE, Inc. is the leading sacroiliac (SI) joint med-
risk of developing disease, guide treatment deci-
tional network of certified and JCAHO-accredited
ical device company dedicated to the development
sions and assess risk of disease progression and
OncoMed pharmacies. In addition to providing ro-
of tools for diagnosing and treating patients with
recurrence.
bust clinical management, compounding, and dis-
low back issues related to SI joint pathology. The
pensing services that meet the highest professional
company is manufacturing and marketing a mini-
NeuroMetrix
standards for quality, safety, and timely and accu-
mally invasive surgical (MIS) technique for the treat-
Exhibit Booth 218
rate treatment delivery, Onco360 provides critical
ment of SI joint disorders. For more information,
The NeuroMetrix NC-stat® DPNCheck™ is a cost-
financial, administrative, and compliance support
visit www.si-bone.com.
effective, point of care test for early and accurate
for oncology and hematology physicians, cancer
detection of diabetic neuropathy. This device is
centers of excellence, cancer patients, pharmaceu-
Salix Pharmaceuticals
frequently used by Medicare Advantage and other
tical manufacturers, and health plans.
Exhibit Booth 211, 213
risk based provider organizations to accurately de-
Salix Pharmaceuticals is a specialty pharmaceuti-
tect risk assess and HCC code their patients. The
PerkinElmer
cal company dedicated to acquiring, developing
technology detects diabetic neuropathy earlier and
Exhibit Booth 204
and commercializing brand name, prescription
more accurately than the commonly used screening
PerkinElmer Managed Markets offers the follow-
pharmaceutical products used in the treatment of
tools such as monofilament and vibration testing.
ing service providers which leverage leading-edge
a variety of gastrointestinal diseases. Salix’s strat-
This one minute test is straightforward and per-
technology and proprietary capabilities: Signature
egy is to identify and acquire late-stage proprietary
formed by ancillary staff.
Genomics. The innovator in microarray as a diag-
pharmaceutical products having an existing base
nostic tool.
of safety and efficacy data in humans for the treat-
We’ve processed over 50,000 cases,
NextWave Pharmaceuticals
more than all other providers combined.
Exhibit Booth 422
Labs.
NTD
ment of gastrointestinal disease, and to apply the
A leader in prenatal screening is the exclu-
Company’s regulatory, product development, and
NextWave is an emerging specialty pharmaceutical
sive provider of the free beta hCG first trimester
sales and marketing expertise to commercialize
company focused on the development and com-
Down syndrome screen.
these products.
mercialization of unique products for the treatment
The nation’s largest provider of newborn screen-
of ADHD and related CNS disorders
ing services. We‘ve screened over 4 million babies
PerkinElmer Genetics.
since 1994.
Novartis Pharmaceuticals
Exhibit Booth 208
Exhibit Booth 304, 306
Purdue Pharma L.P
Novartis Pharmaceuticals is dedicated to discover-
Exhibit Booth 303
ing, developing, manufacturing and marketing
Sequenom Center for Molecular Medicine
Purdue Pharma L.P. is well known for its pioneer-
Tandem Diabetes Care Exhibit Booth 207
prescription drugs that help meet our customers’
ing work on persistent pain, a principal cause of
Tandem Diabetes Care®, Inc. is a privately held
medical needs and improve their quality of life.
human suffering. The company’s leadership and
company located in San Diego, CA dedicated to
Please visit the Novartis exhibit where our repre-
employees are dedicated to providing healthcare
advancing the management of diabetes through
sentatives will be available to discuss our products.
professionals, patients and caregivers with safe and
novel technologies.
effective therapies, and innovative educational re-
t:slim® Insulin Pump, which has the footprint of a
Novo Nordisk
sources and tools that support the therapies’ prop-
credit card and the design of a smart phone. It is
Exhibit Booth 216
er use. Learn more at ww.purdue.pharma.com.
the first insulin pump with a touch screen and an
Tandem has developed the
intuitive interface that is easy to learn and easy to
Novo Nordisk is a global healthcare company with 89 years of innovation and leadership in diabetes
ResMed
use. Categories: Insulin Pump, CSII, Type 1 Diabe-
care. The company also has leading positions with-
Exhibit Booth 406
tes, Type 2 Diabetes
in haemophilia care, growth hormone therapy and
ResMed is a global leader in medical equipment
hormone replacement therapy.
for the screening, treatment, and management of
Terumo BCT
sleep-disordered breathing and other respiratory
Exhibit Booth 317
Onco360
disorders. Their product line includes automatic
Terumo BCT, a global leader in blood component,
Exhibit Booth 307
positive airway pressure devices, bilevel devices,
therapeutic apheresis and cellular technologies,
Onco360™ is an oncology pharmaceutical services
continuous positive airway pressure devices, nasal
is the only company with the unique combination
company dedicated to advancing the continuum of
pillows systems, nasal mask systems, full face mask
of apheresis collections, manual and automated
pharmaceutical cancer care. Onco360 has devel-
systems, humidifiers, and software/clinical systems.
whole blood processing, and pathogen reduction
oped the most unique and supportive pharmaceu-
For more information about the company, please
coupled with leading technologies in therapeutic
tical care model throughout all the phases of the
visit www. resmed.com or call 800.424.0737.
apheresis and cell processing. We believe in the po-
cancer care continuum. Onco360 provides com-
92 Journal of Managed Care Medicine | www.namcp.org | Vol. 15, No. 4
tential of blood to do even more for patients than it
A significant achievement for patients with fecal incontinence (FI)...
A good day.
It’s no accident. Solesta: a unique treatment for FI • An injectable, biocompatible gel • Nonsurgical, in-office procedure • No anesthesia required • May preclude need for more invasive surgical procedures
Durable efficacy with Solesta
Solesta is indicated for the treatment of fecal incontinence in patients 18 years and older who have failed conservative therapy (eg, diet, fiber therapy, anti-motility medications). The most common adverse reactions (incidence >2%) are proctalgia, anorectal hemorrhage, injection site hemorrhage, pyrexia, injection site pain, diarrhea, and anorectal discomfort.
Number of episodes/14 days
Find out more at solestainfo.com.
Solesta should be administered by qualified physicians with experience in the treatment of anorectal conditions. Please see brief summary of full Prescribing Information on following page.
Solesta is a registered trademark of Q-Med AB. © 2012 Salix Pharmaceuticals, Inc. All rights reserved. SOL12/77
25
P=0.001
n=136
20 15 10
53%
15.0 8.6
5
6.2
7.0
7.0
12
24
36
0 Baseline
3
Months
• After injection of Solesta, hold the needle at the injection site for an additional 15-30 seconds to minimize leakage of Solesta. • Injections too close to the dentate line or too deep in the tissue might cause excessive pain. • Injection should be stopped if excessive bleeding or pain occurs. • One sterile needle should be used per syringe and injection. Brief Summary Please consult Package Insert for full prescribing information. Indication for Use Solesta is indicated for the treatment of fecal incontinence in patients 18 years and older who have failed conservative therapy (eg, diet, fiber therapy, antimotility medications). Contraindications Solesta is contraindicated in patients with the following conditions: • Active inflammatory bowel disease • Immunodeficiency disorders or ongoing immunosuppressive therapy • Previous radiation treatment to the pelvic area • Significant mucosal or full thickness rectal prolapse • Active anorectal conditions including: abscess, fissures, sepsis, bleeding, proctitis, or other infections • Anorectal atresia, tumors, stenosis or malformation • Rectocele • Rectal varices • Presence of existing implant (other than Solesta) in anorectal region • Allergy to hyaluronic acid–based products Warnings • Do not inject Solesta intravascularly. Injection of Solesta into blood vessels may cause vascular occlusion. • Injection in the midline of the anterior wall of the rectum should be avoided in men with enlarged prostate. Precautions General precautions • Solesta should only be administered by physicians experienced in performing anorectal procedures and who have successfully completed a comprehensive training and certification program in the Solesta injection procedure. • The safety and effectiveness of Solesta have not been investigated in patients with complete external sphincter disruption or significant chronic anorectal pain. • The safety and effectiveness of Solesta have not been investigated in patients with previous procedures involving the anorectal region: rectal anastomosis <12 cm from anal verge, anorectal surgery within previous 12 months, hemorrhoid treatment with rubber band within 3 months, anorectal implants and previous injection therapy, Stapled Transanal Rectal Resection (STARR) or stapled hemorrhoidectomy. • The safety and effectiveness of Solesta have not been studied in patients under the age of 18 years. • The safety and effectiveness of Solesta have not been studied in pregnant or breastfeeding women. • The durability of Solesta has not been studied past 12 months. • The safety and effectiveness of Solesta have been studied in patients who received one or two treatments. In the Pivotal study, the majority of patients received two treatments, four weeks apart. Patient related precautions • Patients with bleeding diathesis or patients using anticoagulant or antiplatelet agents, as with any injections, may experience increased bleeding at injection sites. • Patients should be counseled that a repeated Solesta injection procedure may be required to achieve a satisfactory level of improvement in incontinence. Procedure related precautions • Adequate bowel preparation of the rectum using enema is required prior to injection. The enema should be given immediately prior to the procedure to ensure evacuation of the anorectum. It is recommended that additional cleansing of the injection area with an antiseptic be performed prior to injection. Use of prophylactic antibiotics is recommended. • Solesta should be injected slowly to avoid undue stress on the Luer-lock connection which could cause leakage of the gel.
Device related precautions • The use of needles other than those supplied may impede injection of Solesta due to the properties of the gel and may cause device malfunction. • Solesta is supplied ready to use in a prefilled syringe with a Luer-lock fitting. Carefully examine the unit to verify that neither the contents nor the package has been damaged in shipment. Do not use if damaged. • Solesta is supplied sterile and is intended for single use only. Do not re-sterilize, as this may damage or alter the product. • In the event of accidental contamination of a needle, discard the needle. • Never mix Solesta with other products. • Solesta is to be stored at up to 25°C (77°F), and used prior to the expiration date printed on the label. Do not expose Solesta to either sunlight or freezing, as this may damage or alter the product. • Care should be taken when handling the glass syringes and disposing of broken glass to avoid laceration or other injury. • After use, syringes and needles should be handled as potential biohazards. Disposal should be in accordance with accepted medical practice and applicable local, state and federal requirements. Adverse Events Potential adverse events include: abdominal discomfort, abdominal distension, abdominal pain, lower abdominal pain, abdominal rigidity, alopecia, anal abscess, anal fissure, anal hemorrhage, anal prolapse, anal pruritus, anorectal discomfort, back pain, constipation, C-reactive protein increased, chills, cold sweat, defecation urgency, dermatitis, diarrhea, device dislocation, dizziness, dyspareunia, escherichia bacteremia, fecal incontinence, feces hard, fatigue, gastrointestinal motility disorder, gastrointestinal pain, genital discharge, genital prolapse, hematochezia, hematospermia, hemorrhoids, infection, injection site abscess, injection site discomfort, injection site hemorrhage, injection site hematoma, injection site inflammation, injection site irritation, injection site nodule, injection site pain, injection site pustule, injection site swelling, injection site ulcer, intestinal mass, malaise, mucosal inflammation, musculoskeletal pain, perineal abscess, nausea, edema, pain, painful defecation, pelvic mass, perineal pain, proctalgia, proctitis, pyrexia, rectal abscess, rectal discharge, rectal hemorrhage, rectal lesion, rectal obstruction, rectal prolapse, rectal spasm, rectal tenesmus, rectovaginal septum abscess, urinary retention, vaginal discharge, vulvovaginal pain. The adverse event profile of Solesta beyond 24 months* is not known, but is under investigation in post-market studies. The safety evaluation of Solesta in the treatment of fecal incontinence (FI) is based on the results from the Pivotal Clinical study, and is supported by the Open-Label multicenter clinical study and one single site Proof-of-Concept study. The analysis of safety was based on the safety cohort of all 206 patients treated in the Pivotal Study with either Solesta or Sham. Safety data for Solesta are available from 359 treatments in 197 total patients followed for up to 18 months post treatment (ie, 136 subjects from the blinded phase and 61 subjects from the open phase). Directions for Use Solesta should be administered by qualified physicians with experience in the treatment of anorectal conditions and who have successfully completed a comprehensive training and certification program in the Solesta injection procedure. Solesta should only be used after a thorough physical evaluation of the patient to exclude treatable underlying disorders. Please consult Package Insert for full directions for use and method of administration. How Supplied Solesta is supplied in a glass syringe with a standard Luer-lock fitting containing 1 mL gel. Each syringe is terminally moist heat sterilized in a pouch. Four pouches, each containing one syringe are packed in a carton together with five Sterican needles (21G x 4¾ inches, 0.80 mm x 120 mm), patient record labels and a Package Insert. The needles are sterilized by ethylene oxide. Storage Store at a temperature up to 25°C (77°F) and protect from sunlight and freezing. 06/11
*Safety information presented in the Package Insert only includes data up to 18 months.
©2012 Salix Pharmaceuticals, Inc.
All rights reserved.
Printed in the USA.
SOL12/57
Fall Managed Care Forum: Guide to Conference Supporters does today. This belief inspires our innovation and
Valeritas
TRELSTAR (tiptorelin pamoate for injectable sus-
strengthens our collaboration with customers.
Exhibit Booth 319
pension) for the palliative treatment of advanced
Valeritas is displaying the V-Go, the first simple, ful-
prostate cancer.
Teva Oncology
ly disposable device for the delivery of basal-bolus
Exhibit Booth 121
insulin therapy for adults with diabetes. The V-Go
WellDyne
Teva Oncology is the U.S.-based branded oncology
provides a continuous preset basal rate of insulin
Exhibit Booth 225
division of Teva Pharmaceutical Industries Ltd., for-
and allows for on-demand bolus dosing around
WellDyne is an industry-leading provider of health
merly known as Cephalon Oncology. The portfolio
mealtimes thereby providing an alternative to tak-
and wellness solutions tailored specifically for to-
currently includes drugs to treat leukemia and lym-
ing multiple daily insulin injections.
day’s health care providers, business leaders, or-
phomas plus a robust pipeline and multiple late-
ganizations, pharmacies and health-conscious con-
stage oncology compounds across cancer thera-
Veracyte, Inc
sumers. Our product and service offerings provide
peutics and supportive care.
Exhibit Booth 232
innovative solutions for any aspect of your health
Veracyte, Inc., offers the Afirma Gene Expression
management needs. With the knowledge, innova-
Teva Pharmaceuticals
Classifier (GEC), a pre-operative genomic test for
tion and technology to ensure continual positive
Exhibit Booth 316
patients with indeterminate or inconclusive thyroid
change within the market, WellDyne is transforming
Teva Pharmaceuticals’ North America Brand Phar-
fine needle aspirate biopsies. The results of a large,
the health care paradigm, implementing new ap-
maceuticals group is built on the knowledge and
prospective validation study published in the New
proaches, delivering better results, lowering costs
expertise of multiple innovative business units, in-
England Journal of Medicine, confirmed that the
and ensuring members live healthier lives.
cluding respiratory, neurology, women’s health and
Afirma GEC identifies benign thyroid nodules with
biologics/specialty products. This brand division
high accuracy. Additional studies show that pa-
XDx
leverages the skills and competencies of each ther-
tients with Afirma GEC Benign results routinely
Exhibit Booth 333
apeutic area, and coordinates and aligns efforts for
avoid diagnostic thyroid surgery, therefore improv-
XDx is a molecular diagnostics company focused on
a more efficient and effective delivery of healthcare
ing quality of care and reducing costs.
the discovery, development and commercialization
solutions.
of gene expression testing in the areas of transplant
Verinata Health
medicine and autoimmunity.
United Seating & Mobility
Exhibit Booth 420
keted product, AlloMap® Testing, a non-invasive
Exhibit Booth 430
Verinata Health is a leader in the field of non-inva-
(blood test) gene expression test that aids in the
For 30 years United Seating and Mobility has fo-
sive testing for the early identification of fetal chro-
management of heart transplant patients.
cused on providing cost-effective, appropriate
mosomal abnormalities. We are a national indepen-
mobility solutions to persons with disabilities. Our
dent laboratory driven by a sole and extraordinary
ZOLL Medical Corporation
care-centered approach involves the right people,
purpose - maternal and fetal health. Our verifi®
Exhibit Booth 309
a passion to make lives better, the most appropri-
prenatal test, a non-invasive blood test, detects
ZOLL Medical Corporation designs, manufactures,
ate technology with the most attentive and efficient
trisomies 21 (Down syndrome), 18 (Edwards syn-
and markets non-invasive resuscitation devices and
process. Please call 800.500.9150 or visit our web-
drome) and 13 (Patau syndrome) as well as Mono-
software solutions, which help diagnose and treat
site at www.UnitedSeating.com for local listings.
somy X (Turner syndrome) from a single maternal
victims of trauma and sudden cardiac arrest, includ-
blood draw as early as 10 weeks.
ing the Code-Ready® R Series® defibrillator, Au-
Uroplasty
XDx has one mar-
toPulse® and Non-invasive Cardiac Support Pump.
Exhibit Booth 113
VIVUS, Inc.
ZOLL’s® LifeVest® wearable defibrillator protects
Uroplasty is a global medical device company that
Exhibit Booth 206
patients at risk of sudden cardiac arrest, during a
develops, manufactures and markets products for
VIVUS, Inc. is a biopharmaceutical company dedi-
patient’s changing condition and when permanent
the minimally invasive treatment of voiding dys-
cated to the development and commercialization
SCA risk has not been established. The LifeVest
functions and pelvic disorders. They offer an inno-
of novel therapeutic products that address unmet
provides patients constant monitoring, immediate
vative platform of office-based solutions for urinary
needs in obesity, diabetes, sleep apnea and sexual
protection, and peace of mind.
incontinence. Urgent® PC Neuromodulation Sys-
health for U.S., European and other world markets.
tem is an office-based, clinically proven and cost-
For more information about the company, please
effective treatment for overactive bladder and as-
visit www.vivus.com.
sociated symptoms of urgency, frequency and urge incontinence. Macroplastique® is a urethral bulk-
Watson Pharmaceuticals
ing agent for the treatment of adult female Stress
Exhibit Booth 125
Urinary Incontinence. Visit www.uroplasty.com for
Watson Pharmaceuticals is a global leader in ge-
more product information.
neric and specialty brand products of which includes RAPAFLO(silodosin), capsules for BPH, Gelnique (oxybutynin chloride) Gel for OAB and
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Health Diagnostic Laboratory Aastrom Biosciences Labcorp Abbott Laboratories NAMCP Would Like to Recognize Our Corporate Lilly Oncology Abbott Diagnostics Members for Their Continued Support Lilly USA, LLC Actelion Pharmaceuticals Liposcience Aerocrine, Inc. Mediterranean Wellness Allergan Medtronic Amarin Pharma Merck Amylin Pharmaceuticals Mylan/Dey Pharma Astellas Pharma Myriad Genetic Laboratories AstraZeneca OncoMed Athersys PerkinElmer Bayer Healthcare Pfizer Inc. Biogen Idec L. Purdue Pharma L.P. Boehringer Ingelheim Salix Pharmaceuticals Bristol-Myers Squibb Seattle Genetics CardioDx Sequenom Center for Celgene Corporation Molecular Medicine Eisai Smith & Nephew Ethicon Endo-Surgery, Inc. Teva Neuroscience Forest Laboratories Teva Oncology GE Healthcare Verinata Health Genentech Vivus, Inc. Genomic Health WellDyne Gilead Sciences
Thank You For Your Continued Support!
GE Healthcare At GE, we believe what’s needed, right now, is a new mindset: that health is everything.
We call it healthymagination Just as we delivered innovation in environmental technology with ecomagination, healthymagination will change the way we approach healthcare, with over 100 innovations all focused on addressing three critical needs: lowering costs, touching more people, and improving quality.
Reduce Costs
Increase Access
Improve Quality
By 2015, our goal is to reduce by 15% the costs of many procedures and processes with GE technologies and services.
By 2015, our goal is to increase by 15% people’s access to services and technologies essential for health, reaching 100 million people every year.
By 2015, our goal is to improve quality and efficiency by 15% for customers by simplifying and refining healthcare procedures and standards of care.
By keeping people well, we all do well.
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