Vol.15, No.2, 2012
Journal of Managed Care Medicine
Decision Making in Advanced Breast Cancer Detection, Treatment and Control: The Keys to Managing Osteoporosis in Postmenopausal Women Fibromyalgia: Improving Diagnostic and Treatment Strategies for Better Patient Outcomes Hyperlipidemia: The Silent CVD Risk Factor with Enormous Impact Improving Outcomes and Reducing Costs with ICS Monotherapy in the Management of Asthma Updates and Controversies in Diabetes Care Clinical and Cost Consequences of Incorporating a Novel Non-Invasive Prenatal Test into the Diagnostic Pathway for Fetal Trisomies Estimation of Long-Term Increased Risk of Coronary Heart Disease and Type 2 Diabetes Associated with Metabolic Complications Observed in the CATIE Study: Relative Risk and the Number Needed to Harm for Second-Generation Antipsychotics PLUS: Spring Managed Care Forum Program Guide
JMCM Journal of Managed care medicine 4435 Waterfront Drive, Suite 101 Glen Allen, VA 23060 (804) 527-1905 fax (804) 747-5316
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. 2, 2012
J. Ronald Hunt, MD
publisher Katie Eads
director of communications Jeremy Williams
TABLE OF CONTENTS Decision Making in Advanced Breast Cancer Michael Naughton, MD....................................................................................... 5 Detection, Treatment and Control: The Keys to Managing Osteoporosis in Postmenopausal Women Ellen Miller, MD................................................................................................... 9
Douglas Murphy Communications Inc. P.O. Box 71895 Richmond, VA 23255-1895 (804) 658-4253 fax (703) 997-5842
Fibromyalgia: Improving Diagnostic and Treatment Strategies for Better Patient Outcomes Don L. Goldenberg, MD.....................................................................................14
Improving Outcomes and Reducing Costs with ICS Monotherapy in the Management of Asthma Dennis Spangler, MD......................................................................................... 24
Barry Barnum firstname.lastname@example.org
Graphic Design Douglas Murphy Communications, Inc.
Custom Article Reprints High quality, custom article reprints of individual articles are available in print and electronic formats. Contact Katie Eads, email@example.com, 804-527-1905 for reprints.
ISSN: 1094-1525. The Journal of Managed Care is published by Association Services Inc. Corporate and Circulation offices: 4435 Waterfront Drive, Suite 101, Glen Allen, VA 23060; Tel (804) 527-1905; Fax (804) 747-5316. Editorial and Production offices: P.O. Box 71895, Richmond, VA 23255-1895; Tel (804) 658-4253; Fax (703) 997-5842. Advertising offices: Sloane Reed, 4435 Waterfront Drive Ste 101, Glen Allen, VA 23060 Tel (804) 527-1905, Fax (804) 7475316. Subscription Rates: one year $95 in the United States; one year $105 in Canada; one year $120 international. Back issues are available for $15 each. 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.
BPA Worldwide Membership Applied for December 2011
Hyperlipidemia: The Silent CVD Risk Factor with Enormous Impact Michael Miller, MD, FACC, FAHA...................................................................... 20
Updates and Controversies in Diabetes Care Tom A. Elasy, MD, MPH..................................................................................... 31 Clinical and Cost Consequences of Incorporating a Novel Non-Invasive Prenatal Test into the Diagnostic Pathway for Fetal Trisomies Susan S. Garfield, DrPH; Shannon O. Armstrong, BA...................................... 34 Estimation of Long-Term Increased Risk of Coronary Heart Disease and Type 2 Diabetes Associated With Metabolic Complications Observed in the CATIE Study: Relative Risk and the Number Needed to Harm for Second-Generation Antipsychotics Sonja V.Sorenson, MPH; Henry Nasrallah, MD; Kafi N. Sanders, MPH........... 42 PLUS: Spring Managed Care Forum Program Guide...................................53
Journal of Managed Care Medicine Instructions for Authors The Journal of Managed Care Medicine is a peer-reviewed national publication. Original articles dealing with the business or clinical side of managed care are welcome. Manuscript length generally should range between 10 to 15 typed pages, including a summary with key points, exhibits, and references. All submissions should include the following elements: • One printed copy of the manuscript, including illustrations/figures/tables • Contact numbers (phone and fax), complete mailing address, and e-mail address for designated corresponding author • Electronic version on CD or via e-mail in Microsoft Word • Bibliography/References, following the format of the AMA Manual of Style, 9th Ed. • Brief biography of author(s) < 50 words and including academic/corporate affiliations • Copyright transfer letter For a complete copy of authors’ guidelines, contact JMCM’s Managing Editor, Barry Barnum, (804) 658-4253. Forward submissions to Journal of Managed Care Medicine P.O. Box 71895 • Richmond, VA 23255-1895
www.namcp.org | Vol. 15, No. 2 | Journal of Managed Care Medicine 3
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
Decision Making in Advanced Breast Cancer Michael Naughton, MD For a CME/CEU version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.
Summary Although breast cancer is very treatable, once the disease has become metastatic it is no longer curable. Treatment will depend on several factors, including patient goals, the type of tumor, and the menopausal status of the patient. New treatments and new ways of targeting therapy are on the horizon and will continue to influence the treatment of advanced breast cancer. Key Points • Breast cancer is a very treatable disease. • Advanced disease is still not curable. • There are distinct clinical subtypes with varying natural history. • Treatment options depend on the type of tumor and the menopausal status of the patient. • Bevacizumab no longer has an FDA approved indication for breast cancer treatment. • Better targeting of therapy is on the horizon with genetic profiling of tumors.
There are approximately 200,000 new cases of breast cancer in the United States annually. Breast cancer is a leading cause of death in women with about 40,000 deaths in the U.S. each year. The mortality from this disease has been gradually declining since the mid-1990s. Screening is one of the reasons for this decline. Through effective screening, the majority of patients (63 percent) are diagnosed with localized disease (Exhibit 1). Localized disease is considered curable. Two out of three women treated for localized disease are cured. Unfortunately, 6 percent of women present with metastatic disease. Many other women will have a relapse of the disease. For patients who have advanced or metastatic disease, the disease is universally fatal with a median survival of 24 to 30 months. There are isolated reports of women with metastatic disease who have long-term survival, but these are rare. Breast cancer is no longer thought of as one disease. There are distinct clinical subtypes with varying natural history. Some women have very aggressive disease with short survival and others have much less aggressive disease. Several factors affect the nature of the disease. These include whether the tumor is hormone sensitive or insensitive (estrogen
or progesterone receptors) or human epidermal growth factor receptor-2 (Her-2) positive or negative. Her-2 is a cell membrane surface-bound receptor tyrosine kinase and is normally involved in the signal transduction pathways leading to cell growth and differentiation. Approximately 20 percent of breast cancers have an amplification of the Her-2 gene or overexpression of its protein product. Patients can have triple negative disease (estrogen, progesterone, and Her-2 negative). Compared to other cancers, there are many therapies available for breast cancer that have a reasonable track record of safety and efficacy. Because it is not curable at this time, the goals in treating advanced breast cancer are to prolong survival and decrease the burden of disease. Most patients will be on therapy for the majority of their expected survival. A major issue with advanced breast cancer treatment is deciding which therapy to use. The benefit of a particular palliative treatment amust be weighed against toxicity for the individual patient. Some of the considerations in deciding benefit include the probability of response, probability of symptomatic improvement, anticipated toxicity, and the patient’s goals. For example, alopecia may be a major concern
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Exhibit 1: Stage Distribution at Diagnosis 6%
Localized Regional Distant Unstaged
Exhibit 2: Metastatic Setting Metastatic Breast Cancer Diagnosed
ER or PR +
No Visceral Crisis
ER and PR -
ER, estrogen receptor; PR, progesterone receptor; OA, ovarian ablation; AI, aromatase inhibitor; Her2, Human epidermal growth factor receptor 2
for some women. There are chemotherapy agents that can spare them from having this adverse effect. The bottom line is to seek the least toxic therapy that achieves disease control. Patients can have many different goals in treatment of their cancer, such as to beat the disease or to live until some particular milestone. Health care providers need to help patients achieve their goals if possible, but they also need to help them understand what realistic goals are for the extent of their disease. There are treatment guidelines to assist in the choice of treatment. The National Comprehensive Cancer Network (NCCN) guidelines are the most often used, are comprehensive, and are frequently updated. The American Society of Clinical Oncology (ASCO) does offer guidelines but these are much more conservative. Exhibit 2 provides an overall scheme of how met-
astatic breast cancer is broken down by different disease type (estrogen receptor positive, Her-2 positive, and triple negative) and what the typical treatment options are for each type. There are a variety of hormone-based therapies for estrogen receptor positive disease. Her-2 positive disease is treated with trastuzumab (HerceptinÂŽ) or lapatinib (TykerbÂŽ). A patientâ€™s tumor can express both estrogen and Her-2 receptors so combination therapy may be used. Chemotherapy is the only treatment strategy for triple negative disease. Hormone-based therapies are relatively nontoxic therapy, which can often provide extended disease control. As shown in Exhibit 3, tumors with both estrogen and progesterone receptors will respond best to hormone-based therapies which decrease the production or effect of estrogen.1 Premenopausal women can be treated with gonadotropin-releasing
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Exhibit 3: Response to Endocrine Therapy Based on Receptor Status1 80
Percent Response to Endocrine Therapy
0 ER-/PgR- ER+/PgR- ER-/PgR+ ER+/PgR+ Receptor Status
hormone agonists (leuprolide, goserelin) to block production of estrogen from the ovaries or antiestrogens (tamoxifen) to block estrogen from entering cancer cells or ovarian ablation. In metastatic breast cancer for premenopausal women, the most effective option is to combine tamoxifen and ovarian ablation. Because their ovaries no longer produce significant amounts of hormones, postmenopausal women have different options. In these women, the majority of the hormones are produced by the adrenal gland. Testosterone produced by the adrenal glands is converted to estrogen by aromatase found in fat tissue. This production can be blocked with aromatase inhibitors. The available agents [letrozole (Femara速), anastrozole (Arimidex速), exemestane(Aromasin速)] are very similar in terms of efficacy and toxicity. Tamoxifen and fulvestrant (Faslodex 速), a pure estrogen antagonist, are also options. When fulvestrant was initially approved, it was used at a lower dose, which was not very effective. Newer data show that a higher dose (500 mg) with an initial loading dose achieves a better outcome. This agent is a monthly injectable, which is well tolerated. Fulvestrant appears to be slightly more effective in terms of time to progression than the aromatase inhibitors.2 Her-2 positive disease is treated with a Her-2 targeting agent. These agents alter down stream cancer cell signaling and halt growth and division. The two currently available agents are trastuzumab, an injectable agent, and lapatinib, an oral agent. Adverse effects leading to dose reduction or discontinuation are more common with lapatinib. Trastuzumab has been shown to increase survival (~5 months in median survival) and lapatinib increases time to progression when added to chemotherapy. Although both target Her-2, they have distinct mechanisms so
they can be used sequentially. Her-2 positive tumors can also be estrogen positive or negative. Women who co-express both are candidates for hormone therapy and a Her-2 targeting agent. Women who are estrogen negative will receive chemotherapy along with a Her-2 targeting agent. Data support continuing the Her-2 targeting agent throughout the disease course even if progression occurs. Thus a woman may be switching chemotherapy or hormone-based therapy because of ineffectiveness, but the Her-2 agent would be continued. There are many new agents in development that target Her-2. One agent under study is trastuzumab bound to a chemotherapy agent (T-DM1). This is trying to deliver chemotherapy directly into the cancer cell. There are numerous scenarios where a woman with breast cancer will end up needing chemotherapy treatment. Chemotherapy is the only option for triple negative disease. Women with estrogen responsive tumors will eventually become resistant and require chemotherapy. One issue with chemotherapy in advanced breast cancer is whether to give agents sequentially or as combination therapy. This is the trade-off between toxicity and benefit. With combination therapy, adverse effects increase but time to progression is longer. Unfortunately, at one year, the survival is no better with combination therapy versus sequential single agent. Combination therapy does increase response rates so if the woman has a high volume of disease, combination therapy would be indicated. First-line chemotherapy response rates will be in the 40 percent range. Response rates decline with each subsequent chemotherapy choice - 20 percent for second line, 10 to 15 percent for third line, etc. Many times women will be treated with anthra-
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cycline-based chemotherapy, which has many therapy limiting adverse effects. A newer agent, pegylated liposomal doxorubicin (Doxil®), is as effective as doxorubicin and epirubicin but results in lower rates of adverse effects. It does not cause alopecia and nausea, which are almost universal with the other two agents. Additionally, it does not have a lifetime dose limit like the other two agents. Capecitabine (Xeloda®), an oral agent, can be a less toxic option than anthracyclines for a woman with a hormone response tumor that has progressed. Getting managed care approval for use can be a problem because it is only FDA approved for use in women who have already been treated with an anthracycline. Eribulin (Halaven®) is the newest chemotherapy agent for breast cancer. It is a synthetic analog of halichondrin B, a natural marine sponge product. It has been studied in women who have previously been treated with multiple chemotherapy agents and showed a higher median progression-free survival (2.6 months).3 Bevacizumab (Avastin®) previously was FDA approved for use in combination with the paclitaxel for those patients who have not been treated with chemotherapy for Her-2 negative metastatic breast cancer. The FDA revoked approval of this agent for the breast cancer indication on November 18, 2011 because “Avastin used for metastatic breast cancer has not been shown to provide a benefit, in terms of delay in the growth of tumors, that would justify its serious and potentially life-threatening risks. Nor is there evidence that use of Avastin will either help women with breast cancer live longer or improve their quality of life.”4
With chemotherapy for metastatic breast cancer, there are no good predictors of efficacy, other than Her-2 status. The current division of disease based on receptors is determined by the immunohistochemistry of the tumor. More is being learned about the molecular composition of tumors. The next wave of classification of breast cancer is molecular profiling looking at the gene patterns and signatures. Conclusion
Breast cancer is a very treatable disease. Unfortunately, advanced or metastatic disease is still not curable. Depending on the type of tumor, there are many treatment options available. In addition, better targeting of therapy is on the horizon with genetic profiling of tumors. Michael Naughton, MD is an Assistant Professor of Medicine at the Washington University School of Medicine in St. Louis, MO.
References 1. Bryan RM, Mercer RJ, Bennett RC, et al. Androgen receptors in breast cancer. Cancer. 1984 ;54:2436-40. 2. Robertson JF, Llombart-Cussac A, Rolski J, et al. Activity of fulvestrant 500 mg versus anastrozole 1 mg as first-line treatment for advanced breast cancer: results from the FIRST study. J Clin Oncol. 2009;27:4530-5. 3. Vahdat LT, Pruitt B, Fabian CJ, et al. Phase II study of eribulin mesylate, a halichondrin B analog, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2009;27:2954-61. 4. FDA Press Release. FDA Commissioner Removes Breast Cancer Indication from Avastin Label. November 18, 2011, Available at http://www.fda.gov/ NewsEvents/Newsroom/PressAnnouncements/ucm279485.htm. 1/13/2012.
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Detection, Treatment and Control: The Keys to Managing Osteoporosis in Postmenopausal Women Ellen Miller, MD For a CME/CEU version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.
Summary Osteoporosis is often a silent disease until it results in a fracture. Because of this silent nature, it is underdiagnosed. Certain patients should be screened for this disease by bone density measurement. There are several effective treatments, but patients have to adhere to therapy for many years to maximize the benefit. Enhancing adherence is an area for managed care intervention. Key Points • The important consequence of osteoporosis is fractures. • Fractures are costly to both the patient and the health care system. • Osteoporosis is preventable and treatable, but it is underdiagnosed and undertreated. • Women meeting certain criteria need to be screened for osteoporosis. • Diagnosis of osteoporosis is based on BMD testing. • Patients with low BMD can be assessed for fracture risk to determine need for treatment. • Patients with osteoporosis require treatment to prevent further bone loss and reduce risk of fracture. • There are numerous therapeutic options for treating osteoporosis. • Adherence to therapy is important for maximizing fracture risk reduction.
Osteoporosis is defined as a systemic skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture. Bone is a dynamic tissue that is constantly being remodeled. Osteoclasts remove old bone and osteoblasts replace the tissue with new fresh bone. In the normal state, before menopause, these two states are totally balanced – the amount of bone removed is replaced on a constant basis. With the loss of estrogen at menopause, there is an increased rate of bone turnover and the osteoblasts cannot keep up which results in a net loss of bone and increased risk of fracture. Osteoporosis is a major national health problem. Approximately 10 million Americans have osteoporosis, and another 34 million have osteopenia, a decreased bone mass. Forty to fifty percent of women aged 50 and older will suffer an osteoporosis-related fracture in their lifetimes.1 Osteoporosis results in 700,000 vertebral fractures and 300,000 hip frac-
tures annually. The prevalence of osteoporosis is expected to increase with the growth of the elderly population. Fractures secondary to osteoporosis result in significant health impact. Patients who experience a vertebral fracture are at greater risk of any subsequent fracture. These patients may become unable to walk unassisted, lose height, develop spinal deformities, experience significant pain, and are at greater risk of death.2 Unfortunately, vertebral fractures are often unrecognized.3 Hip fractures are the most costly complication of osteoporosis. Exhibit 1 illustrates the increased morbidity and mortality after a hip fracture.4 Additionally, osteoporosis has significant economic impact. Each year in the United States, osteoporotic fractures are responsible for more than 500,000 hospitalizations, 800,000 emergency room visits, and 2.6 million physician office visits. The consequences of osteoporotic fractures include
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Exhibit 1: Increased Morbidity and Mortality4 1 Year After Hip Fracture
% of Patients
40 30 20
Death Within Permanent Unable to Walk Unable to Carry Out 1 Year Disability Independently >1 Independent ADL
ADL = activity of daily living
placement of approximately 180,000 individuals in nursing homes yearly. In 2005, osteoporosis-related fractures were responsible for an estimated $19 billion in costs.5 By 2025, experts predict that these costs will rise to approximately $25.3 billion. Osteoporosis is preventable and, once it develops, treatable. Screening for and treatment of osteoporosis in postmenopausal women is cost effective. It results in improved quality of life, which outweighs the treatment costs.6 There are fewer fractures and associated morbidity and a reduction in hospitalizations. Earlier detection and treatment can reduce the economic burden of this disease even further. Additional bone density screening for one million at-risk women could lead to a $77.86 million net savings for Medicare, due to a decrease in fractures.7 This
additional screening might lead to the treatment of 440,000 new patients, preventing more than 35,000 fractures.8 In 2004, the Surgeon General’s report on osteoporosis highlighted the predictive value of bone mineral density (BMD) testing, noting that BMD testing remains the ‘gold standard’ test for those at risk of osteoporosis and that BMD is a strong independent predictor of fracture risk.9 This report further notes that the relationship between BMD and fracture is stronger than the relationship between cholesterol and heart attack. The International Society for Clinical Densitometry recommends a central dual-emission X-ray absorptiometry (DXA) of the spine, proximal femur, and femoral neck for diagnosis of osteoporosis.10
Exhibit 2: Indications for BMD Testing: Risk Factor Profiles11
• Perimenopausal women with a specific risk factor associated with increased fracture risk (e.g., smoking, family history, thinness) • Low impact fracture after age 50 • Adults with a condition (e.g., rheumatoid arthritis) or taking a medication (e.g., glucocorticoids) associated with bone loss • Individuals with primary hyperparathyroidism • Anyone being considered for pharmacologic therapy for osteoporosis • Anyone being treated for osteoporosis, to monitor treatment effect • Postmenopausal women discontinuing estrogen
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This will accurately give a BMD in grams/centimeter2. The diagnosis is based on the patient’s lowest bone density score at any of the three sites screened using their T-score. The T-score is the number of standard deviations above or below the mean for a healthy 30-year-old adult of the same sex and ethnicity as the patient. A T-score between -1.0 and -2.5 is considered osteopenia. A T-score of -2.5 is considered osteoporotic. Peripheral ultrasound measurements of the heel are useful for screening lowrisk patients but should not be used for diagnosis or follow-up. The indications for BMD testing are listed in Exhibit 2.11 All patients with osteoporosis will get treatment but clinicians have to determine what type of treatment to offer people with osteopenia. Because the majority of patients identified with low bone mass will fall in the osteopenia category, the majority of fractures occur in this group. The use of clinical factors can improve identification of people with osteopenia at higher fracture risk so they can be treated. The WHO Frax™ Risk Assessment Tool determines an individual’s 10-year risk of hip and major osteoporotic fracture based on BMD and other important risk factors.12 The risk factors included in this tool are listed in Exhibit 3.12 Patients with a 20 percent or greater risk of a major osteoporotic fracture or a 3 percent or greater risk of hip fracture should be treated with pharmacologic therapy.11 Exhibit 4 includes the other indications for pharmacologic therapy in postmenopausal women. Osteoporosis is underdiagnosed and undertreated. The disease is often silent until it results in a fracture. Although osteoporosis can be prevented through appropriate diet and exercise, adherence to preventive measures is poor. Additionally, adherence to oral pharmacologic treatment is poor. In one study, 20 percent of patients taking daily bisphosphonates abandoned therapy within seven months.13 The development of weekly bisphosphonate therapy improved persistence, but it is still not optimal with these agents because of the strict way they must be taken (i.e., with eight ounces of water, no lying down for two hours afterwards, and 30 minutes before eating any food). Poor adherence leads to compromised fracture risk reduction (Exhibit 5).14 Even small improvements in adherence (i.e., 10 percent) can translate into fewer fractures per patient, resulting in a net reduction in medical costs.15 There are many reasons for adhearence issues in osteoporosis treatment. A major issue is that the treatment of concomitant diseases may take priority over an issue of treatment that has the goal of trying to prevent a fracture from occurring many years into the future.
Exhibit 3: Risk Factors Included in the WHO Fracture Risk Assessment Model12. • Current Age • Use of oral glucocorticoid therapy • Gender • Secondary osteoporosis (e.g., rheumatoid arthritis) • Personal history of a fracture • Personal history of a hip fracture • Femoral neck BMD • Current smoking • Low body mass index (kg/m2) • Alcohol intake of 3 or more drinks/day
The standard interventions for improving adherence for a silent disease should be applied here. Patients need to be educated about the risk of fracture and the reasons for maintaining treatment for many years. Health care providers need to assess patient preferences, medication-taking behaviors, and current polypharmacy burden. Patients can be enrolled in support and adherence programs or given access to case management services for continual care. Improving adherence with osteoporosis therapy is an area for managed care to intervene. Nonpharmacologic interventions that prevent bone loss include calcium 1200-1500 mg/day through diet or supplementation, vitamin D 8001000 IU/day through supplementation, regular weight-bearing exercise, and avoidance of tobacco and excessive alcohol. These interventions are appropriate for all postmenopausal women. Women who have low bone mass should also be instructed in fall prevention strategies. There are multiple pharmacologic agents, which can build bone. Teriparatide (Forteo®), calcitonin (Fortical®, Miacalcin®), raloxifene (Evista®), denosumab (Prolia®), and bisphosphonates are all FDA approved for treating osteoporosis. The bisphosphonates include alendronate (Fosamax ®, generic), ibandronate (Boniva®), risedronate (Actonel®), and zoledronate (Zometa®). Calcitonin is the easiest to take because it is a daily nasal spray. Raloxifene is also approved to reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis or at high risk for developing breast cancer. The bisphosphonates are the most commonly prescribed agents with daily oral, weekly oral, monthly oral, intravenous push every three months (ibandronate),
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Exhibit 4: NOF Guidelines for Initiating Pharmacologic Therapy in Postmenopausal Women11
Initiation of Pharmacologic Therapy Recommended in the Presence of Any of the Following: Fracture
• A vertebral or hip fracture
• T-score = -2.5 at femoral neck or spine
• WHO 10-year probability of any major fracture = 20% • WHO 10-year probability of a hip fracture = 3%
and intravenous infusion yearly (zoledronic acid) formulations. The yearly infusion is done at an infusion center after the patient is hydrated. For prevention, zoledronic acid is given every other year. There are 10-year or greater data on safety and efficacy with bisphosphonates. Bisphosphonates are associated with some rare adverse effects. These include osteonecrosis of the jaw and atypical femoral shaft fractures. Osteonecrosis is an area of exposed bone in the maxillofacial region that does not heal within eight weeks. The majority of cases have occurred in patients receiving high-dose intravenous bisphosphonates for cancer. The mechanism why this occurs is unknown. Some cases have occurred after oral surgery. Many providers question whether these agents should be discontinued before oral surgery. There is no published evidence to support or oppose discontinuation. Because bisphosphonates have very long half-lives in bone, recovery of normal bone turnover and osteoclastic function may be too gradual to have clinical significance. Patients should have any dental issues which might require surgery addressed before starting on a bisphosphonate. Atypical fractures of the femoral shaft have also recently been reported with bisphosphonate use. These are transverse fractures of the femoral shaft that have occurred bilaterally in two-thirds of the reports. Delayed healing or nonhealing is common. These fractures have been associated with prolonged use (> 5 years) of alendronate with or without another anti-resorptive medication. Patients treated with bisphosphonates should be cautioned to report any new hip or thigh pain. These atypical fractures have been rarely reported.
Denosumab, the newest agent, was approved in 2010 for treatment of postmenopausal women with osteoporosis at high risk for fracture. Denosumab is a monoclonal antibody that targets receptor activator of nuclear factor kappa-B ligand (RANK ligand), a protein that acts as the primary signal to promote bone removal. It inhibits osteoclast formation, survival, and function. Denosumab reduces vertebral fractures by 68 percent, hip fracture by 40 percent, and nonvertebral fractures by 20 percent.16 It is given as a subcutaneous injection every six months. To assess therapeutic response to pharmacotherapy, BMD testing should be repeated after two years of therapy. A satisfactory response is when BMD is maintained or increased. If BMD declines, reasons such as technical issues (e.g., validity of DXA comparison), nonadherence, and inadequate vitamin D or calcium should be considered before stopping therapy. Conclusion
Osteoporosis-related fractures can dramatically affect the functional status of women who sustain them. These fractures represent a significant clinical burden; yet they often go unevaluated and untreated. There are effective methods for evaluating individual fracture risk. Management strategies for patients with osteoporosis include ensuring basic bone health needs are met, screening for secondary causes of osteoporosis, and initiating pharmacologic therapy when appropriate. Ellen Miller, MD is an Associate Professor of Medicine at Hofstra North Shore-LIJ School Of Medicine.
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Exhibit 5: Poor Compliance and Persistence Leads to Compromised Fracture Risk Reduction14 N=35,537 12
24-Month Fracture Risk, %
29% Risk Reduction
6 4 2 0 Nonpersistent
9. US Department of Health and Human Services. Bone Health and Osteopo-
1. Chrischilles EA, Butler CD, Davis CS, Wallace RB. A model of lifetime os-
rosis: A Report of the Surgeon General. Rockville, MD: US Department of
teoporosis impact. Arch Intern Med. 1991;151:2026-32.
Health and Human Services, Office of the Surgeon General; 2004.
2. Lips P. Invest in Your Bones: Quality of Life. Why Prevent the First Fracture?
10. International Society for Clinical Densitometry. Official Positions 2007.
International Osteoporosis Foundation. 2003. Available at http://www.iof-
Available at http://www.iscd.org/Visitors/pdfs/ISCD2007OfficialPositions-
Adult.pdf. Accessed 1/12/12
3. US Department of Health and Human Services. Bone Health and Osteopo-
11. National Osteoporosis Foundation. Clinicianâ€™s Guide to Prevention and
rosis: A Report of the Surgeon General. Rockville, MD: US Department of
Treatment of Osteoporosis. 2008.
Health and Human Services, Office of the Surgeon General; 2004.
12. FRAXâ„˘ WHO Fracture Risk Assessment Tool. http://www.shef.ac.uk/
4. Cooper C. The crippling consequences of fractures and their impact on qual-
FRAX/tool.jsp. Accessed 1/12/12.
ity of life. Am J Med. 1997;103:12S-17S.
13. Tosteson AN, Grove MR, Hammond CS, et al. Early discontinuation of
5. National Osteoporosis Foundation. Fast Facts. Available at http://www.nof.
treatment for osteoporosis. Am J Med. 2003;115:209-16.
org/node/40. Accessed January 12, 2012.
14. Siris ES, Harris ST, Rosen CJ, et al Adherence to bisphosphonate therapy
6. Tosteson AN, Melton LJ 3rd, Dawson-Hughes B, et al. Cost-effective osteo-
and fracture rates in osteoporotic women: relationship to vertebral and nonver-
porosis treatment thresholds: the United States perspective. Osteoporos Int.
tebral fractures from 2 US claims databases. Mayo Clin Proc. 2006;81:1013-22.
15. Gold DT, Alexander IM, Ettinger MP. How can osteoporosis patients ben-
7. King AB, Saag KG, Burge RT, et al. Fracture Reduction Affects Medicare
efit more from their therapy? Adherence issues with bisphosphonate therapy.
Economics (FRAME): impact of increased osteoporosis diagnosis and treat-
Ann Pharmacother. 2006; 40:1143-50.
ment. Osteoporos Int. 2005;16:1545-57.
16. Cummings SR, San Martin J, McClung MR, et al. Denosumab for preven-
8. Schousboe JT, Ensrud KE, Nyman JA, et al. Universal bone densitometry
tion of fractures in postmenopausal women with osteoporosis. N Engl J Med.
screening combined with alendronate therapy for those diagnosed with osteo-
porosis is highly cost-effective for elderly women. J of Am Geriatr Soc. 2005;53:1697-1704.
www.namcp.org | Vol. 15, No. 2 | Journal of Managed Care Medicine 13
Fibromyalgia: Improving Diagnostic and Treatment Strategies for Better Patient Outcomes Don L. Goldenberg, MD For a CME/CEU version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.
Summary Fibromyalgia (FM) is a chronic pain disorder that requires accurate diagnosis and management. Many of the medications currently used for this condition are ineffective. There are FDA approved medications and behavioral and physical interventions that are effective, especially when used in combination. Improving diagnosis and management utilizing appropriate specialty referral for difficult to manage patients will help managed care achieve better patient outcomes. Key Points • Chronic widespread pain is a real disease and is common. • FM is a syndrome of altered pain perception. • Diagnosis of FM is good for patients and health care. • FM should be managed by primary care with rheumatology, physical medicine, and mental health specialists as consultants. • Selected patients require multi-component therapy and should be managed by a multidisciplinary team. • Managed care can have an impact with these patients by helping limit use of opioids and other ineffective agents and costly testing and procedures.
Chronic widespread pain affects up to 15 percent of the population, generally with no identifiable structural basis. There are many different “labels” that one can legitimately use for an individual with this type of pain, if one decides to use any label. Fibromyalgia is an arbitrary label for a syndrome of chronic widespread pain. Many functional somatic syndromes overlap, including FM, chronic fatigue syndrome, irritable bowel syndrome, chronic headaches, irritable bladder syndrome, jaw or facial pain disorders, pelvic pain, and vulvodynia. Depending on the specialist seen, the patient may receive a different diagnosis. Additionally, no medical specialty has accepted “ownership” of these patients with chronic widespread pain. Rheumatologists have led the way in research, but many do not care to treat these patients. FM is the most common chronic widespread pain condition worldwide and affects 3 to 5 percent of the population.1 Currently, many fibromyalgia patients
are not diagnosed or require years to get a diagnosis. Patients will have symptoms for an average of a year before seeking care. On average, a patient with FM will require 2.3 years and see 3.7 doctors before receiving a diagnosis.2 The duration of time without a diagnosis adversely affects outcome. Peak age for diagnosis is between the ages of 35 and 60 years, but it affects all ages. Women are affected more commonly than men. Twenty-five to 35 percent of FM patients are unable to work because of symptoms. In addition to widespread pain, the most common symptoms are fatigue, morning stiffness, and sleep disturbances.3 Symptom severity varies over time. Pain and fatigue are the symptoms patients want to see improved the most.4 At the time of FM diagnosis, mood disorders are present in 30 to 50 percent of patients, primarily depression.5 Sleep disruption is prominent and problematic in this disease. FM patients report insomnia, early morning awakenings, and poor quality of sleep.
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Exhibit 1: New Proposed Diagnostic Criteria8 FM can be diagnosed based on a questionnaire that includes:
Symptom severity (SS) score Score ranges from 0 (no problem) to 3 (severe) for each group of symptoms: Fatigue Waking unrefreshed from sleep Cognitive symptoms Plus a score of 0 (no symptoms) to 3 (great deal of symptoms) for all somatic symptoms combined
Widespread Pain Index (WPI): In how many areas has the patient had pain (over the last week)? Score 1 point for each area Shoulder girdle* Upper arm, lower arm* Hip (buttock, trochanter)* Upper leg, lower leg* Jaw* Chest Abdomen Upper back, lower back Neck (*score left & right side separately)
Total SS score = 0-12
Total WPI Score = 0-19
Objective polysomnographic recording shows disordered sleep. Some will also have co-existing sleep apnea or restless leg syndrome which needs to be treated. Disturbance of deep sleep magnifies the affective component of pain.6, 7 FM can be difficult to diagnose. It is the prototype for a fundamentally different type of pain syndrome where pain is not due to damage or inflammation of peripheral tissues. It is frequently accompanied by a variety of other somatic symptoms and syndromes. Because of issues with using the American College of Rheumatology (ACR) diagnostic criteria and accurately completing a tender point count, new criteria have been proposed which use two scores â€“ widespread pain index and symptom severity score (Exhibit 1).8 A patient examination is needed in addition to the criteria to confirm the diagnosis and exclude other chronic pain conditions such as arthritis. The proposed criteria no longer include a tender point count. The diagnostic workup of FM should be inexpensive, but it is sometimes hard to convince primary care doctors not to do additional testing. In addition to a patient history and careful musculoskeletal examination, selected laboratory tests should be used to rule out other diagnoses. The commonly ordered tests include complete blood count, erythrocyte sedimentation rate, and thyroid function tests. Serologic tests for rheumatoid arthritis and other conditions should only be conducted if history or physical exam suggests a rheumatologic diagnosis. X-rays and imaging studies are typically not helpful unless there is strong evidence for a structural disorder.9 An
early referral from primary care to a FM specialist may lead to an earlier diagnosis. The pathophysiology of FM is unknown, but recent data suggest that alterations of the central nervous system (CNS) may contribute to the chronic widespread pain of FM. Central sensitization is emerging as a leading theory of FM pathophysiology.10 Functional MRI data provide supporting evidence that FM is a central pain processing disorder. There is an imbalance between pain augmentation and pain perception. Therapeutic agents that reduce neuronal hyperactivity by reducing the release of neurotransmitters are one way to relieve the chronic pain of FM. Although FM is a central nervous system disorder and not a musculoskeletal disorder, rheumatologists have been taking care of the majority of patients. A neurologist probably should be the specialist caring for these patients, but most do not want to deal with this condition. Exhibit 2 presents an algorithm for managing patients with FM.11,12 Many patients with FM will require a referral to a mental health professional to manage psychosocial and mood issues. Only a few agents have strong evidence for efficacy in managing FM (Exhibit 3).12 Unfortunately, many agents, such as anti-inflammatories and opioids that show no evidence for efficacy, are commonly used. Tricyclic (TCA) and serotonin and norepinephrine reuptake inhibitors (SNRI) antidepressants alter brain levels of neurotransmitters to restore balance in pain perception. They are also effective in
www.namcp.org | Vol. 15, No. 2 | Journal of Managed Care Medicine 15
Exhibit 2: Core Treatment of Fibromyalgia11, 12
Identify important symptom domains, their severity, and level of patient function
Evaluate for comorbid medical and psychiatric disorders
Assess psychosocial stressors, level of fitness, and barriers to treatment
May require referral to a specialist for full evaluation
Provide education about fibromyalgia
Review treatment options Initiate monotherapy based on patient’s presentation and evidencebased guidelines
treating the depression that commonly accompanies chronic pain conditions. The TCAs are effective for all clinical outcomes (pain, quality of sleep, fatigue, and sense of well-being) but have safety and tolerability issues due to nonselective binding to antihistaminergic and α-adrenergic receptors. The SNRIs, duloxetine and milnacipran, are both FDA approved for treating FM and significantly improve clinical outcomes.13,14 Pregabalin, an anticonvulsant, is also FDA approved for managing FM.15 Gabapentin, another anticonvulsant approved for other types of chronic pain, has data to show it is effective but does not have FDA approval.16 None of these agents is dramatically effective. About 50 percent of patients will get a 25 percent reduction in pain relief. Only 25 percent will get a truly meaningful response of a 50 percent reduction in pain. More effective options are needed and patients need education on realistic expectations for pain reduction. For patients who predominately have exhaustion and mood symptoms, an SNRI is suggested as initial therapy. For patients with predominately pain and sleep issues, an anticonvulsant should be the initial
choice. If the initial pharmacotherapy choice does not adequately improve symptoms, it may be better to add a second medication rather than switch, however,combination therapy trials have not yet been published. Nonpharamacologic therapy is as important as medications. The nonpharmacologic strategies with strong evidence for efficacy in this condition are listed in Exhibit 4.12,17,18 Improved outcomes can be obtained by combining pharmacologic and nonpharmacologic treatments. Exercise should be recommended for all FM patients. Patient comorbidities may determine the acceptable types of exercise. Many of these patients have been sedentary for a long time and are difficult to get moving again. Obesity is also common in this patient population. Water-based exercise programs are particularly helpful because they are easiest for patients. Continued exercise is necessary to maintain positive effects on pain. Patient self-efficacy – the belief that he or she can achieve and maintain a program - is essential for sustained participation.19 Home-based ‘lifestyle physical activity’ may be
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Exhibit 3: FM Pharmacological Therapies12
“Antidepressants” Tricyclic compounds (amitriptyline, cyclobenzaprine) SNRIs and NSRIs (milnacipran, duloxetine) Pregabalin
Tramadol Gabapentin Selective serotonin reuptake inhibitors (SSRIs) Gamma hydroxybutyrate Dopamine agonists (Pramipexole)
Growth hormone, 5-hydroxytryptamine, S-adenosyl-L-methionine (SAMe)
Opioids, corticosteroids, nonsteroidal anti-inflammatory drugs, benzodiazepine and nonbenzodiazepine hypnotics, guanifenesin, thyroid hormone
more beneficial than a formal program in some FM patients.20 Cognitive behavioral therapy (CBT) can help to improve coping with pain and to reduce depressed mood and health care-seeking behavior in FM. In one study comparing CBT to standard care, the patients who received CBT had improved physical functioning and decreased pain.21 Patient education is another important aspect of nonpharmacologic therapy. Most patients have chronic, persistent symptoms and need to be educated about what is a realistic outcome for symptoms.
The best approach is to combine pharmacologic, physical, and behavioral therapies, such as medication, exercise, and CBT. The problem for providers is getting insurance reimbursement for interventions outside of pharmacologic therapy. Unfortunately, few patients get all these appropriate therapies. Only 3 percent of FM patients in one study were getting the three types of therapy.22 Diagnosing and treating FM is good for the clinician, patient, and health care system. It reduces health care and societal costs.23 A diagnosis is good for the patient only if it is coupled with accurate
Exhibit 4: Nonpharmacologic Strategies: Evidence of Efficacy12,17,18
• Exercise – Physical and psychological benefits – May increase aerobic performance and tender point pain pressure threshold, and improve pain – Efficacy not maintained if exercise stops
• Strength training • Acupuncture • Hypnotherapy • EMG biofeedback • Balneotherapy (medicinal bathing) • Transcranial electrical stimulation
• Cognitive-behavioral therapy – Improvements in pain, fatigue, mood, and physical function – Improvement often sustained for months
Weak Evidence • Chiropractic • Manual and massage therapy • Ultrasound
• Patient education/self-management – Improves pain, sleep, fatigue, and quality of life
Evolving Evidence • Tender-point injections • Tai-chi, Yoga
• Combination (multidisciplinary therapy)
www.namcp.org | Vol. 15, No. 2 | Journal of Managed Care Medicine 17
Exhibit 5: Interdisciplinary Pain Management Integrated Coordinated Pain Specialist
Psychiatrist Neurologist Physiatrist
Spine Surgeon Primary Clinician and Patient
Psychologist Occupational Therapist
Pharmacist Social Worker Anesthesiologist
information and education. More than 50 percent of visits for FM symptoms are to primary care physicians. Currently, 16 percent of FM visits are to rheumatologists. The ACR suggests that rheumatologists serve as consultants (tertiary care). Other specialists should include physiatrists, pain management experts, and mental health providers. For a subset of the most difficult patients to treat, a multidisciplinary team needs to be involved (Exhibit 5).
2. Choy E, Perrot S, Leon T, et al. A patient survey of the impact of fibromyalgia and the journey to diagnosis. BMC Health Serv Res. 2010;10:102. 3. Wolfe F, Smythe HA, Yunus MB, et al. The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis Rheum. 1990;33:160-72. 4. Bennett RM, Russell J, Cappelleri JC, et al. Identification of symptom and functional domains that fibromyalgia patients would like to see improved: a cluster analysis. BMC Musculoskelet Disord. 2010;11:134. 5. McBeth J, Silman AJ. The role of psychiatric disorders in fibromyalgia. Curr Rheumatol Rep. 2001;3:157-64. 6. Vierck CJ Jr. Mechanisms underlying development of spatially distributed
Chronic widespread pain is real and common. FM is not a distinct entity but rather is at the extreme end of a spectrum of altered pain perception. Diagnosis of FM is good for patients and for health care. It is hoped that earlier diagnosis and treatment will lead to better outcomes. FM should be managed by primary care with rheumatology, physical medicine, and mental health as consultants. Selected patients require multi-component therapy and should be managed by a multidisciplinary team. Managed care can have an impact with these patients by helping limit the use of opioids and other ineffective agents and costly testing and procedures.
chronic pain (fibromyalgia). Pain. 2006;124:242-63. 7. Moldofsky H. The significance of the sleeping-waking brain for the understanding of widespread musculoskeletal pain and fatigue in fibromyalgia syndrome and allied syndromes. Joint Bone Spine. 2008;75:397-402. 8. Wolfe F, Clauw DJ, Fitzcharles MA, et al. The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis Care Res. 2010;62:600-10. 9. Goldenberg DL. Diagnosis and differential diagnosis of fibromyalgia. Am J Med. 2009;122(12suppl):S14-S21. 10. Clauw DJ, Crofford LJ. Chronic widespread pain and fibromyalgia: what we know, and what we need to know. Best Prac Res Clin Rheumatol. 2003;17:685701. 11. Arnold LM. Biology and therapy of fibromyalgia. New therapies in fibromyalgia. Arthritis Res Ther. 2006;8:212. 12. Goldenberg DL, Burckhardt C, Crofford L. Management of fibromyalgia
Don L. Goldenberg, MD is Chief of Rheumatology at Newton-Wellesley
syndrome. JAMA. 2004;292:2388-95.
Hospital in Newton, Massachusetts and a Professor of Medicine at Tufts
13. Arnold LM, Rosen A, Pritchett YL, et al. A randomized, double-blind,
University School of Medicine.
placebo-controlled trial of duloxetine in the treatment of women with fibromyalgia with or without major depressive disorder. Pain. 2005;119:5-15.
14. Gendreau RM, Thorn MD, Gendreau JF, et al. Efficacy of milnacipran in
1. Weir PT, Harlan GA, Nkoy FL, et al. The incidence of fibromyalgia and its
patients with fibromyalgia. J Rheumatol. 2005;32:1975-85.
associated comorbidities: a population-based retrospective cohort study based
15. Arnold LM, Russell IJ, Diri EW, et al. A 14-week, randomized, double-
on International Classification of Diseases, 9th Revision codes. J Clin Rheuma-
blinded, placebo-controlled monotherapy trial of pregabalin in patients with
fibromyalgia. J Pain. 2008;9:792-805.
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16. Arnold LM, Goldenberg DL, Stanford SB, et al. Gabapentin in the treatment
gia is related to activity and rest: role of peripheral tissue impulse input. J Pain.
of fibromyalgia: a randomized, double-blind, placebo-controlled, multicenter
trial. Arthritis Rheum. 2007;56:1336-44.
21. Williams DA, Cary MA, Groner KH, et al. Improving physical functional
17. Williams DA, Cary MA, Groner KH, et al. Improving physical functional
status in patients with fibromyalgia: a brief cognitive behavioral intervention. J
status in patients with fibromyalgia: a brief cognitive behavioral intervention. J
22. Sauer K, Kemper C, Glaeske G. Fibromyalgia syndrome: prevalence, phar-
18. Busch AJ, Barber KA, Overend TJ, et al. Exercise for treating fibromyalgia
macological and non-pharmacological interventions in outpatient health care.
syndrome. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD003786.
An analysis of statutory health insurance data. Joint Bone Spine. 2011;78:80-4.
19. Sarzi-Puttini P, Buskila D, Carrabba M, et al. Treatment strategy in fibro-
23. Annemans L, Wessely S, Spaepen E, et al. Health economic consequences
myalgia syndrome: where are we now? Semin Arth Rheum. 2008;37:353-65.
related to the diagnosis of fibromyalgia syndrome. Arthritis Rheum. 2008;58:895-
20. Staud R, Robinson ME, Weyl EE, Price DD. Pain variability in fibromyal-
www.namcp.org | Vol. 15, No. 2 | Journal of Managed Care Medicine 19
Hyperlipidemia: The Silent CVD Risk Factor with Enormous Impact Michael Miller, MD, FACC, FAHA For a CME/CEU version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.
Summary Hyperlipidemia is a silent but deadly risk factor for developing cardiovascular disease (CVD). The combination of hyperlipidemia with other CVD risk factors significantly increases a patient’s chance for developing CVD. Managed care can have an impact on outcomes related to hyperlipidemia by developing programs to improve screening and treatment to reach appropriate goals. Key Points • Although LDL-C is the primary target of therapy, more emphasis is being placed on non-HDL-C which encompasses all the atherogenic lipoproteins. • Lifetime risk for developing CVD increases with increasing numbers of risk factors. • Pharmacologic therapy for primary prevention is cost effective if a patient’s estimated five-year risk is greater than 8 percent. • Despite national guidelines and quality measures, a large number of patients are not achieving appropriate goals. • Managed care can improve outcomes by implementing interventions to help patients identify and reduce their risk factors and achieve appropriate goals.
Hyperlipidemias are a major public health concern in the U.S. More than 100 million U.S. adults have a dyslipidemia. In addition, an estimated 6 percent of adolescents have elevated lipid values.1 Hyperlipidemia leads to atherosclerosis and cardiovascular disease (CVD). The aplolipoprotein (ApoB) containing lipoproteins are atherogenic. These include low-density lipoprotein cholesterol (LDL-C), intermediate density lipoprotein (IDL), very low- density lipoprotein (VLDL), VLDL remnants, chylomicron remnants, and lipoprotein a [Lp(a)]. Most of these particles are not routinely measured. ApoB recognizes sites on tissues such as macrophages that allows for its unadulterated incorporation into macrophages leading to foam cell formation – the first step in the formation of atherosclerotic plaque. High-density lipoprotein cholesterol (HDL-C) is anti-atherogenic because it is involved in the efflux of lipids for hepatobiliary excretion. LDL-C is the primary target of therapy. LDL-C
levels vary with genetic variations in cholesterol metabolism and diet. Some patients with genetic variants that lead to low LDL-C have long life spans because they don’t develop extensive atherosclerosis. Patients with familial combined hyperlipidemia (FCH, both elevated LDL-C and triglycerides) have about double the risk of heart disease compared to someone without mild elevations of LDL-C alone. Patients with familial hypercholesterolemia (FH) have high and very high LDL-C levels depending on whether they are heterozygous or homozygous. It is critical to understand the role LDL-C plays in the development of disease. LDL-C must be modified to be atherogenic. Three conditions lead to modified LDL-C – diabetes, cigarette smoking, and hypertriglyceride states. In diabetes, LDL-C is glycosylated so it can then be taken up by macrophages in an unregulated manner. Smoking is atherogenic because cigarette smoke contains sugars that can glycosylate proteins including LDL-C. When high triglycerides (TG) are also present, small dense LDL-C particles are formed which are more
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Lifetime Risk for CVD, %
Exhibit 1: Lifetime Risk for CVD Increases with Greater Risk Factor Burden4 Risk Factor Burden at Age 50 (Estimated Risk by Age 95)
30 20 10
0 All Optimal >1 Not >1 Optimal Elevated
Optimal risk factors defined as total cholesterol <180 mg/dL, BP <120/<80 mmHg, nonsmoker, and nondiabetic. Major risk factors are defined as total cholesterol >240 mg/dL, systolic BP >160 mmHg, diastolic BP >100 mmHg, smoker, and diabetic. CVD = cardiovascular disease; BP = blood pressure.
susceptible to modification. Even at “normal” levels, patients with these three conditions have very atherogenic LDL-C. The combination of high LDL-C and TGs leads to significant risk of CVD.2 The combination is worse than either being elevated alone. This appears to be a result of activated proinflammatory pathways.3 This combined dyslipidemia commonly occurs in patients with type 2 diabetes. Metabolic syndrome is another risk factor for developing cardiovascular disease. Metabolic syndrome raises risk of developing type 2 diabetes fivefold and CVD twofold. Lifestyle interventions, started early in the metabolic syndrome process, can reverse the elevated risk of disease. A significant number of adolescents in the U.S. have metabolic syndrome. If these young people continue on this path, there is a good chance that they will develop CVD very early in life. Lifetime risk for developing CVD increases with increasing numbers of risk factors. If a patient has optimal risk factors, they will have an estimated 8 percent risk of developing CVD in their lifetime if they are female and 5 percent for male.(Exhibit 1).4 Optimal risk factors are defined as total cholesterol less than 180 mg/dL, blood pressure less than 120/80 mmHg, nonsmoker, and nondiabetic. All adults should be screened for lipid disorders every five years. There are published screening guidelines for children and adolescents.5 Those with a family history of premature coronary heart disease (<55 in men; < 65 in women) or a cardiovascular risk factor (body mass index > 85th percentile, hyper-
tension, diabetes, or smoking) should be screened. Pharmacologic therapy is recommended in children at least 10 years old when LDL-C is greater than 190 mg/dl or 160 mg/dl with positive family history or two other risk factors after a six-to 12-month trial of dietary management.6 The goal LDL-C is at least less than 130 mg/dl,and optimally it should be reduced to less than 110 mg/dl. Statins are considered first-line therapy in children and adolescents. The currently recommended LDL-C goals for adults are shown in Exhibit 2.7 Although we focus on LDL-C, many other lipoproteins are atherogenic. These other particles are accounted for in non-HDL-C levels – calculated as total cholesterol minus HDL-C. Non–HDL-C is actually superior to LDL-C in predicting CHD risk.8 Non-HDL-C values will likely be given greater importance in the next update of the National Cholesterol Education Program (NCEP) guidelines. Under the current guidelines, non–HDL-C is a secondary target for lipid lowering in patients with elevated triglycerides (200 mg/dl or greater) after reaching their LDL-C goal. A patient���s non-HDL-C goal is their LDL-C goal plus 30 mg/dl. Lifestyle factors play an important role in CVD risk. Dietary changes and physical activity are important in reducing risk. Most clinicians do not recommend a diet that has an induction (i.e., starving) stage. Slow gradual weight loss of one to one and a half pounds per week is more likely to result in long-term weight management. The simplest way to lose weight is to reduce caloric intake or increase energy expenditure to add up to a 500 calories per
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Exhibit 2: Adult LDL-C Goals7 Risk Category
LDL-C Goal mg/dL
Very High CHD plus: diabetes, ACS, metabolic syndrome, or poorly controlled risk factors
<100 <70 (optional)
High CHD, CHD risk equivalenta
Moderately high FRS of 10%-20%; =2 risk factors
<130 <100 (optional)
Moderate FRS<10%; =2 risk factors
Low 0-1 risk factor
a CHD risk equivalent = diabetes, other atherosclerotic disease (e.g., peripheral arterial disease, >50% carotid artery stenosis), 10-year Framingham risk for hard CHD events (nonfatal MI, CHD death) >20%. ATP = Adult Treatment Panel; NCEP = National Cholesterol Education Program; ACS = acute coronary syndromes; FRS = Framingham Risk Score (10year risk for MI or CHD death).
day reduction. For primary prevention, there is data to suggest that pharmacologic therapy with statins is cost effective. At generic prices of $1 per day, the initiation of lifetime 40 mg simvastatin daily in the U.S. is cost effective for people aged 40 to 80 years, who have five-year risk of major vascular events of eight or greater.9 When assessing the overall benefit of primary prevention therapies like lipid lowering, there is a move to assess lifetime risk rather than shorter horizons such as 10- and 20-year risk. A significant number of patients with dyslipidemia are not treated or if treated are not at optimal goals. In the 2011 National Center for Quality Assurance (NCQA) State of Health Care Quality report, 40 to 57.2 percent of patients with known cardiovascular disease (secondary prevention) are not at an LDL goal of 100 mg/dl.10 The rate varies by type of plan with commercial HMOs achieving the best control rate. Managed care can improve outcomes by developing programs which help patients reduce their risk factors, adhere to therapy, and achieve appropriate goals. Nurse case managers can be used to help patients reduce their cardiovascular risk and achieve their lipid goals.11 They can facilitate instituting and maintaining lifestyle changes and help patients be adherent with pharmacotherapy.
develops cardiovascular disease. It remains prevalent with greater risk in association with co-morbidities such as metabolic syndrome and diabetes. LDL-C reduction remains the primary goal of therapy, but non-HDL-C is getting more attention. Statin therapy is cost effective in people with a five-year risk of CVD greater than 8 percent. Managed care can facilitate risk factor modification. Michael Miller, MD, FACC, FAHA is a Professor of Medicine in Epidemiology and Preventive Medicine at the University of Maryland Medical Center in Baltimore, MD.
References 1. Ford ES, Li C, Zhao G, Mokdad AH. Concentrations of low-density lipoprotein cholesterol and total cholesterol among children and adolescents in the United States. Circulation. 2009;119;1108-15. 2. Barter PJ, Rye KA. Is there a role for fibrates in the management of dyslipidemia in the metabolic syndrome? Arterioscler Thromb Vasc Biol. 2008;28:39-46. 3. Libby P. Fat fuels the flame: triglyceride-rich lipoproteins and arterial inflammation. Circ Res. 2007;100:299-301. 4. Lloyd-Jones DM, Leip EP, Larson MG, et al. Prediction of lifetime risk for cardiovascular disease by risk factor burden at 50 years of age. Circulation. 2006;113:791â€“8. 5. Daniels SR, Greer FR; Committee on Nutrition. Lipid screening and cardiovascular health in childhood. Pediatrics. 2008;122:198-208. 6. McCrindle BW, Urbina EM, Dennison BA, et al. Drug therapy of high-risk lipid abnormalities in children and adolescents: a scientific statement from the
Hyperlipidemia is a silent disease until the patient
American Heart Association Atherosclerosis, Hypertension, and Obesity in Youth Committee, Council of Cardiovascular Disease in the Young, with the
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Council on Cardiovascular Nursing. Circulation. 2007;115:1948-67.
United States for people at different vascular risk levels. Circ Cardiovasc Qual
7. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials
for the National Cholesterol Education Program Adult Treatment Panel III
10. NCQA. The State of Health Care Quality 2011. Available at http://www.
guidelines. Circulation. 2004;110:227â€“39.
8. Liu J, Sempos CT, Donahue RP, et al. Non-high-density lipoprotein and
very-low-density lipoprotein cholesterol and their risk predictive values in cor-
11. Ma J, Berra K, Haskell WL, et al. Case management to reduce risk of cardiovas-
onary heart disease. Am J Cardiol. 2006;98:1363-8.
cular disease in a county health care system. Arch Intern Med. 2009;169:1988-95.
9. Heart Protection Study Collaborative Group. Statin cost-effectiveness in the
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Improving Outcomes and Reducing Costs with ICS Monotherapy in the Management of Asthma Dennis Spangler, MD For a CME/CEU version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.
Summary Asthma is a chronic inflammatory lung disease for which there are many treatment options. Despite good therapies and practice guidelines, morbidity and mortality are still an issue. Much of this could be reduced along with the related costs by improving care through use of pulmonary function tests and managed care medication controls. Improved care will require changes in provider and patient behavior. Key Points • Asthma is an inflammatory and chronic disease of the entire lung, which can vary over time. • Anti-inflammatory medication is essential for long-term control. • Disease control also requires management of environmental triggers, lifestyle problems, and concomitant conditions. • Pulmonary function tests should be performed for diagnosis and at follow-up visits to assess control. • Small airway inflammation should be considered in all asthmatic patients. • Only small particle inhaled corticosteroids will reach the smallest airways and should be preferred first-line agents. • All moderate and severe asthmatics should have a consultation with a board certified specialist.
An estimated 20 million Americans currently have asthma. The prevalence of asthma has been increasing across all gender, age, and racial groups since the 1980s. The reasons for the increased prevalence are many, including the rise in obesity. Asthma is more common among children, adult women, and African Americans.1 The annual cost of asthma in the U.S. is estimated at $18 billion.1 Of these costs, $10 billion is for direct medical costs, and $8 billion is for lost earnings due to illness or death. Each year, asthma results in two million emergency department visits, 10 million outpatient visits, 500,000 hospitalizations, 15 million lost workdays due to absenteeism, and 14 million missed school days. Studies have shown that asthma costs are more than two times higher in those with uncontrolled disease and that these costs rise with increasing asthma severity.2,3 Asthma is responsible for more than 4,000 deaths annually. Although the death rate from asthma has declined slightly over the years, it is still significant.
Current asthma control and morbidity is no better than a decade ago (Exhibit 1).4 Thus, something needs to change about the way we manage asthma. Over the past 40 years, the treatment of asthma has transitioned from bronchoconstriction as the major problem to inflammation. Asthma is a chronic inflammatory disease of both the large and small airways. Inflammation occurs in asthma of all severity levels. The inflammation leads to airway hyper-responsiveness which sets the patient up for acute flares when exposed to triggers such as smoke. Nocturnal symptoms are associated with small airway inflammation. Over 33 percent of adults and adolescents with asthma experience nocturnal asthma symptoms. Controlling inflammation is the key to controlling the disease and the related costs. Control of inflammation reduces or eliminates bronchospasm. There are various ways of diagnosing asthma, but pulmonary function testing (PFT) by spirometry is the best method. Unfortunately, most physicians are not doing PFT. Peak flow is the more common
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Exhibit 1: Asthma Morbidity is No Better than a Decade Ago4 Acute care for asthma in the past 12 months (1998â€“2009) AIM 2009 (n=2294)
Any of these
Other unscheduled emergency visit
40 35 30 25 20 15 10 5 0
Percentage of patients
AIA 1998 (n=1788)
AIA=Asthma in America Survey AIM=Asthma Insight and Management Survey
method used, and it is inadequate because it only measures large airway function. It does not give a good measure of total lung function. Peak flow will misdiagnose the control of asthma. One-third of patients will be given a higher asthma severity designation when PFT results are used rather than peak flow. According to the National Asthma Education and Prevention Program (NAEPP), patients can be divided into several disease severity categories on which treatment is based (Exhibit 2).5 Fifty percent of patients with asthma have persistent asthma; of these, 70 percent have mild to moderate disease. Those with mild persistent or worse disease require chronic controller medication. The preferred treatment for mild to moderate persistent asthma is inhaled corticosteroid (ICS) monotherapy. The majority of patients can be controlled on ICS monotherapy. A misconception among physicians is that it is appropriate for patients to need to use a short-acting beta agonist (SABA) inhaler on a regular basis. If a patient is using a rescue inhaler for symptoms more than twice weekly or having nightly symptoms more than twice monthly, they are under poor control. Other indicators of poor control include use of greater than two SABA canisters per year, two unscheduled office visits per year, and two rescue doses of steroids per year. The use of SABA for exerciseinduced bronchospasm does not apply when determining if a patient is well controlled. Allowing
chronic poor control leads to deterioration in lung function over time and exacerbations (Exhibit 3). Everyoneâ€™s lung function declines with aging, but people with uncontrolled asthma decline at a faster rate. Studies show that patients who have had poor control as children have lung function 20 percent below normal by their 20s. Not only are asthmatics not being adequately controlled but many times inappropriate medications are being used for mild disease. Combination therapy of an ICS and a long-acting beta agonist (LABA) is overused in mild persistent asthma.6,7 In addition to overusing combination therapy, excessive doses of ICS tend to be used. Although there is a place for combination therapy, the extensive use of these agents has not changed asthma-related morbidity or mortality. The formulary process can be used by managed care to reduce this inappropriate use. In fact, ICS/LABA combinations are no longer indicated for long-term asthma maintenance therapy. LABAs now have an FDA black box warning because alone they can precipitate severe rapid onset of respiratory failure. LABAs must always be combined with an ICS. There are subsets of patients who may actually have worsening of their asthma with use of LABAs even when combined with ICS. In mild persistent asthma, leukotriene modifiers do not work as well as ICSs to prevent exacerbations.7 They only work about 30 percent of the time and are typically more expensive than ICS monotherapy.
www.namcp.org | Vol. 15, No. 2 | Journal of Managed Care Medicine 25
Exhibit 2: NAEPP Asthma Guidelines for Initiation of Therapy in Adults5 Persistent Asthma: Daily Medication Intermittent
Preferred: SABA PRNa
Preferred: Low-dose ICS
Medium-dose ICS + LABA Alternative: Medium-dose ICS + either LTRA, Theophylline, or Zileuton
High-dose ICS + LABA AND Consider Omalizumab for patients who have allergies
High-dose ICS + LABA + oral corticosteroids AND Consider Omalizumab for patients who have allergies
Alternative: Cromolyn, LTRA, Nedocromil, or Theophylline
Medium-dose ICS, OR Low-dose ICS + LABA Alternative: Low-dose ICS + either LTRA, Theophylline, or Zileuton
SABA as needed for symptoms Clinicians are advised “for patients who have asthma not sufficiently controlled with a low-dose ICS alone, the step-up option to increase the ICS dose should be given equal weight to that of the addition of a LABA to ICS”
In trying to reduce morbidity, mortality, and costs related to asthma, it is important to understand the cause of recurrent exacerbations in asthma. Recurrent exacerbations may be related to infections, inadequate environmental and allergen trigger control, and uncontrolled inflammation. Air trapping in the small airways after expiration is associated with recurrent asthma exacerbations. Air trapping in the distal small airways leads to greater obstruction. The people with recurrent exacerbations – those with many hospital admissions and emergency room visits - have small airway inflammation that is not being treated.8 This small airway inflammation is not detected by peak flow. On PFT, these patients have increased closing volumes and closing capacities compared with patients with similar FEV1 values. As shown in Exhibit 4, some allergen particles are small enough to reach the smallest airways which can be a cause of small airway inflammation. There are steroid receptors all the way into the smallest airways. Studies have shown that particle size of the ICS does make a difference in lung deposition.9-11 The smaller particles stay aerosolized longer and deposit less in the mouth and upper airways, even when used without a spacer. Use of small particle ICS has also been shown to reduce markers of in-
flammation greater than larger particles.12 Treating the smallest airways may require use of the ICS with the smallest particle size (ciclesonide [Alvesco®] and beclomethasone HFA [Qvar ®]). There is a misperception in the medical community that fluticasone (Flovent ®) is a more potent inhaler which as a result is the most commonly prescribed ICS. A comparison of a small particle ICS (beclomethasone HFA) and fluticasone, which has a larger particle size in moderate to severe asthma, found that PFT parameters and albuterol use significantly improved with small particle ICS use.13 A lower dose of a small particle ICS can be used. In a real-world trial of fluticasone versus beclomethasone, the rate of exacerbations was not different, but the beclomethasone patients achieved the same results with a 40 percent lower dose and used less SABA.14 Small particle ICSs have also been shown to reduce air trapping in severe asthma compared with fluticasone.15 Follow-up visits are essential to assess symptom control, adjust medications, and repeat PFTs. Patients are poor judges of how they are doing. PFT need to be done to support what the patient is saying and to assess disease control. Follow-up visits are also a good time to evaluate proper inhaler use, evaluate treatment adherence, reinforce education, re-
26 Journal of Managed Care Medicine | Vol. 15, No. 2 | www.namcp.org
Exhibit 3: Asthma and Airway Remodeling
3.5 3 Remodeling
2 1.5 Asthma
Chronic Persistent Airway Obstruction and Hyperresponsiveness
view environmental controls, and review treatment goals. The importance of weight loss, smoking discontinuation, and treatment of reflux should be reinforced. Patient adherence with medications and environmental controls, and management of complicating conditions is essential. Complicating conditions include reflux, sinusitis, and rhinitis. These can all worsen asthma symptoms. Adherence can be enhanced with oral and written educational materials, action plans, and open communication. Patients should be demonstrating their inhaler technique to providers periodically. All patients with moderate persistent or severe persistent asthma should be seen by a board certified asthma specialist at least for consultation. Once asthma control is established, they could return to primary care for continued care but may still need periodic specialist visits. Patients need written plans, and they require step-up therapy if they are not controlled. Patients should be seen in two to six weeks after starting therapy. Once control is established, therapy should be stepped down. A step down should take place once asthma is well controlled for three months.5 The costs of asthma depend on the severity of disease, the extent of exacerbations, and the extent of avoidance/control measures.16 Patients with uncontrolled asthma use a disproportionate share of resources, however, even mild persistent asthma is costly.17 Of the medical cost for treating asthma, 50 percent is for rescue or emergency treatment and 33 percent is for medications and regular treatments.18 The ICSs are the least costly of the three major controller medications for mild persistent asthma.19
There are several steps that need to be taken to improve asthma care. We need better ways to disseminate and get “buy-in” for the NAEPP guidelines. Patients must be educated on what is “good asthma care”. Additionally, we need to change physician behavior toward asthma. It is not acceptable for a patient to be using a SABA a couple of times a week or to require steroids a couple of times a year. Managed care needs to develop better asthma disease management programs which encourage physicians to do pulmonary function testing. The health care system needs to move from disease control to disease modification to disease prevention (more allergy care, environment controls, weight loss, etc.). From a scientific standpoint, there needs to be better understanding of the phenotypes of asthma. Additionally, there need to be better tools available for evaluating small airways more effectively. Conclusion
Asthma must be treated as an inflammatory disease. ICS monotherapy is the least costly and most effective of the three major controller medications for mild persistent asthma. Although not specified in the current treatment guidelines, based on the evidence a small particle ICS should be the treatment of choice. Managed care could reduce the costs of asthma care by reducing overtreatment with combination therapy, encouraging the use of PFTs and small particle ICSs, and educating practitioners on indicators of control. Dennis Spangler, MD is an Assistant Professor at the Medical College of Georgia and is Section Co-chair of Allergy at Children’s Health Care
www.namcp.org | Vol. 15, No. 2 | Journal of Managed Care Medicine 27
Exhibit 4: Small Particle Allergens and ICS Reach the Smallest Airways Inhaled Corticosteroids
Cockroach, dust mite, mold
rodent, 1.0 µm pet
Mass Median Aerodynamic Diameter (MMAD)
Fluticasone DPI ~4.0 µm Budesonide 4.0 µm Beclomethasone CFC 3.5 µm
Mometasone DPI 2.6-3.3 µm Fluticasone CFC 2.6 µm Fluticasone HFA 2.4-2.6 µm
Beclomethasone HFA 1.1 µm Ciclesonide 1.0 µm
of Atlanta in Atlanta, GA.
12. Ohbayashi H. One-year evaluation of the preventative effect of hydrofluo-
1. Asthma and Allergy Foundation of America. Asthma facts and figures. http://
roalkane-beclomethasone dipropionate on eosinophilic inflammation of asth-
www.aafa.org/display.cfm?id=8&sub=42. Accessed 1/24/2012.
matic peripheral airways. Respiration. 2007;74:146-53.
2. Sullivan SD, Rasouliyan L, Russo PA, et al. Extent, patterns, and burden of
13. Aubier M, Wettenger R, Gans SJ. Efficacy of HFA-beclomethasone dipro-
pionate extra-fine aerosol (800 microg day(-1)) versus HFA-fluticasone propio-
uncontrolled disease in severe or difficult-to-treat asthma. 2007;62:126-33.
nate (1000 microg day(-1)) in patients with asthma. Respir Med. 2001;95:212-20.
3. Colice G, Wu EQ, Birnbaum H, et al. Healthcare and workloss costs associ-
14. Price D, Martin RJ, Barnes N, et al. Prescribing practices and asthma con-
ated with patients with persistent asthma in a privately insured population. J
trol with hydrofluoroalkane-beclomethasone and fluticasone: a real-world ob-
Occup Environ Med. 2006;48:794-802.
servational study. J Allergy Clin Immunol. 2010;126:511-8.
4. 2009 Asthma Insight and Management (AIM) Survey. Available at: http://
15. Thongngarm T, Silkoff PE, Kossack WS, Nelson HS. Hydrofluoroalkane-
takingaimatasthma.com/pdf/executive-summary.pdf. Accessed 1/24/2012.
134A beclomethasone or chlorofluorocarbon fluticasone: effect on small air-
5. National Heart, Lung, and Blood Institute. National Asthma Education and
ways in poorly controlled asthma. J Asthma. 2005;42:257-63.
Prevention Program. Expert Panel Report 3: Guidelines for the Diagnosis and
16. Colice G, Wu EQ, Birnbaum H, et al. Healthcare and workloss costs associ-
Management of Asthma—Full Report 2007. National Institutes of Health; Au-
ated with patients with persistent asthma in a privately insured population. J
gust 28, 2007.
Occup Environ Med. 2006;48(8):794-802.
6. Friedman H, Wilcox T, Reardon G, et al. A retrospective study of the use of
17. Bootman JL, Crown WH, Luskin AT. Clinical and economic effects of
fluticasone propionate/salmeterol combination as initial asthma controller ther-
suboptimally controlled asthma. Manag Care Interface. 2004;17:31-6.
apy in a commercially insured population. Clin Ther. 2008;30:1908-17.
18. Weiss KB, Sullivan SD. The health economics of asthma and rhinitis. I. As-
7. American Lung Association Asthma Clinical Research Centers, Peters SP,
sessing the economic impact. J Allergy Clin Immunol. 2001;107:3-8.
Anthonisen N, et al. Randomized comparison of strategies for reducing treat-
19. Colice GL, Yu AP, Ivanova JI, et al. Costs and resource use of mild persistent
ment in mild persistent asthma. N Engl J Med. 2007;356:2027-39.
asthma patients initiated on controller therapy. J Asthma. 2008;45:293-9.
8. in ‘t Veen JC, Beekman AJ, Bel EH, Sterk PJ. Recurrent exacerbations in severe asthma are associated with enhanced airway closure during stable episodes. Am J Respir Crit Care Med. 2000;161:1902-6. 9. Martin RJ. Therapeutic significance of distal airway inflammation in asthma. J Allergy Clin Immunology. 2002; 109:S447-S460. 10. Leach CL, Davidson PJ, Hasselquist BE, Boudreau RJ. Lung deposition of hydrofluoroalkane-134a beclomethasone is greater than that of chlorofluorocarbon fluticasone and chlorofluorocarbon beclomethasone: a cross-over study in healthy volunteers. Chest. 2002;122:510-16. 11.Leach CL, Bethke TD, Boudreau RJ, et al. Two-dimensional and three-dimensional imaging show ciclesonide has high lung deposition and peripheral distribution: a nonrandomized study in healthy volunteers. J Aerosol Med.
28 Journal of Managed Care Medicine | Vol. 15, No. 2 | www.namcp.org
For patients with severe COPD associated with chronic bronchitis and a history of exacerbations ®
DALIRESP is the first and only selective PDE4 inhibitor to reduce the risk of COPD exacerbations1,2 • Reduces moderate or severe exacerbations by 17% vs placebo1,3,4 • Effective alone or in combination with a bronchodilator1,3 • Effective in older and younger patients (>65 and 40-65 years)1,3 • Statistically significant increase in lung function (pre-bronchodilator FEV1) of 48 mL vs placebo1,4 – DALIRESP is not a bronchodilator; this increase was not clinically significant1,3 • The first class of drugs approved for COPD in 25 years2,5
INDICATIONS AND USAGE DALIRESP is indicated as a treatment to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations. DALIRESP is not a bronchodilator and is not indicated for the relief of acute bronchospasm.
Learn more at Booth #125
IMPORTANT SAFETY INFORMATION Contraindications DALIRESP is contraindicated in patients with moderate to severe liver impairment (Child-Pugh B or C). Warnings and Precautions • DALIRESP is not a bronchodilator and should not be used for the relief of acute bronchospasm. • Prescribers should advise patients, their caregivers, and families to be alert for the emergence or worsening of insomnia, anxiety, depression, suicidal thoughts or other mood changes, and if such changes occur, to contact their healthcare provider. Prescribers should carefully evaluate the risks and benefits of continuing treatment if such events occur. Before using DALIRESP in patients with a history of depression and/or suicidal thoughts or behavior, prescribers should carefully weigh the risks and benefits of treatment with DALIRESP. – Treatment with DALIRESP is associated with an increase in psychiatric adverse reactions. In controlled clinical trials 5.9% of patients treated with DALIRESP reported psychiatric adverse reactions vs 3.3% treated with placebo. The most common psychiatric adverse reactions were insomnia (2.4% vs 1.0%), anxiety (1.4% vs 0.9%), and depression (1.2% vs 0.9%). Three patients treated with DALIRESP experienced suicide-related adverse reactions (one completed suicide and two suicide attempts) compared to one patient (suicidal ideation) treated with placebo. • Patients should have their weight monitored regularly. If unexplained or clinically significant weight loss occurs, weight loss should be evaluated and treatment discontinuation considered. – In addition to weight loss being reported as a common adverse reaction (7.5% of patients treated with DALIRESP vs 2.1% placebo), weight was prospectively assessed in two 1-year clinical trials. In these studies that compared DALIRESP to placebo, 20% vs 7% experienced moderate weight loss (5-10% of body weight) and 7% vs 2% experienced severe weight loss (>10% body weight). During the follow-up period after discontinuing DALIRESP, the majority of patients regained some of the weight they had lost. • Use with strong cytochrome P450 enzyme inducers (eg, rifampicin, phenobarbital, carbamazepine, phenytoin) is not recommended, as they decrease the exposure and may reduce the therapeutic effectiveness of DALIRESP. Adverse Reactions In clinical trials the most common adverse reactions (≥2% and greater than placebo) were diarrhea (9.5% vs 2.7%), weight loss (7.5% vs 2.1%), nausea (4.7% vs 1.4%), headache (4.4% vs 2.1%), back pain (3.2% vs 2.2%), influenza (2.8% vs 2.7%), insomnia (2.4% vs 1.0%), dizziness (2.1% vs 1.1%), and decreased appetite (2.1% vs 0.4%). Please also see Brief Summary of full Prescribing Information on reverse side. COPD=chronic obstructive pulmonary disease.
References: 1. DALIRESP (roflumilast) Prescribing Information. Forest Pharmaceuticals, Inc. St. Louis, MO. 2. US Food and Drug Administration. FDA news release. March 1, 2011. http://www.fda.gov/NewsEvents/newsroom/PressAnnouncements/ucm244989.htm. Accessed November 16, 2011. 3. Data on file. Forest Laboratories, Inc. 4. Calverley PMA, Rabe KF, Goehring U-M, Kristiansen S, Fabbri LM, Martinez FJ; for the M2-124 and M2-125 study groups. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet. 2009;374:685-694. 5. US Food and Drug Administration. Atrovent approval history (NDA 019085, 1986). Drugs@FDA. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed November 16, 2011.
DALIRESP is a registered trademark of Nycomed GmbH. © 2012 Forest Laboratories, Inc. 84-12000159
DALIRESP® (roflumilast) tablets Brief Summary of Full Prescribing Information Initial U.S. Approval: 2011
INDICATIONS AND USAGE DALIRESP® is indicated as a treatment to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations. Limitations of Use DALIRESP is not a bronchodilator and is not indicated for the relief of acute bronchospasm. CONTRAINDICATIONS The use of DALIRESP is contraindicated in the following conditions: Moderate to severe liver impairment (Child-Pugh B or C) [see Clinical Pharmacology (12.3)and Use in Special Populations (8.6)]. WARNINGS AND PRECAUTIONS Treatment of Acute Bronchospasm DALIRESP is not a bronchodilator and should not be used for the relief of acute bronchospasm. Psychiatric Events including Suicidality Treatment with DALIRESP is associated with an increase in psychiatric adverse reactions. In 8 controlled clinical trials 5.9% (263) of patients treated with DALIRESP 500 mcg daily reported psychiatric adverse reactions compared to 3.3% (137) treated with placebo. The most commonly reported psychiatric adverse reactions were insomnia, anxiety, and depression which were reported at higher rates in those treated with DALIRESP 500 mcg daily (2.4%, 1.4%, and 1.2% for DALIRESP versus 1.0%, 0.9%, and 0.9% for placebo, respectively) [see Adverse Reactions (6.1)]. Instances of suicidal ideation and behavior, including completed suicide, have been observed in clinical trials. Three patients experienced suicide-related adverse reactions (one completed suicide and two suicide attempts) while receiving DALIRESP compared to one patient (suicidal ideation) who received placebo. Before using DALIRESP in patients with a history of depression and/or suicidal thoughts or behavior, prescribers should carefully weigh the risks and benefits of treatment with DALIRESP in such patients. Patients, their caregivers, and families should be advised of the need to be alert for the emergence or worsening of insomnia, anxiety, depression, suicidal thoughts or other mood changes, and if such changes occur to contact their healthcare provider. Prescribers should carefully evaluate the risks and benefits of continuing treatment with DALIRESP if such events occur. Weight Decrease Weight loss was a common adverse reaction in DALIRESP clinical trials and was reported in 7.5% (331) of patients treated with DALIRESP 500 mcg once daily compared to 2.1% (89) treated with placebo [see Adverse Reactions (6.1)]. In addition to being reported as adverse reactions, weight was prospectively assessed in two placebo-controlled clinical trials of one year duration. In these studies, 20% of patients receiving roflumilast experienced moderate weight loss (defined as between 5-10% of body weight) compared to 7% of patients who received placebo. In addition, 7% of patients who received roflumilast compared to 2% of patients receiving placebo experienced severe (>10% body weight) weight loss. During follow-up after treatment discontinuation, the majority of patients with weight loss regained some of the weight they had lost while receiving DALIRESP. Patients treated with DALIRESP should have their weight monitored regularly. If unexplained or clinically significant weight loss occurs, weight loss should be evaluated, and discontinuation of DALIRESP should be considered. Drug Interactions A major step in roflumilast metabolism is the N-oxidation of roflumilast to roflumilast N-oxide by CYP3A4 and CYP1A2. The administration of the cytochrome P450 enzyme inducer rifampicin resulted in a reduction in exposure, which may result in a decrease in the therapeutic effectiveness of DALIRESP. Therefore, the use of strong cytochrome P450 enzyme inducers (e.g. rifampicin, phenobarbital, carbamazepine, phenytoin) with DALIRESP is not recommended. [see Drugs That Induce Cytochrome P450 (CYP) Enzymes (7.1) and Clinical Pharmacology (12.3)]. ADVERSE REACTIONS The following adverse reactions are described in greater detail in other sections: • Psychiatric Events Including Suicidality [see Warnings and Precautions (5.2)] • Weight Decrease [see Warnings and Precautions (5.3)] Adverse Reactions in Clinical Studies Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety data described below reflect exposure of 4438 patients to DALIRESP 500 mcg once daily in four 1-year placebo-controlled trials, two 6-month placebo-controlled trials, and two 6-month drug add-on trials [see Clinical Studies (14.1)]. In these trials, 3136 and 1232 COPD patients were exposed to DALIRESP 500 mcg once daily for 6 months and 1-year, respectively.
The population had a median age of 64 years (range 40-91), 73% were male, 92.9% were Caucasian, and had COPD with a mean prebronchodilator forced expiratory volume in one second (FEV1) of 8.9 to 89.1% predicted. In these trials, 68.5% of the patients treated with DALIRESP reported an adverse reaction compared with 65.3% treated with placebo. The proportion of patients who discontinued treatment due to adverse reaction was 14.8% for DALIRESP-treated patients and 9.9% for placebo-treated patients. The most common adverse reactions that led to discontinuation of DALIRESP were diarrhea (2.4%) and nausea (1.6%). Serious adverse reactions, whether considered drug-related or not by the investigators, which occurred more frequently in DALIRESPtreated patients include diarrhea, atrial fibrillation, lung cancer, prostate cancer, acute pancreatitis, and acute renal failure. Table 1 summarizes the adverse reactions reported by ≥ 2% of patients in the DALIRESP group in 8 controlled COPD clinical trials. Table 1: Adverse Reactions Reported by ≥ 2% of Patients Treated with DALIRESP 500 mcg daily and Greater Than Placebo Treatment Adverse Reactions DALIRESP Placebo (Preferred Term) (N=4438) (N=4192) n (%) n (%) Diarrhea 420 (9.5) 113 (2.7) Weight decreased 331 (7.5) 89 (2.1) Nausea 209 (4.7) 60 (1.4) Headache 195 (4.4) 87 (2.1) Back pain 142 (3.2) 92 (2.2) Influenza 124 (2.8) 112 (2.7) Insomnia 105 (2.4) 41 (1.0) Dizziness 92 (2.1) 45 (1.1) Decreased appetite 91 (2.1) 15 (0.4) Adverse reactions that occurred in the DALIRESP group at a frequency of 1 to 2% where rates exceeded that in the placebo group include: Gastrointestinal disorders - abdominal pain, dyspepsia, gastritis, vomiting Infections and infestations - rhinitis, sinusitis, urinary tract infection, Musculoskeletal and connective tissue disorders - muscle spasms Nervous system disorders - tremor Psychiatric disorders - anxiety, depression DRUG INTERACTIONS A major step in roflumilast metabolism is the N-oxidation of roflumilast to roflumilast N-oxide by CYP3A4 and CYP1A2 [see Clinical Pharmacology (12.3)]. Drugs That Induce Cytochrome P450 (CYP) Enzymes Strong cytochrome P450 enzyme inducers decrease systemic exposure to roflumilast and may reduce the therapeutic effectiveness of DALIRESP. Therefore the use of strong cytochrome P450 inducers (e.g., rifampicin, phenobarbital, carbamazepine, and phenytoin) with DALIRESP is not recommended [see Drug Interactions (5.4) and Clinical Pharmacology (12.3)]. Drugs That Inhibit Cytochrome P450 (CYP) Enzymes The co-administration of DALIRESP (500 mcg) with CYP3A4 inhibitors or dual inhibitors that inhibit both CYP3A4 and CYP1A2 simultaneously (e.g., erythromycin, ketoconazole, fluvoxamine, enoxacin, cimetidine) may increase roflumilast systemic exposure and may result in increased adverse reactions. The risk of such concurrent use should be weighed carefully against benefit. [see Clinical Pharmacology (12.3)]. Oral Contraceptives Containing Gestodene and Ethinyl Estradiol The co-administration of DALIRESP (500 mcg) with oral contraceptives containing gestodene and ethinyl estradiol may increase roflumilast systemic exposure and may result in increased side effects. The risk of such concurrent use should be weighed carefully against benefit [see Clinical Pharmacology (12.3)]. USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic effects: Pregnancy Category C: There are no adequate and well controlled studies of DALIRESP in pregnant women. DALIRESP was not teratogenic in mice, rats, or rabbits. DALIRESP should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. DALIRESP induced stillbirth and decreased pup viability in mice at doses corresponding to approximately 16 and 49 times, respectively, the maximum recommended human dose (MRHD) (on a mg/m2 basis at maternal doses > 2 mg/kg/day and 6 mg/kg/day, respectively). DALIRESP induced post-implantation loss in rats at doses greater than or equal to approximately 10 times the MRHD (on a mg/m2 basis at maternal doses ≥ 0.6 mg/kg/day). No treatment-related effects on embryo-fetal development were observed in mice, rats, and rabbits at approximately 12, 3, and 26 times the MRHD, respectively (on a mg/m2 basis at maternal doses of 1.5, 0.2, and 0.8 mg/kg/day, respectively). Nonteratogenic effects: DALIRESP has been shown to adversely affect pup post-natal development when dams were treated with the drug during pregnancy and lactation periods in mice. These studies
found that DALIRESP decreased pup rearing frequencies at approximately 49 times the MRHD (on a mg/mg2 basis at a maternal dose of 6 mg/kg/day) during pregnancy and lactation. DALIRESP also decreased survival and forelimb grip reflex and delayed pinna detachment in mouse pups at approximately 97 times the MRHD (on a mg/m2 basis at a maternal dose of 12 mg/kg/day) during pregnancy and lactation. Labor and Delivery DALIRESP should not be used during labor and delivery. There are no human studies that have investigated effects of DALIRESP on preterm labor or labor at term; however, animal studies showed that DALIRESP disrupted the labor and delivery process in mice. DALIRESP induced delivery retardation in pregnant mice at doses greater than or equal to approximately 16 times the MRHD (on a mg/m2 basis at a maternal dose of > 2 mg/kg/day). Nursing Mothers Roflumilast and/or its metabolites are excreted into the milk of lactating rats. Excretion of roflumilast and/or its metabolites into human milk is probable. There are no human studies that have investigated effects of DALIRESP on breast-fed infants. DALIRESP should not be used by women who are nursing. Pediatric Use COPD does not normally occur in children. The safety and effectiveness of DALIRESP in pediatric patients have not been established. Geriatric Use Of the 4438 COPD subjects exposed to DALIRESP for up to 12 months in 8 controlled clinical trials, 2022 were > 65 years of age and 471 were > 75 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Based on available data for roflumilast, no adjustment of dosage in geriatric patients is warranted [see Clinical Pharmacology (12.3)]. Hepatic Impairment Roflumilast 250 mcg once daily for 14 days was studied in subjects with mild-to-moderate hepatic impairment classified as Child-Pugh A and B (8 subjects in each group). The AUCs of roflumilast and roflumilast N-oxide were increased by 51% and 24%, respectively in Child-Pugh A subjects and by 92% and 41%, respectively in ChildPugh B subjects, as compared to age-, weight- and gender-matched healthy subjects. The Cmax of roflumilast and roflumilast N-oxide were increased by 3% and 26%, respectively in Child-Pugh A subjects and by 26% and 40%, respectively in Child-Pugh B subjects, as compared to healthy subjects. DALIRESP 500 mcg has not been studied in hepatically impaired patients. Clinicians should consider the risk-benefit of administering DALIRESP to patients who have mild liver impairment (Child-Pugh A). DALIRESP is not recommended for use in patients with moderate or severe liver impairment (Child-Pugh B or C) [see Contraindications (4) and Clinical Pharmacology (12.3)]. Renal Impairment In twelve subjects with severe renal impairment administered a single dose of 500 mcg roflumilast, the AUCs of roflumilast and roflumilast N-oxide were decreased by 21% and 7%, respectively and Cmax were reduced by 16% and 12%, respectively. No dosage adjustment is necessary for patients with renal impairment [see Clinical Pharmacology (12.3)]. OVERDOSAGE Human Experience No case of overdose has been reported in clinical studies with DALIRESP. During the Phase I studies of DALIRESP, the following symptoms were observed at an increased rate after a single oral dose of 2500 mcg and a single dose of 5000 mcg: headache, gastrointestinal disorders, dizziness, palpitations, lightheadedness, clamminess and arterial hypotension. Management of Overdose In case of overdose, patients should seek immediate medical help. Appropriate supportive medical care should be provided. Since roflumilast is highly protein bound, hemodialysis is not likely to be an efficient method of drug removal. It is not known whether roflumilast is dialyzable by peritoneal dialysis. Manufactured by: Nycomed GmbH. Production Site Oranienburg Lehnitzstrasse 70 – 98 16515 Oranienburg Germany Manufactured for: Forest Pharmaceuticals, Inc. Subsidiary of Forest Laboratories, Inc. St. Louis, MO 63045, USA Daliresp® is a registered trademark of Nycomed GmbH. © 2010, 2011 Forest Laboratories, Inc. 084-12000414-BS-RMC17137-SEP11 Please also see full Prescribing Information at www.daliresp.com.
Updates and Controversies in Diabetes Care Tom A. Elasy, MD, MPH For a CME/CEU version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.
Summary Although there are many aspects of diabetes management, glucose control has been the most controversial in recent years. As new studies are published, managed care, clinicians and patients have questions on how management of diabetes should change. Key Points • In older patients with pre-existing heart disease, an A1C of less than 7 is an appropriate goal, but A1C should not be reduced to near normal based on the results of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study. • Metformin is initiated at the time of diagnosis unless a contraindication is present. • All the available oral agents have similar efficacy when used as second-line medications. • The choice of a second-line agent will depend on patient factors, adverse effects, convenience, and costs.
Given our population’s increasing weight and age, diabetes is a growing problem in the U.S. The prevalence of diabetes increases with age, with the highest rates in those over 65 (Exhibit 1).1 The highest number of new cases are in the 45 to 65 age group. Some of the current controversies in the management of diabetes include appropriate goals and medications. As new studies are published, managed care and providers must make decisions on whether practice needs to change. ACCORD is an example of a newer study which had a significant impact on care.2 This study in type 2 diabetes found that the use of intensive therapy to target normal glycated hemoglobin (A1C) levels for 3.5 years increased mortality and did not significantly reduce major cardiovascular events. The authors concluded that these findings identify a previ-
ously unrecognized harm of intensive glucose lowering in high-risk patients with type 2 diabetes. The important thing to understand about this study is the subjects were older patients with pre-existing heart disease. The study attempted to achieve near normal glycemic control (A1C of 6%) compared to standard (A1C < 7%). In older patients with preexisting heart disease, an A1C of less than 7 is an appropriate goal but the A1C should not be reduced to near normal based on the results of the ACCORD study. Several controversies related to diabetes medications have occurred in the past few years. Data on rosiglitazone (Avandia) increasing risk of heart attacks and heart failure is just one example. This has led to significantly reduced use of rosiglitazone. Several studies have linked insulin use to increased risk for developing cancer.3-5 Other studies have not
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Exhibit 1: Estimated percentage of people aged 20 years or older with diagnosed and undiagnosed diabetes, by age group, United States, 2005-20081
shown a link.6 The publication of these studies resulted in a flood of emails and calls to many managed care medical directors. At this time, it is unknown whether this is a true effect of the medication or the underlying disease is the reason for possible increased risk. In addition to ongoing controversies about medications, there are many challenges to managing patients with type 2 diabetes. The one challenge that gets the least press is time. Primary care providers do not have enough time to implement the current U.S. preventive service guidelines much less to manage acute problems.7 The health care system needs to get out of the mode of the doctor being responsible for everything during a visit. We need to determine a way to utilize other health care providers to provide the needed services. The other aspects of diabetes management are important but are not as hard or controversial as glucose management. Because the major killer of patients with diabetes is heart disease, other cardiovascular risk factors including hypertension and lipids need to be tightly controlled. To manage glucose, the majority of patients are being treated with oral agents (Exhibit 2).1 The American Diabetes Association (ADA) guidelines recommend metformin as the initial therapy at the time of diagnosis unless a contraindication is present. The recommendations were changed a few years ago to immediately initiate medication rather than giving the patient three to six months to lose weight and exercise.
The efficacy of oral agents as monotherapy depends on the baseline A1C â€“ the higher the baseline A1C, the greater the reduction. On average, oral agents result in a 1 to 2 percent reduction in A1C. Monotherapy fails in the majority of patients either initially because the A1C was excessively high or in the long term given the progressive nature of the disease. When monotherapy fails, addition of a second agent generally has an additive effect with a net additional decline in A1C of 1 to 2 percent. Most patients will require at least two medications to achieve control. The data are uncertain as to what is the most appropriate second-line agent. As of now, there are no known clear efficacy differences for second-line agents. Because the efficacy of all the oral agents as second-line agents is similar, the distinguishing factors between agents are patient factors, adverse effects, convenience, and cost. The two main issues for adverse effects are weight gain and hypoglycemia. Incretin agents are a relatively new area of therapy. Incretins are gut hormones that enhance insulin secretion in response to food (i.e., glucose-dependent insulin secretion). Glucagon like peptide (GLP-1) is the most well-characterized incretin that is secreted from L cells of the intestines. GLP-1 secretion is diminished in type 2 diabetes. The incretin agents are secretogogues which only work in the presence of food so they result in a lower incidence of hypoglycemia compared with the sulfonylureas. Typically, hypoglycemia does not occur at all if they are used as monotherapy. These agents also lead to
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Exhibit 2: Percentage of adults with diagnosed diabetes receiving treatment with insulin or oral medication, United States, 2007-20091
Insulin only Insulin and oral medication Oral medication only No medication
modest weight loss by increasing satiety. This lower rate of the two adverse effects of most concern has lead to wide use of these agents. Exenatide (Byetta®) was first to market, followed by liraglutide (Victoza®). These are widely prescribed injectables that are indicated as adjuncts to other medications. Many more of these are under study and likely to make it to market. The other incretin agents are the dipeptidyl peptidase inhibitors (DPP-IV) inhibitors, which work by inhibiting the enzyme that degrades naturally occurring GLP-1. Sitagliptin ( Januvia®) was first to market with saxagliptin (Onglyza®) being the second agent. These agents have few adverse effects and are weight neutral. These are oral agents with once daily dosing. Many more DPP-IV agents are also likely to come to market. Many patients with type 2 diabetes will require insulin therapy. An important point with insulin therapy is it is a two-step process. Therapy should be initiated and then intensified. Addition of insulin, as a second agent or third agent, is often achieved by adding bedtime NPH, glargine, or detemir. All of these forms of long-acting insulin are effective in reducing A1C by at least an additional 2 percent.
agents have similar efficacy. The choice of agent will depend on patient factors, adverse effects, convenience, and costs. Because new studies are consistently being published, managed care management guidelines will require frequent updating. Tom A. Elasy, MD, MPH is the Medical Director of the Vanderbilt Eskind Diabetes Clinic at Vanderbilt University Medical Center in Nashville, TN.
References 1. National Center for Health Statistics. 2005–2008 National Health and Nutrition Examination Survey. Available at http://www.cdc.gov/nchs/nhanes.htm. Accessed 1/26/2012. 2. Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545-59. 3. Currie CJ, Poole CD, Gale EA. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia. 2009;52:1766-77. 4. Hemkens LG, Grouven U, Bender R, et al. Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study. Diabetologia. 2009;52:1732-44. 5. Colhoun HM; SDRN Epidemiology Group. Use of insulin glargine and cancer incidence in Scotland: a study from the Scottish Diabetes Research Network Epidemiology Group. Diabetologia. 2009;52:1755-65. 6. Ruiter R, Visser LE, van Herk-Sukel MP, et al. Risk of cancer in patients on
insulin glargine and other insulin analogues in comparison with those on hu-
Several new options for therapy of type 2 diabetes have become available in recent years. More of these are to come. First-line therapy for patients with type 2 diabetes is metformin. In developing guidelines for second-line medications, all the available oral
man insulin: results from a large population-based follow-up study. Diabetologia. 2012;55:51-62. 7. Yarnall KS, Pollak KI, Østbye T, , et al. Primary care: is there enough time for prevention? Am J Public Health. 2003;93:635-41.
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Clinical and Cost Consequences of Incorporating a Novel Non-Invasive Prenatal Test into the Diagnostic Pathway for Fetal Trisomies Susan S. Garfield, DrPH; Shannon O. Armstrong, BA
Summary Background: Since 2007, the American College of Obstetricians and Gynecologists (ACOG) has recommended that all pregnant women be offered prenatal screening for fetal aneuploidy (i.e., trisomies 21, 18, 13). Current screening options include tests with sub-optimal sensitivity and specificity rates, while diagnostic procedures are invasive and create risk of procedure related miscarriage. The verifi™ test, a non-invasive test using circulating cell-free DNA (cfDNA), extracted from a maternal blood sample as early as 10 weeks gestation has demonstrated comparable sensitivity and superior specificity to invasive diagnostics in detecting fetal aneuploidy in chromosomes 21, 18, and 13. Methods: A cost-model was developed to evaluate the impact of incorporating this prenatal test into routine high-risk maternal screening practice. The multi-stage transition probability model leveraged published cost estimates from Medicare as well as practice patterns and disease rates from published literature. Results: The model demonstrates that inclusion of the verifi™ prenatal test provides clear clinical benefits. These include a 66 percent reduction in invasive diagnostic induced miscarriages and 38 percent more women receiving a T21 diagnosis. Total costs for prenatal screening and diagnosis for fetal aneuploidies are reduced by 1 percent annually. Conclusion: Significant clinical and cost advantages are likely to occur when novel non-invasive prenatal screening tests with high sensitivity and specificity are incorporated into routine high-risk screening practice. Key Points • High sensitivity and specificity non-invasive prenatal testing has the potential to reshape the prenatal testing paradigm. • When offered to women following a positive result from a screening test, these tests reduce the need for invasive testing. • The reduction in use of invasive prenatal testing reduces number of procedure induced miscarriages and may reduce total costs of prenatal care.
Trisomies 21 (Down syndrome, T21), 18 (Edwards syndrome, T18), and 13 (Patau syndrome, T13) are the most common live born aneuploidies (serious conditions caused by extra chromosomes).1 Trisomy 21 is the most frequently occurring of the three, occurring in, on average, one of every 740 live births, though incidence increases with maternal age.2 The average life expectancy for T21 individuals is 50 years. It is the leading cause of cogni-
tive impairment and affected persons also have a higher incidence of other health conditions including congenital heart disease, hearing, intestinal, and eye problems, celiac disease, leukemia, and thyroid dysfunction.3 Trisomy 18 occurs in about one in 5,000 live births,4 though, like T21, incidence increase with maternal age. Due to the presence of several lifethreatening medical problems, many infants with trisomy 18 die within their first month and as few as
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Exhibit 1: Model Inputs and Outputs Model Inputs
Test specific reimbursement rates
Total costs for prenatal screening and diagnosis of aneuploidies
Test specific acceptance rates differentiated by normal and high risk patients
Total costs by testing modality (trip/quad screen, ultrasound, Amnio, CVS, verifiâ„˘ test)
Age breakdown of pregnant cohort
Invasive procedures (Amnio and CVS) rates
Test specific performance characteristics (sensitivity and specificity)
Miscarriage rates and costs
Miscarriage rates, by aneuploidy
Early identification of fetal aneuploidy rates
Aneuploidy prevalence by age
Total number of each testing modality (first trimester screening tests, trip/quad screen, ultrasound, Amnio, CVS, verifiâ„˘ test) Total diagnosed aneuploidies (T21, T18, T13)
Invasive diagnostic induced miscarriage rates
Amnio rate per diagnosed aneuploidy
Invasive diagnostic testing practice following initial positive screening result
Cost per diagnosed aneuploidy
5 percent survive until their first birthday.4 The condition is associated with severe physical and cognitive disabilities including severe intellectual disability, heart defects and other major organ abnormalities, and low birth weight.4 Less common, trisomy 13 occurs in approximately one in 7,000 to 10,000 live births, likewise increasing with maternal age.5,6 Similar to trisomy 18, most infants with trisomy 13 die within the first seven days of life due to severe anatomic abnormalities, and 91 percent of trisomy 13-affected infants die before their first birthday.7 This condition is associated with severe physical and cognitive disabilities including cleft lip or palate, clenched hands and polydactyl, decreased muscle tone, hernias, severe cognitive defects, seizures, and microcephaly.6 In addition to the above characteristics, infants with trisomy 13 may have a single umbilical artery at birth which can be a sign of congenital heart defects such as abnormal heart placement, atrial or ventricular septal defect, and patent ductus arteriosus.6 Though rare, each of these trisomies creates different degrees of complications for the infant, including high infant mortality with T18 and T13. Due to a host of health concerns associated with aneuploidies, knowledge of fetal status can help clinicians and parents plan for appropriate care. Since 2007, the American College of Obstetricians and Gynecologists (ACOG) has recommended all pregnant women be offered prenatal screening for fetal aneuploidy (i.e., trisomies 21,18,13). Technolo-
Exhibit 2: T21 Incidence at Birth23 Maternal Age
Incidence at birth
Under 30 years old
30-34 years old
35-39 years old
40-44 years old
45-49 years old
gies currently used for routine screening include maternal serum screening (first and/or second trimester) and measurement of nuchal translucency by ultrasound (NT testing, first trimester). Second trimester ultrasound exam of the fetus is also used to detect anatomic abnormalities associated with these conditions and adds information to overall fetal assessment. While these screening modalities are useful in identifying pregnancies at elevated risk for fetal aneuploidy, they are not diagnostic and their sensitivity and specificity along with high screen positive rates lead to a significant number of false positives and, consequently, the possibility of unnecessary invasive diagnostic procedures.8,9,10 The trisomy 21 detection rate for first trimester combined screening is approximately 77 to 86 percent and is associated with a false positive rate of 3.2 to 5.6 percent.8 Sec-
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Exhibit 3: Test Performance Rates
1st Trimester combined screen for T21 (serum plus NT)
1st trimester combined (serum plus NT) screen for T18
2nd Trimester Serum screen for T21 in women <35 years old
2nd Trimester Serum screen for T21 in women <35 years old
2nd Trimester Serum screen for T18 in women < 35 years old
2nd Trimester Serum screen for T18 in women >35 years old
2nd Trimester ultrasound T21
2nd Trimester ultrasound T18
2nd Trimester ultrasound T13
ond trimester serum screening and sequential screenings are associated with a higher detection rate (85 percent and 94 percent, respectively), but also an increased rate of false positive results (8.5 percent and 11 percent).8 Invasive diagnostic testing, such as chorionic villus sampling (CVS) in first trimester or amniocentesis in second trimester, often follows a positive screening test in order to confirm the results. However, these tests carry increased risk to both the pregnant woman and fetus, including an increased risk of miscarriage. While point estimates vary, data from several systematic reviews, randomized controlled trials, and national registry studies suggest a procedure-related miscarriage rate of approximately 0.5 to 1 percent following amniocentesis or CVS.11,12,13,14 While 95 percent of obstetricians report routinely offering screening to all pregnant patients,15 not all women with a positive screening result elect to pursue invasive testing; and some with negative screening results still seek invasive testing. Uptake estimates of invasive diagnostic testing following a positive serum screen vary, with most studies reporting rates of approximately 60 percent.16,17,18,19 The reasons for not having an invasive diagnostic procedure vary, but a high percentage of women report that fear of complications impact their deci-
sions. In contrast, a small proportion of women whose pregnancies are determined to be low risk for fetal aneuploidies elect to undergo additional testing, despite the associated increased risk of miscarriage. Most of these women are found to have fetuses with normal chromosomes (or karyotypes). There is a clear unmet need for accurate, safe, non-invasive prenatal diagnostic technologies that allow for early diagnosis of fetal aneuploidies to provide more accurate information to pregnant women and their clinicians. Recent technological advances have spawned the development of novel prenatal diagnostic tests which are now poised to change the clinical and economic landscape of prenatal testing. Specifically, technologies incorporating the analysis of circulating cell-free DNA (cf DNA) extracted from a maternal blood sample as early as 10 weeks gestation have received widespread interest from the medical community and from women.20,21 These diagnostics have the potential to revolutionize prenatal testing by providing substantially more accurate results and reducing or eliminating the need for invasive procedures and their associated risk of fetal loss. One recently commercialized non-invasive prenatal test that uses maternal whole blood from a single blood draw to detect aneuploidy in chromosomes 21, 18, and 13 by massively parallel DNA sequencing
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Exhibit 4: Cost Inputs
Test Estimated Cost 1st Trimester combined screen
2nd Trimester serum screen
2nd Trimester Ultrasound exam of fetus
Chorionic Villus Sampling
verifiâ„˘ prenatal test cost
maternal plasma DNA 22 is the verifiTM prenatal test (Verinata Health Inc., Redwood City, CA). The blood sample is obtained by routine peripheral venipuncture, and the plasma is then separated from the blood cells. Total DNA in the plasma is then extracted, with the resulting mixture containing cf DNA of both maternal and fetal origin. Massively parallel sequencing (MPS) of DNA is then performed to generate millions of DNA sequence tags which are then aligned with a reference genome DNA sequence and undergo analysis with a proprietary algorithm to yield an aneuploidy classification for the sample for the chromosomes of interest (e.g., 21, 18, and 13). The result, provided within eight to 10 business days of obtaining a blood sample, is reported. The test can be done as early as ten weeks gestation. The MatErnal BLood IS Source to Accurately Diagnose Fetal Aneuploidy (MELISSA) study was designed to demonstrate the performance of the verifiTM test (clinicaltrials.gov identifier NCT01122524). The MELISSA study enrolled patients with pregnancies at high risk for fetal aneuploidy due to at least one of the following factors: advanced maternal age (38 years of age or older in this study), a positive result from a serum screening test, soft or hard markers from ultrasound associated with fetal aneuploidy (e.g., increased NT thickness, cystic hygroma, congenital anomaly or amniotic fluid anomaly), or previous aneuploidy pregnancy. Blood samples were obtained from 2,882 women prior to their undergoing invasive prenatal diagnostic procedures at 60 sites in the United States. All singleton pregnancies with any abnormal karyotype and a random complement of subjects with euploid (normal chromosome number) karyotypes were selected by an independent biostatistician for analysis in a prospective, blinded fashion. Independent classifications of aneuploidy status were made for each sample, namely: chromosome 21,
chromosome 18, and chromosome 13 as affected or unaffected. These classifications were then compared to the corresponding fetal karyotype by the independent biostatistician to determine performance of the verifiTM test. Within the analysis cohort of 532 samples, the test correctly identified 89 of 89 (100 percent; 95 percent CI 95.9-100.0) cases of trisomy 21, 35 of 36 (97.2 percent; 95 percent CI 85.5-99.9) cases of trisomy 18, and 11 of 14 (78.6 percent; 95 percent CI 49.2-99.9) cases of trisomy 13. There were no false positives (specificity = 100 percent).21 Based on the clinical results obtained from the MELISSA study, an economic model was developed to evaluate the cost consequences of practice change given the results found in the study, if the test were incorporated into standard of care. The model details the expected clinical and economic impact of incorporating this test into routine clinical practice for high-risk pregnancies. The impact of test adoption was modeled using cost and assigned test performance variables from the MELISSA trial as well as accepted medical evidence in the field of prenatal screening and diagnosis. The model followed practice patterns of having positive test results followed by an invasive procedure to verify the results. Methodology
Bridgehead developed a detailed transition state probability model in Microsoft Excel that captures the complex screening and diagnostic paradigm from both a cost and clinical practice perspective. The model takes theoretical cohort of 100,000 pregnant women at high risk for fetal aneuploidy based on either first or second trimester screening and assesses expected cost and clinical impact the introduction of the verifiTM test for Trisomy 21, 18, and 13 will have as compared to current practice. The model inputs and outputs are detailed in Exhibit 1.
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Exhibit 5: Adoption Rates of Prenatal Testing Test Normal Risk High Risk 1st Trimester Combined Screening Triple or Quad Serum Screening
2nd Trimester Ultrasound
CVS (without a prior screen)
Amnio (without a prior screen)
CVS (following a positive screen)
Amnio (following a positive screen)
The model divides the cohort into two groups by inherent risk, and each group proceeds through a theoretical pregnancy chronologically. Women may begin prenatal care in either the first or second trimester. It was assumed that 81 percent of women begin their prenatal care in the first trimester. The first testing point offered is the first trimester screen. Under the standard of care, women with a positive from the first trimester screen may be offered either an immediate CVS or a second trimester amniocentesis. With verifiTM testing, women may receive either an immediate verifiTM test or CVS or a second trimester amniocentesis. Positives from the verifiTM test in the first trimester were eligible to receive either CVS or amniocentesis. It was assumed, using published miscarriage rates for each trisomy, that some true positive from the first trimester would miscarry before the second trimester amniocentesis. At the conclusion of the first trimester, all women who had not previously received first trimester screening are offered the second trimester serum screen. Positives from the second trimester serum screen are offered either amniocentesis or verifiTM test followed by amniocentesis. Women are offered second trimester ultrasound independent of any previous testing, with positives from the ultrasound being offered either amniocentesis or verifiTM test followed by amniocentesis. The model utilizes a combination of published incidence and miscarriage rates for T21, T18 and T13, sensitivity and specificity of current prenatal screens and invasive diagnostic procedures, and expected reimbursement rates to estimate the clinical and economic impact of incorporating the test into routine prenatal screening paradigms. Weighted average incidence rates were calculated using clinically acceptable risk formula cited in Cuckle et al (Exhibit 2).23 Test performance characteristics from the literature
were used within the model (Exhibit 3). Because performance of the second trimester serum screen for T21 is dependent on maternal age, performance characteristics used within the model are weighted averages based on maternal age.24 The verifiâ„˘ test was modeled at sensitivity/specificity characteristics of 100 percent/100 percent, 97.2 percent/100 percent, and 78.6 percent/100 percent respectively for Trisomy 21, 18, and 13 (as compared to invasive diagnostic procedures). Costs were estimated using January 2012 Medicare reimbursement rates based on applicable CPT codes plus 20 percent, in order to estimate the actual reimbursement provided by private U.S. health insurance organizations. Costs were considered in their totality, including physicianâ€™s fees, facility fees and laboratory fees for each test, with the exception of serum testing. These blood tests are provided as part of routine prenatal care. They do not require a separate or additional physician visit. Costs for serum testing were considered as the laboratory costs only. Prenatal testing costs used within the model are shown in Exhibit 4. Finally, the adoption rate of current prenatal testing was considered, as not all pregnancies receive prenatal screening or invasive testing. The use of prenatal testing is dependent upon geography, maternal age, and maternal socioeconomic status. The uptake of prenatal testing was stratified based on inherent maternal risk (advanced maternal age or previous aneuploidy pregnancy) and was estimated using a combination of published literature and quantitative primary research with clinicians and patients (Exhibit 5). Rates of amniocentesis uptake following a positive screening test were taken from Mueller et al 2005.17 It was assumed that women receiving a first trimester combined screen would not also receive a
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Exhibit 6: Modeled prenatal diagnostic pathway which incorporates non-invasive prenatal testing
+ Positive Screening Test Result
Non-invasive Prenatal Diagnostic*
Amniocentesis or CVS
– No Further Testing
*Non-invasive prenatal test model is based on data from the MELISSA study, evaluating the performance of the verifi™ test
second trimester screen, though they may receive a second trimester ultrasound. Therefore, the rates of acceptance for second trimester screening (70 percent or 80 percent, depending on baseline risk) were applied to only the women who had not elected a first trimester screen. Similarly, women who had received a first trimester CVS were not eligible to receive a second trimester amniocentesis. The lower uptake of CVS is based on a single study of the impact of first trimester combined screening on invasive diagnostic procedure uptake, showing a preference for amniocentesis over CVS (71 percent versus 29 percent).31 While some women receive a “fully integrated” screen, which uses both the first trimester combined screen and second trimester maternal serum screen, that screening modality was not considered within this model. Women in the model were eligible to receive the verifiTM test in the first trimester following a positive first trimester screen. Additionally, women were eligible to receive the test in the second trimester following a positive result from the second trimester serum screen or second trimester ultrasound. It was not assumed that the test would increase uptake of prenatal testing generally. Within the model, the uptake of the test in either the first or second trimester was confined to the maximum uptake of existing prenatal screening and diagnostics. Further, it was assumed that 80 percent of women at baseline high risk and 71 percent of women at baseline normal risk would choose the test following a positive screening result. This adoption rate assumes a small increase in demand over invasive diagnostic testing for non-invasive follow-up diagnostic testing after a positive screening result due to elimination of miscarriage anxieties. Miscarriage rates of 0.5 percent for amniocentesis and 1 percent for CVS were used to estimate ex-
pected miscarriages in the two scenarios. The model explored the use of the verifiTM test both with and without a confirmatory invasive procedure following a positive test result from the test. A sensitivity analysis was conducted to understand the impact to overall results of each component variable. The sensitivity result findings were used to identify areas of high impact as well as to determine where future work should be focused. Results
The model demonstrates that inclusion of the verifiTM test into the prenatal testing paradigm for high-risk women will provide clear clinical benefits. The biggest benefit to women comes from a reduction in miscarriages due to invasive testing. In the modeled population of five million covered lives with 100,000 pregnancies annually, invasive diagnostic induced miscarriages are reduced from 60 to 20, a 66 percent reduction. When an invasive procedure is never used following a positive test result, miscarriages are further reduced to 18. Another clinical benefit of the verifiTM test is an earlier and accurate diagnosis of fetal aneuploidy. Testing with this novel blood test is possible as early as the tenth gestational week. The high performance of this test, regardless of gestational age, allows more women to receive an earlier definitive diagnosis. The adoption of the novel test results in 15 percent more women receiving a T21 diagnosis (148 with the standard of care versus 170 with verifi™ testing) and 2 percent more women receiving a T18 diagnosis (44 with the standard of care versus 45 with verifiTM testing), in the modeled population of 100,000 pregnancies. Finally, the cost impact of the verifiTM test is an important consideration for health plans. In addition to being clinically beneficial compared to the current prenatal testing paradigm, use of the test prom-
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ises to moderately reduce overall costs. Total costs for prenatal screening and diagnosis for fetal aneuploidies is expected to be $59,748,721 for 100,000 pregnancies under the current standard of care. The total cost for prenatal testing which incorporates the verifiâ„˘ test is expected to be $59,228,142 for 100,000 pregnancies, a savings of $520,578 or nearly 1 percent annually. The inclusion of verifiTM testing is driven by an important assumption within the model. A higher acceptance rate for verifiTM testing has been assumed as compared to acceptance rates for either CVS or amniocentesis. It has been anticipated that more women will accept a non-invasive blood test with no miscarriage risk. While the use of CVS and amniocentesis has been reduced by 72 percent in this model through the introduction of verifiTM testing, 927 more women receive some form of follow-up diagnostic after a positive screen in the verifiTM scenario than in the standard of care. While seemingly moderate, the 1 percent savings is accompanied by an improved clinical experience by ruling out the need for clinically unnecessary invasive testing for many women. The model shows that with this test, the number of invasive procedures necessary in order to diagnosis a single aneuploidy is reduced by 81 percent from 43 to eight. Sensitivity analysis reveals several important drivers of overall costs within the model. The cost of the verifiTM test had a large impact on the overall cost benefit of testing. With pricing of up to $1,200 per test, adoption of the verifiTM test yields cost savings when provided to women with a positive screening test. The cost of amniocentesis is also an important determinant of total costs. As the cost of amniocentesis increases, total cost benefit of the verifiTM test also increases. Because uptake of screening tests ultimately determines eligibility for testing, the use of screening tests is an important driver of costs. Most significant to cost outcomes is the rate of second trimester ultrasound as many fetal trisomies are first identified during ultrasound. As use of the second trimester ultrasound drops, fewer women are indicated for invasive testing, resulting in fewer diagnoses, but lower costs. Testing with verifiTM remains cost effective at ultrasound adoption rates below 40 percent. Similar to adoption rates, the specificity of prenatal screening is an important driver of costs and outcomes as specificity determines the total number of clinically unnecessary invasive tests. Specificity of ultrasound, second trimester serum screening, and first trimester screen were impactful to overall cost benefit. Conclusions
The availability of a highly sensitive test that identifies risk for major aneuploidy disorders (i.e., Down
syndrome, Edwards syndrome, Patau syndrome) is a major change in prenatal screening. With sensitivity and specificity approaching or equaling 100 percent, the significantly improved accuracy will almost certainly lead to rapid practice change among obstetricians and maternal and fetal medicine specialists and uptake by pregnant women. Payers will be challenged to consider how to cover the verifiTM test and other novel non-invasive prenatal diagnostics, either enabling broad-based access or limiting coverage to a pre-defined population of women determined to be high risk. The findings of the model suggest a highly sensitive and specific test that identifies trisomy 21,18, and 13 would be cost saving by offsetting costs associated with clinically unnecessary invasive tests and resulting miscarriages. The high economic and emotional costs of amniocentesis and CVS could be significantly curtailed by use of non-invasive prenatal diagnostics, leading to more rational use of health care resources. While several non-invasive prenatal diagnostics are currently in development, tests with the highest sensitivity and specificity will have the most positive economic impact to payers by decreasing false positive rates and associated unnecessary follow-up costs for invasive tests by 71 percent. These economic savings can be considered alongside the significant decrease in anxiety and reassurance women will have with safer, earlier, and improved availability of results. These types of advancements in care are rare. Today, the clinical evidence for most non-invasive prenatal tests recently launched or soon to enter the market focuses on high-risk pregnancies (i.e., > age 35, previous aneuploidy birth, etc.). However, as data emerge about the utility of these tests as true screeners in the general population more economic analysis will be required to fully quantify the likely impact. Preliminary assessment using the performance variables from current studies on the theoretical cohort of 100,000 pregnancies suggest that screening all pregnancies would reduce unnecessary invasive tests by 88 percent and prevent 53 pregnancies from falling victim to diagnostic induced miscarriage. This significant clinical benefit comes at some cost when broadly applied. As such, ongoing modeling efforts can be used to detail the implications of different price, utilization, and performance variables to ongoing cost-effectiveness. Ultimately, payers and other policy makers need to work with manufacturers, clinicians, and womenâ€™s health organizations to facilitate patient education about the availability of these novel diagnostics. Additionally, given the cost-effectiveness and clinically superior performance non-invasive prenatal tests provide compared to current practice, coverage
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policies should be developed that enable access for all indicated women. Further study is warranted to assess patient acceptance, clinician adoption, and real-world impact on practice patterns and behavior.
chorionic villus sampling for prenatal diagnosis. Cochrane Database System Rev. 2003; 3: CD003252 14. Tabor A, Alfirevic Z. Update on Procedure-related Risks for Prenatal Diagnosis Techniques. Fetal Diagn Ther. 2010; 27:1-7. 15. Driscoll DA, Morgan MA, Schulkin J. Screening for Down syndrome: chang-
Susan Garfield, DrPH a Vice President at Bridgehead International, is
ing practice of obstetricians. Am J Obstet Gynecol. 2009;200: 459.e1-459.e9
a health economist with expertise in market access, reimbursement
16. Beekhuis JR, de Wolf BTHM, Mantingh A, Heringa MP. The influence of
and novel technologies. Prior to joining Bridgehead, she was the
serum screening on the amniocentesis rate in women of advanced maternal age.
Director,Global Reimbursement, Policy and Economic Strategy at QIA-
Prenat Diagn. 1994; 14(3): 199-200.
GEN Corporation. She received her Doctorate of Public Health from
17. Mueller VM, Huang T, Summers AM, Winsor SHM. The influence of risk
estimates obtained from maternal serum screening on amniocentesis rates. Pre-
Shannon Armstrong, BA is a Consultant at Bridgehead Internation-
nat Diagn. 2005; 25(13): 1253-1257.
al. She has developed economic models highlighting the clinical and
18. de la Vega A, Verdiales M, Leavitt G. Method of risk assessment affects ac-
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19. Jaques AM, Collins VR, Amor DJ, et.al. Uptake of prenatal diagnostic test-
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20. Sehnert AJ, Rhees B, Comstock D et al. Optimal Detection of Fetal Chro-
Funding for this research was provided by Verinata Health Inc. (Red-
mosomal Abnormalities by Massively Parallel DNA Sequencing of Cell-Free
wood City, CA)
Fetal DNA from Maternal Blood. Clinical Chemistry. 2011, 57:7
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21. Bianchi D, Platt L, Goldberg J, et al. Genome wide fetal aneuploidy detec1. Kagan KO, Wright D, Valencia C, Maiz N, Nicolaides KH. Screening for
tive, blinded, multicenter study. AJOG. 2012; 206(1): S367.
trisomies 21, 18 and 13 by maternal age, fetal nuchal translucency, fetal heart
22. Verinata Health Inc. MatErnal BLood IS Source to Accurately Diagnose Fetal
rate, free -hCG and pregnancy-associated plasma protein-A. Human Repro-
Aneuploidy (MELISSA). In: ClinicalTrials.gov [Internet]. Bethesda (MD): Na-
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2. National Library of Medicine. Down syndrome. Available at: http://ghr.nlm.
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nih.gov/condition/down-syndrome. Accessibility verified January 23, 2012
23. Cuckle HS, Wald NJ, Thompson SG. Estimating a woman’s risk of having a
3. National Institutes of Health. Down Syndrome. Available at: http://www.
pregnancy associated with Down’s syndrome using her age and serum a-feto-
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protein level. Br J Obstet Gynaecol. 1987; 94:387–402.
January 23, 2012.
24. Cuckle HS, Benn PA. Multi-Marker Maternal Serum Screening for Chro-
4. National Library of Medicine. Trisomy 18. Available at: http://ghr.nlm.nih.
mosomal Abnormalities. In: Milunsky A, Milunsky J. Genetic Disorders and
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the Fetus: Diagnosis, Prevention and Treatment: 6th Edition. Wiley-Blackwell.
5. Savva GM, Walker K, Morris JK. The maternal age-specific live birth preva-
lence of trisomies 13 and 18 compared to trisomy 21 -(Down syndrome). Pre-
25. Tul N, Spencer K, Noble P, et al. Screening for trisomy 18 by fetal nuchal
natal Diagnosis. 2010;30: 57-64.
translucency and maternal serum free beta-hCG and PAPP-A at 10-14 weeks of
6. National Library of Medicine. Trisomy 13. Available at: http://www.ncbi.nlm.
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26. Benn PA, Kaminsky LM, et al. Combined Second-Trimester Biochemical
7. Rasmussen SA, Wong LYC, Yang Q, May KM, Friedman JM. Population-based
and Ultrasound Screening for Down Syndrome. Obstet Gynecol. 2002;100(6):
analyses of mortality in trisomy 13 and trisomy 18. Pediatrics. 2003;111(4): 777-784.
8. Malone FD, Canick JA, Ball RH, Nyberg DA, Comstock CH et al. First-
27. Nyberg DA, Souter VL, El-Bastawissi A, Young S, Luthhardt F, Luthy DA.
trimester or second-trimester screening, or both, for Down’s syndrome. New
Isolated sonographic markers for detection of fetal Down syndrome in the sec-
England Journal of Medicine. 2005; 353: 2001–2011.
ond trimester of pregnancy. J Ultrasound Med. 2001; 20(10):1053-63.
9. Egan JFX, Kaminsky LM, DeRoche ME, et al. Antenatal Down syndrome
28. Lehman CD, Nyberg D, Winter TC III, Kapur RP, Resta RG, Luthy DA.
screening in the United States in 2001: a survey of maternal-fetal medicine
Trisomy 13 syndrome: Prenatal US findings in a review of 33 cases. Radiology.
specialists. American Journal of Obstetrics and Gynecology. 2002;187:1230-4
10. Wald NJ, Rodeck C, Hackshaw AK, et al. First and second trimester antena-
29. Hahnemann JM, Vejerslev LO. Accuracy of cytogenetic findings on chori-
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onic villus sampling (CVS)--diagnostic consequences of CVS mosaicism and
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non-mosaic discrepancy in centres contributing to EUCROMIC 1986-1992.
11. Mujezinovic F, Alfirevic Z: Procedure-related complications of amniocen-
Prenat Diagn. 1997 Sep;17(9):801-20.
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30. Midtrimester amniocentesis for prenatal diagnosis. Safety and accuracy.
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www.namcp.org | Vol. 15, No. 2 | Journal of Managed Care Medicine 41
Estimation of Long-Term Increased Risk of Coronary Heart Disease and Type 2 Diabetes with Metabolic Complications Observed in the Catie Study: Relative Risk and the Number Needed to Harm for Second-Generation Antipsychotics Sonja V.Sorenson, MPH; Henry Nasrallah, MD; Kafi N. Sanders, MPH
Summary Second-generation antipsychotic agents have variable liability to cause weight gain, dyslipidemia, hyperglycemia, and associated cardiovascular complications. We sought to model change in 10-year risk for coronary heart disease (CHD) and type 2 diabetes mellitus as a function of change in the fasting metabolic parameters of patients with schizophrenia enrolled in phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study. This model incorporated risk equations from the Framingham Heart Study (FHS) for CHD and from national epidemiologic surveys for diabetes. Annual incidence rates were estimated for primary and secondary CHD, stroke events, and new-onset diabetes. Risks for each second-generation antipsychotic included in the CATIE study were quantified using relative risk (RR) vs ziprasidone. The model estimated that over a 10-year time period treatment with olanzapine, and to a lesser extent quetiapine and risperidone, would increase the risk for CHD and diabetes in both men and women. In contrast, the model indicated that ziprasidone would not increase the risk for CHD or diabetes relative to no treatment (no change from patients’ baseline metabolic status). Key Points • Global mortality statistics indicate that cardiovascular disease is the leading cause of death in patients with schizophrenia and other major mental illnesses.1-3 • We estimated medication-attributable risk for CHD and diabetes in a simulation model by applying validated prediction algorithms to the changes in weight and other metabolic parameters observed in phase 1 of the CATIE study for patients treated with second-generation antipsychotics.4,5 • Second-generation antipsychotic treatment selection, as well as adherence to metabolic testing guidelines (as recommended by the American Diabetes Association/American Psychiatric Association), should be carefully considered in patients with schizophrenia.
Global mortality statistics indicate that cardiovascular disease is the leading cause of death in patients with schizophrenia and other major mental illnesses, and contributes to a 3-fold increase in age-adjusted mortality.1-3 Additional evi-
dence documents that cardiovascular risks including overweight status and obesity, diabetes, dyslipidemia, and smoking have a higher prevalence in patients with schizophrenia and other major mental illnesses compared with the general population.6 However, existing data do not provide clarity about
42 Journal of Managed Care Medicine | Vol. 15, No. 2 | www.namcp.org
Exhibit 1: Model Structure
Continue Treatment (no additional switch)
No Treatment Switch
No Psychiatric Relapse Discontinue Treatment (remain off treatment)
Metabolic Effects/ Weight Gain
Other Adverse Events No Other Adverse Events
No Metabolic Effects/Weight Gain
Other Adverse Events No Other Adverse Events
Metabolic Effects/ Weight Gain
Other Adverse Events No Other Adverse Events Other Adverse Events No Other Adverse Events
No Metabolic Effects/Weight Gain
EPS Sexual Dysfunction Insomnia
Same as above
Ziprasidone Patient Characteristics Time Invariant: Sex Smoking status Age at disease onset
Adult Patients with Chronic/Recurrent Schizophrenia Other Atypical Antipsychotic Agent: (1) Olanzapine (2) Risperidone (3) Quetiapine
remain off treatment
Same as above
Same as above
Update Annually: Age Hypertension status Lipid levels CHD history
Treatment-related Adverse Events (Metabolic) Elevated lipid levels, Weight gain
Risk of Type 2 Diabetes and Complications Function of weight gain, Baseline risk factors
Assess Risk of CHD Events Using Framingham Risk Equations Elevated lipid levels, Diabetes and Hypertension status
Exhibit 2: 9-month Estimated Change From Baseline in Weight- and Exposure-Adjusted Mean Lipid Concentrations Based on the CATIE Population*
Weight (lb) TC (mg/dL) TG (mg/dL) LDL-C (mg/dL)a
18.0 9.4 40.5 1.3
4.5 6.6 21.2 2.4
3.6 –1.3 –2.4 –0.8
–2.7 –8.2 –16.5 –4.9
Source: Lieberman 2005.7
TC = total cholesterol; TG = triglycerides; LDL-C = low-density lipoprotein cholesterol. * For weight, monthly rate of change from CATIE data multiplied by nine; for lipids, exposure-adjusted mean is the least-squares mean from an analysis of covariance adjusting for whether the patient had had an exacerbation in the preceding 3 months and for duration of exposure to study drug during phase 1. a LDL-C derived as follows: LDL-C = TC – HDL-C – (1/5*TG), assuming no change in HDL-C.
the differential impact of individual second-generation antipsychotic medications on the long-term risk of developing type 2 diabetes mellitus or cardiovascular complications (e.g., angina, myocardial infarction [MI], and stroke).7,8 Current antipsychotic consensus guidelines and second-generation antipsychotic class warnings describing cardio-metabolic risk among antipsychotic users were derived from the findings in retrospective-cohort and case-report studies.9,10 Completion of the CATIE study (funded by the National Institute of Mental Health) provided further supporting evidence from a randomized, double-blind, pragmatic clinical trial indicating medication-related
changes in weight, lipid, and glucose parameters assessed in a fasting state.4 The results of the CATIE study (N = 1460) describe increases in bodyweight of >7 percent in 7 to 30 percent of second-generation antipsychotic users who were prescribed olanzapine, quetiapine, risperidone, or ziprasidone. Overall mean weight change from baseline to endpoint ranged from -0.3 lb/month to 2.0 lb/month.4 Worsening of other metabolic parameters over time, including glycosylated hemoglobin, total cholesterol, and triglyceride concentration, is also described in the study results.4 In descending order, the agents that caused the greatest adverse changes were olanzapine, quetiapine, and risperidone; ziprasidone was
www.namcp.org | Vol. 15, No. 2 | Journal of Managed Care Medicine 43
Exhibit 3: 10-year Event Rate per 10,000 Population and Number Needed to Harm (NNH) Event Type
Ziprasidone Rate (2.5% - 97.5% percentiles)
1,294.5 (944.8 – 2,557.7)
Rate (2.5% - 97.5% percentiles)
458,991 1,521.3 (963.3 – 2,619.4)
Rate (2.5% - 97.5% percentiles)
Rate (2.5% - 97.5% percentiles)
1,351.1 (945.7 – 2,563.0)
1,351.1 (939.3 – 2,558.1)
No Antipsychotic NNHa
Rate (2.5% - 97.5% percentiles)
1,294.5 (957.3 – 2,617.7)
CHD events Angina
270.7 (247.8 – 305.1)
317.2 (280.4 – 338.3)
296.7 (275.1 – 330.8)
283.0 (260.4 – 315.0) –5,736 284.7 (264.5 – 316.2)
295.2 (272.4 – 324.5)
344.4 (308.8 – 361.6)
322.4 (301.2 – 350.1)
307.9 (286.2 – 334.7)
–6,074 309.6 (290.1 – 334.6)
118.6 (115.8 – 122.9)
–24,747 120.8 (117 – 124.3)
119.4 (116.7 – 124.2)
–180,185 119.0 (116.2 – 123.4)
All CHD Death
94.6 (88.5 – 106.1)
–4,051 104.7 (95.7 – 115.2)
99.7 (93.5 – 111.2)
266,785 97.1 (91.1 – 108.8)
779.0 (726.0 – 856.8)
15,029.1 (10,551.6 –19,594.9)
–0.398 10,676.3 (7,648.7 – 14,171.3)
2,064.7 (1,304.1 – 2,806.0)
309,937 2,391.9 (1,388.2 – 2,875.2)
887.1 (803.2 – 937.9)
838.1 (787.6 – 914.6)
–0.339 17,508.3 (13,785.0 – 21,500.4)
28,882 119.0 (116 – 123.6) 3,790
97.1 (90.9 – 108.0) 807.0 (754.8 – 878.6)
–2,934 810.4 (762.5 – 881.7)
–0.441 13,470.6 (10,088.7 – 16,750.1)
–0.374 40,174.6 (40,161.6 – 40,182.6)
2,202.6 (1,320.8 – 2,827.6)
2,202.6 (1,324.6 – 2,827.4)
2,064.6 (1,276.8 – 2,878.0)
CHD events Angina
782.2 (309.4 – 873.3)
944.8 (384.4 – 1032.4)
896.9 (364.1 – 988.7)
833.7 (334.6 – 918.3) –6,183 835.3 (336.4 – 924.1)
361.2 (172.0 – 391.3)
424.7 (210.3 – 458.2)
408.0 (198.3 – 439.1)
380.3 (184.1 – 408.8) –2,214 384.8 (185.5 – 409.6)
58.8 (52.2 – 64.8)
–19,695 60.9 (53.4 – 66.8)
60.1 (53.0 – 66.1)
11,842 59.6 (52.7 – 65.4)
29,923 59.3 (52.4 – 66.0)
All CHD Death
62.1 (44.1 – 70.6)
–4,001 71.6 (50.7 – 80.0)
68.0 (48.0 – 76.9)
65.1 (46.2 – 73.5)
21,435 64.6 (46.2 – 74.0)
1,264.3 (580.8 – 1,391.6)
1,433.1 (665.3 – 1,560.3)
1,338.7 (619.6 – 1,456.0)
–1,875 1,344.0 (622.3 – 1,463.0)
15,062.9 (10,332.6 – 20,267.7)
1,502.0 (702.9 – 1,627.2)
–0.397 10,701.0 (7,299.2 – 14,196.7)
–0.338 17,547.9 (13,832.9 – 21,276.4)
not associated with weight gain or worsening of metabolic parameters. The complete results of the CATIE study have been previously published.11 Notwithstanding the importance of the CATIE trial in clarifying the metabolic effects of the second-generation antipsychotic agents, the duration of medication exposure (median = six months) and post-treatment metabolic assessments were insufficient to examine directly the subsequent diabetes and cardiovascular disease events. To obtain longterm disease estimates, CATIE investigators applied the 10-year prediction algorithms from the FHS to the phase 1 baseline metabolic assessments to estimate the risk for a primary CHD event at enrollment. Results indicated a 34 percent higher risk in men and a 50 percent higher risk in women for CHD than in age- and gender-matched controls in the general population. Elevations in CHD risk were attributable to substantially higher rates of smoking (68 percent vs 35 percent); diabetes, defined as fasting blood sugar ≥126 mg/dL, or treat-
–0.440 13,500.9 (10,082.9 – 16,986.8)
40,265.7 (40,252.0 – 40,285.9)
ment with oral hypoglycemic agents or insulin (13 percent vs 3 percent); hypertension, defined as systolic blood pressure (SBP) ≥140, diastolic blood pressure ≥90 mmHg, or treatment with antihypertensive medication (27 percent vs 17 percent); and lower serum concentrations of high-density lipoprotein cholesterol (HDL-C) (43.7 mg/dL vs 49.3 mg/dL).7 The CATIE study is also ideal for assessing medication-attributable risk because of the study’s randomized, double-blind, pragmatic design and fasting laboratory assessments, which allow potential confounders such as lifestyle, behavior, access to medical care, and medication history to be controlled more effectively than in previous research. As a result, estimates of CHD and diabetes risk derived from the CATIE study may complement existing retrospective studies and case reports12,13 about the long-term disease consequences of treatment with second-generation antipsychotics. These studies largely support the hypothesis that olanzapine
44 Journal of Managed Care Medicine | Vol. 15, No. 2 | www.namcp.org
Table 4. Relative Risk of Events
1.18 (1.00 – 1.54)
1.04 (1.00 – 1.30)
1.04 (0.65 – 1.38)
All CHD death
Total CHD (95% CI)
1.14 (1.06 to 1.16)
1.08 (1.04 to 1.13)
1.04 (0.97 to 1.11)
1.16 (1.00 to 1.29)
1.07 (1.00 to 1.13)
1.07 (1.00 to 1.14)
All CHD death
Total CHD (95% CI)
1.19 (1.12 to 1.83)
1.13 (1.07 to 1.70)
1.06 (0.99 to 1.59)
Males Diabetes (95% CI) CHD events
Females Diabetes (95% CI) CHD events
increases the risk of diabetes compared with no treatment or treatment with other antipsychotics (except clozapine), but are inconclusive with regard to other second-generation antipsychotics.8,13 The primary objective of the present study was to estimate 10-year risk for CHD and diabetes in a simulation model by applying validated prediction algorithms to the changes in weight and other metabolic parameters observed in phase 1 of the CATIE study for patients treated with second-generation antipsychotics.4,5 Medication-attributable risk for each antipsychotic was quantified as relative risk (RR) and number needed to harm (NNH). Methods
A Markov model was developed to estimate CHD and diabetes risk over a 10-year time period in 10,000 U.S. adult patients (≥18 years) with chronic schizophrenia treated with second-generation antipsychotics. A risk-prediction algorithm derived from the FHS14 that included factors relevant to secondgeneration antipsychotic agents, such as triglyceride (TG) concentrations and predictors of primary as well as secondary cardiovascular events, was incorporated into the model (Exhibit 1). At baseline, the simulated patients with chronic schizophrenia were assigned a specific treatment and baseline risk profile
(e.g., age, sex, smoking status, body-mass index [BMI], lipid levels, and alcohol use). At each one-year cycle, patients’ risk profiles were updated and patients were assigned a treatment-specific risk of: (1) acute psychiatric relapse/hospitalization, (2) nonmetabolic adverse events (i.e., extrapyramidal symptoms, insomnia, and sexual dysfunction) based on the CATIE study data, (3) diabetes (accounting for BMI and age), (4) hypertension, and (5) primary or secondary CHD and stroke events. Each treatment-specific risk was based on the magnitude of changes in BMI and lipid levels resulting from the treatment to which they were assigned, as well as other risk factors (e.g., age, sex, diabetes, and smoking status). Exhibit 2 shows the changes in weight and lipid levels used in the model; it was assumed that these changes occur within the first year of treatment and remain stable thereafter. Patients were also assigned a risk of noncardiovascular death. To derive 10-year risk estimates, the annual incidence of CHD and diabetes was multiplied by the number of patients expected to survive in the prior year. The values, calculated for each year, were then summed to provide 10-year risk estimates. The model simulated risk in hypothetical patients with characteristics derived from patients enrolled in phase I of the CATIE study.4
www.namcp.org | Vol. 15, No. 2 | Journal of Managed Care Medicine 45
The annual probability of primary and secondary CHD events (e.g., angina, MI, and CHD death) was estimated using previously published FHS equations.14 Separate risk equations for initial and subsequent CHD events were employed to account for the increased likelihood of subsequent cardiovascular events after an initial episode. An additional FHS risk equation was used to estimate the annual probability of stroke and has been previously published.15 Risk equations based on the U.K. Prospective Diabetes Study (UKPDS) were used to predict annual CHD and stroke events in patients with diabetes because the FHS was not powered to evaluate CHD in this population.16 The D’Agostino equation independently predicted primary and subsequent CHD events, including angina, coronary insufficiency, MI, and CHD death (sudden and nonsudden). To differentiate between events, the Markov model applied the relative frequency of each event reported by D’Agostino then stratified cohorts by sex and primary vs subsequent events to determine the relative proportion of different CHD events. Only Framingham equations were used in the sensitivity analyses. Diabetes Risk
The probability of developing diabetes, given an individual’s BMI and age, was estimated using data from two large national surveys: for men, the Health Professionals’ Follow-up Study17-a study of 51,529 male health professionals followed over five years and for women, the Nurses’ Health Study,18 which followed a cohort of 113,861 women aged 30-55 years for over eight years (no participant had diabetes at study entry). Each study found a strong association between BMI and risk of onset of diabetes. For the model, we fitted exponential curves, one for men and one for women, based on the RRs reported for BMI categories, 9 for women (<19 – >28.9 kg/m 2 ) and 8 for men (<23 – >34.9 kg/m 2 ). The resultant curves fit the original data well (R 2 =0.98 for men; R 2 =0.96 for women). Equation 1, Males y = 0.0016 exp 0.2748*BMI Equation 2, Females y = 0.0008 exp 0.2797*BMI Note: exp denotes the exponential function ex, where e is the number (approximately 2.718281828) for which the function ex is its own derivative; x is the product of the terms to the right of exp; y is expressed as incidence of diabetes per 1000 per year. For BMI values above the upper limit of the high-
est BMI category, linear curves were fitted (For men: y = 16.9590 + 0.2362* BMI; for women: y = 7.6054 + 0.0956 *BMI). These represent a conservative assumption because risk was increasing exponentially, rather than linearly, prior to that point. The annual incidence of diabetes was then further adjusted for age, so the transition probability for diabetes in a given year was: Equation 3 P(Diabietesyear)=P(Diabete|BMI)*RR (Diabetes|Age year) Equation assumptions
Based on data from a study by McEvoy et al., CHD and diabetes risk was estimated for a 39-year-old male or a 44-year-old female patient with schizophrenia having similar demographic and cardiovascular risk factors of patients in the CATIE study.4,19 Height, which was not published for CATIE subjects, was set at 69.2 inches for men and 63.7 inches for women, based on data from the Third National Health and Nutrition Examination Survey.20 The proportion of smokers (men, 73 percent; women, 56 percent), individuals with diabetes (men, 11 percent; women, 16 percent) and hypertension (20 percent), and the levels of total cholesterol (TC) (men, 203.7 mg/dL; women, 208.3 mg/dL) and HDL-C (men, 42.3 mg/dL; women, 47.7 mg/dL) were derived from CATIE baseline values.7,19,21 Low-density lipoprotein cholesterol (LDL-C) levels were calculated with the empirically-derived Friedewald equation (equation 4), which assumes that TG concentrations are <400 mg/ dL. Baseline LDL-C levels were 122.5 mg/dL and 125.8 mg/dL for men and women, respectively. Equation 4 LDL-C = TC – (HDL-C + 0.2 * triglycerides) SBP (men, 123.9 mm Hg; women, 122.3 mm Hg), baseline BMI (men, 28.8; women, 32.8), and TG concentrations (men, 194.7 mg/dL; women, 173.8 mg/ dL) were derived from a study by McEvoy et al.19 Change from baseline in weight and laboratory values of TC and TG concentrations (exposure-adjusted means) were obtained from the CATIE study,4 and change in LDL-C was computed from these values. The changes in weight and lipid concentrations used in the model are listed in Exhibit 2. Changes in HDL-C and SBP were not reported by Lieberman et al.,4 therefore these values were set to zero in all analyses. Sensitivity analyses explored the effect of allowing HDL-C to decline as a result of treatment with olanzapine, quetiapine, risperidone, and ziprasidone. Measures
The primary measures were the rate of primary
46 Journal of Managed Care Medicine | Vol. 15, No. 2 | www.namcp.org
Exhibit 5: Sensitivity Analysis
Ziprasidone Olanzapine Risperidone
Scenario: 20% increase in baseline weight
Scenario: including treatment-specific HDL-C changes
Scenario: all Framingham equations
Scenario: 5-year time period
Scenario: 15-year time period
Scenario: 20-year time period
Scenario: starting age of 35 years
Scenario: starting age of 45 years
Scenario: starting age of 55 years
Scenario: all males (starting age of 39 years)
Scenario: all females (starting age of 44 years)
Scenario: starting BMI 10 percent lower
Scenario: starting BMI 10 percent higher
a Includes CHD (angina and myocardial infarction) and stroke. CVD = cardiovascular disease; HDL-C = high-density lipoprotein cholesterol; BMI = body mass index.
www.namcp.org | Vol. 15, No. 2 | Journal of Managed Care Medicine 47
CHD events (acute MI, coronary insufficiency, angina pectoris, sudden CHD death, nonsudden CHD death) and the rate of type 2 diabetes per 10,000 treated patients. Secondary measures included the rate of angina events, acute MI, ischemic or hemorrhagic stroke, CHD-related deaths, total primary and secondary CHD events excluding CHD-related deaths, and total primary and secondary CHD events including death per 10,000 treated patients. One-way sensitivity analyses
One-way sensitivity analyses varied the following parameters and scenarios: age of population at start of the model (35 and 55 years), HDL-C levels (2mg/dL decline for olanzapine and risperidone and a 3-mg/dL decline for quetiapine consistent with published research 22 ), use of only FHS risk equations14,15 to predict CHD events, baseline BMI, and allowing for switching/discontinuation. Statistical Analyses
The risk equations and model analyses were programed in Excel.23 Statistical analyses used RR ratios and NNH. The RR ratio was calculated as the ratio of events for a given antipsychotic relative to ziprasidone and relative to baseline. (Confidence intervals [CIs] for RR ratios were derived from the modelâ€™s probabilistic sensitivity analysis and are different from calculations of CIs based on empirical data.) NNH quantifies the tendency of a treatment to produce negative effects, using the absolute difference in rates of adverse events between treated and control groups. NNH is interpreted as the number of patients who need to be treated to cause harm to one patient. It is calculated as the inverse of the absolute difference in the rate of harm in treated vs control patients. Results
The predicted number (and simulated 2.5 percent and 97.5 percent confidence limits) of diabetes, angina, MI, stroke, and CHD death events for each antipsychotic agent per 10,000 patients over the 10year period for men (starting age 39 years) and women (starting age 44 years) are presented in Exhibit 3. Of patients treated with antipsychotics, ziprasidone had the lowest predicted number of CHD events per 10,000 patients over 10 years in men (270 angina events and 295 MIs) and women (782 angina events, 361 MIs). Olanzapine had the greatest predicted incidence of angina (N = 317 for men; N = 945 for women) relative to the other agents. Olanzapine and quetiapine had the highest number of predicted MIs (olanzapine, 344 for men and 425 for women; quetiapine, 322 for men and 408 for women). Metabolic
changes had little effect on the predicted number of strokes or CHD-related mortality, which were similar across all antipsychotics. The predicted number of psychiatric relapses/hospitalizations per 10,000 patients treated with each antipsychotic agent over a 10-year time period was lowest for olanzapine (N = 10,676 for men and N = 10,701 for women), intermediate for risperidone (N = 13,471 for men and N = 13,501 for women) and ziprasidone (N = 15,029 for men and N = 15,063 for women), and highest for quetiapine (N = 17,508 for men and N = 17,548 for women) (Exhibit 3). Comparing NNH to a reference case of no antipsychotic exposure, olanzapine resulted in lower NNHs for angina and MI events for both men and women compared with the other antipsychotic agents, showing that fewer patients needed to be treated with olanzapine to cause harm to one patient (Exhibit 3). For men, relative to no antipsychotic exposure, the NNH to result in one case of diabetes was 44 for olanzapine compared with 177 for quetiapine and risperidone; similar results were predicted for women. Given the similar diabetes incidence for ziprasidone-treated patients vs those with no antipsychotic exposure, the NNH for ziprasidone was over 400,000. Among ziprasidone-treated patients, the NNH for CHD events was lower than the baseline rate because ziprasidone lowered weight and other metabolic risk factors, on average, during the course of the CATIE study. The RR ratios were calculated for each antipsychotic compared with ziprasidone (Exhibit 4). Olanzapine increased the RR of CHD by elevating the RR of MI to 1.17 in men and 1.18 in women. Quetiapine showed similar elevations in the RR of MI and other CHD events. Relative to ziprasidone, olanzapine also increased the risk for diabetes, by 1.18 in men (95 percent CI, 1.00 to 1.54) and 1.16 in women (95 percent CI, 1.00 to 1.29). Sensitivity analyses
None of the scenarios tested in our sensitivity analyses produced results that were materially different from the base-case scenario (Exhibit 5). CHD and diabetes events correlated positively with age, such that a younger starting age produced lower rates of diabetes. In another scenario, we incorporated some worsening of HDL-C in to the model (consistent with prior studies of olanzapine, risperidone, and quetiapine),22 which also slightly increased the expected number of CHD events for these secondgeneration antipsychotics. Using only the FHS risk equations to predict CHD risk resulted in a higher number of cases in each treatment arm.
48 Journal of Managed Care Medicine | Vol. 15, No. 2 | www.namcp.org
The present study models data from a randomized, controlled trial to evaluate the long-term medication-attributable risk of CHD and diabetes in patients with schizophrenia. Whether it was due to the intrinsic nature of schizophrenia and/or the effects of previously administered antipsychotics, patients in the CATIE study entered with an elevated risk of type 2 diabetes mellitus and CHD at baseline. These findings suggest that the magnitude of metabolic changes observed during the course of the CATIE study may have important implications for understanding the health consequences of second-generation antipsychotic treatment and for the long-term management of patients with schizophrenia.24 Given the differential impact of specific secondgeneration antipsychotics on these metabolic parameters, the model predicted that treatment with olanzapine, and to a lesser extent quetiapine and risperidone, further elevates the risk of CHD and diabetes compared with baseline or treatment with ziprasidone, assuming that the metabolic parameters remain constant over the 10-year time period. In particular, the relatively low NNH values for olanzapine suggest that this treatment may pose the greatest increased risk for CHD and diabetes with long-term use. For example, olanzapine has an estimated NNH for diabetes of 44 and 31 in men and women, respectively. Longer medication exposure may place patients at a greater risk than is estimated in this study. In contrast, there was no evidence of medication-attributable risk of CHD and diabetes in ziprasidone-treated patients relative to baseline. The present findings are consistent with previous analyses. A recent analysis estimating the 10-year CHD risk for the CATIE population also determined that olanzapine was associated with an increased risk of CHD (0.5 percent [standard error (SE) 0.3]) as was quetiapine (0.3 percent [SE 0.3]). Ziprasidone was predicted to have a decrease in CHD risk (−0.6 percent [SE 0.4]). The difference in estimated 10-year CHD risk between olanzapine and ziprasidone patients 40 years of age was statistically significant (p=0.004).25 A retrospective analysis of data from more than 100,000 Medicaid patients revealed that in patients screened for pre-existing diabetes, who were on antipsychotic monotherapy, and in whom diabetes was identified with prescription claims only, patients treated with olanzapine had an increased risk for diabetes relative to patients who did not receive treatment (odds ratio [OR] = 1.149).26 A study of more than 19,000 patients in the U.K.-based General Practice Research Database demonstrated that patients treated with olanzapine had significantly increased odds of devel-
oping diabetes compared with nonusers of antipsychotics (OR = 5.8, 95 percent CI: 2.0 to 16.7) and patients treated with conventional antipsychotics (OR = 4.2, 95 percent CI: 1.5 to 12.2).27 The results of this model suggest that clinicians need to be aware of the possibility that long-term treatment with olanzapine and quetiapine and, to a lesser extent, risperidone, may increase patients’ risk for CHD events and type 2 diabetes mellitus. It is tempting to think that attentive clinicians would routinely provide interventions for modifiable metabolic risk factors as necessary during the management of patients with schizophrenia. However, in the total CATIE population, high percentages of patients had metabolic disorders at baseline and, moreover, a high percentage of patients with these disorders were untreated at baseline. 28 Specifically, dyslipidemia, when defined by elevated TG levels (in fasting patients, N = 690) and low HDL-C levels (in all subjects, N = 1445), was found in 47 percent and 48 percent of CATIE patients, respectively. The overall prevalence of diabetes was 10 percent; 11 percent when applied only to patients whose fasting glucose results were obtained ≥8 hours after the last meal. The overall prevalence of hypertension was 33 percent. The rates of nontreatment for these conditions were 88 percent for dyslipidemia, 62 percent for hypertension, and 30 percent for diabetes.28 Limitations
The current model has limitations that must be considered when evaluating these results. First, due to the inaccessibility of patient-level CATIE data, the model was populated with data from published summary statistics on patient characteristics and metabolic changes attributable to each second-generation antipsychotic. However, there is no clear evidence to suggest that this methodology is the most reasonable substitute for patient-level data. Secondly, this is not a prospective study; 10-year risk estimates were model-derived by applying 10 one-year risk estimates using risk equations developed by D’Agostino et al., Wolf et al., and the UKPDS14,15,16 and accumulating the results over 10-yearly cycles. Thirdly, despite its rigor and suitability for assessing medication-attributable risks, the CATIE study involved relatively short periods of medication exposure. Longer medication exposures may lead to higher event rates and, conversely, patients stopping medication altogether or switching to medications without weight gain or other metabolic disturbances, which may in fact lower their subsequent risk for disease. Finally, the equations used are somewhat dated; newer risk equations (e.g., Wilson) 29 may
www.namcp.org | Vol. 15, No. 2 | Journal of Managed Care Medicine 49
have altered the assumptions and yielded different results. One strength of the model is that whereas Goff et al. estimated only the risk for primary CHD events using a single, 10-year prediction equation derived from Wilson et al.,7, 29 the current model includes both primary and secondary CHD events.7 Despite these differences in the application of risk-prediction methods, a comparison of the methods reveals that treatment groups are affected in similar ways: while the overall number of events predicted for each treatment is subject to change based on the method of risk prediction, the marginal difference between treatments is not significantly changed over the 10-year time period used by the model.
in decision-analytic modeling across numerous therapeutic areas, including schizophrenia and dyslipidemia. Her probabilistic and deterministic models have included budget impact models for formulary decision-making and cost-effectiveness models for global and U.S. settings. Henry Nasrallah, MD is an internationally recognized psychiatrist, educator, and researcher. He is the Associate Dean for Faculty Development, Professor of Psychiatry and Neuroscience, and Director of the Schizophrenia Program at the University of Cincinnati College of Medicine, OH. His research focuses on the neurobiology and psychopharmacology of psychosis and bipolar disorder. Kafi N. Sanders, MPH is Associate Director of Outcomes Research at Pfizer and has held positions in the Cardiovascular/Metabolic, Neuroscience, and Pulmonary Vascular Disease groups for the last five years. She supports in-line projects and in-licensing opportunities at the United States, country, and regional levels. She is currently a doctoral
Our results underscore the conclusions of the American Diabetes Association/American Psychiatric Association Consensus Statement (2004) that olanzapine-treated patients are at an elevated risk for weight gain, diabetes, and dyslipidemia compared with patients receiving other second-generation antipsychotics or no treatment; the risk for patients treated with quetiapine and risperidone, while still elevated in this model, was of a lesser magnitude.9 Consistent with clinical trial data and other evidence, comprehensively reviewed by Newcomer, ziprasidone-attributable risk for diabetes and CHD in our model was zero (RR = 0.96 for total CHD and 1.00 for diabetes).13 An important contributor to this finding was the reduction in weight and associated reduction in diabetes risk in phase 1 of the CATIE study.4 Other important determinants of the effects of ziprasidone were the mean reductions from baseline in LDL-C and TGs in ziprasidone-treated patients. In view of the Food and Drug Association’s warnings and consensus guidelines regarding metabolic complications associated with some second-generation antipsychotics, and in view of the apparent inattention by some clinicians to the problem,30 this remains an important issue in patient care. While the primary goal of treatment is to control the symptoms of schizophrenia and avoid acute exacerbations (especially those resulting in hospitalization), it is important to balance the risk-benefit profile of these treatments. Per treatment guidelines, optimal care would involve routine testing for metabolic changes, documentation of medical interventions, and, possibly, adjustments to the patient’s antipsychotic drug regimen.
candidate in Public Health. Disclosures This research was funded by Pfizer Inc. Dr. Sonja V. Sorensen, Dennis Revicki, and Lael S. Cragin are currently employed by the United BioSource Corporation (UBC), which provides consulting and other research services to pharmaceutical, device, government, and nongovernment organizations. Timothy Baker was employed by UBC during the conduct of the research and development of the manuscript. UBC was a paid consultant to Pfizer to develop the model that constitutes the basis for this manuscript. No financial payment was made for the development of the manuscript. Henry Nasrallah is Professor of Psychiatry, Neurology, and Neuroscience, and Director of the Schizophrenia Program at the University of Cincinnati College of Medicine, OH. Dr. Nasrallah has received research grants from the following industry sources: Forest, GSK, Janssen, Otsuka, Pfizer Inc, Roche, Sanofi-Aventis, and Shire. He is on the advisory boards and speakers’ bureaus of AstraZeneca, Janssen, Pfizer Inc, Novartis, and Merck. He does not own stocks of any pharmaceutical company. James Harnett and Kafi N. Sanders are employees of Pfizer Inc. Funding This study was sponsored by Pfizer Inc. Editorial support was provided by Frances Brentson, MS, Annie Nield, PhD, and Bill Kadish, MD at PAREXEL and was funded by Pfizer Inc.
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provides critical financial, administrative, and
driven platforms with R&D expenditure totaling
have access to the highest caliber of managed care
compliance support for oncology and hematology
more than 21% of Group sales. The Group has total
talent. If you have an available position of have
physicians, cancer centers of excellence, cancer
worldwide staff of close to 4,500 employees.
an interest in our placement service, please give
patients, pharmaceutical manufacturers, and
us a call.
Otsuka America Pharmaceutical
part of the Johnson & Johnson Family of Companies
Booth 214 and 216
LifeScan & Animas Corporation, part of the John-
Otsuka America Pharmaceutical, Inc. (OAPI) is a
son & Johnson Family of Companies – Our vision
Located in East Hanover, N.J., Novartis Pharma-
successful, innovative, fast-growing healthcare
is to create a world without limits for people with
ceuticals Corporation is an affiliate of Novartis AG,
company that commercializes Otsuka-discovered
LifeScan & Animas Corporation
www.namcp.org | Vol. 15, No. 2 | Journal of Managed Care Medicine 57
Spring Managed Care Forum: Guide to Conference Supporters and other product opportunities in North America,
base of safety and efficacy data in humans for the
with a strong focus on, and commitment, to neuro-
treatment of gastrointestinal disease, and to apply
science, cardiovascular, oncologic, and gastroin-
the Company’s regulatory, product development,
Valeritas is launching the V-Go, the first simple,
testinal therapeutic treatments.
and sales and marketing expertise to commercial-
fully disposable device for the delivery of basal-
ize these products.
bolus insulin therapy for adults with diabetes. The
For additional information, please visit www. otsuka-us.com.
V-Go provides a continuous preset basal rate of
insulin and allows for on-demand bolus dosing
around mealtimes thereby providing an alternative
SeniorBridge is a national health management
to taking multiple daily insulin injections.
PerkinElmer Managed Markets offers the following
company with an 11-year heritage of managing the
service providers which leverage leading-edge
care of people with complex chronic conditions
Verinata Health, Sponsor
technology and proprietary capabilities: Signa-
and functional limitations in their homes. The com-
Booth 200, 202
ture Genomics. The innovator in microarray as a
pany’s interdisciplinary approach, developed by
Verinata is driven by a sole, extraordinary purpose
diagnostic tool. We’ve processed over 50,000
experts in the field of aging, utilizes an integrated
– maternal and fetal health. Our initial focus is to
cases, more than all other providers combined.
care management team of nurse practitioners,
develop and offer non-invasive tests for early iden-
NTD Labs. A leader in prenatal screening and
nurses and social workers who coordinate and
tification of fetal chromosomal abnormalities using
the exclusive provider of the free beta hCG first
provide personalized care resulting in decreased
our proprietary technologies. We aim to reduce
trimester Down syndrome screening. PerkinElmer
hospital admissions, readmissions, emergency
the anxiety associated with today’s multi-step
Genetics. The nation’s largest provider of newborn
room visits and medical expenses.
process, the unacceptable false-positive rates, the
screening services. We‘ve screened over 4 million babies since 1994.
non-specific and sometimes confusing results of
Smith & Nephew
current prenatal screening methods, as well as the
risk of current invasive procedures. In support of
Smith & Nephew has EXOGEN 4000+, only FDA-
national guidelines recommending first trimester
approved orthobiologic bone healing device
aneuploidy risk assessment, we believe women
ResMed is a global leader in medical equipment
for non-invasive treatment of indicated fresh
who desire such an assessment should be offered
for the screening, treatment, and management of
fractures and reduce the incidences of non-unions.
a single blood draw test with a definitive result.
sleep-disordered breathing and other respiratory
Smith & Nephew has helped millions of patients
Verinata has completed its blinded pivotal study
disorders. Our product line includes automatic
reduce pain from osteoarthritis of the knee with
to clinically validate the sensitivity and specificity
positive airway pressure devices, bilevel devices,
SUPARTZ® Joint Fluid Therapy, with over 230
of its first prenatal test. The verifi™ prenatal test
continuous positive airway pressure devices, nasal
million injections worldwide and over 20 years of
is a non-invasive assay for the determination of the
pillows systems, nasal mask systems, full face
experience. Visit www.smith-nephew.com for more
three primary chromosomal aneuploidies for tri-
mask systems, humidifiers, and software/clinical
information on these and other products that help
somies 21, 18 and 13. For more information about
alleviate pain in joints and promote healing.
Verinata, please go to www.verinata.com.
Tandem Diabetes Care
SI-BONE, Inc. is the leading sacroiliac (SI) joint
After years of research, and thousands of in-depth
medical device company dedicated to the de-
conversations with people with diabetes and their
velopment of tools for diagnosing and treating
health care providers, Tandem Diabetes Care™
patients with low back issues related to SI joint
has developed t:slim™, the first touch screen
pathology. The company is manufacturing and
insulin delivery system. t:slim’s vivid color touch
marketing a minimally invasive surgical (MIS) tech-
screen is your window to an easy-to-use interface
nique for the treatment of SI joint disorders.
that provides quick access to all features. With the footprint of a credit card and the design of a smart
phone, t:slim is the modern way to deliver insulin.
Booth 107 and 109 Salix Pharmaceuticals is a specialty pharmaceuti-
cal company dedicated to acquiring, developing
and commercializing brand name, prescription
Terumo BCT is the world leader in blood compo-
pharmaceutical products used in the treatment of
nent technologies and an innovator in the field of
a variety of gastrointestinal diseases. Salix’s strat-
cell culture and cell therapy. TerumoBCT.com
egy is to identify and acquire late-stage proprietary pharmaceutical products having an existing
58 Journal of Managed Care Medicine | Vol. 15, No. 2 | www.namcp.org
W ve. r u c ea e h t re m f onths ahead o ca
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Data on file. Verinata Health, Inc.
To learn more about the verifi™ prenatal test, contact us: 1• 855 • BMOMKND (1• 855 • 266 • 6563)
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