Vol.15, No.3, 2012
Journal of Managed Care Medicine
Perspectives on Immunization Childhood Immunization Information System Exchange with Payers: State and Federal Policies Chronic Migraine: Overview of the Disease State and Management Cost-Effective Glaucoma Care in the Managed Care Setting Economic Implications of Early Diagnosis of Hyperthyroidism Management Strategies for Improving Outcomes in Pulmonary Arterial Hypertension Improving MS Care: Perspectives from a Pharmacy Director and Medical Director Overcoming Challenges and Improving Outcomes in the Management of Type 2 Diabetes Breaking Down the Barriers: Innovative Approaches to the Management of Hypertension Effective Treatment Strategies in the Management of Advanced Nonâ€“Small Cell Lung Cancer Evolving Treatment Strategies in the Management of Metastatic Breast Cancer
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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. 3, 2012
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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) 6584253; Fax (703) 997-5842. Advertising offices: Sloane Reed, 4435 Waterfront Drive Ste 101, Glen Allen, VA 23060 Tel (804) 527-1905, Fax (804) 7475316. 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.
Perspectives on Immunization Gary S. Marshall, MD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Childhood Immunization Information System Exchange with Payers: State and Federal Policies Erika M. Hedden, PhD; Amy B. Jessop, PhD, MPH; Robert I. Field, JD, MPH, PhD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Chronic Migraine: Overview of the Disease State and Management Peter J. McAllister, MD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 Cost-Effective Glaucoma Care in the Managed Care Setting Steven D. Vold, MD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 Economic Implications of Early Diagnosis of Hyperthyroidism Theo McCormick and Jerold Share, MD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 Management Strategies for Improving Outcomes in Pulmonary Arterial Hypertension Deborah Jo Levine, MD, FCCP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 Improving MS Care: Perspectives from a Pharmacy Director and Medical Director Sheldon J. Rich, RPh, PhD and Maria Lopes, MD, MS. . . . . . . . . . . . . . . . . . . 44 Overcoming Challenges and Improving Outcomes in the Management of Type 2 Diabetes Ann Peters, MD, CDE. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 Breaking Down the Barriers: Innovative Approaches to the Management of Hypertension Larry Georgopoulos, PharmD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 Effective Treatment Strategies in the Management of Non-Small Cell Lung Cancer Howard West, MD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69 Evolving Treatment Strategies in the Management of Metastatic Breast Cancer Michelle E. Melisko, MD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
BPA Audited Publication
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Editorial Review Board Alan Adler, MD, MS Medical Director Independence Blue Cross Madeleine Biondolillo, MD Director, Healthcare Safety and Quality Massachusetts Department of Public Health Paul Bluestein, MD Chief Medical Officer Connecticare Anthony Bonagura, MD Medical Director Aetna Inc. Philip M. Bonaparte, MD Chief Medical Officer Horizon NJ Health D. Kete Cockrell, MD Medical Director International Medical Group Pat Deverka, MD, MS, MBE Senior Research Director Center for Medical Technology Policy Stan N. Finkelstein, MD Co-Director, Program on the Pharmaceutical Industry Director, Harvard-MIT Division of Health Sciences & Technology Massachusetts Institute of Technology Howard Garber, MD, MPH Medical Director Johns Hopkins Health Care Mary Parish Gavinski, MD Chief Medical Officer Community Care Annetine Gelijns, PhD Co-Director International Center for Health Outcomes and Innovation Research (InCHOIR) Columbia University Uwe G. Goehlert, MD, MSC, MPH, MBA, FAAFP Staff Physician Northwestern Medical Center Department of Emergency Medicine Steven E. Goldberg, MD, MBA VP and Chief of Medical Affairs Express Scripts Atul Grover, MD, PhD Associate Director Association of American Medical Colleges Humberto Guerra-Garcia, MD, MPH, FACP Chief Medical Officer United Healthcare Community PlanDelaware
Leo M. Hartz, MD, MHM VP Clinical Advocacy/Chief Medical Officer Blue Cross of Northeast PA
Gary R. Proctor, MD Chief Medical Officer, Federal Division ValueOptions Inc.
Barry K. Herman, MD, MMM Executive Medical Director Clinical Research and Medical Affairs Sunovion Pharmaceuticals, Inc.
John W. Richards Jr., MD, MMM, CPE President/CEO Innovative Health Strategies
Kathy Hudson, PhD Director, Genetics and Public Policy Center Johns Hopkins University Thomas Kaye, RPh, MBA, FASHP Senior Pharmacy Director Passport Health Plan Stephen Keir, DrPH Co-Director Center for Quality of Life/Supportive Care Research Robert Preston Tisch Brain Tumor Center Duke University Medical Center Fernando C. Larach, MD, FACR, MBA President A-Bay Area Medical Clinics, PA Catherine Marino, MD Chief Medical Officer MagnaCare Jeff Martin, PharmD Clinical Account Director Innoviant Inc. Peter W. McCauley Sr., MD, CPE Medical Director Gottlieb/West Towns PHO Inc. Wesley Mizutani, MD Talbert Medical Group Thomas Morrow, MD Director Genentech Lawrence Mullany, MD, MBA Medical Director United Healthcare Ray Mummery, MD, CMCE Chief Medical Officer, Dimension Health Denis O’Connell, MD Regional Medical Director Blue Cross Blue Shield of NC A. Mark Parker, MD, MBA Medical Director Quality Assessment Systems Inc.
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Kevin Roache, MD, MMM, CPE, FACPE Vice President Medical Affairs Peoples Health, Inc. Aran Ron, MD, MBA, MPH President and Chief Operating Officer Group Health Inc. Mark R. Rosenberg, MD, PhD President/CEO BHM Healthcare Solutions Jay Schechtman, MD, MBA Senior VP, Chief Medical Officer Healthfirst Nancy Single, PhD Assistant Director for Strategic Planning and Program The Ohio State University Comprehensive Cancer Center Robert H. Small, MD Behavioral Health Medical Director TriWest Healthcare Alliance Jacque J. Sokolov, MD Chairman SSB Solutions Scott Spradlin, DO, FACPF, ACOI VP Medical Affairs/Chief Medical Officer Group Health Plan Bruce Steffens, MD Market Medical Director Iowa– Central Illinois United Healthcare William D. Strampel, DO, FACOI Dean, Michigan State University College of Osteopathic Medicine Jeff Taylor, RPh, MS Pharmacy Director Aetna Prentiss Taylor Jr., MD Regional Medical Center Director Advocate Health Care Pam Thomas, MD, MPH, FACOEM Consulting Medical Director Wellness, Health and Productivity Management Strategies
Perspectives on Immunization Gary S. Marshall, MD For a CME/CEU version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.
Summary Amazing progress in the development of vaccines has been made since the late 1950s including the elimination of many diseases. Vaccines continue to evolve and are one of the most cost- effective medical interventions. There are some challenges which need to be overcome to ensure adequate vaccination of everyone. Key Points • The growth in vaccine development has been tremendous in the last 50 years. • Even as the number of recommended vaccines increased, the antigen burden from childhood vaccines significantly declined between 1960 and 2010. • In terms of cost effectiveness, vaccines are a value. • Managed care should consider how to incentivize providers to use combination vaccines to ensure childhood vaccination schedule compliance. • There are technological, logistical, and societal challenges for continued improvements in vaccinology. • More vaccines are on the horizon.
The modern era of vaccination began in the late 1950s with the development of the polio vaccine. In the ‘60s, there was the development of human diploid cell lines, which could support the growth of viruses that could be used to make vaccines. The measles vaccine was developed in the 1960s, and there was a call for a call for smallpox eradication. The last indigenous case of smallpox on earth occurred during the 1970s. The first recombinant vaccine and first cancer vaccine (Hepatitis B) was introduced in the 1980s. The 1990s were packed with significant developments. This included the first polysaccharide conjugate vaccine (Haemophilus influenzae type b, HibD), live-attenuated herpes virus vaccine (varicella, VAR), acellular pertussis vaccine (DTaP), and the first animal-human reassortant vaccine (rhesus-human rotavirus reassortant-tetravalent, RRV-TV). The protein polysaccharide conjugate vaccines were a significant advance in providing a much better antibody response and long- term improved immunity (Exhibit 1). Due to routine use of the Hib conjugate vaccine since 1990, the incidence of Hib disease in infants and young children has decreased by 99 per-
cent to fewer than one case per 100,000 children under 5 years of age.1 In the United States, Hib disease occurs primarily in under-immunized children and among infants too young to have completed the primary immunization series. Pneumococcal disease has also declined significantly since the development of the polysaccharide pneumococcal vaccine. We have also seen herd immunity develop in older people who are not vaccinated. In the last decade, 13 strain and 27 strain vaccines were developed that replaced the initial 7 strain vaccine. Higher valance vaccines will continue to be needed to stay one step ahead of the constantly changing S. pneumoniae organism. The 1990s also marked the last case of wild-type polio in the Western Hemisphere. When the polio vaccine was introduced, the number of cases in the U.S. fell to five to 10 cases per year during the 1970s. In Scandinavian, cases fell to zero in the same time period. This difference occurred because the Scandinavian countries never switched from inactivated to live vaccine like the U.S. did. They never used the live vaccine. In 1963, the U.S. switched to the live vaccine because it seemed to work better. The
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Exhibit 1: Protein-Polysaccharide Conjugate Vaccines Property Polysaccharide Conjugate B-cell response
Immunol pathway Extrafollicular Germinal center Response in infants
vaccine caused all of the polio cases occurring in the U.S. in the 1970s and ‘80s. That is why in 2000, the U.S. switched back to the inactivated vaccine. In a country where there is no live wild polio, it is unacceptable to use a vaccine that can cause polio, albeit less than one in a million times. With the evolution of vaccines since the 1960s, we have gone from fear of the disease, where parents would not let their children swim in the summer for fear of them contracting polio, to fear of the vaccine in the absence of natural disease. The live-attenuated herpes virus vaccine (varicella) was another advance in the 1990s that was significant because this was the first live vaccine that was giving a virus that stays alive in your body for the rest of your life. Like all herpes viruses, the varicella virus stays in the dorsal nerve root ganglia for a lifetime and can reactivate to cause shingles. The virus from the vaccine reactivates much less commonly than the natural virus. The acellular pertussis vaccine was revolutionary because the acellular vaccine causes fewer adverse reactions than the whole cell vaccine. One of the reasons a single disease vaccine for pertussis was developed was an organization called Dissatisfied Parents Together, which believed the DPT vaccine caused encephalopathy and other serious adverse events. This organization was a political force to motivate manufacturers to develop purer vaccines. In adding vaccines to the recommended immunization schedule, parents have become confused between vaccines and antigens. Some of them complain about the number of vaccines given to children, which is true if you look from 1960 to 2010 (Exhibit 2).2,3 Parents do not understand that the numbers of antigens given are actually much less than they used to be. This is because we are giving
purer vaccines. Vaccines have been isolated down to just the proteins needed to produce protection. The 1990s ended with the first human animal reassortant vaccine. It was proven long ago that an animal virus (cowpox) could be given to humans to protect them from human diseases (varicella). The first rotovirus vaccine used rhesus monkey rotovirus (Rotashield®). The problem was that this particular vaccine caused a form of bowel obstruction - intussusception. One in 11,000 vaccines developed this side effect. The natural risk of intussusception is about one in 2,000. Although the risk from the vaccine was much less than natural risk, the continued use of this vaccine was considered too risky and it was withdrawn from the market. Two subsequent rotovirus vaccines are now available (RV1 [Rotarix ®] and RV5 [RotaTeq®]). Data have shown an association between intussusception and RV1 vaccine in Mexico and Australia. It has not been seen in the U.S. The attributable risk is about one in 51,000. The withdrawal of the Rotashield® vaccine brings up the issue of what should be the attributable risk for withdrawing a vaccine. Thousands of babies were not admitted to the hospital for diarrhea and dehydration as a benefit of that particular vaccine. Acceptable risk has not been defined and may depend on the consequences of the disease being prevented. Vaccines are always a balance of benefit (risk of disease) versus risk of the vaccine. Another example of known risk is febrile seizures after measles, mumps, rubella, varicella vaccine (MMRV [Proquad®]). These occur in one in 2,300-2,600. Although this can be a frightening thing for parents, it is not for pediatricians and is not a reason to avoid the vaccine. The 2000s brought the first diptheria/tetanus/ acellular pertussis/haemophilus influenzae type b combination vaccine (DTaP-Hib). Combination
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Exhibit 2: Antigen Burden2,3 Vaccine
vaccines are an important advance because we keep adding vaccines to the recommended schedule. The more vaccines added, the harder it is to keep children compliant. Combination vaccines have been demonstrated to improve vaccine coverage rates and timeliness in several studies.4-6 Managed care should consider how to incentivize providers to use combination vaccines to ensure childhood vaccination schedule compliance. More combinations are in development. We also saw the first intranasal vaccine (live attenuated influenza vaccine [FlumistÂŽ]) and the second cancer vaccine (Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine, HPV, [GardasilÂŽ]) in the 2000s. The HPV vaccine was the first virus-like particle vaccine. This is also an inactive form of the virus that cannot cause disease. Over six million HPV infections in the U.S. every year ultimately lead to 10,000 cancers. Virtually every one of those cancers is vaccine preventable. Currently, 80 percent of the cancer causing HPV strains are covered by the vaccine but soon there will be a vaccine that covers more. Immunizing all 11- to 12-yearold females will cost $3,000 per quality adjusted life year (QALY) saved compared with $40,000 for
breast cancer screening and $25,000 for cervical cancer screening.7,8 There is now a recommendation to immunize all young males against HPV which is cost effective as long as female immunization rates are as low as they currently are (~30 percent). If every female had the HPV vaccine as a child, male vaccination would not be necessary. The 2000s also brought the advent of new vaccine adjuvants. Adjuvants help in the activation of innate immune mechanisms by potentiating adaptive immune response, causing protection against additional strains and increasing bonding of antibodies to antigens. For years we have had adjuvants, but the only one that has been licensed in the U.S. until recently was alum (aluminum salts). Monophosphoryl lipid A (ASO4) is the first new adjuvant licensed in the U.S. in 80 years. It is used in the human papillomavirus bivalent (types 16 and 18) vaccine (Cervarixďƒ’). Parents may have concerns about this vaccine because of Internet-based information stating it contains a poison. The adjuvant is actually endotoxin. Endotoxin is secreted by gram-negative bacteria and can be the cause of death from these infections. Endotoxin is very good at stimulating the innate immune response. It stimulates toll-like re-
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Exhibit 3: Vaccine Programs Initiated Before and After 198010 Vaccines Before 1980 Historical Peak
Cases Deaths Cases Deaths Diphtheria
Congenital rubella syndrome
Vaccines After 1980
ceptor (TLR) 4 on macrophages and dendritic cells just waiting to find an invader. The vaccine contains miniscule amounts of endotoxin, which are just enough to stimulate TLR4. Antibody titers are much higher with this vaccine than with Gardasil®. Other adjuvanted vaccines such as adjuvanted influenza vaccine have higher efficacy than non-adjuvant forms. The advent of these “super” vaccines will be an issue for the CDC Advisory Committee on Immunization Practices (AICP). In the past, the AICP has not preferred one vaccine over another but vaccines with adjuvants with demonstrated improved efficacy probably should be preferred. There are many other adjuvants under investigation. Another innovation in the 2000s was the first intradermal vaccine (intradermal influenza, Fluzone®). This is an improvement because the antigen presenting cells (dendritic cells) are in the dermis.
For 60 years, we have been giving vaccines in muscles, but muscles do not have a lot of dendritic cells. It makes more sense to give vaccines in the dermis which gives a better immune response. The last innovation of vaccines that occurred recently has been the approval of two vaccines for infant meningococcal disease (MenACWY-D [Menactra®] and MenACWY-CRM [Menveo®]). Another (HibMenCY-TT [MenHibrix ®]) is still under FDA review. The question is whether these vaccines should be used in all infants. Meningococcal vaccines work very well in adolescents, and we have a universal two-dose schedule for them. The overall incidence of meningococcal disease is significantly declining.9 We do not know why the disease incidence has gone down. The incidence of this disease is highest in the under 1-year-old population, but the case fatality rate is higher in adolescents
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and adults. Currently, the vaccine should be used in high-risk infants. The problem with this vaccine is the time it takes to develop immunity and it does not protect against serogroup B meningococcal disease, the most common infecting strain. The small number of deaths from meningococcal disease that occur very early in life (first 6 months) could not be prevented because of the delay in immunity development. Protection during the first 6 months of life might be possible with vaccination of mothers when they were teenagers. There are many issues which will need to be resolved with infant meningococcal vaccination. Vaccination has come a long way with one disease completely eliminated from the planet (smallpox) and several eliminated from the U.S. (polio, measles, and rubella). Polio only occurs in about four countries in the world. Exhibit 3 shows the impact in the U.S. of vaccines instituted since 1980.10 In terms of cost effectiveness, vaccines are a value. They are one of the least costly per QALY gained interventions. Every dollar spent on vaccines results in $5 in direct medical cost savings and $11 in societal cost savings.11 In the near future, there will also be higher valence vaccines for HPV and pneumococcus and vaccines for additional diseases such as cytomegalovirus and parvovirus. Of course, the additional vaccines will raise many questions about which ones to use in which populations. We also need malaria, HIV, and a better tuberculosis vaccine. There are technological, logistical, and societal challenges for continued improvements in vaccinology. An HIV vaccine is a good example of a technological challenge. The exact antigenic determinant protein needed for a vaccine is known; the problem is this protein is hidden in the virus so the immune system cannot identify it. The technology of the future is reverse vaccinology. Years ago, researchers started with the bacteria or virus, injected animals, and then tried to figure out which proteins were immunogenic. Now, the bacteria or virusâ€™ genome is analyzed. Genes for proteins that might be expressed on the cell surface and would be good immunogens are identified. The protein genes are cloned to produce the designated protein to make a vaccine. The logistical challenges have to do with delivery of vaccines to everyone who needs them. It takes several years after introduction of a vaccine to get sufficient numbers of children vaccinated. At this point, 30 percent of children are not getting all the vaccines that they need.12 The numbers are even worse for teenagers.13 The vaccination rates for adults are horrendous. For 10 years, the rates of
adult pneumococcal and influenza vaccination have not changed. We have made progress in terms of disparities. White/black disparity in childhood vaccination has now been erased. There are still disparities based on poverty, independent of race. For example, the areas of the county with the most poverty have the least HPV vaccine penetration and the highest rates of cervical cancer. Another logistical challenge is how to pay for all the vaccines. As the number of vaccines has increased, so has the cost to fully immunize a child. Childhood vaccine funding is derived approximately half from the private sector and half from public funds. Much of the public funding is from the Vaccines for Children (VFC) program. VFC is an entitlement â€“ if AICP recommends a vaccine, it will be covered under VFC. Another public portion of vaccine funding comes from Section 317 funds, which are an annual discretionary appropriation. Because less money has been appropriated in recent years through Section 317, a gap has arisen between the private sector and VFC covered children and those not covered by either. There is insufficient financing to immunize the children in the middle. Health care reform will fix this problem with required coverage for recommended vaccines for all children. The main societal challenge to adequate childhood vaccination comes from parent worries about adverse effects. There has been a lot of negative publicity related to adverse effects. The good news is most parents believe vaccines are a good way to protect their children. The problem is half of them believe vaccines have adverse events we are not telling them about. One-fourth of parents still believe vaccines cause autism. Measles, mumps, and rubella were almost eliminated in the United Kingdom prior to the publication of the fraudulent paper on MMR vaccine and autism.14 Because parents refused to have their children vaccinated, the cases of these diseases dramatically increased. Identification of vaccine adverse effects is difficult because many of them are rare and also the background rate of a particular adverse effect needs to be known. There is a difference in what we are afraid of and the real risk of the disease we are talking about preventing. The real risk for adults in the U.S. is influenza, not anthrax or smallpox, which are what people worry about. People trust their family doctor so that is where the accurate scientific information on vaccinations should come from.15 Conclusion
Vaccinology has made tremendous strides since the 1960s and continues to improve. We have now
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eliminated several diseases from the U.S. There are challenges to continued improvement in vaccines and achieving adequate vaccine coverage for all children.
combination vaccine on immunization timeliness in a state Medicaid population. Pediatr Infect Dis J. 2009;28(2):98-101. 7. Elbasha EH, Dasbach EJ, Insinga RP. Model for assessing human papillomavirus vaccination strategies. Emerg Infect Dis. 2007;13(1):28-41. 8. Kim JJ, Goldie SJ. Health and economic implications of HPV vaccination in
Gary S. Marshall, MD is Chief of the Division of Pediatric Infectious
the United States. N Engl J Med. 2008;359(8):821-32.
Diseases, Professor of Pediatrics, and Director of the Pediatric Clinical
9. McNabb SJ, Jajosky RA, Hall-Baker PA, et al. Summary of notifiable diseas-
Trials Unit at the University of Louisville School of Medicine in Louis-
es--United States, 2006. MMWR Morb Mortal Wkly Rep. 2008;55(53):1-92.
10. Roush SW, Murphy TV; Vaccine-Preventable Disease Table Working Group. Historical comparisons of morbidity and mortality for vaccine-prevent-
able diseases in the United States. JAMA. 2007;298(18):2155-63.
1. CDC. Progress Toward Elimination of Haemophilus influenzae Type b Inva-
11. Zhou F, Santoli J, Messonnier ML, Yusuf HR, et al. Economic evaluation of
sive Disease among infants and children, United States, 1998-2000. MMWR.
the 7-vaccine routine childhood immunization schedule in the United States,
Vol 51, No 11;234.
2001. Arch Pediatr Adolesc Med. 2005;159(12):1136-44.
2. Offit PA, Quarles J, Gerber MA, et al. Addressing parentsâ€™ concerns: do mul-
12. CDC. National and state vaccination coverage among children aged 19-35
tiple vaccines overwhelm or weaken the infantâ€™s immune system? Pediatrics.
months--United States, 2010. MMWR Morb Mortal Wkly Rep. 2011;60(34):1157-63.
13. CDC. National and state vaccination coverage among adolescents aged 13
3. Marshall GS. The Vaccine Handbook: A Practical Guide for Clinicians. 3rd
through 17 years--United States, 2010. MMWR Morb Mortal Wkly Rep.
Edition. West Islip, NY: PCI Books. 2010.
4. Marshall GS. One for all: newer combination vaccines in practice. Pediatr
14. Leask J. Target the fence-sitters. Nature. 2011;473(7348):443-5.
15. Kennedy A, Basket M, Sheedy K. Vaccine attitudes, concerns, and informa-
5. Marshall GS, Happe LE, Lunacsek OE, et al. Use of combination vaccines is
tion sources reported by parents of young children: results from the 2009
associated with improved coverage rates. Pediatr Infect Dis J. 2007;26(6):496-500.
HealthStyles survey. Pediatrics. 2011;127 Suppl 1:S92-9.
6. Happe LE, Lunacsek OE, Kruzikas DT, Marshall GS. Impact of a pentavalent
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Childhood Immunization Information System Exchange with Payers: State and Federal Policies Erika M. Hedden, PhD; Amy B, Jessop, PhD,MPH; Robert I. Field, JD, MPH, PhD
Summary Federal passage of the HITECH Act in 2009 encourages use of Electronic Health Records, which now includes submission of Immunization Information Systems (IIS) records. IIS were developed to improve health care quality and reduce infectious diseases, health disparities, and costs. These advantages are available to all IIS users, which may include public and/or private payers. Laws that govern IIS data exchange are developed at the state-level, and may interact with federal policies, and impact utility for all those with a stake in maintaining appropriate immunization levels. This study examines IIS and immunization records laws in 56 Grantees (50 states, five cities and Washington D.C. that receive public health funds) that specify payer information exchange. Of the 56 Grantees, 31 (55.4 percent) have payer exchange provisions (private or public), 20 of which allow direct access by payers for quality assurance, reimbursement, or evaluation purposes. The laws vary by type of exchange and allowable purpose for exchange. HIPAA is applicable when grantee law does not specify exchange. IIS can be used to facilitate measurement and immunization program evaluation, including for public and private payers. All stakeholders, including payers, should be involved in the policy making process, to improve efficiencies intended by IIS and furthered in the HITECH Act. Key points • HIPAA allows state law to require reporting for public health and health plan quality review purposes. • Over half of the Grantees have laws that specify immunization data exchange with payers, 20 allow payer access. • Grantees laws that allow two-way exchange may be better placed leverage payer data for improved IIS value and IIS data for payer HEDIS reporting and cost savings.
Immunization Information Systems (IIS) are “confidential, computerized information systems that collect and consolidate vaccination data from multiple health-care providers...”1 which are maintained by health departments at the state and city levels. IIS can assist clinicians and health plans track individual immunizations and ensure appropriate and timely administration, and enhance public health surveillance of immunization levels and disparities. IIS participation was deemed “a public health imperative” to improve quality of care, promote efficiency, ease burden and lessen health disparities.2 Recognizing the potential of IIS, the government has encouraged use of IIS through funding and le-
gal channels. Beginning in 1993 with implementation of the federal Vaccines for Children (VFC) program, the National Immunization Program of the CDC supported immunization registry development through the 317b Public Health Service Act grant process.3 This funding mechanism allowed autonomy to allot funding specific to registries as each “Grantee” deemed necessary.3 CDC grants for IIS have varied in purpose (for example development or capacity building) and amount from year to year with funding estimates ranging from a high of $42.5 million in 1996 to $1.04 million in 2010.3-7 IIS could serve as “building blocks” to a more broad national health information system.8 At the federal level, passage of the Health Information Technology for Economic and Clinical Health (HITECH) Act in 2009 encourages use of Electronic
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Exhibit 1: Immunization Records Laws that Specify Payers by Grantee
IIS law Other law Both
Health Records (EHRs) to: improve quality, coordination of care and public health activities; reduce costs; guide medical decisions; facilitate research; promote competition and improved outcomes; and reduce disparities.9 The Act specifies that EHRs should be used in a “meaningful” manner to improve quality care and measures.10 The U.S. Department of Health and Human Services developed Meaningful Use (MU) guidelines that offer health care providers with explicit instruction for the development and application of EHRs, including submission of EHRs to IISs. As a part of what is termed “Stage 1,” the Centers for Medicare & Medicaid Services offer incentive payments to eligible professionals who test the ability to submit EHRs to an IIS, if the test is successful.11 Using the World Health Organization Working Group definition, it can be argued that IIS is a “public good.”12 In other words, its social value (or the “positive externalities”13 of overall quality of care improvement, and reduction in infectious diseases, health disparities, and costs) far exceeds private individual stakeholder value. However, in order to achieve this wide-ranging value for everyone in society, both public and private participation is a must. And not only must IIS be “used” by all, but each stakeholder should be an active participant in populating IIS.
From the individual stakeholder perspective, most providers and administrators know, over immunization can waste vaccine and administrative resources and under immunization may produce the need for expensive treatment of disease. IIS can prevent or reduce these costs,14-16 including cost savings to managed care organizations (MCOs) for production of their Healthcare Effectiveness Data and Information Set (HEDIS) reports.4,17 HEDIS measures are developed by the National Committee for Quality Assurance and used by 90 percent of U.S. health plans, allowing consumers and employers to compare quality across health plans and health plans to identify areas for quality improvement.18 Based on the 2010 HEDIS Childhood Immunization Status (CIS) measures include percentage of: “children 2 years of age who had four diphtheria, tetanus and acellular pertussis (DTaP); three polio (IPV); one measles, mumps and rubella (MMR); two H influenza type B (HiB); three hepatitis B (HepB), one chicken pox (VZV); four pneumococcal conjugate (PCV); two hepatitis A (HepA); two or three rotavirus (RV); and two influenza (flu) vaccines.”19 IIS offers administrative efficiencies for outreach efforts and more efficient use of health care dollars for taxpayers (Medicaid) and employers purchasing coverage. At least one health plan showed that use of IIS as its data source for HEDIS compliance can re-
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Exhibit 2: Direction of Data Exchange Specified in the Laws
18 Number of Grantees
16 14 12 10 8 6 4 2 0 HCPs to Release / Exchange Release by Payers to payers access to to / from payers IIS payers payers Other
duce the administrative burden of chart reviews and realize a benefit-to-cost ratio of 8.06.17 To realize this potential, participation in IIS must be high and data exchange with MCOs must be permitted. Present IIS participation is currently at 75 percent of all U.S. children aged <6 years.20 Healthy People 2010 and 2020 set the goal of 95 percent.21,22 As new immunizations are added to the HEDIS CIS and cost savings are measured,23 IIS is one possible source that may provide even greater savings. In the United States, public health laws are generally the province of the state laws and local health ordinances.24 State legislatures can enact statutes, state regulatory bodies can enact regulations or rules, and local health bodies can pass city ordinances (all henceforth referred to as “laws”). Laws which relate to many aspects of IIS have been passed in states and cities, which are Grantees of the Public Health Services Act, which relate to many aspects of IIS. These laws governing IIS are complex, may interact with federal policies, and impact utility of IIS for all stakeholders. The information presented here is part of a study identifying and cataloging Grantee IIS laws. The objective of this component is to identify and describe elements of laws for immunization information data exchange with payers. The results can inform payers of allowable exchange, and inform all stakeholders of the complexity and need for better policy options for improving the value and utility of IIS. Methods
The study population is 56 U.S. “Grantees” (50 states, five cities and Washington, D.C.) receiving
funds under section 317b of the Public Health Service Act. IIS relevant statutes and regulations were identified for each of the Grantees via legal databases and systematically reviewed for content. For those Grantees without IIS or immunization record laws, general health or medical records laws, if available, were used as a proxy to determine allowable exchanges of data. Content of the laws was coded into categories using a coding instrument developed for a study identifying and cataloging Grantee IIS laws. The coding categories were derived from previous IIS and public health law studies25-29 and a preliminary review of the laws. The Delphi technique was used to obtain expert input for the coding document. The 131 variable instrument received 93.7 percent agreement and a K-α of 0.791. The coding categories specific to payers were extracted from the resultant database and tabulated to determine Grantees laws that specified payer immunization data exchange or access. The specifications within these laws is described and presented in graphic form. Possible interactions with Grantee IIS exchange laws and the Health Insurance Portability and Accountability Act (HIPAA) Privacy Rule are also described. Results
Of the 56 Grantees examined, 31 (55.4 percent) had IIS or other immunization record laws that indicate payers immunization records exchange. Laws governing exchange with payers include IIS-specific laws (those governing IIS establishment and operation) and other laws such as immunization reporting or insurance laws. Payer exchange provisions were
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Exhibit 3: Type of Use Specified for Payer Data Exchange
Specifies Medicaid as payer Payer IIS/record access/exchange (disease control, immunization evaluation, and/or cost efficiences) Data in aggregate for evaluation IIS law Other law
Data for reimbursement
From payer to state for review
12 14 16 18 20
Number of Grantees
noted in 11 Grantee IIS laws, 15 Grantee “other” laws, and five Grantees had provisions in both IIS and “other” laws (Exhibit 1). The payer access provisions of the laws vary by Grantee. Exhibit 2 depicts the types of information exchange indicated and the types of laws where the provision is indicated. The laws may indicate several types of data exchange, and provisions may appear in several types of laws. Payer data exchange was described in the laws as records transfer or access with IIS, health departments, health care providers (HCPs), or health plan review committees. Exhibit 2 also depicts the frequency of Grantees with IIS or immunization laws with different directions of exchange or access specified. The type of exchange specified in Grantee laws was not mutually exclusive. For example, a Grantee’s law(s) could specify that payers may access IIS and also that they must report to the IIS. The most frequent reference relates to payer access to IIS. The most frequent purpose of payer exchange specified was for IIS access, or exchange with an IIS, for the patients/members that they serve, which supports IIS use for HEDIS compliance. Frequency by purpose is shown in Exhibit 3. These figures are not mutually exclusive. Laws specifying payer data exchange were classified as either 1) IIS development and implementation laws or 2) other applicable immunization records laws. Descriptions of the laws follow below. IIS Laws
Grantees in this category have specific IIS creation
and implementation laws that reference payers. They include: California, Colorado, Delaware, Hawaii, Indiana, Maryland, New Jersey, Tennessee, Utah, and Vermont. California’s IIS law allows the State Department of Health Services to disclose immunization data to health plans covering immunization services for the patient, local health departments and the State Department of Health Services. The law specifies the purposes of health plan access are for payment and immunization assessment. Similarly, Delaware’s law allows IIS data release to the patient’s insurer, while New York’s IIS statute allows immunization records to be available to authorized users, including payers. IIS laws in five states (Colorado, Maryland, New Jersey, Tennessee, and Utah) mention two-way data exchange. Colorado’s IIS statue allows state and local health officials to gather information for the IIS from MCOs or health insurance plans and the Department of Health Care Policy and Financing (Medicaid) for medical assistance patients. Additionally, all data sources, including health care providers and health plans, are allowed to release immunization records to each other for treatment purposes and to provide an individual with a complete immunization record. Maryland’s IIS statute authorizes gathering information for the registry from payers and allows the state Secretary of the Health Department to designate payers as IIS users. New Jersey’s IIS laws allow payers to collect immunization data for their members, authorize providers, payers and health officers/agencies to exchange data for IIS administration and payers to request data on their prior members for HEDIS reporting and
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quality assurance or accreditation. The law also allows providers to report to the IIS through the NJ Medicaid program among others. (Tennessee is covered under the section IIS and other laws, because it has both types of laws.) Utah’s IIS rule references a statute allowing release of data to insurers to obtain payment, while the rule itself allows exchange of the IIS with payers and access by payers. Hawaii’s IIS statute only authorizes the health care provider to disclose immunization information to a payer for reimbursement purposes. Indiana’s IIS statute allows release of IIS data to the state’s Medicaid office. New Hampshire’s IIS rule allows IIS data to be released in aggregate to payers, researchers and other government agencies. Vermont mandates immunization data reporting by health care providers and insurers to the health department. Of the five city-level Grantees, only Philadelphia’s IIS regulation mentions payers as possible authorized IIS users. The other cities – Chicago, Houston, New York, and San Antonio – would follow the law of their respective state. IIS and Other Applicable Laws
This section includes Grantees that have IIS laws as above and immunization records laws that specify payers. Four Grantees (Alabama, New Mexico, Tennessee and Oregon) have payer provisions in both IIS and other immunization records laws. Alabama statute requires providers to supply immunization information to other providers, insurers and Medicaid, and authorizes payers as possible users of the IIS. New Mexico’s IIS statute “limits access” to certain specified entities, including payers. It contains a rule mandating “reporting health plans” or those licensed in New Mexico or meeting other requirements as specified, to submit HEDIS data elements to the health department. Further, New Mexico has two Medicaid-related regulations. One that governs the state’s Medicaid managed care program, states that the MCO will encourage providers to report to the IIS, but does not specify Medicaid access. The other requires the state Medicaid office to maintain the records, but states nothing specifically about exchange of the data to Medicaid. Tennessee has two different statutes allowing payer release of immunization data to the IIS and payer access to the IIS. Tennessee also has an IIS provision in a medical records law that requires that the Medicaid fraud unit have access to the data. Texas laws require payers to report immunization data received (for those under 18, with consent) to the health department, while another law requires immunization data collection for each person receiving Medicaid.
Oregon’s IIS statute allows for exchange among authorized users, including payers. Its public health emergency statute authorizes release of information to authorized users, including payers. And finally, its IIS rule authorizes exchange among authorized users and payer access to their member information. Other Applicable Laws
The types of laws governing IIS exchange with payers under other applicable laws include Health Information Exchange (HIE), immunization reporting, medical records or insurance laws. Fifteen Grantees fall under this category; Alaska, the District of Columbia, Illinois, Florida, Louisiana, Minnesota, Mississippi, Nebraska, North Carolina, Rhoda Island, South Carolina, Virginia, Washington, West Virginia, and Wyoming. Alaska has a HIE statute that authorizes information exchange with payers. The District of Columbia’s immunization reporting law authorizes release of immunization information to a patient’s insurer regarding immunization due dates, or those that were missed or are overdue. Seven states have medical records laws that might be applied to immunization records, where no other immunization records law exists. Illinois has a medical records statute allowing immunization data release to payers for reimbursement. Florida has a health professions law that allows release of records by the state health department to the state Medicaid Fraud Control Unit upon request. An immunization records section in a Minnesota health records law allows payers to exchange information with providers and other specified entities providing services on behalf of the patient. A Rhode Island health records statute allows release of records to payers related to business operations and utilization review and release to the Medicaid fraud control unit. South Carolina’s medical records statute allows physicians to release medical information to insurers, if the insurance claim authorization is on file. Virginia has a medical records statute that references HIPAA and allows the sharing of data with payers. Washington’s statute allows release of medical records to payers. Another Washington regulation is related to chronic care data sharing requirements under Medicaid programs, but only specifies exchange with the Department of Social and Health Services and care contractors. Wyoming statute allows release of hospital records to payers. Wyoming also has a regulation regarding eligibility for state and federal provided vaccine program (WyVIP, VFC, and Medicaid), but with no specific mention of reporting to the Medicaid office. Several Grantees also have insurance laws that ref-
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erence medical or immunization records. Louisiana has a Medicaid Managed Care Immunization Payfor-Performance rule that requires physicians to report to the state’s IIS, with the implication (not specifically stated) that the Medicaid office will access the data. Mississippi’s insurance law allows release of data to review committees, while its Medicaid HMO contract rule requires the release of immunization records by payers to the Division of Medicaid. The Mississippi Division of Medicaid is also granted access to the data that providers participating in Medicaid programs are required to keep under two separate rules. Nebraska has a regulation that sets out the requirements for providers to participate in the state’s Medicaid HMO Program, including IIS participation and exchange with the state Medicaid HMO. North Carolina also has an insurance statute with an immunization record provision and another immunization reporting statute that both allow for release of this information by insurers to the health department, while an immunization information rule allows the health department and physicians to release to HMOs. South Carolina’s insurance statute related to external review of insurance adverse determination allows for release of information by payers. West Virginia’s HMO statute authorizes payers to release data to facilitate assessment of quality of care or review grievance, pursuant to statute or court order, in event of claim or litigation, with written consent, or pursuant to contract with department of the state. HIPAA
Health care providers and payers, as covered entities under HIPAA Privacy Rule, must follow HIPAA specifications except under certain circumstances, in which state law would apply. State law is an exception to HIPAA if it allows or requires reporting for public health surveillance, investigation, or intervention. These circumstances apply to IIS. HIPAA also allows state laws requiring a health plan to report or allow access to data for audits, program evaluation, or licensure. Immunizations are program evaluation measures under HEDIS, and therefore an exception to HIPAA. Discussion
In order to realize the full benefits if IIS, including age-appropriate immunization administration and levels and associated cost efficiencies, all immunization stakeholders must work together to ensure completeness of records. Health care provider, organization and health plan contribution and access are key components in the process, and all have a interest in improving outcomes. In this study, half of Grantees
had laws with provisions for payer participation in IIS, although the provisions varied by Grantee. One potential payer benefit of IIS is availability of data for HEDIS reporting. Insurers in eleven, possibly twelve, Grantee localities (Alabama, California, Colorado, Delaware, Maryland, New Jersey, New Mexico, New York, Oregon, Philadelphia, Tennessee, Utah, and potentially Alaska) are authorized to collect or receive data from IIS for this purpose. A second potential benefit for payers is reduced cost for HEDIS-related data collection compared to traditional chart reviewing. Payers in the above Grantee locales are in a position to test the benefit-to-cost of IIS-based HEDIS data collection. Some Grantees specify one-way data transfer, but there are benefits to exchange in both directions. MU provides incentives to providers who receive funding from the Centers for Medicare and Medicaid to report to IIS. However, children may switch providers or see providers with inconsistent IIS submission practices. Data from payers in the form of reimbursement requests could contribute valuable information that improves appropriate immunization, identifies immunization disparities, and reduces costs associated with over and under immunization. Laws allowing private payer contribution to add value to the IIS would also help to eliminate the possible question of free rider use of this public good. Grantees could examine the efficiencies of reporting from multiple sources. Payers are key stakeholders in the successful immunization process, adding value to an IIS, and can potentially benefit from IIS participation in terms of cost savings and improved quality service provision. Therefore, payers may want to collaborate with public health officials and policy makers to improve allowable access and exchange. Additionally, payers could partner with health care providers to promote participation in IIS systems to improve completeness of data and, therefore IIS utility to all users. This study’s collection and presentation of the payer provisions of Grantee IIS-related laws may provide policy makers with models that can be referenced in the development of policy that encourage IIS use among all stakeholders. Laws that limit information to uni-directional or aggregate data or certain data elements, may not facilitate most efficient use and promote duplication and wasted resource. However, Grantees laws without mention of payers may not have an obstacle, if their law delegates to the health department how information will be collected, exchanged and stored. Limitations
The study was designed to capture IIS and immuni-
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zation record laws, and considered only Grantee IIS or immunization record-applicable insurance laws. Potentially relevant insurance law that did not explicitly note immunization records may have been missed. Further, this study focused only on childhood immunization records. Laws that specified childhood immunization or did not specify an age group were considered. Adult immunization records laws were excluded. Conclusion
MPH, from The Task Force for Global Health; Gail Horlick, MSW, JD from the CDC; Sherry Riddick, RN, MPH, from AIRA and Washington state; Susan Salkowitz, MA, MGA, from AIRA; Barbara Watson, MD formerly of Philadelphia Department of Health; Amy Wishner, MSN, RN from the American Academy of Pediatrics. Additional thanks to Vishal Zaveri from the University of the Sciences for test coding assistance, and to Joseph Pecora from the Earle Mack School of Law at Drexel University for data coding assistance. Finally, much appreciation to Deborah M. Tortu, an independent consultant with significant experience in the managed care industry, for her thoughtful comments on a previous draft.â€ƒ
IIS is a valuable public good. In order to reach its full potential, IIS must be populated. The HITECH Act encourages use of EHRs and exchange with IIS has been one established channel, under MU. Providers of Medicare and Medicaid have incentives to report to IIS, but payers can also serve as a data source for IIS. Equally, IIS can provide a cost-efficient data source for health plan HEDIS reporting. This synergy can only be realized if all of the data are centrally located and accessible to those providing services to the patient. HIPAA allows states to require public health reporting to IIS and for health plans to report for program review. Grantees that allow payer access to, or exchanges with, IIS, provide payers with the means to implement this cost savings. Further, payers that are adding value to the system by providing information can also offset any notions of free ridership. Payers and policymakers should work together to ensure that value is added in both directions.
This work was supported by a dissertation completion grant from the University of the Sciences in Philadelphia.
References 1. Centers for Disease Control and Prevention. Immunization information system progress--United States, 2003. MMWR Morb Mortal Wkly Rep. 2005 Jul 29;54(29):722-4. 2. Enhancing Participation in Immunization Information Systems (IIS): Recommendations to the National Vaccine Advisory Committee. United States Department of Health and Human Services Web site, 2008. 3. Linkins RW, Feikema SM. Immunization registries: The cornerstone of childhood immunization in the 21st century. Pediatr Ann. 1998 June 1998;27(6):349-54. 4. Hinman AR, Urquhart GA, Strikas RA, National Vaccine Advisory C. Immunization information systems: National Vaccine Advisory Committee progress report, 2007. J Public Health Manag Pract. 2007 Nov-Dec;13(6):553-8. 5. Hollar DW. Progress along developmental tracks for electronic health records implementation in the United States. Health Res Policy Syst. 2009;7:3. 6. Immunization Grants and Vaccines for Children Program. Centers for Disease Control and Prevention, 2007.
7. Centers for Disease Control and Prevention. Immunization Information Sys-
Erika M. Hedden, PhD, spent the past two years researching IIS poli-
cies and assisted with other research projects at the University of the
do?mode=VIEW&oppId=54760>. Accessed 2011 October 30. Grants.gov,
Sciences in Philadelphia. Recently, Dr. Hedden has provided communi-
cation and research services for InforMed. She received her doctorate
8. Hinman AR, Ross DA. Immunization registries can be building blocks for
in health policy from the University of the Sciences.
Apr;29(4):676-82. Amy B. Jessop, PhD, MPH is Assistant Professor of Health Policy
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10. Centers for Medicare & Medicaid Services. CMS EHR Meaningful Use
Dr. Jessop is also the Director of HepTREC, a center at the University.
Sheâ€™s been engaged in immunization activities for more than 15 years.
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Health and Human Services, Baltimore, MD, 2011. Robert I. Field, JD, MPH, PhD is Professor of Law at the Earle Mack
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13. Mankiw NG. Principals of Economics. Third ed. Mason, OH: Thomson: South-Western; 2004.
14. Bartlett DL, Washington ML, Bryant A, Thurston N, Perfili CA. Cost sav-
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and Andrew M. Peterson, PharmD, PhD from the University of the Sci-
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www.allkidscount.org/iz/whatsnew/cost.html>. Accessed 2009 October 14,
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objectiveslist.aspx?topicId=23>. Accessed 2011 October 23. U.S. Department
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23. Ahmed F, Elbasha EE, Thompson BL, Harris JR, Sneller VP. Cost-benefit
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analysis of a new HEDIS performance measure for pneumococcal vaccination.
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Health. Washington, DC: U.S. Government Printing Office, 2000:14.1-.59.
immunization registries. Am J Prev Med. 2001 Apr;20(3):208-13.
22. U.S. Department of Health and Human Services. Immunization and Infec-
29. Pritts JL. Altered states: state health privacy laws and the impact of the Fed-
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18 Journal of Managed Care Medicine | Vol. 15, No. 3 | www.namcp.org
A noninvasive prenatal laboratory-developed test for the detection of an increased amount of chromosome 21, 18 and 13 The MaterniT21 PLUS laboratory-developed test is well studied, published and can accurately 99 detect three of the most common autosomal aneuploidies. The test was developed and validated by Sequenom CMM, is supported by the National Society of Genetic Counselors1 and International Society of Prenatal Diagnosis, for women at increased risk for aneuploidy.2 Use of the MaterniT21 PLUS LDT may reduce the need for unnecessary invasive procedures 99 that pose a risk to women and their pregnancies. Sequenom holds an exclusive platform-independent license for fetal nucleic acid detection in 99 serum and plasma.
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of aneuploidy • Personal/family history of chromosomal abnormalities • Positive serum screening test
1. Devers PL, Cronister A, Ormond KE, Facio F, Brasington CK, et al; for the NSGC Public Policy Committee. Noninvasive Prenatal Testing/Noninvasive Prenatal Diagnosis: the position of the National Society of Genetic Counselors. Adopted February 18, 2012. http://www.nsgc.org/Advocacy/PositionStatements/tabid/107/ Default.aspx#noninvasive Accessed June 28, 2012. 2. Benn P, Borrell A, Cuckle H, Dugoff L, et al. Prenatal Detection of Down Syndrome using Massively Parallel Sequencing (MPS): a rapid response statement from a committee on behalf of the Board of the International Society for Prenatal Diagnosis, 24 October 2011. Prenat Diagn. 2012 Jan;32(1):1-2. doi: 10.1002/pd.2919. Epub 2012 Jan 24. 3. DNA sequencing of maternal plasma to detect Down syndrome: an international clinical validation study. Palomaki GE, Kloza EM, Lambert-Messerlian GM, Haddow JE, Neveux LM, Ehrich M, van den Boom D, Bombard AT, Deciu C, Grody WW, Nelson SF, Canick JA. Genet Med. 2011 Nov;13(11):913-920.
Chronic Migraine: Overview of the Disease State and Management Peter J. McAllister, MD
Summary Chronic migraine is the most common form of chronic headache. Because chronic migraine is so disabling, the condition is costly both from an economic and social viewpoint. Appropriate diagnosis and management can lead to improved outcomes such as reduced disability, reduced resource utilization, and reduced costs. Key Points • Chronic migraine is a disabling, underdiagnosed, and undertreated disorder. • Chronic migraine results in far greater suffering, disability, and health care costs than episodic migraine. • It is important to try limit the progression of migraines from episodic to chronic. • Medication overuse is the major trigger for transformation from episodic to chronic. • Chronic migraine is not cured; it is managed. • Two major goals of management are to revert the headache pattern back to episodic and minimize the use of acute medications. • Drop-in headache clinics are one way to reduce health care costs and improve outcomes in patients with chronic migraine.
Headaches are an extremely common problem for many people. They can be either primary or secondary disorders (Exhibit 1). Secondary headache disorders have an identifiable cause such as brain tumor, subdural hematoma, and meningitis. Primary headache disorders can be classified into episodic or chronic categories based on the number of days per month that they occur Chronic headaches can be further subdivided into short- and long-duration chronic headache. Short-duration chronic headache includes cluster headaches; these occur episodically with each episode lasting less than four hours. Primary chronic daily headache of long duration is a syndrome characterized by headaches not attributable to a secondary disorder that last more than four hours a day and occur 15 or more days per month.1,2 Chronic daily headache of long duration (CDH) affects 3 to 5 percent of the general population worldwide and approximately 40 percent of patients seen in headache clinics.3-5 CDH encompasses four main diagnoses - chronic migraine, chronic ten-
sion-type headache, new daily persistent headache, and hemicrania continua (Exhibit 2). Chronic migraine accounts for about 95 percent of all chronic daily headaches. Migraines, either episodic or chronic, occur in about 12 percent of Americans with women more commonly affected.6 The major distinguishing factor between chronic and episodic migraine is the number of headache days per month. Someone is said to have episodic migraines if they have headache on less than 15 days per month. Chronic migraine is defined as migraine with or without aura on 15 days or more per month for at least three months, and has unilateral or bilateral pain and a pulsating quality.7 Chronic migraine is a clinical diagnosis; there are no tests to identify migraines. Between 8 and 10 percent of those with migraines will have chronic migraines at some point in their lives. Patients tend to start with episodic migraines which progress in frequency to become chronic. The frequency can increase to an everyday headache. Risk factors for developing chronic migraines
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Exhibit 1: Primary Headache Disorders: Frequency Classification After Secondary Causes Are Ruled Out
Primary Headache Disorders
Chronic Headache Frequency >15 days/month
Short-Duration Chronic Daily Headache
Episodic Headache Frequency <15 days/month
Chronic Daily Headache (Long Duration) Daily or near-daily headache lasting >4 hours
Duration <4 hours or multiple discrete episodes
With or Without Medication Overuse
Exhibit 2: Differential Diagnosis of Chronic Daily Headache
Chronic Daily Headache >4 hours
Migraine or specific acute Yes medications >8 days/month
No Continuous unilateral pain Yes with autonomic features and an indomethacin response
Clear onset as Yes New Daily Persistent a daily syndrome Headache No
Pain and associated symptom Yes Chronic Tension-Type profile (non-migrainous) Headache
include female gender, inactive lifestyle, obesity, and medication overuse. Medication overuse is the major factor for converting from episodic to chronic. The most common medications that result in transformation are moderate narcotics such as Percocet ® and Vicodin®, and barbiturate-containing products such as Fiorinal®, Fioricet ®, and Excedrin® Migraine. Opioids’ association with migraine progression is dosedependent (critical dose of exposure: eight days/ month) and more pronounced in men.8 Barbiturates also induce migraine progression with a dose-dependent effect (five days/month or more) but more often in women. 8 Triptans induce migraine pro-
gression only in those with high migraine frequency at baseline (>14 days/month), but not overall.8 Caffeine containing over-the-counter products such as Excedrin® Migraine increase the risk of progression. Nonsteroidal anti-inflammatories (NSAIDs) protect against migraine progression unless individuals treat 10 or more headache days monthly; then they become inducers, rather than protective. The headaches that result from medication overuse are essentially caused by medication withdrawal. Eliminating medication overuse can revert headaches back to an episodic pattern.9 Chronic migraine is an underdiagnosed and undertreated disorder.10 The American Migraine Prev-
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Exhibit 3: High Annual Indirect and Direct Cost of Headache per Patient in Chronic Migraine15
Cost Per Chronic Migraine Patient (n=359)
Cost Per Episodic Migraine Patient (n=7437)
$1291.34 $5392.03 $482.59 Pain clinic/Urgent care visit Neurology visit Primary care visit ER visit Hospital stay *Cost calculated in 2006 dollars. ER = emergency room.
Medication cost Lost productive time
alence and Prevention (AMPP) study found that only 20 percent of patients who met the criteria for chronic migraine were actually diagnosed, despite approximately 80 percent having seen a health care professional for their headaches.11 An accurate diagnosis will decrease the number of specialists the patient seeks out in order to find a diagnosis. An early accurate diagnosis may also prevent episodic patients from progressing to chronic migraine. Population surveys demonstrate that only 13 percent of those with reported chronic migraine are treated with preventive therapy.11 In addition to being underdiagnosed and undertreated, migraines cause significant disability. Migraines cause moderate to severe pain and the severity of pain drives disability. Chronic migraine results in a greater severity and duration of pain than episodic migraine.12 Severe migraine is ranked in the highest disability class by the World Health Organization.13 Chronic migraine patients are more disabled and have worse health-related quality of life than episodic migraine patients.12 Importantly from an economic perspective, migraines result in work absenteeism and presenteeism. Chronic migraine patients are also less likely to be employed full time.
The clinical course of migraine can be conceptualized as progression (movement from one category to a higher frequency category), remission (movement from one category to a lower frequency category), or no change in headache frequency. Over a twoyear study period, persistent chronic migraine sufferers experienced an increase in headache-related disability, while those with remitted migraine experienced a substantial decrease in headache-related disability.14 Thus, chronic migraine that is untreated progresses over time, which has patient quality of life and health care cost implications. Appropriate management can lead to remission and reduced disability. Chronic migraine also results in significant direct and indirect costs. The AMPP study estimated the total direct and indirect costs associated with chronic migraine.15 The average per person annual total costs were 4.4-fold greater for chronic migraineurs than for episodic migraineurs (Exhibit 3).15 Chronic migraineurs have 2.8-fold higher acute prescription medication costs than episodic migraineurs. Chronic migraineurs are significantly more likely to visit the emergency room, their primary care physician, a neurologist, or a headache specialist. Migraine is the third or fourth most common discharge diagnosis
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from the emergency room. Because chronic migraine patients utilize significant health care resources, methods for providing cost-effective care in these patients has been investigated. One option is the use of an office-based, drop-in headache center. These centers utilize intravenous non-narcotic infusions to halt migraines, which results in significant pain improvement within 45 minutes. These centers have been shown to reduce emergency room use by chronic migraine patients and to improve their care.16 Avoiding the emergency room also avoids the use of commonly ordered expensive tests such as an MRI or spinal tap used to evaluate severe headaches. In addition to being undertreated, chronic migraine is frequently inappropriately treated based on an outdated understanding of the disorder. The old understanding of migraine was it was a blood vessel abnormality or vascular headache. Migraine is now best understood as a primary disorder of the brain. Two non-mutually exclusive hypotheses have been advanced to account for the initiation of migraine – one focusing on the hyperexcitability of the cortex, and the other on the dysmodulated brainstem. Both event mechanisms could contribute to the pathophysiology of migraine. The first hypothesis proposes that the brain of migraineurs is hyperexcitable. According to this idea, common triggers may initiate a cortical spreading depression in the brain; this would then lead to the activation of the trigeminal system and development of the migraine attack.17 The cortical spreading depression is what causes the aura in migraineurs. Depending on where this spreads to within the brain, there will be different aura symptoms – visual changes, motor weakness, tingling, or confusion. The second hypothesis proposes that the brain of migraineurs is dysmodulated as a result of dysfunctional sensory processing within the brainstem.18 The dysmodulation would lead to enhanced sensory sensitivity, which could account for the symptoms of migraine. Dysfunction within the brainstem during a migraine attack is supported by imaging studies.19 Both hypotheses point toward primary pathology within the neuronal tissue of the brain. This change in understanding of the pathophysiology of the disease has lead to a better understanding of appropriate treatment. The overall treatment goal with chronic migraine is to convert the patient back into an episodic pattern. If the chronic pattern is allowed to continue, patients will continue to worsen and the pattern may no longer be reversible. Reverting to an episodic pattern will decrease health care utilization and improve quality of life.
A holistic approach is needed to discover what is driving the headaches and what initiated them. Understanding the current medical and emotional state of the patient is of paramount importance in designing effective therapies. The brain has to be “taught” how to have reduced pain and frequency of headaches. Even before medication is prescribed, nonpharmacologic therapies should be implemented – exercise, good sleep hygiene, and elimination of potential triggers. Additionally, the patient needs to be educated about the disease, treatment, and goals of therapy. Clinicians need a thorough understanding of the patient’s current medication use to identify medication overuse. Patients will have to be tapered off chronic pain medications over time. An attempt should be made to limit use of acute medication to treatment of no more than two or three headaches per week and with no more than two doses per headache. After nonpharmacologic therapy is initiated and medication overuse is eliminated, preventive medication is then used to stabilize the neuronal network that is over firing. The only approved medication for chronic migraine is botulinum toxin (Botox ®) but many agents approved for episodic migraine are used in chronic disease. Effective preventive medications include valproic acid derivatives, topiramate, and beta blockers. The goal with preventive medication is to reduce the number of headache days per month to a manageable number (i.e., three or four days per month). The patient would then use their abortive medication on those days. An important point for patient education is that migraine is not cured; it is managed. Response to therapy should be monitored with patient completed headache diaries. Survey tools such as the Headache Impact Test (HIT-6) can also be useful.20 It can also be valuable to assess and monitor the patient’s level of headache-related disability. Conclusion
Chronic migraine is a disabling, costly, underdiagnosed, and undertreated disorder. Studies of chronic migraine hypothesize a pathophysiological state in which the brain exhibits enduring and pervasive alterations. Important components of chronic migraine management include accurate diagnosis, patient education, management of overuse of acute medications, use of a headache diary, and use of preventive medications where appropriate. Peter J. McAllister, MD is a board-certified Neurologist and Clinical Assistant Professor of Neurology at Yale University School of Medicine in New Haven, CT.
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burden, and the need for preventive therapy. Neurology. 2007;68:343-9.
1. Silberstein SD, Lipton RB, Sliwinski M. Classification of daily and near-
12. Blumenfeld AM, Varon SF, Wilcox TK, et al. isability, HRQoL and re-
daily headaches: field trial of revised IHS criteria. Neurology. 1996;47:871-875.
source use among chronic and episodic migraineurs: results from the Interna-
2. Dodick D. Chronic daily headache. N Engl J Med. 2006;354:158-165.
tional Burden of Migraine Study (IBMS). Cephalalgia. 2011;31:301-15.
3. Scher AI, Stewart WF, Liberman J, Lipton RB. Prevalence of frequent head-
13. Menken M, Munsat TL, Toole JF. The global burden of disease study: im-
ache in a population sample. Headache. 1998;38:497-506.
plications for neurology. Arch Neurol. 2000;57:418-20.
4. Castillo J, Munoz P, Guitera V, Pascual JG. Epidemiology of chronic daily
14. Lipton RB, Manack A, Buse DC, Serrano D, Turkel CC. Disability impact
headache in the general population. Headache. 1999;39:190-6.
following remission from chronic migraine to episodic migraine. Results from
5. Lanteri-Minet M, Auray J-P, El Hasnaoui A, et al. Prevalence and description
the American Migraine Prevalence and Prevention (AMPP) Study. Poster pre-
of chronic daily headache in the general population in France. Pain.
sented at: European Headache and Migraine Trust International Congress
2008, London. UK.
6. Natoli JL, Manack A, Dean B, et al. Global prevalence of chronic migraine:
15. Munakata J, Hazard E, Serrano D, et al. Economic Burden of transformed
a systematic review. Cephalalgia. 2010;30:599-609.
migraine: Results from the American Migraine Prevalence and Prevention
7. Headache Classification Committee; Olesen J, Bousser MG, Diener HC, et
(AMPP) Study. Headache. 2009;49:498-508.
al. The International Classification of Headache Disorders: 2nd edition. Cepha-
16. McAllister PJ et al. Implementation of an Office-Based Drop-in Headache
lalgia. 2004;24(suppl 1):9-160.
Clinic: Providing Quality, Cost-Effective Care to Migraineurs. Abstract F56.
8. Bigal ME, Lipton RB. Overuse of acute migraine medications and migraine
50th Annual Meeting of the American Headache Society. 2008
chronification. Curr Pain Headache Rep. 2009;13:301-7.
17. Pietrobon D. Migraine: new molecular mechanisms. Neuroscientist.
9. Seok JI, Cho HI, Chung CS. From Transformed Migraine to Episodic Mi-
graine: Reversion Factors. Headache. 2006;46:1186-90.
18. Goadsby PJ. Migraine pathophysiology. Headache. 2005;45(suppl 1):S14-S24.
10. Bigal ME, Serrano D, Reed M, Lipton RB. Chronic migraine in the popu-
19. Fridi SK, Matharu MS, Lee L et al. A PET study exploring the laterality of
lation: burden, diagnosis, and satisfaction with treatment. Neurology.
brainstem activation in migraine using glyceryl trinitrate. Brain. 2005;128:932-39.
20. Kosinski M, Bayliss MS, Bjorner JB, et al. A six-item short-form survey for
11. Lipton RB, Bigal ME, Diamond M, et al. Migraine prevalence, disease
measuring headache impact: The HIT-6â„˘. Qual Life Res. 2003;12:963-74.
24 Journal of Managed Care Medicine | Vol. 15, No. 3 | www.namcp.org
Introducing the Biogen Idec Managed Markets Portal
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www.biogenidecmm.com to register. BIOGEN IDEC, MS ACTIVESOURCE, and the BIOGEN IDEC logo are registered trademarks of Biogen Idec. MS ACTIVESOURCE is sponsored by Biogen Idec and Elan Pharmaceuticals, Inc. ©2012 BiogenIdec. All rights reserved. Printed in USA. 04/12 X-XXXX-XX
Cost-Effective Glaucoma Care in the Managed Care Setting Steven D. Vold, MD
Summary Glaucoma is a major cause of vision loss that can be prevented with treatment. Early detection and treatment of ocular hypertension and eye damage can prevent progression. Although treatment of glaucoma has traditionally been medical, evolving minimally invasive surgical procedures result in good outcomes and avoid the issue of adherence problems seen with medications. Key Points • Glaucoma is a silent thief of eyesight. • Early detection and appropriate treatment is cost effective. • Ocular hypertension is a treatable risk factor for developing glaucoma. • Treatment of ocular hypertension should be based upon a risk assessment. • African Americans are at higher risk for developing glaucoma. • In patients with diagnosed glaucoma, a 1 mm Hg decrease in intraocular pressure results in a 10 percent reduction in glaucoma progression risk. • Minimally invasive surgery is a rapidly advancing area of glaucoma treatment.
Glaucoma is optic nerve damage that leads to a loss of peripheral vision initially and ultimately central vision. Glaucoma is the number one cause of irreversible blindness worldwide. It has been called the silent thief of eyesight because the vision loss occurs insidiously over many years. Unfortunately, many patients do not realize they are losing vision until central vision is affected. By this time, they have lost 90 to 95 percent of their optic nerve function. Health care providers do not always realize how important vision is to patients. In fact, for many patients, their number two fear, just behind cancer, is blindness. Sixty million people are estimated to have glaucoma worldwide. Annual expenditures for glaucoma in the United States are greater than $2.5 billion. The mean costs increase as the disease progresses from ocular hypertension to glaucoma. Additional costs associated with glaucoma include falls, driving accidents, poor quality of life, depression, and poor general health. The current health care environment requires cli-
nicians to be more conscious of providing not only high quality, but also cost-effective care. Formulary restrictions and capitated payment per glaucoma patient can impact both providers and managed care. Capitated payment may include patient visits, visual field examination, disc photography, corneal pachymetry, imaging, and laser and incisional surgeries. Clinicians also need to make more costconscious medication decisions. Individual medications to treat glaucoma, which are typically applied directly to the eye, can range from less than $200 per year to over $1000 per year. Patients may require three or four medications to control their disease. Early detection of glaucoma is critical for preventing eyesight loss and for providing cost-effective care because fewer treatments will typically be needed to control the disease. Early detection is important, but we have to figure out how to screen patients in a cost-effective manner. Imaging studies can be helpful in early detection and determining progression in glaucoma because of the pattern of loss that occurs in this disease; reti-
26 Journal of Managed Care Medicine | Vol. 15, No. 3 | www.namcp.org
Exhibit 1: Structural - Functional Relationship in Glaucoma1
RNFL, retinal nerve field loss; Disc, optic disc; VF, visual field
Exhibit 2: Differences in Risk of Developing Glaucoma
Patient 1: 60-year-old Caucasian female • IOP 24 / 24 • C/D ratio 0.1 • Corneal thickness 600 μ • Risk of glaucoma ~ 1% / 5 years Patient 2: 60-year-old Caucasian female • IOP 24 / 24 • C/D ratio 0.5 • Corneal thickness 490 μ • Risk of glaucoma ~ 20% / 5 years Patient 3: 70-year-old African American male • IOP 25 / 25 • C/D ratio 0.6 • Corneal thickness 510 μ • Risk of glaucoma ~ 35% / 5 years
IOP, intraocular pressure; C/D ratio, cup to disk ratio
nal nerve field loss occurs first then optic disc damage. Visual field changes occur late in the disease (Exhibit 1).1 Ocular Hypertension
Ocular hypertension (OH) is the only marker for glaucoma development that is treatable. Ocular hypertension is elevated inter-ocular pressure (IOP) in the absence of clinically detectable optic nerve or visual field changes. Lowering pressure can protect the optic nerve. About one in 10 patients with ocular hypertension will go on to develop glaucoma. Treating ocular hypertension has been shown to prevent the development of open angle glaucoma. The Ocular Hypertension Treatment (OHT) study was designed to determine whether medical reduction of IOP prevents or delays the onset of glaucomatous visual field loss and/or optic nerve damage.
This study found that medications produced about a 20 percent reduction in IOP. Treatment reduced the incidence of open angle glaucoma in the study participants by more than 50 percent at five years.2 There was little evidence of safety concerns with glaucoma medications. The OHT study also sought to produce data to assist in identifying and quantifying risk factors for developing open angle glaucoma. This study found that the use of optic nerve photos allowed earlier diagnosis of glaucoma than visual fields. Visual fields may not change until at least 50 percent of the optic nerve function is lost. An important finding of the OHT study was that thin corneas predispose people to develop glaucoma. Thus, central cornea thickness is a very powerful tool for predicting who will develop glaucoma. The other factors based on multivariate analysis that
www.namcp.org | Vol. 15, No. 3 | Journal of Managed Care Medicine 27
Figure 3: Guidelines for Target IOP7
Patientâ€™s Clinical Status Target IOP Reduction Ocular hypertension
Early to moderate glaucoma
Severe glaucoma; rapidly progressing damage; higher IOP; multiple risk factors
Eye exam indicates progression since Additional therapy was initiated 15%
Exhibit 4: Recommended Follow-up7
Target Progression Duration Visual Field Optic Nerve IOP of Damage Control Follow-up Follow-up Achieved (mos) Interval (mos) Interval (mos) Yes
were found to be important predictors were age, IOP, pattern standard deviation (a measure of visual field loss), and cup to disk ratio of the optic disk (a measure of damage to the optic nerve). African Americans are at higher risk for developing glaucoma. It is the number one cause of blindness among this group. The OHT study suggested that this racial effect might be due to thinner central corneas and larger cup/disc ratios. In the OHT study, it was found that medications were less protective for developing glaucoma in the African American population. This appears to be because they have a more aggressive form of disease. Because not every patient with OH will develop glaucoma, not every patient with OH should be treated. Treatment should be offered to the patient at moderate to high risk of developing glaucoma taking into consideration age, medical status, life expectancy, and likely treatment benefit. Clinicians are not just treating an IOP; they are making sure a patient can see for the rest of their lifetime. A glaucoma risk calculator can be used to estimate an
individualâ€™s risk in order to decide on a treatment plan (example at www.discoveriesinsight.org/glaucomarisk.htm). Exhibit 2 shows examples of the difference in risk of developing glaucoma in two women who are the same age but who have different risk factors and an older African American male. Patient 1 would likely have her eyes monitored, whereas Patients 2 and 3 should be treated to lower their IOP to reduce their risk of vision loss. Normal Tension Glaucoma
For many years, normal tension glaucoma (NTG) was thought to be a very small portion of the overall glaucoma patient population. A study published in the late 1990s found that almost one- third of patients with glaucoma have IOPs in the normal range.3 These normal tension patients had optic nerve damage and visual field loss characteristic of that seen in patients with glaucoma with elevated pressures. IOP is part of the pathogenic process of NTG, even if it is not elevated. Lowering normal pressure
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Exhibit 5: Ex-PRESS Specifications
Beveled Tip Enables precise and controlled insertion
Faceplate Prevents device intrusion
Spur Prevents device extrusion
Relief Port Allows uninterrupted aqueous flow Total span 2.64mm
Axial Lumen Main fluid conduit 50μ or 200μ
Shaft 27 gauge 0.4mm outer diameter
Scleral Slot Accommodates secure device placement
30 percent reduces the risk of eye damage.3 If a patient is placed on treatment and a 30 percent IOPlowering goal is set, it can be achieved at least half the time with medications. The other 50 percent of patients will require surgery. Although filtration surgery (trabeculectomy) can achieve a greater IOP lowering, it results in a higher incidence of cataract formation. Risk factors for progression of NTG are female gender, migraine, disc hemorrhage at diagnosis, and low systemic blood pressure.4 With migraine, there appears to be issues with autoregulation of the blood vessels in the eye. Self-declared history of family with or treated for glaucoma does not appear to affect the rate of progression.4 Glaucoma Treatment
When a patient is first diagnosed with glaucoma, a decision as to whether to treat with medication or surgery must be made. Traditionally in the U.S. glaucoma has primarily been treated initially with medications. In other countries, surgery is the initial treatment of choice. Treatment with medication or treatment with trabeculectomy for newly diagnosed open-angle glaucoma appears effective based upon the first five years of follow-up in the Collaborative Initial Glaucoma Treatment study.5 In this study, medication reduced IOP greater than 35 percent, whereas surgery reduced it 40 percent. Visual field loss was greater
Vertical Channel Alows optimal aqueous flow
in the surgery group during the first three years of the study, but these differences largely disappeared during years four and five of follow-up. Few major complications of surgery or major side effects of medications were reported. In patients with diagnosed glaucoma, a 1 mm Hg decrease in IOP results in a 10 percent reduction in risk of glaucoma progression.6 Guidelines for target IOP are given in Exhibit 3.7 Exhibit 4 provides follow-up guidelines based on achieving target pressures and measures of progression.7 Patients with advanced glaucoma have significant eye changes and visual field losses. They require significant IOP reduction to prevent further vision loss; attaining pressures of 14 mm Hg or less reduces the risk of further progression. Additionally, they require relatively steady pressures without significant fluctuations. The goal IOP does not have to be adjusted for other patient factors such as age, general health, etc. Medication therapy does have to be individualized. It can require one to four medications to adequately control IOP. Each medication addition adds potential adverse effects so medication adherence should be assessed before additional medications are added to a patient’s regimen. Medication Adherence
Medication adherence is a huge problem for most
www.namcp.org | Vol. 15, No. 3 | Journal of Managed Care Medicine 29
patients with glaucoma because of the number of medications that can be required to control IOP, the inherent difficulty of applying medications to the eyes and the silent nature of the disease. Medication cost is also a very frequent issue. Adherence with medications is important because fluctuations in IOP may affect disease progression. Patients need to maintain IOP control over time. Based on managed care data, the best persistency for a one drop per day eye medication is 60 percent of patients still on at one year. This is not adequate for preventing vision loss. To improve persistency, we need better medications that require infrequent dosing. Surgery is a longer lasting treatment option; 80 percent of patients treated surgically will still be under control at one year. For medication noncompliant patients, it is a very viable treatment option. Patients need to be educated on the role of medicines in maintaining eyesight and the need for maintaining a consistently low IOP. Showing them the techniques for applying drops is very important. Additionally, eye drops can seem unimportant to non-eye health care providers. Many times a patientâ€™s glaucoma medications get discontinued during hospitalization or other change in health care setting because providers do not understand their importance.
ting. To have a long-lasting surgical procedure that eliminates the need for medications for the majority of patients is the ultimate goal. Conclusion
In order to provide cost-effective care, glaucoma needs to be detected and treated early. Glaucoma risk factor assessment and eye imaging techniques can assist in early detection and treatment determination. Appropriate target pressures, medication selections, and surgical decisions have to be individualized for every patient. As surgical procedures improve, this will become a surgically managed disease rather than medically managed. Steven D. Vold, MD is CEO of Vold Vision, PLLC in Springdale, AR.
References 1. Adapted from Professor Robert N. Weinreb. Hamilton Glaucoma Center, University California San Diego. 2. Gordon MO, Beiser JA, Brandt JD, et al. The Ocular Hypertension Treatment Study: baseline factors that predict the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;120:714-20. 3. Collaborative Normal Tension Glaucoma Study Group. Comparison of glaucomatous progression between untreated patients with normal-tension glaucoma and patients with therapeutically reduced intraocular pressures. Am J Ophthalmol. 1998;126:487-97. 4. Anderson DR, Drance SM, Schulzer M, et al. Risk Factors for Progression
The optimal glaucoma surgery would be safe, easy, effective, repeatable, and combinable with cataract surgery. The trabecular network in the eye is thought to contribute to the increased eye pressure in glaucoma. Trabeculectomy has been the standard surgical method for treating glaucoma but is really a procedure for advanced stage disease. A newer option is minimally penetrating glaucoma surgery. One type of minimally penetrating surgery is the use of the Ex-PRESS device (Exhibit 5). The Ex-PRESS is a very small (<3mm) stainless steel implant that reduces intraocular pressure by diverting the aqueous humor from the anterior chamber of the eye to the subscleral space. This implant is inserted in a minimally invasive procedure under a scleral flap with no tissue removal. Post-op aqueous outflow is controlled by a unique flow-modulating design in the implanted device and the scleral flap. This procedure is at least as effective as trabeculectomy at five years. It appears to reduce postoperative complications and recovery period when compared to trabeculectomy. It is an excellent surgical option in most patients with moderate to severe glaucoma. With the amazing progress that is being made with minimally invasive procedures, these procedures will ultimately be performed in the office set-
of Visual Field abnormalities in Normal Tension Glaucoma. Am J Ophthalmol. 2001;131:699-708. 5. Musch DC, Gillespie BW, Niziol LM, et al. Intraocular pressure control and long-term visual field loss in the Collaborative Initial Glaucoma Treatment Study. Ophthalmology. 2011;118:1766-73. 6. Heijl A, Leske MC, Bengtsson B, et al. Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch Ophthalmol. 2002;120(:1268-79. 7. American Academy of Ophthalmology. Primary Open Angle Glaucoma Preferred Practice Patterns. 2010. Available at www.aao.org.
30 Journal of Managed Care Medicine | Vol. 15, No. 3 | www.namcp.org
Economic Implications of Early Diagnosis of Hyperthyroidism Theo McCormick and Jerold Share, MD
Summary There is significant variation in how clinicians follow up abnormal thyroid function tests and arrive at a diagnosis of hyperthyroidism. Updated guidelines have been published which simplify the process of screening and diagnosis, but these need to be more widely adopted. Managed care plans should consider examining the use of thyroid tests by their providers. If problems are identified, several interventions can be implemented to streamline the diagnosis of hyperthyroidism to provide costeffective care. Key Points • Many patients with low thyroid-stimulating hormone (TSH) are not followed up. • Without appropriate guidance, providers use many different tests to arrive at a hyperthyroidism diagnosis. • Managed care plans should examine the use of thyroid tests by their providers. • Interventions to improve diagnosis of hyperthyroidism include automatic followup of abnormal TSH values and implementation of updated guidelines for diagnosis. • The early use of thyroid-stimulating immunoglobulin (TSI) when Graves’ disease is suspected leads to earlier diagnosis.
Approximately 1.2 percent of the U.S. population has hyperthyroidism. Overt disease occurs in about 0.5 percent and 0.7 percent have subclinical disease. The most common causes of hyperthyroidism are Graves’ disease, accounting for 60 to 80 percent, toxic multinodular goiter, and toxic adenoma.1 Graves’ disease is an autoimmune disorder that is seven times more prevalent in women than in men. The auto-antibody associated with Graves’ disease — thyrotropin receptor antibody (TRAb) — can essentially mimic the action of the thyroid-stimulating hormone. Therefore, TRAb overrides normal regulation of the thyroid and results in overproduction of thyroid hormones. The peak incidence of Graves’ disease occurs between ages 20 and 40. An overt Graves’ disease presentation with typical findings of exophthalmos and goiter is easy to diagnose. Other symptoms of hyperthyroidism are less specific, including insomnia, hand tremor, hyperactivity, hair loss, excessive sweating, heat intolerance,
weight loss despite increased appetite, tachycardia, palpitations, and muscle weakness. Delays in diagnosis are known to be costly in many diseases. The major consequences of untreated hyperthyroidism are an increased risk of atrial fibrillation and stroke. About 15 percent of patients with new onset atrial fibrillation will have hyperthyroidism. It can also result in accelerated bone loss, particularly in women, which leads to premature development of osteoporosis. Numerous laboratory tests can be ordered to evaluate thyroid function. Exhibit 1 shows the frequency which these tests were ordered in an analysis by Management Science Associates, Inc. of a nationwide laboratory claims database. The large number of different thyroid function assays can lead to inappropriate laboratory ordering when providers don’t have guidance on the appropriate tests to order. As expected, TSH accounted for more than half of all orders, as this assay is a preliminary step for most testing. TSH typically is ordered for one of four
www.namcp.org | Vol. 15, No. 3 | Journal of Managed Care Medicine 31
Exhibit 1: Orders for Thyroid Related Testing 21,000,000
6,000,000 5,000,000 4,000,000 3,000,000 2,000,000 1,000,000 0
TSH T4 FT4 T3RU FT1
TRAb TBG T4-TBG
TSH, thyroid stimulating hormone; T4, thyroxine; FT4, free thyroxine; T3RU, T3 uptake; T3, triiodothyronine; FT3, free triiodothyronine; FTI, free thyroxine index; T4-TBG, T4-thyroid binding globulin index; TPO, thyroid peroxidase antibody; TGAB, antithyroglobulin antibody; TG, thyroglobulin; TSI, thyroid stimulating immunoglobulin; TRAb, thyrotropin receptor antibody; TBG, thyroxine binding globulin Source: Management Science Associates, Inc.
Exhibit 2: ICD-9 Usage for Thyroid Related Testing
PRIMARY DIAGNOSIS DESCRIPTION ICD-9 CODE ASSAYS Unspecified Acquired Hypothyroidism
Routine General Medical Exam
Other Malaise And Fatigue
Other And Unspecified Hyperlipidemia
Benign Essential Hypertension
Diabetes Unspecified Essential Hypertension Disorders of lipid metabolism Long-term (current) use of other medications.
Source: Management Science Associates, Inc.
reasons: screening for thyroid disease, confirmation of thyroid disease before moving on to more tests, monitoring efficacy of medications, and monitoring efficacy of thyroid surgery or ablation. Exhibit 2 lists the reasons, based on ICD-9, that thyroid function tests were ordered. As expected, women were much more frequently tested than men. Women have higher incidences of thyroid disorders and visit clinicians more frequently then men. For all of the thyroid assays, 64 percent were ordered by a family practice or internal medi-
cine provider. In other words, initial thyroid disease screening, diagnosis, assessment, and monitoring is predominantly done by primary care. Out of 20 million TSH assays in this analysis, 3,100 patients had a low TSH discovered on an annual physical and were subsequently diagnosed with Gravesâ€™ disease. More than half the patients waited over one month after a low TSH before the diagnosis appeared in their records. Ten percent of patients waited over six months for a diagnosis. Overall, it took an average of 77 days from the initial TSH to
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Exhibit 3: A “Low” TSH doesn’t mean you get follow-up care…2 300000 250000 200000 150000 100000 50000 0 Low (Below 0.004 to 0.051 to Detection) 0.050 0.100
0.101 to 0.150
0.151 to 0.200
0.201 to 0.250
0.251 to 0.300
0.301 to 0.350
Black - Follow-up, Teal - No Follow-up
Exhibit 4: Time to Diagnosis of Graves’ Disease By Endocrinologists with and without TSI
1 year +
9 month - 1 year
3 week - 1 month
Cum%-TSI Cum%-No TSI
100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0%
Cumulative % of the cohort
N=726 (TSI=228; No TSI=498)
Source: Management Science Associates, Inc.
obtain a Graves’ disease diagnosis. Of interest is that of over 800,000 patients who had a low TSH initially, only 40 percent were followed up. This may have represented data loss because the person went to another lab for that followup or 60 percent of people with low TSH on testing actually do not get followed up. Exhibit 3 shows there was no relationship between the actual TSH value and follow-up.2 Endocrinologists were most likely to follow-up a low TSH,whereas gynecolo-
gists were least likely. There was a trend that older patients were more likely to get follow-up care. Providers need a consistent algorithm dictating when follow-up of a low value is necessary. This analysis found that clinicians used more than 1,000 different assay combinations to get from a low screening TSH to a diagnosis of Graves’ disease. The most common test after a low TSH was another TSH. Free T4 and T4 were the second and third most frequently ordered assay after a low TSH. An
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Exhibit 5: A Simplified and Efficient Laboratory Approach Toward the Patient with Low TSH3 1) Asymptomatic Patient 1) Suspected Patient 2) No Previously Documented 2) No Previously Documented Thyroid Disease Thyroid Disease
1) Symptomatic Patient 2) No or Inconclusively Documented Thyroid Disease 3) Suspect Graves’ Disease (Due to Goiter, Exophthalmos, Tremor, Tachycardia, NewOnset Atrial Fibrillation, etc.)
For Thyroid Screening
Check TSH Check Free T4
Check TSH Check Free T4 Check Total T3 Check TSI*
TSH < 0.4 µIU/ml.? Yes
TSH < 0.4 µIU/ml.? No Yes
Check Free T4
TSH < 0.4 µIU/ml.?
Yes Free T4 Elevated? No Yes
Free T4 (and Total T3) Elevated?
Yes Non-autoimmune hyperthyroidism * diagnostic methodologies for Graves’ Disease include TSI, thyroid uptake/scan, and thyroid ultrasound with Doppler
Check TSI* +Check Total T3 No
Consider: Toxic multinodular goiter, hyperfunctioning (hot) nodule, subacute thyroiditis, factitious disease, druginduced, and pregnancy (hOG effect). Also: autoimmune post-partum thyroiditis.
TSI elevated? Yes
(Autoimmune) Graves’ Disease* *diagnostic methodologies for Graves’ Disease include TSI, thyroid uptake/scan and thyroid ultrasound with Doppler
average of five laboratory assays was used to reach a diagnosis. The analysis attempted to determine if there were approaches that streamlined the process of diagnosis. For the definitive diagnosis of Graves’ disease, thy-
roid-stimulating immunoglobulin (TSI) assay can be used. As shown in Exhibit 4, the use of TSI by endocrinologists did modestly accelerate by an average of seven days the finding of Graves’ as compared with endocrinologists that did not use the TSI assay.
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For all patients, the use of TSI by any type of practitioner resulted in the shortest time to diagnosis. The use of multiple pathways to reach a diagnosis can result in multiple office visits and laboratory tests before an accurate diagnosis is made, which ultimately increases costs to the payer. The numerous and sometimes conflicting diagnostic algorithms available from national professional organizations, individual health care systems, and laboratories are one driver for the use of multiple pathways. Another driver is lack of guideline adherence by clinicians. As shown in the analysis presented here, there are issues with appropriate thyroid function test ordering and follow-up. Managed care should examine their order patterns for thyroid function tests. Some of the tests are only appropriate for select situations. For example, thyroglobulin (TG) is primarily used as a tumor marker to evaluate the effectiveness of treatment for thyroid cancer and to monitor for recurrence. Although the various thyroid function assays are not excessively expensive individually, incorrect ordering can lead to additional expenses such as radiologic tests to follow-up. Managed care plans can perform their data analysis internally or contract with one of the various data mining groups to examine how thyroid function tests are being used. If a problem with thyroid function testing is identified, managed care plans can consider two options for improving the diagnosis of thyroid disease. One option is to have contracted laboratories do automatic follow-up testing of low TSH values according to a specific algorithm. Automatic testing simplifies ordering for the clinician, relieves the patient of additional blood draws and, most importantly, automatically utilizes the appropriate assay. The second intervention which can be done concurrently with automatic testing is implementing the new guidelines from the American Thyroid Association (ATA) and American Association of Clinical Endocrinologists (AACE).3 These updated guidelines simplified the diagnosis and management of all forms of hyperthyroidism. The ATA/AACE guidelines break the workup of patients with hyperthyroidism into three pathways as shown in Exhibit 5. The first pathway is for screening asymptomatic patients and a TSH is the initial recommended test. In the second pathway for patients with suspected thyroid disease, ordering TSH and free T4 at the same time increases diagnostic accuracy from 90 percent to 99 percent. In pathway three (symptomatic patients and those with suspected Graves’ disease), ordering the indicated tests, including TSI initially, saves time and money compared with the old diagnostic approach. Now, the diagnosis of Graves’ disease can be made in as
little as 48 hours. Prior to the introduction of TSI, it would have taken an average of seven weeks to obtain a diagnosis because the patient would have to be treated with anti-thyroid medication for several weeks before being able to undergo a radioactive iodine uptake study to confirm the disease. Conclusion
Data mining can help managed care uncover issues with thyroid function assay ordering. A national database analysis has shown there is significant variability in a clinician’s approach to the evaluation of low TSH values and the diagnosis of Graves’ disease. Significant numbers of patients are not getting follow-up after a low TSH result, many different pathways are being used to arrive at a Graves’ disease diagnosis, and there is a significant delay in reaching this diagnosis. Updated guidelines from ATA/ AACE can simplify diagnosis and streamline testing. In order to improve laboratory ordering for the evaluation of abnormal TSH values, managed care should implement these guidelines for their providers and should consider automatic follow-up testing for abnormal TSH values. Theo McCormick is Director RxDx Services at Management Science Associates, Inc. Jerold Share, MD is a Clinical Assistant Professor of Medicine at Georgetown University Medical Center.
References 1. Singer PA, Cooper DS, Levy EG, et al. Treatment guidelines for patients with hyperthyroidism and hypothyroidism. Standards of Care Committee, American Thyroid Association. JAMA. 1995;273:808-12. 2. Segall D, McCormick T, Gischer J, Olivo P. Diagnostic Delay in Graves’ Disease. AMIA Annual Meeting. Poster 0115-A2011, October 2011. 3. Bahn RS, Burch HB, Cooper DS, et al. Hyperthyroidism and Other Causes of Thyrotoxicosis: Management Guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid. 2011;21:593-646.
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Management Strategies for Improving Outcomes in Pulmonary Arterial Hypertension Deborah Jo Levine, MD, FCCP For a CME/CEU version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.
Summary Pulmonary arterial hypertension (PAH) is a progressive, fatal disease, but prognosis improves with therapy. Unfortunately, diagnosis is often delayed because of the nonspecific symptoms of the disease. There are now several effective medications for treating this disease. Consensus evaluation and management guidelines are available and should be followed to optimize treatment of these patients. Key Points • PAH is a progressive, fatal disease that has nonspecific symptoms and an insidious onset. • There is an average 14-month delay from initial presentation of PAH to diagnosis. • Right heart catheterization is essential to accurately diagnose PAH, to delineate the hemodynamics of the disease, and to select therapy. • There are several approved medications, which can increase exercise tolerance, decrease symptoms, improve hemodynamics, delay need for lung transplant, and possibly delay progression. • The use of consensus management guidelines can steer appropriate therapy based on hemodynamics and risk data.
Pulmonary hypertension (PH) is an observation of elevated pressure within the pulmonary circulation. It encompasses a diverse group of conditions that lead to elevated arterial and/or venous pulmonary pressures. It is defined hemodynamically as mean pulmonary arterial pressure (PAP) greater than 25 mm Hg at right heart catheterization, but this definition does not reveal etiology or pathophysiology of the increased pressures. PH can be divided into pre-capillary and postcapillary hypertension. Pre-capillary is pulmonary arterial hypertension (PAH) and is defined by pulmonary wedge pressure (PWP) of 15 mm Hg or less. This type of PH is usually due to lung disease, chronic thromboembolic disease, or unclear or multifactorial mechanisms. Post-capillary is pulmonary venous hypertension with PWP greater than 15 mm Hg and is due to left sided heart disease.1 Exhibit 1 shows the World Health Organization classification of PH.2 Patients with PAH are the largest group. Appropriate classification of PH based on right heart cauterization data is important so ef-
fective treatment can be selected. For example, the medications for PAH are not effective for pulmonary venous hypertension. Chronic thromboembolic pulmonary hypertension (CTEPH) is the only type of PH that is potentially curable. The curative treatment is endarterectomy, which is only performed at certain surgical centers. Because of the potential for cure, it is important that this type of PH be identified. PH is a progressive and life-limiting disease (Exhibit 2).3 As the vascular lesions of PH progress over time, hemodynamic status and clinical symptoms worsen. All of the various kinds of PAH in Group 1 of Exhibit 1 have the same pathological lesion, same progression, and same very high risk of death without treatment. Additionally, these patients are the most difficult to treat. Many different specialists may be involved in the initial diagnosis and treatment of PH patients. The presenting symptoms of dyspnea, fatigue, chest pain, and syncope may result in referral to multiple specialists for evaluation. It is important that PAH be
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Exhibit 1: WHO Clinical Classification of Pulmonary Hypertension2 1. Pulmonary Arterial Hypertension • Idiopathic PAH • Heritable • Drug- and toxin-induced • Persistent pulmonary hypertension of newborn • Associated with: −Connective tissue disease −HIV infection −Portal hypertension −Coronary heart disease −Schistosomiasis −Chronic hemolytic anemia 2. Pulmonary Hypertension Secondary to Left Heart Disease • Systolic dysfunction • Diastolic dysfunction • Valvular disease
looked for in the patients with the conditions that frequently are associated with PAH such as HIV or connective tissue diseases. Exhibit 3 shows the breakdown of associated PAH in the U.S.4 A diagnosis of PAH should be considered when a patient has unexplained exercise limitation, symptoms and/or signs of right heart dysfunction, systemic diseases known to be associated with PAH, or abnormal right heart findings on echocardiogram. Because the symptoms can be insidious and nonspecific, clinicians need a high index of suspicion for this disease. Unfortunately, there is an average 14-month delay from initial presentation to diagnosis. Diagnosis will require various tests such as an echocardiogram, pulmonary function tests, chest x-rays, CT scans, ventilation-perfusion scans, and right heart catheterization.1 Right heart catheterization is essential to accurately diagnose PAH, to delineate the hemodynamics of the disease, and to select therapy. The goals of treatment are fewer for less severe symptoms, improved exercise capacity, improved hemodynamics, prevention of clinical worsening, improved quality of life, and improved survival. Prior to 1995, there were no medications approved for treating PAH. There are now seven FDA-approved agents. Management of PAH patients will require many different medications and other interventions. Various agents are used as chronic adjuvant therapy; they manage the consequences of the disease or symptoms but not the underlying pathology. Digoxin, oxygen, diuretics, and anticoagulation are the major agents which may be used. Digoxin and anticoagulation are the most controversial with the least evi-
3. Pulmonary Hypertension Secondary to Lung Diseases and/or Hypoxia • Chronic obstructive pulmonary disease • Interstitial lung disease • Other pulmonary diseases with mixed restrictive and obstructive pattern • Sleep-disordered breathing • Alveolar hypoventilation disorders • Chronic exposure to high altitude • Developmental abnormalities 4. Chronic Thromboembolic Pulmonary Hypertension 5. Pulmonary Hypertension With Unclear Multifactorial Mechanisms • Hematologic disorders • Systemic disorders - sarcoidosis, pulmonary Langerhans cell histiocytosis, vasculitis lymphangioleiomyomatosis, neurofibromatosis • Metabolic disorders - glycogen storage disease, Gaucher disease, thyroid disorders
dence.5-7 Pulmonary rehabilitation has been shown to be beneficial, but reimbursement for it can be difficult to obtain because of strict eligibility criteria. Immunizations are important to prevent infections such as pneumonia, which will further compromise lung function. Contraception, if appropriate, is also important in the management. Many women of childbearing age have PAH. Avoiding pregnancy is vital because there is a 50 to 60 percent mortality rate in women with PAH who become pregnant. Additionally, some of the medications used to treat PAH are teratogenic. Women who are treated with the teratogenic agents, including endothelin receptor antagonists, should be using at least two forms of contraception. Oral contraceptives are avoided because of their risk for thromboembolic complications. During the diagnostic right heart catheterization, patients will have a vasoreactivity test to determine which medications would be most beneficial with the least risk. Positive vasodilation tests only occur in about seven percent of PAH patients.7 Patients with a positive test will be treated with oral calcium channel blockers. Long-acting nifedipine, diltiazem, or amlodipine are the most commonly used agents. Prior to 1995, all patients with PAH were treated with calcium channel blockers, but these agents are very dangerous in patients without a positive vasoreactivity test. Unfortunately, calcium channel blockers only work for about a year; therefore, even responders will have to move on to other therapy. For the non-vasodilator responders, an assessment of risk for death needs to be made to determine which therapy to choose. Factors that place a patient
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Exhibit 2: Progressive and Life-limiting Disorder3 Pathological changes in the pulmonary arteries
CO mPAP PVR
CO, cardiac output, mPAP, mean pulmonary artery pressure; PVR, pulmonary vascular resistance
Exhibit 3: PAH Distributions in the U.S. REVEAL Registry4
Overall Heritable (2.7%)
Associated Pulmonary veno-occlusive (0.4%)
Connective tissue/ collagen vascular (49.9%)
Drugs/Toxins (10.5%) Portopulmonary (10.6%)
Congenital heart disease (19.5%)
in the high-risk category are poor functional status by WHO/New York Heart Association classification, inability to walk for six minutes, and severe hemodynamic parameters.8,9 Comorbidities, other current medications, patient preference, and the ability to pay for medications also have to be considered. For example, a patient with heart disease
who is treated with nitrates cannot be treated with sildenafil or tadalafil. Most of these medications are very expensive so third-party coverage will also be a deciding factor in choosing a medication. Exhibit 4 includes the American College of Cardiology Foundation/American Heart Association consensus PAH treatment algorithm.7 In addition
38 Journal of Managed Care Medicine | Vol. 15, No. 3 | www.namcp.org
Exhibit 4: ACCF/AHA Consensus PAH Treatment Algorithm7 Anticoagulate ± Diuretics ± Oxygen ± Digoxin
Acute Vasoreactivity Testing
ERAs or PDE-5 I (oral) Epoprostenol or Treprostinil (IV) Iloprost (inhaled) Treprostinil (SC, inhaled)
Epoprostenol or Treprostinil (IV) Iloprost (inhaled) ERAs or PDE-51 (oral) Treprostinil (SC)
Reassess: consider combo-therapy
Atrial septostomy Lung Transplant
CCB, calcium channel blocker; ERA, Endothelin Receptor Antagonists; PDE-5 I, Phosphodiesterase-type 5 Inhibitors
Exhibit 5: PAH-specific Therapies Approved for Use in the U.S. Endothelin Receptor Antagonists
Phosphodiesterase- type 5 inhibitors
Bosentan (Tracleer ®, PO) Sildenafil (Revatio®, PO) Epoprostenol (Flolan® or Veletri®, IV)
Ambrisentan (Letairis®, PO) Tadalafil (Adcirca®, PO) Iloprost (Ventavis®, inhaled)
Treprostinil (Remodulin® - IV, SC, and Tyvaso® -inhaled)
to calcium channel blockers, three other classes of medications used for PAH are phosphodiesterasetype 5 inhibitors (PDE-5 I), endothelin receptor antagonists (ERA), and prostanoids (Exhibit 5). The PDE-5 I agents are oral agents which are nitric oxide contributors that lead to vasodilation in the pulmonary vasculature. The ERA agents block the vasoconstricting effects of endothelin. The prostanoids are prostacyclin analogs that provide vasodilation. In clinical trials, all these agents have been shown to increase exercise tolerance, decrease symptoms, improve hemodynamics, and some have shown delay
in clinical worsening.10-15 Intravenous prostanoids, epoprostenol and treprostinil, are difficult to take but are lifesaving medications. They are given as a continuous intravenous infusion with a pump via a Hickman catheter. In addition, epoprostenol must be kept cold; therefore, the medication has to be kept on ice in the pump. Iloprost and treprostinil are available as inhaled products. The inhaled prostanoids have to be given multiple times per day (4 to 9) and are used in less severely ill patients. The prostanoids all have to be carefully titrated to minimize adverse effects.
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Therapy is initiated with monotherapy, but as they progress, most patients will end up on combinations of the various classes of PAH medication. Many studies are ongoing to determine the best combinations and optimal timing for adding new agents. If patients are progressing on maximal medications, lung transplantation is the remaining therapeutic option. Lung transplant is considered in patients with poor functional status despite medical therapy and is the only definitive treatment for PAH. Since the introduction of effective medications, the number of lung transplants for PAH has declined.16 The medications appear to be delaying the need for transplants.
6. Badesch DB, Abman SH, Simonneau G, et al. Medical therapy for pulmonary arterial hypertension: updated ACCP evidence-based clinical practice guidelines. Chest. 2007;131:1917-28. 7. McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol. 2009;53:1573-1619. 8. Humbert M, Sitbon O, Chaouat A, et al. Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era. Circulation. 2010;122:156-63. 9. Benza RL, Miller DP, Gomberg-Maitland M, et al. Predicting survival in pulmonary arterial hypertension: insights from the Registry to Evaluate Early
PAH is a progressive disease, but prognosis improves with therapy. Suspicion of the disease given the patient’s risk factors, signs and symptoms is essential. The evaluation and treatment of PAH should adhere to established guidelines. Therapies and management strategies continue to evolve.
and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL). Circulation. 2010;122:164-72. 10. Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002;346:896-903. 11. Channick RN, Simonneau G, Sitbon O, et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet. 2001;358(9288):1119-23. 12. Galiè N, Rubin Lj, Hoeper M, et al. Treatment of patients with mildly
Deborah Jo Levine, MD, FCCP is an Associate Professor of Medicine
symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a
and CT Surgery with the University of Texas Health Science Center in
double-blind, randomised controlled trial. Lancet. 2008;371(9630):2093-100.
13. Galiè N, Olschewski H, Oudiz RJ, et al. Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arte-
rial hypertension, randomized, double-blind, placebo-controlled, multicenter,
1.Galie N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and
efficacy (ARIES) study 1 and 2. Circulation. 2008;117:3010-19.
treatment of pulmonary hypertension. Eur Heart J. 2009;30:2493-537.
14. Galiè N, Ghofrani HA, Torbicki A, et al. Sildenafil citrate therapy for pul-
2. Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification
monary arterial hypertension. N Engl J Med. 2005:353:2148-57.
of pulmonary hypertension. J Am Coll Cardiol. 2009;54;S43-S54.
15. Galiè N, Brundage BH, Ghofrani HA, et al. Tadalafil therapy for pulmonary
3. Gaine S. Pulmonary hypertension. JAMA. 2000;284:3160-8.
arterial hypertension. Circulation. 2009;119;2894-903.
4. Badesch DB, Raskob GE, Elliott CG, et al. Pulmonary arterial hypertension:
16. Hertz MI, Aurora P, Christie JD, et al. Scientific Registry of the Interna-
baseline characteristics from the REVEAL Registry. Chest. 2010;137:376-87.
tional Society for Heart and Lung Transplantation: introduction to the 2010
5. Badesch DB, Abman SH, Ahearn GS, et al. Medical therapy for pulmonary
annual reports. J Heart Lung Transplant. 2010; 29:1083-1141.
arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest. 2004;126:35S-62S.
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CT SCANS confirmed responses in relapsed patients
120.0 kV 280.0 mA 1.3 mm/-0.5:1 Tilt: 0.0 0.0s Lin:DCM/Lin:DCM/id:ID W:200 L25
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855.4SEAGEN (855.473.2436) SeaGenSecure.com
Please see Brief Summary of full Prescribing Information, including Boxed WARNING, on the last page of this ad. REFERENCE: 1. ADCETRIS [Prescribing Information]. Bothell, WA: Seattle Genetics, Inc; 2012. US/BVP/2011/0104d
After multiple failures,
single-agent response Indicated for the treatment of: • Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT)1 • HL in patients who are not ASCT candidates after failure of at least 2 multiagent chemotherapy regimens1
• Systemic anaplastic large cell lymphoma (sALCL) after failure of at least 1 multiagent chemotherapy regimen1
HL: 73% objective response rate (ORR) (95% CI: 65%-83%)
complete remission (95% CI: 23%-42%)1
partial remission (95% CI: 32%-49%)1
N = 102, 15-77 years (median: 31 years)1
sALCL: 86% ORR (95% CI: 77%-95%)
complete remission (95% CI: 44%-70%)1
partial remission (95% CI: 18%-41%)1
N = 58, 14-76 years (median: 52 years)1
The indications for ADCETRIS™ (brentuximab vedotin) are based on response rate. There are no data available demonstrating improvement in patient-reported outcomes or survival with ADCETRIS.1
Important Safety Information BOXED WARNING
Progressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS.
Concomitant use of ADCETRIS and bleomycin is contraindicated due to pulmonary toxicity.
Warnings and Precautions:
• Peripheral neuropathy: ADCETRIS treatment causes a peripheral neuropathy that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. ADCETRIS-induced peripheral neuropathy is cumulative. Treating physicians should monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness and institute dose modifications accordingly. • Infusion reactions: Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If an infusion reaction occurs, the infusion should be interrupted and appropriate medical management instituted. If anaphylaxis occurs, the infusion should be immediately and permanently discontinued and appropriate medical management instituted. • Neutropenia: Monitor complete blood counts prior to each dose of ADCETRIS and consider more frequent monitoring for patients with Grade 3 or 4 neutropenia. If Grade 3 or 4 neutropenia develops, manage by dose delays, reductions or discontinuation. Prolonged (≥1 week) severe neutropenia can occur with ADCETRIS. • Tumor lysis syndrome: Patients with rapidly proliferating tumor and high tumor burden are at risk of tumor lysis syndrome and these patients should be monitored closely and appropriate measures taken.
• Progressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death has been reported in ADCETRIS™ (brentuximab vedotin)–treated patients. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider the diagnosis of PML in any patient presenting with new-onset signs and symptoms of central nervous system abnormalities. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture or brain biopsy. Hold ADCETRIS if PML is suspected and discontinue ADCETRIS if PML is confirmed. • Stevens-Johnson syndrome: Stevens-Johnson syndrome has been reported with ADCETRIS. If Stevens-Johnson syndrome occurs, discontinue ADCETRIS and administer appropriate medical therapy. • Use in pregnancy: Fetal harm can occur. Pregnant women should be advised of the potential hazard to the fetus.
ADCETRIS was studied as monotherapy in 160 patients in two phase 2 trials. Across both trials, the most common adverse reactions (≥20%), regardless of causality, were neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper respiratory tract infection, diarrhea, pyrexia, rash, thrombocytopenia, cough and vomiting.
Patients who are receiving strong CYP3A4 inhibitors concomitantly with ADCETRIS should be closely monitored for adverse reactions.
Brief Summary of Prescribing Information (see Package Insert for full Prescribing Information)
WARNING: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS. Indications and usage These indications are based on response rate. There are no data available demonstrating improvement in patient reported outcomes or survival with ADCETRIS. ADCETRIS™ (brentuximab vedotin) is indicated for treatment of patients with Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates. ADCETRIS is indicated for treatment of patients with systemic anaplastic large cell lymphoma (sALCL) after failure of at least one prior multi-agent chemotherapy regimen.
Contraindications Pulmonary toxicity: Concomitant use of ADCETRIS and bleomycin is contraindicated due to pulmonary toxicity. In a clinical trial that studied ADCETRIS with bleomycin as part of a combination regimen, the rate of non-infectious pulmonary toxicity was higher than the historical incidence reported with ABVD (adriamycin, bleomycin, vinblastine, dacarbazine). Patients typically reported cough and dyspnea. Interstitial infiltration and/or inflammation were observed on radiographs and computed tomographic imaging of the chest. Most patients responded to corticosteroids.
Warnings and precautions Peripheral neuropathy
ADCETRIS treatment causes a peripheral neuropathy that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. ADCETRIS-induced peripheral neuropathy is cumulative. In the HL and sALCL clinical trials, 54% of patients experienced any grade of neuropathy. Of these patients, 49% had complete resolution, 31% had partial improvement, and 20% had no improvement. Of the patients who reported neuropathy, 51% had residual neuropathy at the time of their last evaluation. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness. Patients experiencing new or worsening peripheral neuropathy may require a delay, change in dose, or discontinuation of ADCETRIS.
Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If anaphylaxis occurs, immediately and permanently discontinue administration of ADCETRIS and administer appropriate medical therapy. If an infusion-related reaction occurs, the infusion should be interrupted and appropriate medical management instituted. Patients who have experienced a prior infusion-related reaction should be premedicated for subsequent infusions. Premedication may include acetaminophen, an antihistamine and a corticosteroid.
Complete blood counts should be monitored prior to each dose of ADCETRIS and more frequent monitoring should be considered for patients with Grade 3 or 4 neutropenia. Prolonged (≥1 week) severe neutropenia can occur with ADCETRIS. If Grade 3 or 4 neutropenia develops, manage by dose delays, reductions, or discontinuations.
Tumor lysis syndrome
Tumor lysis syndrome may occur. Patients with rapidly proliferating tumor and high tumor burden may be at increased risk of tumor lysis syndrome. Monitor closely and take appropriate measures.
Progressive multifocal leukoencephalopathy
JC virus infection resulting in PML and death has been reported in ADCETRIS-treated patients. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider the diagnosis of PML in any patient presenting with new-onset signs and symptoms of central nervous system abnormalities. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture or brain biopsy. Hold ADCETRIS dosing for any suspected case of PML and discontinue ADCETRIS dosing if a diagnosis of PML is confirmed.
ADCETRIS™ (brentuximab vedotin) was studied in 58 patients with sALCL in a single arm clinical trial in which the recommended starting dose and schedule was 1.8 mg/kg intravenously every 3 weeks. Median duration of treatment was 24 weeks (range, 3 to 56 weeks). The most common adverse reactions (≥20%), regardless of causality, were neutropenia, anemia, peripheral sensory neuropathy, fatigue, nausea, pyrexia, rash, diarrhea, and pain. The most common serious adverse reactions experienced by patients with sALCL were septic shock (3%), supraventricular arrhythmia (3%), pain in extremity (3%), and urinary tract infection (3%).
Drug interactions In vitro data indicate that monomethyl auristatin E (MMAE) is a substrate and an inhibitor of CYP3A4/5.
Effect of other drugs on ADCETRIS
CYP3A4 Inhibitors/Inducers: MMAE is primarily metabolized by CYP3A. Co-administration of ADCETRIS with ketoconazole, a potent CYP3A4 inhibitor, increased exposure to MMAE by approximately 34%. Patients who are receiving strong CYP3A4 inhibitors concomitantly with ADCETRIS should be closely monitored for adverse reactions. Co-administration of ADCETRIS with rifampin, a potent CYP3A4 inducer, reduced exposure to MMAE by approximately 46%.
Effect of ADCETRIS on other drugs
Co-administration of ADCETRIS did not affect exposure to midazolam, a CYP3A4 substrate. MMAE does not inhibit other CYP enzymes at relevant clinical concentrations. ADCETRIS is not expected to alter the exposure to drugs that are metabolized by CYP3A4 enzymes.
Use in specific populations Pregnancy
Pregnancy Category D. There are no adequate and well-controlled studies with ADCETRIS in pregnant women. However, based on its mechanism of action and findings in animals, ADCETRIS can cause fetal harm when administered to a pregnant woman. Brentuximab vedotin caused embryo-fetal toxicities in animals at maternal exposures that were similar to human exposures at the recommended doses for patients with HL and sALCL. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. In an embryo-fetal developmental study, pregnant rats received 2 intravenous doses of 0.3, 1, 3, or 10 mg/kg brentuximab vedotin during the period of organogenesis (once each on Pregnancy Days 6 and 13). Drug-induced embryo-fetal toxicities were seen mainly in animals treated with 3 and 10 mg/kg of the drug and included increased early resorption (≥99%), post-implantation loss (≥99%), decreased numbers of live fetuses, and external malformations (i.e., umbilical hernias and malrotated hindlimbs). Systemic exposure in animals at the brentuximab vedotin dose of 3 mg/kg is approximately the same exposure in patients with HL or sALCL who received the recommended dose of 1.8 mg/kg every three weeks.
It is not known whether brentuximab vedotin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ADCETRIS a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
The safety and effectiveness of ADCETRIS have not been established in the pediatric population. Clinical trials of ADCETRIS included only 9 pediatric patients and this number is not sufficient to determine whether they respond differently than adult patients.
Clinical trials of ADCETRIS did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Safety and efficacy have not been established.
The kidney is a route of excretion for MMAE. The influence of renal impairment on the pharmacokinetics of MMAE has not been determined.
The liver is a route of clearance for MMAE. The influence of hepatic impairment on the pharmacokinetics of MMAE has not been determined.
Overdosage There is no known antidote for overdosage of ADCETRIS. In case of overdosage, the patient should be closely monitored for adverse reactions, particularly neutropenia, and supportive treatment should be administered.
Stevens-Johnson syndrome has been reported with ADCETRIS. If Stevens-Johnson syndrome occurs, discontinue ADCETRIS and administer appropriate medical therapy.
Dosage and administration
Use in pregnancy
The recommended dose is 1.8 mg/kg administered only as an intravenous infusion over 30 minutes every 3 weeks. The dose for patients weighing greater than 100 kg should be calculated based on a weight of 100 kg. Do not administer as an intravenous push or bolus. Continue treatment until a maximum of 16 cycles, disease progression or unacceptable toxicity.
There are no adequate and well-controlled studies of ADCETRIS in pregnant women. However, based on its mechanism of action and findings in animals, ADCETRIS can cause fetal harm when administered to a pregnant woman. Brentuximab vedotin caused embryo-fetal toxicities, including significantly decreased embryo viability and fetal malformations, in animals at maternal exposures that were similar to human exposures at the recommended doses for patients with HL and sALCL. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential hazard to the fetus.
Adverse reactions ADCETRIS was studied as monotherapy in 160 patients in two phase 2 trials. Across both trials, the most common adverse reactions (≥10%), regardless of causality, were neutropenia, anemia, thrombocytopenia, lymphadenopathy, peripheral sensory neuropathy, peripheral motor neuropathy, headache, dizziness, fatigue, pyrexia, chills, pain, edema peripheral, upper respiratory tract infection, nausea, diarrhea, abdominal pain, vomiting, constipation, rash, pruritus, alopecia, night sweats, dry skin, cough, dyspnea, oropharyngeal pain, arthralgia, myalgia, back pain, pain in extremity, muscle spasms, insomnia, anxiety, decreased appetite and weight decreased. ADCETRIS was studied in 102 patients with HL in a single arm clinical trial in which the recommended starting dose and schedule was 1.8 mg/kg intravenously every 3 weeks. Median duration of treatment was 27 weeks (range, 3 to 56 weeks). The most common adverse reactions (≥20%), regardless of causality, were neutropenia, peripheral sensory neuropathy, fatigue, upper respiratory tract infection, nausea, diarrhea, anemia, pyrexia, thrombocytopenia, rash, abdominal pain, cough, and vomiting. The most common serious adverse reactions experienced by patients with HL include peripheral motor neuropathy (4%), abdominal pain (3%), pulmonary embolism (2%), pneumonitis (2%), pneumothorax (2%), pyelonephritis (2%), and pyrexia (2%).
General dosing information
Peripheral Neuropathy: Peripheral neuropathy should be managed using a combination of dose delay and reduction to 1.2 mg/kg. For new or worsening Grade 2 or 3 neuropathy, dosing should be held until neuropathy improves to Grade 1 or baseline and then restarted at 1.2 mg/kg. For Grade 4 peripheral neuropathy, ADCETRIS should be discontinued. Neutropenia: Neutropenia should be managed by dose delays and reductions. The dose of ADCETRIS should be held for Grade 3 or 4 neutropenia until resolution to baseline or Grade 2 or lower. Growth factor support should be considered for subsequent cycles in patients who experience Grade 3 or 4 neutropenia. In patients with recurrent Grade 4 neutropenia despite the use of growth factors, discontinuation or dose reduction of ADCETRIS to 1.2 mg/kg may be considered.
ADCETRIS, SeaGen Secure and their logos are trademarks and Seattle Genetics and are US registered trademarks of Seattle Genetics, Inc. © 2012 Seattle Genetics, Inc., Bothell, WA 98021 All rights reserved. Printed in USA
Improving MS Care: Perspectives from a Pharmacy Director and Medical Director Sheldon J. Rich, RPh, PhD and Maria Lopes, MD, MS For a CME/CEU version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.
Summary Significant advances in the treatment of multiple sclerosis have been made with the advent of disease modifying therapy, which decrease relapses and disease progression. Given that disease modifying therapies are a significant portion of total direct costs of this disease, ensuring appropriate use will maximize outcomes while minimizing overall costs. In addition to improving the utilization of disease modifying therapy, managed care has significant opportunities to optimize the care of patients with MS by improving care coordination and symptom management through the use of multidisciplinary approaches. Key Points • Disease modifying therapy decreases relapses and disease progression but is not a cure for MS. • Because irreversible damage occurs early in the course of the disease, early treatment with disease modifying therapy is important. • MS is a costly disease and pharmacotherapy contributes mostly to its costs. • Adherence and persistence with disease modifying therapy are vital to achieving maximal benefit from these expensive agents. • To maximize outcomes, a multidisciplinary approach should be used to manage MS.
Multiple sclerosis (MS) is a chronic, multifocal, inflammatory disease that affects the central nervous system (CNS), including the brain and spinal cord. The disease process has several targets, including myelin proteins, myelin producing cells, and neurons, resulting in myelin loss and the injury and destruction of axons. Typically, the age of onset for MS is 15 to 50 years of age, with two to three females being affected to every one male. There are approximately 500,000 cases in the United States, with 8,500 to 10,000 new cases occurring annually. The incidence of MS increases with greater distance from the equator, however changing “risk zones” reduces the incidence only if done before puberty. Interestingly, epidemics of MS, such as that reported during World War II in the Faroe Islands, have been described. Early exposure to Epstein-Barr virus and tobacco smoke are linked to an increased risk of developing MS. The primary impact of MS on patients is extremely diverse, involving many body systems, and is also
non-specific in some respects. The widespread effects in the body include neuromuscular function abnormalities, such as gait impairment and spasticity, vision impairment, and bladder and sexual dysfunction. The perception of pain and sensation are also impaired, such that patients experience fatigue, psychiatric depression, and cognitive dysfunction. Any function of the CNS can be affected and can result in presenting symptoms. The diagnosis of MS is a clinical one, in that it involves a thorough medical history and physical exam to identify the signs and symptoms associated with the disease. Laboratory studies must indicate the presence of an inflammatory, multifocal CNS disease that changes over time. Symptoms or laboratory findings alone are insufficient. A thorough examination that includes an MRI and spinal fluid examination will rule out other disease processes, which can mimic MS. There are four types of MS: relapsing-remitting, primary-progressive, secondary-progressive, and
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Exhibit 1: Course of Disease in MS3 1. Relapsing-remitting Increasing disability
progressive-relapsing. Relapsing-remitting MS (RRMS) is the most common form.1,2 Over time, as shown in Exhibit 1, the distribution of occurrence changes due to gradually increasing number of attacks, such that half of individuals will go on to having secondary-progressive MS (SPMS).3 More recent data have shown a delay in this progression to secondary-progressive disease suggesting that newer disease modifying therapy is having a positive effect on disease progression. Several factors that affect the prognosis of MS exist, and they can be divided into two primary categories: those that are favorable and those that are not. Favorable factors include low attack rate, a long interval to second attack, complete recovery from first attack, younger age at onset, female gender, and low disability at two and five years. Unfavorable factors are high attack rate, short interval to second attack, lack of recovery from first attack, older age at onset, and early cerebellar involvement.4 Disease Modifying Therapy
Long-term disease modifying therapy (DMT), which includes the immunomodulators and immunosuppressants, is available for MS.. The immunomodulators include glatiramer acetate (Copaxone®) and interleukins [IFNß-1a (Rebif ®), IFNß-1a (Avonex ®), IFNß-1b (Betaseron® or Extavia®)]. The immunomodulating therapies shift the immune balance toward an anti-inflammatory response. The
Exhibit 2: Benefits of DMTs • Relapse free at 1 year: 51%–80% • Relative decrease in absolute relapse rate (ARR): 30%–80% • ARR: .15%–.7% • Relative decrease in sustained progression: 31%–42% • Absolute rate of disease progression: 9%–18%
immune suppressants include mitoxantrone (Novantrone®), natalizumab (Tysabri®), and fingolimod (Gilenya®). Conventional immunosuppresants, such as mitoxantrone, have broad cytotoxic effects on B cells, T cells, and macrophages which suppresses the pathogenic immune response in MS with high efficacy but is also associated with high toxicity, limiting the long-term use of these agents. Natalizumab, a monoclonal antibody, acts on immune-cell surface ligands and has narrower immunosuppressive actions and different safety profiles compared with conventional immunosuppressants. Immunomodulators have targeted actions on the immune system, but affect a greater number of immunopathogenic processes than monoclonal antibodies. Fingolimod is a sphingosine 1-phosphate receptor modulator, which sequesters lymphocytes in lymph nodes, pre-
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Exhibit 3: Symptom Impact of Treatment19 eAppendix B. Presence of Medical Conditions of Interest in Newly Treated Multiple Sclerosis Patients (n = 1840) Patients, % Percent Condition (ICD-9-CM Code)a 2005 2006 Change Pb Abnormality of gait (781.2) 10.1 6.2 -38.6 <.01 Ataxia (781.3) 6.6 2.0 -69.7 <.01 Burning, numbness, tingling 40.7 12.5 -69.3 <.01 sensations (782) Cognitive impairment (294.1*) Convulsions (780.3*)
Diplopia (368.2) Dizziness (780.4)
Fecal incontinence (787.6) Fibromyalgia (729.1)
Malaise and fatigue (780.7*)
Only want items outlined in red in table
venting them from contributing to an autoimmune reaction. Fingolimod is the first oral agent for MS but there are a number of other oral agents in clinical trials. Several new products for MS will likely make it to market in the next 15 to 18 months. DMT is not a cure for MS. Patients can, and do, experience relapses while on therapy, but these therapies are effective in reducing several components of MS including the number of relapses, the severity of relapses, and disease activity on MRI. They may also reduce the accumulation of disability. Interferons and glatiramer reduce the frequency of relapses by 30 percent compared to placebo in the first year of treatment. With use of DMT, there is a slower conversion to the more progressive forms of MS and a slower progression of disability as measured by the Expanded Disability Status Scale (EDSS). In terms of relapse rates and disability progression, the patient today who has MS is very different from the patient five or 10 years ago who did not have DMT. Exhibit 2 provides an overview of the benefits of DMT. Since it is known that irreversible changes occur early in the course of MS, treating patients early provides benefits in limiting these occurrences. One of the quandaries with DMT is how early should a patient be treated. Clinically isolated syndrome (CIS) is the first episode of MS symptoms but may not be recognized as such until a second episode occurs. Unfortunately, function that is lost is seldom regained. There needs to be better recognition of CIS and better guidelines on when to initiate DMT.
Persistence and Adherence with DMT
Persistence and adherence with DMT are vital to achieving the benefits outlined in Exhibit 2. Regrettably, nonpersistence and nonadherence with DMT are all too common. Between 17 and 40 percent of patients stop taking DMT within one year of initiation.5-7 The reasons for nonpersistence are multifactorial but include a perceived lack of efficacy, adverse effects, and new onset or worsening depression.5-8 Much of this nonpersistence could be prevented. When patients stop therapy because of a perceived lack of efficacy, this may be a failure of health care providers providing adequate education on treatment expectations. Although DMT can cause significant adverse effects, many of them can be treated or prevented. In one study, within six months of treatment initiation, 41 percent of patients had new or increased depression.8 Whether this is related to their drug therapy, their disease or some outside factor is unknown. Given the high incidence of depression, all patients with MS should be screened and treated if appropriate. In another study of adherence with DMT, more patients with SPMS stopped therapy than those with RRMS. Higher EDSS scores at study entry was the main factor that predicted discontinuation of therapy.6 Studies have found short-term nonadherence rates of 12 to 27 percent and long-term nonadherence in the 30 to 46 percent range.9 In a longitudinal, prospective study of patients with definite MS taking DMT, 73 percent missed doses and 10 percent
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Exhibit 4: Multidisciplinary Team Approach Neurologist Pharmacist
Nurse/Advanced Practice Nurse
Patient Social Worker
Urologist Orthopedist Speech Pathologist Vocational Counselor
Exhibit 5: Specialty Pharmacy Constituents Patients - Access and ease of administration - Insurance & coverage assistance support - Training & information - Optimized outcomes Manufacturers - Reliable and controlled distribution - Increased product penetration - Access to utilization data Pharmacy Medical - Patient and physician services - Optimized outcomes
Physicians - Reduce administrative burden - Product access - Health & safety monitoring - Support patient education and follow-up - Optimized outcomes
Health Plans - Lower drug cost - Product access - Utilization management - Patient & physician satisfaction - Optimized outcomes
missed more than 10 doses in a six-month period.10 Numerous and divergent factors influenced missed doses. One reason was alcohol intake. Additionally, in this study, a history of missed doses predicted future missed doses. Gaps in DMT adherence greater than 90 days lead to a twofold increased relapse rate.11 Nonadherence with a prescribed DMT is a worst
case scenario â€“ the medication is being paid for, the patient is not using it correctly, and the health plan is incurring costs because of the increased relapse rate. Substantial numbers of MS patients confront personal, financial and health plan related barriers to obtaining MS drugs which contribute to nonpersistence and nonadherence. Patients with MS experi-
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ence a fear of medications and their costs, a poor understanding of their disease, concerns over side effects, fear of injections, insurance issues, unaffordable co-pays, and misinformation about MS and its treatment. Patients and their families have to deal with formulary restrictions, the prior-authorization process, and timing delays. The effect of these barriers was examined in a recent study by Lezzoni et al.12 In this study, 36.8 percent of uninsured MS patients had never used a DMT, whereas 21.2 percent of insured had not. Sixteen percent of patients with public health insurance received an initial denial for MS medication. Overall, 22.3 percent of patients reported not filling an MS prescription and 22.5 percent worried â€œa lotâ€? about getting MS medications. All the various reasons for nonadherence and nonpersistence with DMT indicate a need for a multifaceted approach to improving use. Patient education is one way to improve use and maximize benefits from DMTs. For patients on therapies that require injection, education on injection techniques to reduce the number of adverse effects and increase the ease of injections can improve adherence. These include rotating injection sites, use of an autoinjector (typically available at no charge from manufacturer), injecting medication at room or body temperature, icing the area before and after injecting the medication, and massaging the area before and after injection. Patients need to have administration training so they are doing the injections correctly. They also need to understand appropriate storage requirements, especially when traveling. In addition, setting realistic expectations with the patient includes counseling the patient that therapies are not a cure but have been shown to reduce relapses, reduce MRI activity, and attenuate disease activity. Attenuated disease activity may lead to more patients retaining employment. But, patients with MS must also realize that DMT only works if taken, is not a cure for MS, may not eliminate MS symptoms, does not reverse existing damage to the CNS, and does not completely eliminate future disease activity. Pharmaco- and Socioeconomic Considerations in MS Therapies
MS patients are costly to manage. In one claims analysis, new MS patients were 3.5 times more likely to be hospitalized than those without MS.13 They were twice as likely to have at least one emergency department visit and 2.4 times more likely to have at least one visit for physical, occupational, or speech therapy. MS patients had higher mean 12-month costs compared to healthy cases: total
average 12-month cost ($18,829 versus $4038), inpatient services ($4110 vs. $836), radiology services ($1693 vs. $259), emergency department ($849 vs. $310), office visits ($849 vs. $310), therapies ($295 vs. $81), and pharmacy cost ($6151 vs. $817). Twenty-four percent of total all-cause health care costs were attributable to injectable MS medications. The pharmacy cost per member is 7.5 times higher than for patients without MS. Costs of MS have been rapidly increasing over the last few years. In one analysis, medical costs (without pharmacy) increased by 24.3 percent from $12,535 per person per year in 2006 to $15,577 in 2009.14 Combined medical and pharmacy costs increased by nearly 27 percent from $29,652 per person per year in 2006 to $37,592 in 2009. These cost trends are for a fixed cohort followed over four years and may be confounded by worsening disease resulting in increased medical and pharmacy expenditures. However, pharmacy biologic expenditures are unlikely to be influenced by worsening disease as combination biologic therapy is not approved by the FDA. The annual gross cost per day of biologic DMT for MS have increased in a similar manner. The per day cost increased by 20.2 percent from $67.52 in 2008 to $81.15 in 2009.15 Although MS is a rare disease, MS pharmacotherapy consumes $1 of every $40 of pharmacy benefit dollars to pay for 82.2 claims per month per 100,000 insured members.16 Total medication expenditures for these products over the past three years has increased 13.6 percent annually and are predominately driven by price increases. Price inflation in the MS category is four times the standard inflationary rate for all consumer goods and is two times the inflation rate for commonly used branded prescription medications. The introduction of fingolimod, the first approved oral DMT, has added to the price pressure. The average wholesale price of this agent is $158 per capsule, or $4740 per month.14 At $56,000 per year, this agent is significantly more expensive than the competing first-line treatment injectable biologics. Polypharmacy in MS is also expensive to the health care system. In one study, 41.3 percent of MStreatment utilizers were also on antidepressants. Almost 32 percent received concomitant therapy with central muscle relaxants, 27.4 percent an anticonvulsant, and another 0.2 percent were on corticotropin, with an average cost per day of over $2,000.17 The addition of dalfampridine (AmpyraÂŽ) is another cost driver in MS care. Dalfampridine is FDA approved to improve walking in patients with MS. The average wholesale price is $21.12 per 10 mg tablet, or $1267.20 per month, equating to more than $15,000/year.14 The cost for this agent is in
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addition to, rather than replacing any cost associated with DMT. In a patient who is on a disease modifying drug plus dalfampridine, pharmacy costs are projected to exceed 70 percent of total direct health costs.18 Studies have shown that only about a third of MS patients taking dalfampridine may benefit from its use.18 The good news with this very expensive agent is that patients, if they are going to respond, usually do so within two to three months of therapy initiation. Ensuring that patients who are not responding have therapy discontinued would be a cost saving measure for managed care. From a managed care payer and societal perspective, the impact of DMT and other expensive therapies on the overall costs of MS disease treatment must be considered. In one claims analysis, there has been a significant decrease in inpatient and outpatient utilization.19 With the use of DMT, there has been a significant decrease in coding of certain ICD conditions typically seen with MS (Exhibit 3).19 It appears from claims data that DMT is impacting symptoms and relapse rates which may translate into lower total costs over time. Cost comparisons of the DMT agents have yielded mixed results. The majority of studies have revealed cost-effectiveness ratios that were above usual willingness-to-pay thresholds of public decision makers.20 Noyes and her colleagues employed qualityadjusted life years (QALY) to evaluate the health effects and cost effectiveness of DMT. QALY is a standard tool used to evaluate disease burden by estimating the improved quality of life gained over time by taking a particular medication or course of therapy. A general rule of thumb among health policy experts is that for an intervention to be judged â€œcost-effectiveâ€? it should cost $100,000 or less to produce an extra QALY. According to this study, DMT for MS costs more than $800,000 per QALY, and individuals taking DMT experienced modest improvement in health.21 For example, MS patients taking interferon beta-1a gained about two qualityadjusted months over 10 years compared to those who did not take DMT. Patients taking interferon beta-1b had an average of six out of 10 years free of relapses compared to five years for those not taking the drugs. The authors also found that the benefit to patients was greater if they began taking DMT early during the onset of the disease.21 The authors also point out that if the cost of DMT were in line with what pharmaceutical companies charged other industrialized countries, the cost-benefit ratio could be significantly improved since reducing the cost of DMT had by far the greatest impact on cost effectiveness of treatment. A cost reduction of 67 percent would improve the probability of interferon beta-1b
being cost-effective at $164,000/QALY to 50 percent.21 Even though DMT is costly, managed care typically covers these therapies. The strategies for dealing with high cost have been multifold. Typically payers have covered these agents under specialty tier copays to increase patient cost sharing. Many require prior authorization or step therapy. Some require patients to fail self-injectable DMT prior to intravenous infusion therapy or oral fingolimod. There has been little focus on adherence and persistence given the uncertainty around long-term safety and efficacy versus short-term cost. Beyond direct costs of MS, the indirect costs of this disease are enormous. The total annual costs for MS in the United States are greater than $6.8 billion of which 75 to 80 percent are indirect to patients or caregivers.22 In 2010, the estimated total lifetime cost per patient was $4.1 million in U.S. dollars.21 A hallmark of the disease is disability; 65 percent of patients are non-ambulatory 25 years from disease onset.23 Additionally, MS reduces lifespan by eight years on average.23 More than 50 percent of people with MS are unemployed within 10 years of diagnosis.23 Unemployment is strongly related to EDSS score. Sixtysix percent of employed patients had RRMS; 78.3 percent of unemployed patients had progressive MS. At follow-up the risk of becoming unemployed due to MS was 17.5 times greater for those with EDSS scores of greater than 5.5 compared to those with a score less than 3.0.24 Reducing progression with DMT will hopefully reduce the disability and unemployment rate in MS patients. Improving MS Care
There are several significant opportunities for managed care to improve MS care. These include better symptom management through the use of multidisciplinary teams, improved care coordination for MS patients, improved management of underserved populations, and maximization of value from DMT by increasing adherence and persistence and utilizing specialty pharmacy services. Management of MS symptoms is severely underutilized by most physicians that treat the MS patient. There are numerous pharmacologic and nonpharmacologic strategies for positively impacting patients. Some of the more common symptoms that can be managed include those related to bladder and bowel difficulties, fatigue, depression and emotional lability, tightness and spasticity, leg jerking, especially at night, and certain kinds of pain. Because the symptoms of MS are so varied and impact many functions, there should be a multidis-
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ciplinary team approach to care (Exhibit 4). Every individual with MS should have a primary care physician as well as a neurologist in the multidisciplinary team overseeing his or her care. In addition, the management of primary, secondary, and tertiary symptoms of MS may involve specialists from many areas, such as nurses, pharmacists, vocational rehabilitation counselors, physical therapists, psychologists/ neuropsychologists, and occupational therapists. Because so many specialties are involved in the care of these patients, care coordination can be an issue. Improving care coordination can be done through several interventions. Collaboration between the patient, physician, pharmacist, nurse, specialists, and health plan is one way. Additionally, there are comprehensive MS care centers available. These centers use a team approach and integration of programs or services. They provide neurologic services plus medication management, treatment for cognitive limitations, medical rehabilitation services, and support for psychosocial problems. Comprehensive MS centers result in better access to health care services and better perception of the health care experience.25 There are also significant opportunities to improve care in underserved populations. Because many of them do not have a primary care provider, Medicaid patients with MS are more likely to present to and be admitted from the emergency department. Thirty-two percent of the Medicaid MS population is not taking DMT and 32 percent have never seen an MS specialist.23 Managed care needs to look for ways to maximize the value from DMT. There are many opportunities to improve care as nonadherence and nonpersistence leads to waste. There is increasing attention around when therapy should be initiated and how long it should continue. There is a need for better guidelines on when to start and stop therapy. Unfortunately, many times managed care is paying for medications that are not being taken or are being taken inappropriately. Currently, when MS is diagnosed, there is no way to know what the rate of progression will be or who will respond well to a particular medication. Use of a specialty pharmacy is another opportunity to optimize value from DMT. For a managed care organization, contracting with a specialty pharmacy organization is common for provision of MS medications. There are many benefits for plans, patients, physicians, and manufacturers in using a specialty pharmacy (Exhibit 5). Along with MS, some of the other common chronic diseases covered under specialty pharmacies include hepatitis C, cancer, hemophilia, and pulmonary arterial hyper-
tension. The common factors determining whether specialty pharmacy is used include high-cost therapies, special handling requirements, reimbursement complexities, complex regimens, or clinical support requirements. Other factors include the need for customized dosing, small number of patients, complex administration methods such as subcutaneous, intramuscular, or intravenous. Because many of the newer oral agents are expensive and potent, they are moving to specialty distribution. Overall, specialty pharmacy use may provide lower drug cost, improved product access, improved utilization management, better patient and physician satisfaction, and optimized outcomes. Specialty pharmacy use should be considered when prescription volume is limited such as with a niche disease or smaller population, in which patients are likely to have co-pay issues, prior authorizations are likely, appeals will be necessary, or ongoing patient education and training will be needed. Other reasons for selecting specialty pharmacy distribution include the need to manage major side effects, have quality data available, and receive a quick response to patient or provider concerns. Lastly, if better adherence and persistence are needed a specialty pharmacy may be the best choice. All of these make specialty pharmacy an ideal choice for managing many of the medications used for MS. Effects of Health Care Reform on MS Care
Health care reform has attempted to close the gap regarding issues that preclude patients from remaining adherent to therapy. Some of the initiatives impact patients with MS and managed care plans that cover these patients. These initiatives are designed to decrease the overall cost burden to patients, their families, and the health care system as a whole. Under proposed reform measures, there would be guaranteed insurance coverage for those participating in clinical trials. There would also be eventual closing of the Medicare Part D prescription drug gap (so called doughnut hole). Because DMTs are expensive, most MS patients bypass the gap in coverage very quickly. A major issue is removal of the lifetime cap on insurance coverage which became effective in late 2010. For these very expensive to manage patients, this will have a significant impact on managed care. Medicare reimbursement cuts for diagnostic imaging and a requirement for health plans to spend a minimum of 80 percent of premiums on medical claims took effect in 2011. Another reform that took effect in 2011, which affects patients with MS, is the prohibition against purchase of a power wheelchair unless rented for 10 months. Starting in 2013, there will be a 2.3 percent excise tax on medical devices.
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Depending on the fall elections, if health care reform continues, several measures are slated to begin in 2014 or later. These include: insurers being unable to impose coverage restrictions on pre-existing conditions; insurers required to offer coverage to anyone wanting a policy and every policy has to have renewable limits on out-of-pocket cost sharing; and physician pay-for-quality program. One of the primary features of health care reform involves the evolution of Accountable Care Organizations, or ACOs. Basic features of ACOs include enrollment initiatives, methods for measuring performance, the ability to implement programs for shared savings and costs, and the ability to coordinate care. Through the development of ACOs, pharmacists will have the opportunity to provide Medication Therapy Management, or MTM, programs. Numerous examples of positive outcomes from MTM exist in the literature, and involving pharmacists in direct patient care has shown benefit. MTM programs are another avenue for managed care to utilize to improve DMT adherence and persistence.
Neurology. 1996;46:907-911. 4. Weinshenker BG, Rice GP, Noseworthy JH, et al. The natural history of multiple sclerosis: a geographically based study. 3. Multivariate analysis of predictive factors and models of outcome. Brain. 1991;114 (Pt 2):1045-56. 5. Clerico M, Barbero P, Contessa G, et al. Adherence to interferon-beta treatment and results of therapy switching. J Neurol Sci. 2007;259:104-8. 6. Río J, Porcel J, Téllez N, et al. Factors related with treatment adherence to interferon beta and glatiramer acetate therapy in multiple sclerosis. Mult Scler. 2005;11:306-9. 7. Daugherty KK, Butler JS, Mattingly M, Ryan M. Factors leading patients to discontinue multiple sclerosis therapies. J Am Pharm Assoc. 2005;45:371-5. 8. Mohr DC, Goodkin DE, Likosky W, et al. Treatment of depression improves adherence to interferon beta-1b therapy for multiple sclerosis. Arch Neurol. 1997;54:531-3. 9. Klauer T, Zettl UK. Compliance, adherence, and the treatment of multiple sclerosis. J Neurol. 2008;255(suppl 6):87–92. 10. Tremlett H, Van der Mei I, Pittas F, et al. Adherence to the immunomodulatory drugs for multiple sclerosis: contrasting factors affect stopping drug and missing doses. Pharmacoepidemiol Drug Saf. 2008;17:565-76. 11. Patti F. Optimizing the benefit of multiple sclerosis therapy: the importance of treatment adherence. Patient Prefer Adherence. 2010;4:1-9. 12. Iezzoni LI, Ngo LH, Kinkel RP. Working-age persons with multiple sclerosis and access to disease-modifying medications. Mult Scler. 2008;14:112-122.
13. Asche CV, Singer ME, Jhaveri M, et al. All-cause health care utilization and
MS is a costly disease and pharmacotherapy contributes mostly to its costs. The decision to initiate therapy in MS is complex and involves a well-informed patient and physician. As more treatment options emerge, the need for guidelines and clear “start and stopping rules” becomes even more complex. There is a need for better decision support tools to assist members and their treating physician with education, balancing efficacy, safety, convenience, and patient choice. There are significant opportunities for managed care to improve care coordination for MS patients and to improve the appropriate use of disease modifying therapy.
costs associated with newly diagnosed multiple sclerosis in the United States. J Manag Care Pharm. 2010;16(9):703-12 14. Schafer JA, Gunderson BW, Gleason PP. Price increases and new drugs drive increased expenditures for multiple sclerosis. J Manag Care Pharm. 2010;16:713-17. 15. Theodorou AA, Johnson KM, Ruf S, Szychowski JA. Prescription Utilization by Multiple Sclerosis Patients in the United States. Am J Pharm Benefits. 2010;2:147-151. 16. Kunze AM, Gunderson BW, Gleason PP, et al. Utilization, cost trends, and member cost-share for self-injectable multiple sclerosis drugs--pharmacy and medical benefit spending from 2004 through 2007. J Manag Care Pharm. 2007;13:799-806. 17. CVS Caremark Industry Analytics Jan 2008-Dec 2009. 18. Tran T, Gunderson BW, Schafer J, Gleason PP. Multiple Sclerosis Medical and Pharmacy Cost Trends 2006 to 2009 (Poster Presentation). J Manag Care
Sheldon J. Rich, RPh, PhD is President of SJR Associates, LLC in Palm
Beach Gardens, Florida and is an Adjunct Clinical Assistant Professor
19. Aforismo JF, Pill MW, Prescott JD. Initiating Drug Therapy in Multiple Scle-
at University of Michigan and Adjunct Assistant Professor at Wayne
rosis Patients: Effect on Healthcare Costs. Am J Pharm Benefits. 2010;1:59-65.
20. Sharac J, McCrone P, Sabes-Figuera R. Pharmacoeconomic considerations in the treatment of multiple sclerosis. Drugs. 2010;70(13):1677-91.
Maria Lopes, MD, MS is Chief Medical Officer at AMC Health in
21. Noyes K, Bajorska A, Chappel A, et al. Cost-effectiveness of disease-modi-
fying therapy for multiple sclerosis: a population-based study. Neurology. 2011;77:355-63.
22. Rajagopalan K, Brook RA, Beren IA, Kleinman NL. Comparing costs and
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23. Lad SP, Chapman CH, Vaninetti M, et al. Socioeconomic trends in hospi-
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Overcoming Challenges and Improving Outcomes in the Management of Type 2 Diabetes Ann Peters, MD, CDE For a CME/CEU version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.
Summary There are many challenges in managing a population of patients with type 2 diabetes or at risk for developing diabetes. Prevention is the key to slowing the current epidemic of this disease and needs to be a community effort. Once diagnosed, individualized glycemic goals need to be set for patients. To maximize the outcomes from treatment, patients need to achieve and maintain these goals. Standardized care using treatment algorithms can assist health systems in achieving goals and managing patients with type 2 diabetes. Key Points • Type 2 diabetes can be prevented. • Diabetes prevention should be a community effort. • Glycemic control goals need to be individualized for a given patient, documented, and achieved. • Achieving A1C values less than 7% provides significant benefit but may not be possible or appropriate in patients with long-standing disease. • Once medication is required, metformin is the initial agent of choice. • Other agents are added to help the patient achieve their A1C goal. • Treatment algorithms can be used to standardize care within a given setting, achieve A1C goals, and can be individualized for a given community.
Currently, there is an epidemic of type 2 diabetes in the United States with 14.7 percent of the population estimated to have diabetes. By the year 2050, it is projected that 33 percent of the U.S. population will have diabetes.1 Probably another third of the population will have prediabetes. Obviously, as the percentage of the population with diabetes grows, so will the costs of treating these patients projected to grow. The epidemic of diabetes is a major issue because type 2 diabetes is a disease state that leads to many other abnormalities and long-term complications.2 A number of studies over the years have demonstrated the benefits and the risks of treating this disease. Initiating treatment early and achieving hemoglobin A1C (A1C) values less than 7% provides the most benefit.3-5 Glycemic control long term reduces both microvascular (i.e., retinopathy) and macrovascular (i.e., myocardial infarction) complications. Once a
patient has established disease, particularly cardiovascular complications, treatment does not have as much impact and carries a higher risk of severe hypoglycemia, especially when A1C values are lowered to less than 7%. Long-term follow-up of subjects in the large diabetes trials have found that even though patients have poorer control after leaving the intense support of a trial, they have a persistent benefit from the several-year period of intensive control while on the trial.4,5 Once patients leave a trial, their A1C values tend to increase to the 8% range because they are no longer being closely followed. Thus, early treatment that achieves glycemic control provides long-term benefit even if control is not intense for the long term. To achieve early treatment, patients must get diagnosed early in the disease process. Unfortunately, approximately one-third of patients already have
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Exhibit 1: Public Health and Clinical Care: The Balance of Diabetes Care and Prevention
Clinical care delivery
Drug and device
complications when they are diagnosed. The damage from type 2 diabetes actually begins many years before glucose is sufficiently elevated to lead to the classic symptoms. Ideally, patients would be identified when they have prediabetes and would have lifestyle changes implemented. It is possible to prevent the development of type 2 diabetes with lifestyle changes.6-9 Although it does not work in everyone, the risk of developing disease can be reduced 29 to 69 percent by lifestyle changes. Preventing diabetes does require intense support for a long duration of time. Lifestyle intervention is most effective in preventing or delaying the onset of type 2 diabetes in those at highest risk based on family history, elevated glucose, and/or being part of a high-risk population. The intervention must include efforts to achieve normal or near normal glucose. The lifestyle therapy that works involves three core features: balanced low-calorie nutrition, regular physical activity, and frequent intervention and support. Balanced lowcalorie nutrition is not dieting; it is changing the way someone eats. Regular physical activity should be at least 150 minutes per week. Diabetes prevention requires lifestyle interventions to be broadly integrated into community programs because the health care system cannot do it all (Exhibit 1). In addition to lifestyle changes, metformin has also been shown to prevent the development of type 2 diabetes in someone who is prediabetic.8 A person with prediabetes has a one-third chance of either reverting to normal, progressing to type 2 diabetes,
or staying in the prediabetes range. The patient with the slowly trending upward A1C is the one with failing beta cells who is going to progress and may require metformin in addition to lifestyle intervention to prevent disease. For patients with diagnosed diabetes, the American Diabetes Association (ADA) recommends achieving an A1C less than 7%. The A1C goal should be individualized based on various factors as illustrated in Exhibit 2.10 Setting goals in patients with type 2 diabetes has changed in the last five years because of the impact of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. ACCORD found that patients with long-standing disease who receive aggressive treatment are at higher risk for mortality.11 There is a point at which increasing therapy to try and achieve A1C goals becomes detrimental to the patient. A rational approach to setting A1C goals is to get as low as possible, as early as possible, for as long as possible, and as safely as possible. The goal for an individual patient and the reasons for choosing that goal should be documented in the medical record. The ADA is currently revising their treatment guidelines. Currently, metformin is the initial medication of choice, except in patients with renal disease. Sulfonylureas,which cause weight gain and hypoglycemia, do still have a role in low doses to help patients get to target. These agents do lose efficacy over time. Thiazolidinediones (TZDs) are a class of medications which can prevent progression of disease. Low doses of TZDs can be used to
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Exhibit 2: Individualizing Glycemic Targets in Diabetes10
Behavioral – social - economic Higher motivation, knowledge Greater self-care capacity, insight, support
Less motivated, non-adherent, Limited self-care capacity, insight support Hypoglycemia risk
Established Complications None Early Micro
help preserve beta cell function while minimizing the weight gain associated with higher doses. There are adverse effect issues with this class including increased risk of osteoporosis and heart failure. The glucagon-like peptide (GLP-1) agonists [Exenatide (Byetta®) and Liraglutide (Victoza®)] are one of the newer classes of agents for type 2 disease. These work by helping people to decrease how much they eat, regulating gastric emptying and glucagon production which lowers post prandial glucose, and enhancing glucose-dependent insulin secretion from the pancreas. These agents are generally used in combination with one or two oral agents. They lower A1C by approximately 1% with associated weight loss in 40 percent of patients. Gastrointestinal side effects are most common; nausea occurs in one-third of patients. These agents do require one or two injections daily. The dipeptidyl peptidase 4 (DPP-4) inhibitors are the other new class. These are oral agents [Sitagliptin ( Januvia®), Saxagliptin (Onglyza®), Linagliptin (Tradjenta®)] which are given once a day. They cause fewer adverse effects than the GLP-1 inhibitors and are generally well tolerated. They do not cause weight gain or loss and do not cause hypoglycemia. This class is only moderately effective compared with the other classes (A1C reduction ~0.5-0.8%), but some patients will have a larger response. They are can be used in combination with
CV Advanced Micro
other agents or as monotherapy. Patients with diabetes can be on very complicated medication regimens, which lead to nonadherence. There needs to be a relationship between a patient and their providers to achieve the goals both have. Because diabetes is a long-term disease, providers need to provide education and support. They need to help patients understand this is a progressive disease in order that patients realize they are not failing when medication has to be added. Providers need to make sure the patient is part of the team. Treatment algorithms can be used to standardized care within a given setting and can be individualized for a given community. These should be developed using a multidisciplinary team approach. The algorithms should be evidence-based, updated on a regular basis, and include treatment targets and timelines. Training support on use is essential to ensure appropriate use. An example is the development of standardized guidelines for the Los Angeles County Department of Health Services. Within the county, there are six centers for diabetes care, which treat difficult to control patients referred by primary care. The program A1C goal is 8%. Patients stay in the program for six months and are then sent back to their primary care provider. As shown in Exhibit 3, the program achieves A1C around 7% in this underserved population. The program uses face-to-face visits,
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Figure 3: A1C Diabetes Programs CRM LA DHS
11 10 9
7 6 5 LAC+USC Harbor Long Humphrey High Beach Desert
phone calls, and education classes. The major issue for making this work over the long term is maintaining the patientâ€™s success once they return to primary care.
Diabetes Study. Diabetes Care. 1997;20:537-44. 7. Tuomilehto J, LindstrĂśm J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001;344:1343-50. 8. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the inci-
dence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med.
Given the current epidemic of type 2 diabetes, more needs to be done to prevent the disease and, if not prevented, identify it early. Early treatment that achieves individualized glycemic goals can significantly improve the ultimate outcomes for patients.
2002;346:393-403. 9. Ramachandran A, Snehalatha C, Mary S, et al. The Indian Diabetes Prevention Programme shows that lifestyle modification and metformin prevent type 2 diabetes in Asian Indian subjects with impaired glucose tolerance (IDPP-1). Diabetologia. 2006;49:289-97. 10. Ismail-Beigi F, Moghissi E, Tiktin M, et al. Individualizing glycemic targets
Ann Peters, MD, CDE is a Professor of Medicine at the University of
in type 2 diabetes mellitus: implications of recent clinical trials. Ann Intern Med.
Southern California Keck School of Medicine and Director of the USC
Clinical Diabetes programs.
11. ACCORD Study Group, Gerstein HC, Miller ME, et al. Long-term effects
of intensive glucose lowering on cardiovascular outcomes. N Engl J Med. 1. Boyle JP, Thompson TJ, Gregg EW, et al. Projection of the year 2050 burden of diabetes in the US adult population: dynamic modeling of incidence, mortality, and prediabetes prevalence. Popul Health Metr. 2010;8:29. 2. Kendall DM, Harmel AP. The metabolic syndrome, type 2 diabetes, and cardiovascular disease: understanding the role of insulin resistance. Am J Manag Care. 2002;8(20 Suppl):S635-53. 3. Stratton IM, Adler AI, Neil HAW, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321:405-412. 4. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. N Engl J Med. 2000;342:381-9. 5. Holman RR, Paul SK, Bethel MA, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359:1577-89. 6. Pan XR, Li GW, Hu YH et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT and
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Breaking Down the Barriers: Innovative Approaches to the Management of Hypertension Larry Georgopoulos, PharmD
Summary Hypertension is a common cause of cardiovascular (CV) morbidity and mortality that places a large clinical and economic burden on our society. Data from the 20032006 National Health and Nutrition Examination Survey indicate that approximately one-third (74.5 million) of the adult population 20 years of age or older is hypertensive. In 2010, the estimated direct and indirect cost of hypertension in the United States was $76.6 billion, according to the American Heart Association (AHA). The direct medical costs of CV disease may be substantially higher than AHA estimates because of secondary CV hospitalization. Blood pressure control in Americans currently is less than optimal despite the availability of evidence-based guidelines for the treatment of hypertension and a wide variety of antihypertensive drug therapies. Various patient-, provider-, payer-, and pharmacologic-related factors, including patient nonadherence to antihypertensive drug therapy and clinical inertia (the failure of clinicians to initiate or intensify treatment when indicated) prevent optimal blood pressure control in patients with hypertension. These barriers to blood pressure control contribute to excessive health care utilization and costs. The need for health plans to refine population management strategies is emergent as the number of patients with hypertension within health plans is expected to increase; further, government interventions via the Patient Protection and Affordable Care Act (PPACA), coupled with pressure from employers, will likely drive changes to population management strategies across chronic conditions, including hypertension. Moreover, the successful treatment of hypertension has been shown to increase life expectancy and reduce health care spending. Aggressive hypertension management using innovative approaches that engage all stakeholders (employers, members, providers, and payers) is needed to overcome the barriers to control and improve outcomes. Key Points • Hypertension is a costly condition affecting one-third of the population, leading to significant morbidity and mortality when not treated or optimally controlled. • The management of hypertension is hampered by inertia that exists in patients, providers, and payers and limits optimal treatment. • Health plans are being pressured by various stakeholders to change overall care strategies for the chronically ill, including the hypertensive population. • Payers and providers need to develop and implement innovative strategies to overcome barriers in order to positively impact morbidity, mortality, and escalating health care costs.
Hypertension (systolic blood pressure [SBP] >140 mm Hg, diastolic blood pressure [DBP] >90 mm Hg, or receiving antihypertensive drug therapy) is a common but often silent cause of cardiovascular (CV) morbidity and mortality in the United States.1 An estimated 74.5 million—roughly
one in three —Americans have hypertension.1 The prevalence of hypertension has increased from 23.9 percent to 29 percent over the past two decades despite the availability of comprehensive, authoritative, evidence-based guidelines from the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High
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Exhibit 1: Potential Barriers to Controlling Blood Presure10-13 Patient-related barriers • Low health literacy (i.e., lack of knowledge about hypertension and the treatment)10 • Problems accessing healthcare10 • High cost of drug therapy10 • Concerns about adverse effects from drug therapy10 • Inertia11 Physician-related barriers • Lack of education, training and experience in hypertension treatment10 • Poor communication with patients10 • Lack of practice structure to achieve and maintain therapeutic goals through effective patient monitoring10 • Lack of investment in technology to facilitate patient monitoring and optimize outcomes10 • Clinical inertia, which includes, but is not limited to, time constraints and competing priorities10,12,13 Payer-related barriers • High cost of medication (formulary placement including tiering payments)10 • Lack of clinical reimbursement for care that is not provided face-to-face10 • Failure to provide clinicians with incentives for adherence to treatment guidelines and achievement of treatment goals10 Pharmacologic-related barriers • Adverse effects10 • Complexity of drug regimen (s)12
Blood Pressure ( JNC 7) and the American Heart Association (AHA).2-4 The prevalence of high blood pressure in black adults has increased from 35.8 percent to 41.4 percent, which was particularly high among black women at 44 percent.1 Hypertension in the United States is more prevalent in men <45 years of age, in women >65 years of age, and among blacks.1 Additionally, one of every five American adults with hypertension is unaware of their disease.2 Those with high blood pressure are at risk for CV events, as approximately 69 percent of patients who experience a first heart attack, 77 percent of patients who have a first stroke, and 74 percent of patients with congestive heart failure have high blood pressure.1 Overall life expectancy is around five years less for men and women with hypertension.1 Economic Impact of Hypertension
In 2010, the estimated direct and indirect cost of hypertension in the United States was $76.6 billion, according to the AHA.1 The direct medical costs of CV disease (CVD) may be substantially higher than AHA estimates because of secondary CV hospitalization.5 In fact, it is estimated that direct medical care costs for people with established CVD is $18,953 per patient per year, and those who had a secondary hospitalization had costs that were 4.5 times higher than those for patients who did not have a secondary hospitalization.5 Health Plan Outcomes in the Hypertensive Population
Health plans are increasingly being held accountable for clinical outcomes in patients with hyper-
tension through the use of performance and quality measures, such as the Healthcare Effectiveness Data and Information Set (HEDIS).6 The HEDIS hypertension control measure estimates the percentage of patients 18 to 85 years of age with a diagnosis of hypertension whose blood pressure was adequately controlled (<140/90 mm Hg based on evidencebased guidelines) during the measurement year.6 Commercial plans have had greater success than have public health plans (i.e., Medicare and Medicaid) in controlling blood pressure. Commercial rates of control have risen from 39.0 percent in 1999 to 64.1 percent in 2009; however, more than 35 percent of patients are still uncontrolled.6 Whereas control rates assessed by Medicare and Medicaid rose from around 53 percent in 2001 to 59.8 percent and 55.3 percent in 2009, respectively.6 In short, although health plan interventions have increased control of hypertension, there is still significant room for improvement. Value of Aggressive Hypertension Management for Health Plans
In March 2010, President Obama signed into law the PPACA.7 Under this new law, all U.S. citizens and legal residents are required to have health care coverage or face an annual tax penalty.7 The law also provides premium credits and cost-sharing subsidies so that individuals and families can purchase coverage through health insurance exchanges.7 Similarly, employer groups of more than 50 employees will be required to offer a health care plan or face a penalty.7 The government is also providing tax credits to encourage small employer groups (those with ≤25
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Exhibit 2: Advantages and Disadvantages of Selected Antihypertensive Drugs3,4,21,22
Drug Class Advantages Disadvantages Thiazide diuretics • Preferred as initial • Risk of electrolyte therapy for most abnormalities21 patients3 • Can worsen • Low cost3,21 hyperglycemia3 ß-Blockers • Useful after acute • Risk of MI and in patients bronchospasm in with CAD and patients with stable angina or asthma21 heart failure3,4 • Risk of • Low cost21 bradycardia (for agents without ISA)21 • May mask symptoms of or potentiate hypoglycemia in patients with diabetes4,21 ACE inhibitors • Useful after acute • Risk of intolerence MI and for patients due to dry cough22 with CKD3 • Low cost21 Angiotensin receptor • Useful for patients blockers CKD3 • Useful alternatives to ACE inhibitors in patients with intolerence21
• High cost21
Calcium channel blockers • Low cost21 • Risk of peripheral • Useful alternatives edema, dizziness, to ß-blockers in and headache21 patients with CAD • Not recommended and stable angina4 after acute MI or in patients with heart failure3 ACE, angiotensin-converting enzyme; CAD, cardiovascular artery disease; CKD, chronic kidney disease; ISA, intrinsic sympathomimetic activity; MI, myocardial infarction
employees) to provide health care coverage.7 Additionally, PPACA supports wellness and prevention efforts as a means of reducing/delaying the development of chronic conditions. The government has committed to spending $7 billion a year from 2010 to 2015 for prevention research, health screening, and prevention/wellness activities.7 The government is also extending wellness to Medicare and Medicaid beneficiaries by eliminating cost sharing for proven preventive services, such as immunizations, comprehensive risk assessments, and incentives for completing behavior-modification programs.7 Comparative effectiveness research is also being supported through PPACA, which established the nonprofit Patient-Centered Outcomes Research In-
stitute (PCORI). PCORI has been tasked to organize and prioritize research comparing the clinical effectiveness of various treatments/interventions. A pilot program that looks at using a bundled-payment system to reimburse for various health care services and develop value-based purchasing programs for skilled nursing facilities, home health agencies, and ambulatory surgical centers is also being established by the government.7 These are just a sampling of highlights of this comprehensive reform measure. Overall, these government-driven interventions have the potential to increase the number of enrollees within health plans, drive aggressive management of all chronic conditions including hypertension, and influence the provision of care by reshaping both how care is provided and what care is provided.
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Exhibit 3: Level of Activation for U.S. Adults with Chronic Conditions, 200740 50 45 40
Level of Activation (%)
1 Multiple Condition 2 Multiple Conditions 3 Multiple Conditions 4 Hypertension
39.6 37.7 35.1 33.0 32.6
30 25 19.8
15 11.7 9.0
5 0 Level 1 (Least Activation) Level 2 Level 3 Level 4 (Most Activation) Chronic Condition
Employer groups also recognize the need to address the rising prevalence of chronic disease that is escalating health care costs. Employer groups are calling for managed care organizations (MCOs) to better manage costly chronic conditions, including hypertension. Employers are aware that chronic illness not only impacts the health of their workforce but also causes a drain on resources because of lost productivity, absenteeism, and presenteeism. JNC 7 task force members reported that, based on population studies, SBP reductions of 2 to 5 mm Hg may potentially reduce CV mortality.3 Keeping blood pressure under control and treating patients earlier have a significant effect on outcomes and costs. One study demonstrated that patients who were treated earlier had 28 percent fewer strokes and 15 percent fewer overall CV complications.8 The downstream consequences of hypertension in the form of CVD and stroke may be mitigated through treatment and control of hypertension. If one considers that there is nearly $50,000 difference in health care costs between a patient who has had a secondary CVD hospitalization and a patient who has had no secondary CVD hospitalization, the beneficial effects in terms of outcomes and costs for identifying, treating, and controlling patients with hypertension become clear.5 Further, the successful
treatment of hypertension in a person 51 or 52 years of age is expected to increase life expectancy by approximately two years and reduce lifetime health care spending by more than $13,702 despite the longer life.9 Barriers to Blood Pressure Control
Various patient-, provider-, payer-, and pharmacologic-related factors can interfere with blood pressure control (Exhibit 1).10-13 Hypertension often goes undiagnosed or treated but uncontrolled despite patient access to the health care system, and these problems tend to involve older adults.14 The asymptomatic nature of hypertension and adverse effects from antihypertensive drug therapy contribute to nonadherence to prescribed treatment and poor blood pressure control.10 Overall, these factors are major contributors to the less-than-optimal treatment and management of hypertension. Patient Inertia
Patient inertia (the failure of patients to take responsibility for health conditions and engage in proactive change) is a significant barrier to adequate blood pressure control.11 Patient nonadherence to treatment also has been attributed to an inability to pay, difficulty remembering to take doses, and
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feeling better during therapy.11 With better adherence, outcomes and costs improve. A retrospective analysis demonstrated that the need for hospitalization and emergency department (ED) visits and total health care costs are $387 to $813 lower in patients with hypertension who are adherent to antihypertensive drug therapy than in those who are not adherent.15 Physician Inertia
Physician or therapeutic inertia (the failure of clinicians to initiate or intensify treatment when indicated) is a major cause of inadequate blood pressure control.10 Failure to initiate antihypertensive therapy promptly after diagnosis is a cause of preventable CV complications. A study that compared immediate vs. delayed hypertensive treatment in 4,695 patients showed that early treatment reduced fatal and nonfatal stroke by 28 percent, CV complications (myocardial infarction [MI], MI and sudden death, heart failure, and other cardiac events) by 15 percent, and all-cause mortality by 13 percent.8 Physician adherence to evidence-based guidelines for the treatment of hypertension is often suboptimal. This was found to be especially true in cases of uncontrolled hypertension, where mean overall adherence to guidelines was 53.5 percent and did not change significantly over time.16 One Midwest survey found that 93 percent of primary care patients identified with hypertension had a SBP >140 mm Hg, but only 38 percent had a blood pressure medication initiated or changed while visiting their physician.17 Another study from 62 physician practices in North Carolina, South Carolina, and Georgia showed that medication changes occurred only 13 percent of the time when an elevation in blood pressure was recorded.18 Patient nonadherence does not explain therapeutic inertia.13 Rather, possible barriers to guideline adherence and blood pressure control include physician lack of knowledge (i.e., awareness of or familiarity with guidelines), attitudes (e.g., lack of agreement with guidelines), lack of self-efficacy (i.e., ability to follow the guidelines), lack of expectation that guideline adherence will result in the desired outcome, and the inertia of previous practice habits.19 Additionally, this inertia has been attributed to: Time constraints10 Competing priorities (e.g., multiple preventive care needs)10 Acceptance of poor blood pressure control10 Overestimation of the care provided13 Inaccurate perceptions that blood pressure is controlled12
Concerns that combination drug therapy will be problematic because of complexity, cost, and safety issues12 Pharmacologic Challenges
As was noted in the JNC 7 guidelines, there are excellent clinical outcome trial data proving that lowering blood pressure with several classes of drugs, including angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), Ă&#x;-blockers, calcium channel blockers, and thiazidetype diuretics, will all reduce the complications of hypertension.3 The guidelines recommend monotherapy with thiazide diuretics as the preferred, initial therapy for most patients with hypertension.3 However, combination therapy with at least two drugs, usually a thiazide diuretic plus an ACE inhibitor, ARB, Ă&#x;blocker, or calcium channel blocker,3 is needed for optimal blood pressure control in most patients with hypertension.3 Tolerability problems with antihypertensive agents may be minimized by using lowdose combination therapy because many adverse effects are dose related.20 Exhibit 2 lists some of the advantages and disadvantages of each of these antihypertensive drug classes.3,4,21,22 Despite the availability of numerous agents, there is a continued gap in regard to achievable blood pressure control compared to current levels. Blood pressure still is controlled in only about half of patients with hypertension.2 The availability of agents with greater efficacy, compared to that of existing agents, and an improved safety program would be ideal. Coupling appropriate pharmacologic treatment with population management strategies is needed to reduce the overall burden of hypertension. Managed Care Inertia
Payer-related barriers to blood pressure control include competing priorities,10 lack of educational resources for both physicians and members,10 lack of clinician incentives10 designed to achieve and maintain therapeutic goals, and complacency regarding the problems associated with uncontrolled blood pressure, resulting in inertia.10 In his review article, White highlighted that blood pressure may vary over a 24-hour period and elucidated how this circadian variation in blood pressure may be linked to CV events.23 Ambulatory blood pressure monitoring with telephone or electronic transmission of data to the clinician is a good method with which to confirm that patients have adequate blood pressure control over a 24-hour period.23 Investments in health information technology that allow for the electronic transmission of real-time patient data
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will be necessary to give physicians the information that they need to make informed decisions. Policies that provide clinicians with reimbursement only for face-to-face interactions with patients serve as a disincentive to provide follow-up care by telephone or through electronic means.10 Such follow-up is associated with member satisfaction. In one study, 80 percent of patients reported being either satisfied or very satisfied with a self-measurement and self-titration program, and compliance with the program was found to be very good in 78 percent (self-measurement) and 51 percent (self-titration) of those participating.24 A lack of MCO investment in the technology needed to manage patient information and monitor patient outcomes (e.g., electronic medical records and appointment-scheduling systems) could lead to less-than-optimal blood pressure control and member dissatisfaction with plans.10 Aggressive hypertension management using innovative approaches that engage all stakeholders (i.e., patients, clinicians, and providers) is needed to overcome existing inertia and other barriers to blood pressure control, while improving patient outcomes and employer and plan member satisfaction. Innovative Strategies
Evidence of improved long-term clinical outcomes and cost savings from traditional disease management strategies is inconclusive, despite improvements in processes of care from these strategies.25,26 Therefore, new strategies have been proposed to improve the overall management of chronic conditions such as hypertension. Medical Home Model
The medical home model is an approach to the delivery of consistent, comprehensive primary care (i.e., acute, chronic, preventive, and end-of-life care) coordinated by a personal physician across the health care continuum (i.e., hospitals, nursing homes, the patient’s home), with enhanced patient access to care and the use of innovative communication methods.27 The model provides payment for services associated with the coordination of care, including care that is not provided face-to-face.27 The attainment of optimal patient-centered outcomes through efforts to ensure the quality and safety of care is emphasized.27 Group Health Cooperative in Seattle, Washington, is an example of a health plan that is piloting the medical home model.28 Group Health Cooperative’s evaluation has shown significant success and rapid return on investment (ROI).28 In one year, the Patient-Centered Medical Home (PCMH) pilot, compared to controls, reduced ED/urgent care visits
by 29 percent and inpatient hospital stays for patients with conditions such as diabetes, chronic obstructive pulmonary disease, congestive heart failure, and asthma by 11 percent—all while improving indicators of quality of care and care team satisfaction.28 A meta-analysis of studies of interventions involving one or more elements of a medical home model revealed beneficial effects on clinical outcomes and processes of care for patients with chronic diseases (asthma, congestive heart failure, depression, and diabetes).29 In Tsai and colleagues’ analysis, it was found that a number of chronic care model elements were associated with better outcomes and processes, such as delivery system design (relative risk [RR], 0.77; 95% confidence interval [CI], 0.62, 0.96, clinical outcomes derived from dichotomous variables), self-management support (RR, -0.22; 95% CI, -0.38, -0.05, clinical outcomes derived from continuous variables), and decision support (RR,1.29; 95% CI, 1.08, 1.54), which were adjusted for the presence of other elements if the intervention contained more than one element.29 In a separate analysis of four primary care sites in the United States, the annual risk-adjusted total health care spending per capita was 15 percent to 20 percent lower with a medical home model than that with regional peers, without compromising quality of care.30 Value-Based Benefit Design
Value-based insurance design, also known as valuebased benefit design (VBBD), is a strategy developed at the University of Michigan Health System to optimize the use of high-value health care services ( i.e., services with substantial proven effectiveness and benefits) and to reduce the use of lowervalue services so that employers obtain the greatest return on their investment in health care.31 The VBBD approach involves removing barriers to the use of high-value services, which is much more than copayment reductions, and includes other patient cost-sharing mechanisms to establish incentives that will increase patient use of these services. The initial cost increases that MCOs will incur that are associated with reduced patient cost sharing may be offset by cost reductions associated with ED use and hospitalizations as a result of improved health.31 Even though pharmacy costs may increase with increased utilization, the medical offsets can still potentially generate savings when the underlying risk of an adverse outcome is high, consumers are responsive to lower copays, and the targeted service prevents an adverse outcome.31 Because cost sharing discourages the use of both high-value and low-value services and the value of some services varies among different patient popu-
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lations, some VBBD programs are structured with different levels of cost sharing for different patient populations.31,32 For example, the copayment for a high-value service might be nominal for patients with borderline hypertension who do not have comorbid conditions and waived for patients with hypertension who are at particularly high risk for CV events and other morbidity and mortality due to diabetes, chronic kidney disease, or other comorbid conditions. This approach promotes the use of services in the patients most likely to benefit and discourages the use of services in patients least likely to benefit. Sophisticated computer systems are required to support this approach. The likelihood of improving patient outcomes and obtaining a favorable ROI in these VBBD programs hinges on the ability to accurately identify which patient populations derive the greatest benefit from a service.31 The VBBD concept was incorporated into the PPACA by mandating the elimination of patient copayments for certain evidence-based preventive health services.33 The use of VBBD is increasing, as was found in the Mercer National Survey of Employer-Sponsored Health Plans, with four out of five large employers (81 percent, 211 of 259 surveyed in 2007) planning to implement it in the near future; less than 20 percent of those surveyed were using VBBD at the time of the survey.34 Experience to date with VBBD is limited, but early reports of outcomes are promising. For example, when copayments were eliminated for generic medications and reduced for brand name medications as part of a large VBBD program offered by Blue Cross and Blue Shield of North Carolina, adherence to calcium channel blockers, diuretics, Ă&#x;-blockers, and ACE inhibitors was higher among program participants than nonparticipants.35 This program was offered to 750,000 employees taking these medicines. Medication adherence improved by 2 percent to 4 percent in the six categories of medicine in the program.35 Medication Therapy Management
The Medicare Modernization Act of 2003 (MMA) which provided the Medicare Part D prescription drug benefit included provisions requiring Part D sponsors to provide a medication therapy management program (MTMP) in their planâ€™s benefit structure.36 MTMPs are designed to ensure that medications are used appropriately in order to optimize therapeutic outcomes for targeted beneficiaries, and reduce the risk of adverse drug events and other medication related problems. MTMPs can improve clinical outcomes, improve patient medication adherence, enhance medication safety, and reduce
health expenditures. According to the Centers for Medicare and Medicaid Services (CMS), MTMP services can be provided by pharmacists or other qualified providers.36 Many Part D sponsors have developed individual training programs necessary for credentialing an MTMP provider. Unfortunately, there is little standardization of the training and there are unnecessary and frustrating time commitments of potential medication therapy management (MTM) providers to complete all the various programs. Additionally, there is currently no validated mechanism to ensure the competency of MTM providers. Furthermore, CMS MTMP requirements for contract year 2011 have become more prescriptive with respect to MTM services, now requiring direct patient intervention by MTM providers and also requiring that Medicare beneficiaries MTMP participation be changed from voluntary participation to mandatory (or opt-out).36 As a result, the demand for MTM services and qualified MTM providers is projected to increase. Aligning Incentives
When implemented together, the medical home model and VBBD are complementary strategies that can be mutually reinforcing, and improve ROI in health care.37 Both PCMH and VBBD use the concept of alignment of incentives in order to maximize outcomes. By structuring cost sharing to encourage patients to seek high-value services and avoid low-value services, efficiencies are gained in terms of maximum outcome per service used. In the management of chronic illness and especially in the management of hypertension, where there is poor control and significant potential for improvement, as well as significant gains to be had from improvement in terms of morbidity and mortality and costs, it is very important that all stakeholders involved understand the importance of identifying, treating, and maintaining control of blood pressure in patients who have hypertension. The alignment of incentives will ensure that appropriate treatments are selected and barriers to access will be minimized. Payers can ensure alignment of incentives for this purpose by putting in organizational structures in health plans that address therapeutic inertia and by structuring benefit plans so that they are value-based to encourage the use of the highest-value treatments. Providers must be incentivized to adhere to guidelines, and practice organizations need to be structured to promote the monitoring and maintenance of blood pressure control.10 However, these strategies are not the only methods to be considered. It is important to note that, when aligning incentives among key stakeholdersâ€”
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patients, providers, employers, and payersâ€”each situation will dictate the scope and breadth of the clinical, economic, and organizational changes to be implemented.38 These elements may include reimbursement systems, administrative processes, and coordination of care.38 Aligning incentives will help support clinical models of quality improvement and cost-effective decision making.38 An integral part of aligning incentives is to understand the needs of key stakeholders.39 Basically, patients want to feel better; providers want good patient clinical outcomes, practice efficiency, and fair compensation; and payers want to manage their populations in the most cost-effective manner while achieving optimal clinical outcomes.39 One of the ways for payers and providers to improve outcomes is to get their members engaged in managing their health care. Patientsâ€™ ability to actively manage their health and health care is defined as patient activation.40 It has been shown that patients with higher levels of patient activation have better health and health outcomes. According to a new study by the Center for Studying Health Systems Change, levels of patient activation were defined: Patients in Level 1 were overwhelmed and not ready to actively participate in their health41; patients in Level 2 were unable to self-manage their health because they lacked the knowledge and confidence to do so41; patients in Level 3 began to take action but still lacked the confidence and skill to fully manage their health41; and patients in Level 4 adopted behaviors to manage their health but could not maintain these behaviors during times of stress.41 It should be noted that activation levels differ among people with chronic conditions, including hypertension.40 People with multiple chronic conditions are less activated in their health care than are those with a single condition.40 As Exhibit 3 shows, activation levels for hypertension are nearly equal to those levels for patients with two chronic conditions.40 Additionally, it has been shown that activation levels are lower for people with low incomes and less education. Thus, education is the key, because beliefs and knowledge can be influenced by education. Coordinating Care
Along with organizational changes, as seen with PCMH, and changes in incentives and responsibilities, as seen with accountable care organizations (ACOs), pharmacists are becoming recognized as an important ally, not just as physician extenders, in the provision of effective care for patients with hypertension. Many studies have shown that physician/pharmacist collaborative care for hypertension results in better outcomes.
In a study (N=101) conducted by Von Muenster and colleagues, the researchers found that pharmacist/physician comanagement of blood pressure can be effective at reducing and improving blood pressure control rates.42 Pharmacists made 628 recommendations, of which 267 consisted of recommendations to change therapy.42 Therapy changes included adding a new antihypertensive agent (46.4 percent) or increasing the dose (33.3 percent), with the largest percentage of pharmacist recommendations at baseline (41.6 percent) and at the two-month visit (76.8 percent).42 When the study concluded at nine months, 89.1 percent (P<.001) of participants had reached their blood pressure goal.42 As noted by Von Muenster et al, pharmacists recognize the need for aggressive management of hypertension in order to achieve control.42 Thus, pharmacist interventions can offer extensive improvements in blood pressure control.42 A meta-analysis of 298 studies showed that pharmacist direct care has a significant (Pâ‰¤.01) impact on health outcomes for the management of diabetes, high cholesterol levels, blood pressure, and adverse drug events.43 In another study, patients who had access to clinical pharmacists who provided patient education and made treatment recommendations as part of a physician pharmacist comanagement program (intervention group [n=98]) achieved better blood pressure control than did the control group (n=99).(60 percent vs. 43 percent, P=.02].44 Additionally, reduced overall average visit costs per patient were realized for the intervention group ($160 vs. $195, P=.02).44 It was also found that pharmacist/ physician collaborative management of hypertension resulted in a greater rate of control (75 percent vs. 50.7 percent of the usual-care group, P<.001) as measured by 24-hour blood pressure measurement.45 A randomized controlled trial (N=463) showed that patients in the pharmacist/physician collaborative group (n=142 completers), compared with those in the usual-care group (n=130 completers), had better blood pressure control (137/75 mm Hg vs. 143/78 mm Hg; P=.007 for SBP, P=.003 for DBP), were more likely to achieve control (62 percent vs. 44 percent, P=.003), had fewer physician visits (P<.0001; however, more total office visits due to a greater number of pharmacist visits), and were prescribed more antihypertensive medications (P=.02) but did not take more antihypertensive pills per day.46 Patient quality of life or patient satisfaction between groups was not significantly altered.46 Another study (N=778) explored a new model of care that used patient Web services, home blood pressure monitoring, and pharmacist-assisted care.47 Patients were assigned to usual care (n=258), home
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blood pressure monitoring and Web-based patient services (n=259), and home blood pressure monitoring and pharmacist Web communication (n=261).47 At the end of the trial, there was no difference between the usual care group and the blood pressure and Web-based group in the percentage of patients with blood pressure control.47 There was a significant difference, however, between the patients who had pharmacist assistance and the usual care group, and the home blood pressure monitoring and Webbased patient services group (56 percent vs. 31 percent and 36 percent, respectively; P<.001).47 Pharmaceutical care ensures that medications are used appropriately to improve patients’ health status. This essential activity is coordinated through the collaborative efforts of a team of physicians, nurses and other health practitioners. A randomized clinical trial (N=56) evaluating the impact of pharmacotherapy consultation on the cost and outcome of medical therapy demonstrated that pharmacists collaborating with physicians to care for high-risk patients reduced the number of prescriptions per patient and saved nearly $600 per year per patient in drug costs.48 In an analysis of the economic benefits of pharmacist and physician collaboration, Schumock and colleagues found that in 16 studies evaluating the benefit:cost ratio of pharmacists providing pharmaceutical care services, ROIs ranged from $1.70 to $17, median/mean $4.68/$5.54, per patient for every dollar invested.49 In a study that evaluated direct relationships and associations between clinical pharmacy services, staffing and total cost of care in U.S. hospitals, Bond et al, found that pharmacists that provided pharmaceutical care in 1,016 hospitals saved approximately $5.3 billion (1992 dollars) in health care costs.50 Furthermore, Munroe and colleagues concluded in a study evaluating the economic impact of patient-focused pharmacist intervention in a retail setting (N=589), that those pharmacists who provided disease management services (hypertension, diabetes, asthma, and/or hypercholesterolemia) in their community (n=188) recognized savings that ranged from $1,700 to $3,500 per patient per year in total medical costs.51 Managed care plans need to integrate pharmaceutical care provided by pharmacists working in collaborative practices in their PCMH initiatives. Effective Communications
Effective communications among employers, plans, members, and providers is essential for successful population management. Chronic health conditions require new ways of communicating, which now is more focused on collaborative care. This method
encompasses the PCMH, VBBD, and aligning incentives approaches to managing populations with chronic disease.52 Communication is important in terms of who is communicating, what is being communicated, and which medium is used for communication. This includes patient educational materials that are targeted to the correct audience based on particular demographics, including age, sex, ethnicity, and level of health literacy, and disease-specific variables that may have an impact on an individual’s ability to process and comprehend the message. The mode of communication is important. Plans should make use of all available means of communication and tailor the message and the medium to the target audience. Effective communications also require effective feedback and monitoring systems for providers to track their patients’ blood pressure control and adherence. They also provide the effective dissemination of guidelines and development of policies that encourage making changes in therapy when necessary. There are many potential barriers to effective communications for special populations such as the elderly or non–English-speaking patients. Barriers to communication can have a significant effect on the degree in which they are engaged or activated in their health care. Older patients have circumstances that require effective and empathetic communications. They may be isolated, be emotionally vulnerable, suffer from depression, and have lower income levels. Language barriers, however, impact patient activation. Alegría and colleagues determined that interventions that improve patient activation had an impact on the quality of care for Latinos.53 Beneficial outcomes for Latino patients are associated with improved patient activation.53 If these patients believe that their engagement impacts/improves their health care, a collaborative relationship can be developed to achieve increased patient activation.53 Conclusion
Hypertension is a costly condition that causes substantial morbidity and mortality in the United States, affecting one in three Americans and resulting in more than $76 billion in direct and indirect costs annually. Blood pressure control is inadequate despite the availability of evidence-based guidelines for the treatment of hypertension and a wide variety of affordable and effective antihypertensive agents. The need for health plans to refine population management strategies is emergent as the numbers of patients with hypertension within health plans is expected to increase as a result of health care reform, the aging population, and the rise of chronic illness across all age groups due to poor lifestyle choices.
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These increases mean a potential shortage of resources to provide optimal care for these patients. Further, government interventions via PPACA, coupled with pressure from employers, will likely drive changes to population management strategies across chronic conditions, including hypertension. Payers can look at this as an opportunity to identify the barriers to treatment, take action to identify patients who are undiagnosed and undertreated, and bring their blood pressure under control. The barriers to adequate control are found in the common behaviors contributing to patient, provider, and payer inertias. Patients tend to be nonadherent and do not actively become engaged in the management of their own health care. Providers are reluctant to initiate treatment or intensify treatment even when doing so is indicated by established guidelines. Payers do not have adequate organizational structure and controls in place to facilitate and create incentives for both patients and providers to actively monitor and adjust treatment plans in order to achieve and maintain health goals. It is evident that there is opportunity for improving the situation. Actively engaging all stakeholders in the aggressive management of hypertension has the potential for significant savings and improved health outcomes. Innovative strategic approaches for gaining and maintaining control include: Aligning incentives for all stakeholders to encourage adherence to medication and adherence to guidelines and developing benefit designs that steer patients and providers toward high-value treatments Making the most of available resources through organizational structures such as PCMH or ACOs and including pharmacists as part of the care team, providing active counsel and education to patients Improving communications between patients and providers Overcoming these barriers will improve hypertension management, achieve desired clinical outcomes, and control health care costs. Larry Georgopoulos, PharmD is Associate Dean for Clinical Affairs and Professor of Pharmacy Practice at the University of New Mexico, College of Pharmacy, and Health Sciences Center in Albuquerque, New Mexico. Dr. Georgopoulos was formerly Director of Pharmacy Services for Presbyterian Health Plans.
Kathlene Graziano, Program Manager, Strategic Healthcare Alliance, has no direct relationship, financial or otherwise, with Takeda Pharmaceuticals North America, Inc. John Frick, Medical Writer, has no direct relationship, financial or otherwise, with Takeda Pharmaceuticals North America, Inc. Acknowledgements The author would like to thank Kathlene Graziano from Strategic Healthcare Alliance and John Frick for their assistance in preparing this manuscript.
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Effective Treatment Strategies in the Management of Non-Small Cell Lung Cancer Howard West, MD For a CME/CEU version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.
Summary Significant advances are being made in the treatment of non-small cell lung cancer (NSCLC). It has been discovered that different types of tumors respond differently to chemotherapy and other treatments and certain new therapies benefit patients with specific gene mutations. Some of the new therapies are providing dramatic improvements in certain patients even with very advanced disease. Key Points • In NSCLC, the type of tumor a patient has is used to select the best treatment. • Data on specific molecular markers that predict response or resistance to therapy are continuing to evolve. • EGFR mutation and EML4-ALK translocation are two markers that are being used to select appropriate therapy in NSCLC. • Targeted therapies such as erlotinib and crizotinib are producing dramatic but not necessarily long-lasting results in NSCLC. • Maintenance therapy should be considered in all patients who finish initial therapy without progression or severe adverse effects.
Lung cancer is the number one cancer leading to death in the U.S. in both men and women. It accounts for 28 percent of cancer deaths, which is more than breast, prostate, and colon cancer combined. Exhibit 1 illustrates the breakdown of lung cancer types in the U.S.1 Because of decreased smoking, the incidence of small cell lung cancer has been declining. The majority of patients have non-small cell lunch cancer (NSCLC), which include adenocarcinoma, squamous cell, large cell, and others. Adenocarcinoma is the most common. There have been significant improvements in lung cancer treatment in the last decade. Previous to recent improvements in treatment, all patients with lung cancer were grouped based on smoking status and histology; they were all treated with platinumbased chemotherapy which was overall not very efficacious. Emerging data indicate that specific regimens show greater benefit depending on tumor histology. Immunohistochemistry is used to distinguish the
type of cancer and where it originated (i.e., lung vs. other organ). The immunohistochemistry findings can be used to select further molecular testing of the tumor and to select the best treatment. One example of selecting therapy based on tumor type comes from a study of cisplatin and pemetrexed (Alimta®) combination compared with cisplatin and gemcitabine (Gemzar ®). Patients with nonsquamous cell lung cancer responded better to the cisplatin/gemcitabine combination, whereas those with squamous disease responded better to the other combination.2 There is much investigation ongoing in determining specific molecular markers that predict response or resistance to therapy. A few examples are thymidylate synthase, which appears to confer fluoropyrimidine resistance, excision repair cross-complementing gene 1 (ERCC1) for platinum resistance, and ribonucleotide reductase subunit 1(RRM1) for gemcitabine resistance. Many tests for molecular markers are heavily marketed to physicians and patients but the data to support their use are still evolving. At this time, none of these are of established
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Exhibit 1: Lung Cancer Subtypes1 Other (including NSCLC, NOS) 26%
Large cell carcinoma 5%
Small cell carcinoma 13% SCC 20% SCC = squamous cell carcinoma; NSCLC NOS = non-small cell lung cancer not otherwise specified
Exhibit 2: PFS in EGFR Mutation Positive and Negative Patients2
EGFR Mutation Positive Gefitinib (n = 132) Carboplatin/paclitaxel (n = 129) HR (95% CI) = 0.48 (0.36–0.64) No. events gefitinib: 97 (73.5%) No. events CP: 111 (86.0%)
Probability of PFS (%)
Probability of PFS (%)
EGFR Mutation Negative Gefitinib (n = 91) Carboplatin/paclitaxel (n = 85) HR (95% CI) = 2.85 (2.05–3.98) p < .0001 No. events gefitinib: 88 (96.7%) No. events CP: 70 (82.4%)
0.8 0.6 0.4 0.2 0.0
0.8 0.6 0.4 0.2 0.0
Treatment by subgroup interaction test, p < .0001 ITT population; Cox analysis with covariates.
value or are recommended in American Society of Clinical Oncology (ASCO) or National Comprehensive Cancer Network (NCCN) guidelines. Targeted therapies are another area of advance in NSCLC treatment. Adding bevacizumab (Avastin®) to standard platinum-based chemotherapy in patients who do not have squamous cell cancer improves overall survival.3 It is now standard of care for eligible patients. Because of the risk for fatal hemoptysis, patients with squamous disease or who have any history of hemoptysis should not receive
bevacizumab. Another targeted therapy is cetuximab (Eribitux ®). It has not yet been widely adopted for use in NSCLC for several reasons; it only modestly prolongs survival (1.2 months), must be given by weekly infusion, can lead to significant adverse effects, and is costly. There is work ongoing to better define the subset of patients who would likely receive the most benefit from this agent. It appears that patients with high epidermal growth factor receptor (EGFR) expression will have a greater benefit (two
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months or more). Genetics are playing a significant role in selecting therapy for lung cancer. Gefitinib and erlotinib are targeted tyrosine kinase inhibitors, which are effective in patients with EGFR mutations. In a study comparing gefitinib with platinum-based chemotherapy in nonsmokers with adenocarcinoma, 71 percent of the patients with EGFR mutation responded to gefitinib, whereas only 1 percent of those without the mutation had a response (Exhibit 2).4 In North American, 10 to 15 percent of patients with NSCLC have an EGFR mutation.5 Mutation is seen in approximately 35 percent of Caucasian nonsmokers and 65 percent of Asian nonsmokers. For patients who do not have an EGFR mutation, it may be detrimental to select initial therapy incorrectly. If these patients get the tyrosine kinase inhibitor first, their response and overall survival is lower than if they get chemotherapy first.6 This is an incentive to do testing before treatment. EML4-ALK translocation is another tumor genetic marker that has been identified as a predictor of therapy response to a newer agent, crizotinib (Xalkori®). This marker occurs in approximately 4 percent of NSCLC patients; it is primarily seen in younger adenocarcinoma patients with minimal or no smoking history.7 Crizotinib can lead to dramatic tumor reductions in patients with this mutation. Patients who respond to crizotinib or the tyrosine kinase inhibitors will typically have a response for a year and then will develop resistance, but the responses seen are like nothing that has been seen before in advanced lung cancer. The current issue with EGFR, ALK, and other genetic marker testing is determining who should be tested. There are different recommendations from
Exhibit 3: Who To Test High priority (higher probability of EGFR or ALK) – Adenocarcinoma, never or light-smoker – EGFR and, if EGFR neg, ALK testing Moderate priority (average probability for EGFR or ALK) – Adenocarcinoma, significant smoking history – Possibly other non-squamous – Same testing as above No clear value – all others – EGFR TKI still helpful as 2nd or later line, with or without mutation; ALK rearrangement very unlikely
different groups. The NCCN guidelines recommend testing for EGFR mutation for non-squamous NSCLC; the ASCO guidelines state that molecular testing remains investigational and these have not been proven to improve survival. Exhibit 3 provides some guidelines on which patients to test for genetic mutations. Once patients complete initial therapy for NSCLC without progression or significant adverse effects, a decision must then be made about whether to initiate maintenance therapy and if so, which agent. The goal with maintenance therapy is to limit tumor growth with a tolerable therapy. Continuation maintenance is the use of the agent that was given in first-line therapy and switch maintenance is initiation of a different agent that was not given as first-line therapy. Continuation maintenance became the de facto standard of care for NSCLC without proven benefit. One reason for this was to keep the patient receiving something. If therapy is stopped and the patient is only monitored for progression, many patients are lost to follow-up;
Exhibit 4: Weighing Maintenance Therapy
Pros • Improved progression free survival with pemetrexed, erlotinib or erlotinib + bevacizumab • Improved overall survival with pemetrexed or erlotinib • Improve pain control with erlotinib • Do not lose the opportunity for second-line treatment
Cons • Side effects with treatment • No clear improvement in quality of life or symptom control • Loss of chance for treatment holiday •
Patients may live as long treated at progression as long as they are given timely, appropriate second-line therapy
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up to one- third were lost in one study.8 For patients who actually receive planned maintenance therapy, whether immediately after initial therapy or at progression, overall survival is the same, but they have to get the therapy.8 Maintenance therapy does provide a modest benefit in progression free survival. If the patient had a benefit with the initial agent, that can be used for maintenance. It has not been proven yet which approach to maintenance is most effective â€“ continuation or switch. Exhibit 4 illustrates the pros and cons of maintenance therapy.
References 1. Govindan R, Page N, Morgensztern D, et al. Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database. J Clin Oncol. 2006;24:4539-44. 2. Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008;26:3543-51. 3. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355:2542-50. 4. Mok TS, Wu YL, Thongprasert S, Yang CH, et al. Gefitinib or carboplatinpaclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361:947-57.
The method for selecting therapy in NSCLC has changed greatly over the past 10 years and continues to evolve. In addition to the type of NSCLC a patient has, two markers, EGFR mutation and EML4ALK translocation, are being used to select therapy. Evidence firmly supports first-line treatment with tyrosine kinase inhibitors in patients known to have EGFR mutation and not giving these agents firstline to unselected patients or those EGFR mutation negative. Maintenance therapy should be considered in all patients who complete first-line therapy without progression or significant toxicity. These are the patients most likely to benefit from further therapy, but only if they actually receive it.
5. Jackman DM, Sequist LV, Cioffredi L, et al. Impact of EGFR and KRAS genotype on outcomes in a clinical trial registry of NSCLC patients initially treated with erlotinib or gefitinib. ASCO 2008 Annual Meeting. Abstract 8035. 6. Gridelli C, Ciardiello F, Feld R, et al. International multicenter randomized phase III study of first-line erlotinib (E) followed by second-line cisplatin plus gemcitabine (CG) versus first-line CG followed by second-line E in advanced non-small cell lung cancer (aNSCLC): The TORCH trial. ASCO 2010 Annual Meeting. Abstract 7508. 7. Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007;448:561-6. 8. Fidias PM, Dakhil SR, Lyss AP, et al. Phase III study of immediate compared with delayed docetaxel after front-line therapy with gemcitabine plus carboplatin in advanced non-small-cell lung cancer. J Clin Oncol. 2009;27:591-8.
Howard West, MD is a Medical Oncologist with the Swedish Cancer Institute in Seattle, WA.
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Evolving Treatment Strategies in the Management of Metastatic Breast Cancer Michelle E. Melisko, MD For a CME/CEU version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.
Summary Unfortunately, metastatic breast cancer is not curable at this time. Treatment aims to prolong survival and decrease burden of disease with various hormonal agents, chemotherapy, and targeted therapies. Many of the newer agents have improved efficacy, adverse effect profiles, or ease of administration. Key Points • Because it is not curable, the goals in treating advanced breast cancer are to prolong survival and decrease burden of disease. • Fulvestrant is an intravenous hormone therapy which may significantly improve compliance compared with the aromatase inhibitors. • Patients with metastatic disease may be treated with hormonal therapies initially but will usually progress and require chemotherapy. • Sequential chemotherapy is preferred over combination chemotherapy. • Nanoparticle albumin-bound paclitaxel appears to have some advantages over older taxanes, but cost-effectiveness analyses still need to be conducted. • Oral capecitabine offers significant advantages over intravenous 5-FU. • Trastuzumab in the adjuvant setting has lead to a huge reduction in the rate of development of metastatic disease in HER-2 positive patients. • Bone-modifying agent therapy is recommended for patients with evidence of bone metastases.
Metastatic breast cancer is a leading cause of death in women with about 40,000 deaths in the United States each year. The vast majority of deaths occur in patients relapsing after having received adjuvant treatment for early stage disease. Most relapses occur in the first five years after initial treatment, but can occur at any time. Up to one-fifth occur after 10 years. One to 5 percent of women with breast cancer have metastatic disease at initial presentation. For patients who have advanced or metastatic disease, the disease is universally fatal with a median survival of 24 to 30 months. Because it is not curable at this time, the goals in treating advanced breast cancer are to prolong survival and decrease burden of disease. Most patients will be on some type of therapy for the majority of their survival. There are numerous possible therapies for advanced or metastatic breast cancer. Exhibit 1 provides a general overview of treatment selection.1 Therapy may include hormonal therapies such as tamoxifen, steroidal and non-steroidal aromatase in-
hibitors, fulvestrant (Faslodex ®), megestrol acetate, or high dose estrogens. Chemotherapy alone or in combination is also used. Biological therapies including trastuzumab, lapatinib, or bevacizumab also have a place in treating metastatic breast cancer. Each of the hormonal agents has a different mechanism of action. Aromatase inhibitors (AI) inhibit conversion of androgens to estrogens via the aromatase enzyme. Tamoxifen competes with estrogen by binding to the estrogen receptor (ER). ER antagonists (fulvestrant) compete with estrogen by binding, blocking and causing conformational changes to the estrogen receptor leading to a downregulation of receptor levels. The aromatase inhibitors and tamoxifen have been compared and have similar efficacy; fulvestrant has been compared to aromatase inhibitors. Fulvestrant is as effective as anastrozole but does result in a longer time to progression than anastrozole with a similar adverse event profile.2 Because this is a monthly injectable agent, there is improved compliance. It has been estimated that 30 percent of women are noncompliant with their AI
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Exhibit 1: Treatment Selection Overview1 Advanced Breast Cancer
• • • •
Limited metastases (bone & soft tissue) Positive hormone receptors Hormone sensitive Recurrence-free interval > 1–2 years
• Extensive metastases or visceral crisis • Negative hormone receptors • Not sensitive to hormones
First-line hormonal therapy
Progression of disease
If disease progresses, second-line hormonal therapy
Exhibit 2: Phase III Trial of Nanoparticle Albumin-Bound Paclitaxel (ABI-007) vs Standard Paclitaxel: Time to Progression4 ABI-007 (n=229) Paclitaxel (n=224)
Proportion not progressed
Median (wk) 23.0 16.9
0.60 P = 0.006 0.50
8 16 24 32 40 48 56 64 72 80 88 96 104 112 120 Weeks
therapy in the adjuvant setting. In advanced breast cancer, tumors usually progress on hormonal agents. Most patients will be tried on various agents and will eventually exhaust the available options. Patients will ultimately need chemotherapy. Although there is significant debate over sequential or combination chemotherapy, at this time, there is no compelling evidence that combination chemotherapy regimens are superior to sequential single agents. The National Comprehensive Cancer Network (NCCN) and American Society of Clinical Oncology (ASCO) publish recommendations for preferred chemotherapy agents.
The taxanes are commonly used chemotherapy agents. There are three approved taxanes: docetaxel, paclitaxel, and nanoparticle albumin-bound paclitaxel. Docetaxel (Taxotere®) is given as an every three-week infusion. Every three-week docetaxel is slightly more effective than every three-week paclitaxel. Paclitaxel (Taxol®) given once a week achieves a better response rate than giving it every three weeks, is less expensive, and causes fewer adverse effects.3 Nanoparticle albumin-bound paclitaxel (Abraxane®) is the newest taxane. It has been compared with paclitaxel and results in higher overall response rate and longer time to progression (Exhibit 2).4 Abraxane appears to have a similar adverse event pro-
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Subjects Without SRE (%)
Exhibit 3: Time to First On-Study Skeletal Related Event8
Patients at risk, n Zoledronic acid Denosumab
HR: 0.82 (95% CI: 0.71-0.95; P = .0096, superiority)
1.0 0.8 0.6 0.4 0.2
Denosumab Zoledronic acid
KM Estimate of Median Mos 32.4 27.4
15 18 Study Mo
• Other endpoints: no difference in OS or time to overall disease progression between denosumab and zoledronic acid arms
file with a lower rate of neutropenia than standard paclitaxel. A cost-effective analysis of comparing overall costs of treating patients with the different taxanes has not been done but would be valuable and is needed. Capecitabine (Xeloda®) is the first oral fluoropyrimidine approved for patients failing anthracyclines and taxanes. It is a prodrug that is converted to an active metabolite, 5-flurouracil (5-FU). 5-FU is preferentially generated and concentrated within the tumor. The oral administration of capecitabine enables chronic daily dosing, thus mimicking continuous infusion of 5-FU without the complications, such as needle-site infection and blood clotting, and inconvenience associated with central venous access and the use of infusion pumps. In addition, it offers the potential for a convenient, oral, outpatient treatment, which most patients prefer to intravenous therapies. Gemcitabine (Gemzar ®) is another chemotherapy agent frequently used in the metastatic setting. It is approved for use in combination with taxanes but is most often used as a single agent. Eribulin (Halaven®), a novel microtubule inhibitor, is one of the newest agents approved for metastatic breast cancer. Eribulin exerts its anticancer effects by triggering apoptosis of cancer cells following prolonged and irreversible mitotic blockade. This agent modestly improves overall survival (~2.5 months) and progression free survival compared to standard treatments in patients who have been pretreated with anthracycline and taxanes. Eribulin is associated with a high incidence of serious hematologic toxicity and peripheral neuropathy. Patients who respond to first-line chemotherapy will eventually have progression. After progressing,
a patient would be switched to capecitabine or a taxane, whichever they did not receive first. The significant costs (new scans, blood work, visits, etc.) to switching therapies given the modest benefits should be considered. Clinical trial enrollment should be considered after failure of first-line chemotherapy if not before then. Angiogenesis plays an essential role for local tumor growth and distant metastases in breast cancer. Thirty to 60 percent of breast cancers over-express vascular endothelial growth factor (VEGF). Inhibiting VGEF can inhibit tumor growth. The rationale for combining anti-angiogenesis agents with chemotherapy includes hitting different targets, a lack of cross-resistance patterns, and an assumption of additive effects in antitumor activity. Additionally, lack of myelosuppression with angiogenesis inhibitors allows administration of full doses of all agents. Bevacizumab (Avastin®), a recombinant humanized anti-VEGF antibody, was the first agent in this class approved. In addition to bevacizumab, there are numerous other anti-angiogenesis agents under study. Randomized clinical trials in metastatic breast cancer document that the addition of bevacizumab to some first- and second-line chemotherapy agents modestly improves time to progression and response rates but does not improve overall survival. Bevacizumab previously was FDA approved for use in combination with 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
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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.”5 HER-2 Breast Cancer
Trastuzumab (Herceptin) is a humanized antiHER2 monoclonal antibody. The use of trastuzumab in the adjuvant setting has lead to a huge reduction in the development of metastatic disease in HER-2 positive patients. For patients who do progress while on trastuzumab, lapatinib (Tykerb), a reversible dual tyrosine kinase inhibitor (TKI) that inhibits HER-2 and HER-1, is an option. It binds to the intracellular ATP binding site of epidermal growth factor receptor (EGFR) and HER2 preventing phosphorylation and activation. This blocks downstream signaling of EGFR and HER2. Dual blockade of signaling may be more effective than the single-target inhibition provided by trastuzumab.6 When combined with capecitabine, lapatinib improved overall response and time to progression but not overall survival. Lapatinib in combination with capecitabine is FDA approved for HER2 positive metastatic breast cancer that has progressed on an anthracycline, taxane, and trastuzumab without a survival benefit. A promising agent under study is TDM-1 which is trastuzumab bound to a potent cytotoxic medication, DM-1. The presence of the trastuzumab allows binding of this molecule to the HER-2 receptor on the tumor cell. The molecule is then transported into the tumor cell where the DM-1 leads to cell death. The systemic adverse effects of this agent are limited because of low HER-2 expression on normal cells. As first-line therapy for metastatic breast cancer, this agent improves progression free survival by approximately five months compared to trastuzumab and docetaxel. It also appears to have a significantly lower rate of severe adverse effects than combination of trastuzumab and docetaxel. It has also been studied in patients who have been heavily pretreated (median eight prior treatments for metastatic disease).7 Hopefully, this agent will be FDA approved in the near future. Bone-modifying agent therapy
Many patients with breast cancer will develop bone metastases and several of the medications used to treat the cancer can lead to accelerated bone loss. Patients can have an increased risk of fracture both from metastases and bone loss. The ASCO recommends bone-modifying agent therapy only for patients with evidence of bone metastases. The options are denosumab (Xgeva®) subcutaneous injections, pamidronate (Aredia®) intravenous infusion, or
zoledronic acid (Zometa®) intravenous infusions. Pamidronate and zoledronic acid are both bisphosphonates which slow bone loss by inhibiting osteoclast activity. Denosumab is an antibody to human receptor activator of nuclear factor kappa-B ligand (RANKL). Unopposed RANKL is responsible for bone loss in osteoporosis, bone metastases, and cancer treatment-induced bone loss. Denosumab appears to be superior to zolendronic acid in reducing skeletal related events (Exhibit 3).8 It is FDA approved for preventing skeletal related events in patients with solid tumors and bone metastases. Because of the possible adverse event of jawbone osteonecrosis, all patients should receive a dental examination and appropriate preventive dentistry before bone-modifying agent therapy and maintain optimal oral health. The use of biochemical markers to monitor bone-modifying agent use is not recommended. Conclusion
The treatment of metastatic breast cancer continues to evolve. Although it is not curable, there are many different treatment options which can be used to help prolong survival and reduce disease burden. With each new evolution, therapies are becoming better targeted and tolerated and easier for patients to comply with. Michelle E. Melisko, MD is an Associate Clinical Professor of Medicine at the UCSF Helen Diller Family Comprehensive Cancer Center.
References 1. Hortobagyi GN. Treatment of Breast Cancer. N Engl J Med. 1998;339:974-84. 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. Jones SE, Erban J, Overmoyer B, et al. Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer. J Clin Oncol. 2005;23:5542-51. 4. Gradishar WJ, Tjulandin S, Davidson N, et al. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol. 2005;23:7794-803. 5. 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. Accessed 6/11/2012. 6. Konecny GE, Pegram MD, Venkatesan N, et al. Activity of the dual kinase inhibitor lapatinib (GW572016) against HER-2-overexpressing and trastuzumab-treated breast cancer cells. Cancer Res. 2006;66:1630-9. 7. Burris HA 3rd, Rugo HS, Vukelja SJ, et al. Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer after prior HER2-directed therapy. J Clin Oncol. 2011;29:398-405. 8. Stopeck A, Martin M, Ritchie D, et al. Effect of denosumab vs zoledronic acid treatment in patients with breast cancer and bone metastases: results from the extended blinded treatment phase. Cancer Res. 2010;70:457s. Abstract P6-14-01.
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Do you know the hidden costs of some TG-lowering therapies? High triglycerides (TGs) should be considered along with LDL-C as part of a comprehensive approach to lipid management Reduction of low-density lipoprotein cholesterol (LDL-C) is now well established as the primary treatment target in lipid management as reflected in the current HEDIS and 5-Star quality ratings.1-3 However, recently published guidelines by the American Heart Association and the American College of Cardiology Foundation recommend a more comprehensive approach to lipid management that also considers the significance of biomarkers other than LDL-C, such as total cholesterol, non-high density lipoprotein cholesterol (non-HDL-C), very-low density lipoprotein-cholesterol (VLDL-C), high sensitivity C reactive protein (hs-CRP), apolipoprotein B (apo B), and triglycerides (TGs).1,4
TG reduction with concurrent increases in LDL-C or adverse events may compromise lipid treatment goals Several therapies are used in the clinical setting for lowering TGs, such as fenofibrates, niacin, and prescription omega-3 fatty acids. Although these therapies effectively lower TGs, some have the potential to significantly increase LDL-C levels, while others have tolerability issues.1 Niacin, while effective at lowering TGs and boosting HDL-C, does have adverse events such as truncal and facial flushing, and can negatively impact levels of glycosylated hemoglobin (HbA1c).1,5,6 In patients with very high TGs, studies have shown that fenofibrates and omega-3 acid ethyl esters (principally made up of eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) may increase LDL-C up to 45%.7,8 Recent studies suggest that DHA may be responsible for a rise in LDL-C levels.9
Visit www.LipidU.org to find out more about the complex issues impacting lipid management today. References: 1. National Institutes of Health, National Heart, Lung, and Blood Institute. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III): Final Report. Bethesda, MD: National Institutes of Health; September 2002. NIH Publication No. 02-5215. 2. National Committee for Quality Assurance. The State of Health Care Quality National Committee for Quality Assurance: Reform, The Quality Agenda and Resource Use. Washington, DC: National Committee for Quality Assurance; 2010. 3. Centers for Medicare & Medicaid Services. Medicare Health & Drug Plan Quality and Performance Ratings 2012 Part C & Part D Technical Notes. Baltimore, MD: Centers for Medicare & Medicaid Services; 2011. 4. Smith SC Jr, Benjamin EJ, Bonow RO, et al. AHA/ACCF secondary prevention and risk reduction therapy for patients with coronary and other atherosclerotic vascular disease: 2011 update: a guideline from the American Heart Association and American College of Cardiology Foundation endorsed by the World Heart Federation and the Preventive Cardiovascular Nurses Association. J Am Coll Cardiol. 2011;58(23):2432–2446. 5. Knodel LC, Talbert RL. Adverse effects of hypolipidaemic drugs. Med Toxicol. 1987;2(1):10–32. 6. Kamal-Bahl S, Watson DJ, Ambegaonkar BM. Patients experiences of niacin-induced flushing in clinical practice: a structured telephone interview. Clin Ther. 2009;31(1):130-140. 7. Trilipix [package insert]. North Chicago, IL: Abbott Laboratories; 2011. 8. Lovaza [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2010. 9. Wei MY, Jacobson TA. Effects of eicosapentaenoic acid versus docosahexaenoic acid on serum lipids: a systematic review and meta-analysis. Curr Atheroscler Rep. 2011;13:474–483.
Get connected to the perspectives of 100 stakeholders who manage 143 million covered lives Connecting you with relevant information is part of our commitment to you. That’s why Lilly commissioned the publication of a report based on the Managed Care Oncology Index.* This study surveyed managed care executives, practicing oncologists, and oncology practice managers who shared their views on interesting oncology topics such as: • Coverage and reimbursement of oncolytics • Oncology management strategies • Clinical pathways The publication, Trend Report on Oncology Management, is just one example of how Lilly Oncology can connect you with important information to assist your organization in managing members with cancer. To get your copy of the trend report, simply call 1-800-247-7832 and a Lilly Account Manager–Oncology Payer Services will contact you to arrange delivery of your copy and answer any questions you might have about other available services. Visit www.lillyoncology.com.
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