Vol. 17, No. 2, 2014
Educating Medical Directors of Employers, Health Plans and Provider Systems
FEATURED ARTICLES INCLUDE: Current Immunization Updates for the Management and Prevention of Influenza Overcoming Challenges in the Management of Obesity: A Closer Look at Emerging Therapeutic Options Chemotherapy-Induced Nausea and Vomiting (CINV): Perceptions, Mechanisms, and Treatment Guidelines PLUS: Spring Managed Care Program Guide
A significant achievement for patients with fecal incontinence (FI)...
A good day.
It’s no accident. Solesta: a unique treatment for FI • • • •
An injectable, biocompatible gel Nonsurgical, in-office procedure No anesthesia required May preclude need for more invasive surgical procedures
Find out more at solestainfo.com. Indication Solesta is indicated for the treatment of fecal incontinence in patients 18 years and older who have failed conservative therapy (eg. diet, fiber therapy, anti-motility medications).
Number of episodes/14 days
Durable efficacy with Solesta 25
Important Safety Information about SOLESTA SOLESTA® (hyaluronic acid/dextranomer) is contraindicated in patients with active inflammatory bowel disease, immunodeficiency disorders or ongoing immunosuppressive therapy, previous radiation treatment to the pelvic area, significant mucosal or full thickness rectal prolapse, active anorectal conditions (including abscess, fissures, sepsis, bleeding, proctitis, or other infections), anorectal atresia, tumors, or malformation, rectocele, rectal varices, presence of existing implant (other than SOLESTA) in anorectal region, or allergy to hyaluronic acid-based products. SOLESTA must not be injected intravascularly as injection of SOLESTA into blood vessels may cause vascular occlusion. Injection in the midline of the anterior wall of the rectum should be avoided in men with an enlarged prostate. SOLESTA should only be administered by physicians experienced in performing anorectal procedures and who have successfully completed a comprehensive training and certification program on the SOLESTA injection procedure. The most common adverse reactions with SOLESTA (incidence >4%) in the clinical study were proctalgia, anorectal hemorrhage, injection site hemorrhage, pyrexia, injection site pain, diarrhea, and anorectal discomfort. Please see brief summary of full Prescribing Information on following page. Solesta is under license from and manufactured by Q-Med AB for Salix Pharmaceuticals, Inc. Solesta is a registered trademark of Galderma S.A. © 2013 Salix Pharmaceuticals, Inc. All rights reserved. SOL 13/121
Please consult Package Insert for full prescribing information.
Indication for Use
Solesta is indicated for the treatment of fecal incontinence in patients 18 years and older who have failed conservative therapy (e.g., diet, fiber therapy, anti-motility medications).
Solesta is contraindicated in patients with the following conditions: • Active inflammatory bowel disease • Immunodeficiency disorders or ongoing immunosuppressive therapy • Previous radiation treatment to the pelvic area • Significant mucosal or full thickness rectal prolapse • Active anorectal conditions including: abscess, fissures, sepsis, bleeding, proctitis, or other infections • Anorectal atresia, tumors, stenosis or malformation • Rectocele • Rectal varices • Presence of existing implant (other than Solesta) in anorectal region • Allergy to hyaluronic acid based products
• Do not inject Solesta intravascularly. Injection of Solesta into blood vessels may cause vascular occlusion. • Injection in the midline of the anterior wall of the rectum should be avoided in men with enlarged prostate.
The primary safety data set includes data from 206 patients treated with either Solesta or Sham in the Pivotal study. The data show that a total of 232 treatment-related adverse events for either Solesta or Sham were reported up to 18 months after treatment. Three (3) adverse events assessed as related to Solesta, or 1.3% of the treatment-related adverse events, were deemed serious by the investigators. These three (3) serious adverse events occurred in three (3) patients, including one case of an E. coli bacteremia, and two (2) cases of rectal abscesses (one event per patient). All of these serious adverse events resolved following treatment without any sequelae within approximately 30 days of treatment. Overall, 96% of the 203 Solesta treatment-related adverse events in the Pivotal study were of mild to moderate intensity and 97% of the events required no intervention or required medical or simple non-invasive interventions, including application of local pressure, silicone ointment, water irrigation and warm baths. Seven (7) events required more invasive procedures including: perianal drainage of abscesses (4 events), one (1) case of rubber band ligation of an anal prolapse, one (1) case of lancing of a hemorrhoid, and one (1) case of a Kenalog injection in a pre-existing anal scar. The most frequent adverse events following Solesta treatment pertained to post-treatment proctalgia, minor anal or rectal bleeding, post-treatment fever, abdominal complaints (such as diarrhea and constipation), and events potentially related to peri-operative infection.
Patient Counseling Information
The patient should be advised that Solesta treatment is not effective for all patients with fecal incontinence and that repeat treatment might be required for treatment effect. It should also be made clear to the patient that the available clinical study data are not sufficient to predict in whom Solesta treatment will be effective. The patient should be informed about post-treatment care and potential adverse events. The patient should also be made aware that the implants might be detected during future anorectal examinations and radiographic imaging of the pelvis. Patients should be instructed to inform all future treating physicians about the presence of Solesta gel. If there should be a need for future surgery (e.g., hemorrhoidectomy) the Solesta implant can be resected.
Directions for Use
Solesta should be administered by qualified physicians with experience in the treatment of anorectal conditions and who have successfully completed a comprehensive training and certification program in the Solesta injection procedure. Solesta should only be used after a thorough physical evaluation of the patient to exclude treatable underlying disorders. Please consult Package Insert for full directions for use and method of administration.
1. The patient should be instructed to avoid taking hot baths during the first 24 hours post-treatment. 2. The patient should be informed of the risk of infections and bleeding. 3. The patient should be instructed to contact the clinic or physician’s office immediately if symptoms of rectal bleeding, bloody diarrhea, fever, tenesmus or problems with urinating occur. 4. Anti-diarrheal drugs should not be used for one week after treatment. 5. Stool softeners may be used until the first defecation occurs. 6. Analgesics other than Non-steroidal Anti-inflammatory Drugs (NSAIDs) may be prescribed, if needed. 7. The patient should be instructed to: – Avoid physical activity for 24 hours – Avoid sexual intercourse and strenuous physical activity for one week (e.g., horse back riding, bicycling and jogging, etc.) – Avoid anal manipulation for one month (e.g., insertion of suppositories or enemas and rectal temperature recording)
1. If the patient does not have an adequate response to Solesta after the first injection, a re-injection with a maximum of 4 mL Solesta can be performed, no sooner than 4 weeks after the first injection. 2. The re-treatment procedure and all pretreatment preparations are performed the same way as the initial treatment procedure. All pretreatment preparations and injection procedures should be performed as described in “Methods of Administration” above. However, the point of injection should be made in between the initial injections, shifted one-eighth of a turn (e.g., left posterolateral, left anterolateral, right anterolateral, and right posterolateral).
Solesta is supplied in a glass syringe with a standard Luer-lock fitting containing 1 mL gel. Each syringe is terminally moist heat sterilized in a pouch. Four pouches, each containing one syringe are packed in a carton together with five Sterican needles (21G x 4¾ inches, 0.80 mm x 120 mm), patient record labels and a package insert. The needles are sterilized by ethylene oxide.
Store at a temperature up to 25°C (77°F) and protect from sunlight and freezing. To report adverse events, a product complaint, or for additional information, call: 1-800-508-0024. Solesta is under license from and manufactured by Q-Med AB for Salix Pharmaceuticals, Inc. Solesta is registered trademark of Galderma S.A.
©2013 Salix Pharmaceuticals, Inc. All rights reserved. Printed in the USA. SOL-RALAB18-102013
11/19/13 12:14 PM
General precautions • Solesta should only be administered by physicians experienced in performing anorectal procedures and who have successfully completed a comprehensive training and certification program in the Solesta injection procedure. • The safety and effectiveness of Solesta have not been investigated in patients with complete external sphincter disruption or significant chronic anorectal pain. • The safety and effectiveness of Solesta have not been investigated in patients with previous procedures involving the anorectal region: rectal anastomosis <12 cm from anal verge, anorectal surgery within previous 12 months, hemorrhoid treatment with rubber band within 3 months, anorectal implants and previous injection therapy, Stapled Transanal Rectal Resection (STARR) or stapled hemorrhoidectomy. • The safety and effectiveness of Solesta have not been studied in patients under the age of 18 years. • The safety and effectiveness of Solesta have not been studied in pregnant or breastfeeding women. • The durability of Solesta has not been studied past 12 months. • The safety and effectiveness of Solesta have been studied in patients who received one or two treatments. In the Pivotal study, the majority of patients received two treatments, four weeks apart. Patient related precautions • Patients with bleeding diathesis or patients using anticoagulant or antiplatelet agents, as with any injections, may experience increased bleeding at injection sites. • Patients should be counseled that a repeated Solesta injection procedure may be required to achieve a satisfactory level of improvement in incontinence. Procedure related precautions • Adequate bowel preparation of the rectum using enema is required prior to injection. The enema should be given immediately prior to the procedure to ensure evacuation of the anorectum. It is recommended that additional cleansing of the injection area with an antiseptic be performed prior to injection. Use of prophylactic antibiotics is recommended. • Solesta should be injected slowly to avoid undue stress on the Luer-lock connection which could cause leakage of the gel. • After injection of Solesta, hold the needle at the injection site for an additional 15-30 seconds to minimize leakage of Solesta. • Injections too close to the dentate line or too deep in the tissue might cause excessive pain. • Injection should be stopped if excessive bleeding or pain occurs. • One sterile needle should be used per syringe and injection. Device related precautions • The use of needles other than those supplied may impede injection of Solesta due to the properties of the gel and may cause device malfunction. • Solesta is supplied ready to use in a prefilled syringe with a Luer-lock fitting. Carefully examine the unit to verify that neither the contents nor the package has been damaged in shipment. Do not use if damaged. • Solesta is supplied sterile and is intended for single use only. Do not re-sterilize, as this may damage or alter the product. • In the event of accidental contamination of a needle, discard the needle. • Never mix Solesta with other products. • Solesta is to be stored at up to 25°C (77°F), and used prior to the expiration date printed on the label. Do not expose Solesta to either sunlight or freezing, as this may damage or alter the product. • Care should be taken when handling the glass syringes and disposing of broken glass to avoid laceration or other injury. • After use, syringes and needles should be handled as potential biohazards. Disposal should be in accordance with accepted medical practice and applicable local, state and federal requirements. Adverse Events Potential adverse events include: abdominal discomfort, abdominal distension, abdominal pain, lower abdominal pain, abdominal rigidity, alopecia, anal abscess, anal fissure, anal hemorrhage, anal prolapse, anal pruritus, anorectal discomfort, back pain, constipation, C-reactive protein increased, chills, cold sweat, defecation urgency, dermatitis, diarrhea, device dislocation, dizziness, dyspareunia, escherichia bacteremia, fecal incontinence, feces hard, fatigue, gastrointestinal motility disorder, gastrointestinal pain, genital discharge, genital prolapse, hematochezia, hematospermia, hemorrhoids, infection, injection site abscess, injection site discomfort, injection site hemorrhage, injection site hematoma, injection site inflammation, injection site irritation, injection site nodule, injection site pain, injection site pustule, injection site swelling, injection site ulcer, intestinal mass, malaise, mucosal inflammation, musculoskeletal pain, perineal abscess, nausea, edema, pain, painful defecation, pelvic mass, perineal pain, proctalgia, proctitis, pyrexia, rectal abscess, rectal discharge, rectal hemorrhage, rectal lesion, rectal obstruction, rectal prolapse, rectal spasm, rectal tenesmus, rectovaginal septum abscess, urinary retention, vaginal discharge, vulvovaginal pain. The adverse event profile of Solesta beyond 18 months is not known, but is under investigation in post-market studies.
The safety evaluation of Solesta in the treatment of fecal incontinence (FI) is based on the results from the Pivotal clinical study, and is supported by the Open-Label multicenter clinical study and one single site Proof-of-Concept study. The analysis of safety was based on the safety cohort of all 206 patients treated in the Pivotal study with either Solesta or Sham. Safety data for Solesta are available from 359 treatments in 197 total patients followed for up to 18 months post treatment (i.e., 136 subjects from the blinded phase and 61 subjects from the open phase).
More than 19,000 Physicians and 400,000 Cancer Patients Have Used the Oncotype DX速 Test to Help Guide Their Breast, Colon and Prostate Cancer Treatment
JMCM Journal of Managed care medicine 4435 Waterfront Drive, Suite 101 Glen Allen, VA 23060 (804) 527-1905 fax (804) 747-5316
Editor-In-Chief J. Ronald Hunt, MD
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. 17, No. 2, 2014
TABLE OF CONTENTS
publisher Katie Eads
director of communications
A Closer Look at Targeted Therapies in Metastatic Colorectal Cancer Bassel F. El-Rayes, MD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Journal management Douglas Murphy Communications Inc. P.O. Box 71895 Richmond, VA 23255-1895 (804) 387-7580 fax (703) 997-5842
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Douglas Murphy Communications, Inc.
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Current and Emerging Treatment Options in the Management of Relapsed/Refractory Myeloma Melissa Alsina, MD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Current Immunization Updates for the Management and Prevention of Influenza Kevin Sherin, MD, MBA, MPH, FACPM . . . . . . . . . . . . . . . . . . . . . 17 Emerging Treatment Strategies for ACS Management: Improving Patient Outcomes Frederick Korley, MD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 New Developments in the Treatment and Management of Multiple Sclerosis Myla D. Goldman, MD, MS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 Closing Performance Gaps in the Diagnosis and Management of Osteoporosis Andrea J. Singer, MD, FACP, CCD. . . . . . . . . . . . . . . . . . . . . . . . . 31 Overcoming Challenges in the Management of Obesity: A Closer Look at Emerging Therapeutic Options Tirissa J. Reid, MD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 Chemotherapy-Induced Nausea and Vomiting (CINV): Perceptions, Mechanisms, and Treatment Guidelines Charles Loprinzi, MD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 Spring Managed Care Program Guide. . . . . . . . . . . . . . . . . . . . 51
POSTMASTER: Send address changes to The POSTMASTER: Send address changes to The Journal of Managed Care Medicine, 4435 WaterJournal of Managed Waterfront Drive, Suite 101,Care GlenMedicine, Allen, VA4435 23060. front Drive, Suite 101, Glen Allen, VA 23060.
www.namcp.org | Vol. 17, No. 2 | Journal of Managed Care Medicine 5
Editorial Review Board Alan Adler, MD, MS Medical Director Independence Blue Cross
Sarath Gunatilake, MD, DrPH Professor, Health Science Department California State University, Long Beach
Philip Painter, MD Chief Medical Officer Humana
Devena Alston-Johnson, MD Medical Director CIGNA
John W. Heryer, MD, FACS Medical Director Blue Cross Blue Shield of Kansas City
Mary H. Pak, MD Medical Director Unity Health Plans Insurance Corporation
E. Paul Amundson, MD Chief Medical Officer Dakotacare
Kathy Hudson, PhD Director, Genetics and Public Policy Center Johns Hopkins University
Gary R. Proctor, MD Chief Medical Officer, Federal Division ValueOptions, Inc.
Larry L. Hsu, MD Medical Director Blue Cross Blue Shield of Hawaii (HMSA)
Carlos Ramirez, MD Chief Medical Officer Valley Baptist Health Plans
Richard Bock, MD, MBA Chief Medical Officer Molina Health Care of California
Stephen Keir, DrPH Co-Director, Center for Quality of Life Support Care Research Robert Preston Tisch Brain Tumor Center
Paul Rein, DO Medical Director Port Warwick Ambulatory Surgery Center
Anthony Bonagura, MD Chief Medical Officer Aetna, Inc.
John Knispel, MD, CPE, FACOG Regional Medical Officer Humana
Philip M. Bonaparte, MD Chief Medical Officer Horizon NJ Health
Karen Knowles, MD Internal Medicine Physician HCA/Emcare
Salil V. Deshpande, MD Market Medical Officer United Healthcare
Catherine Marino, MD Chief Medical Officer MagnaCare
Michael Fine, MD Medical Director Health Net
Jeff Martin, PharmD Clinical Account Director Innoviant, Inc.
John K. Fong, MD, MBA Vice President Blue Cross Blue Shield of North Carolina
Monte Masten, MD, MBA, MPH Vice President, Health Guidance Humana
Jacque J. Sokolov, MD Chairman SSB Solutions
Stephen Friedhoff, MD Senior Vice President, National Medical Director Amerigroup/Wellpoint
Wesley Mizutani, MD Talbert Medical Group Thomas Morrow, MD Genentech
Scott Spradlin, DO, FACPF, ACOI Vice President Medical Affairs/Chief Medical Officer Group Health Plan
Ronald Y. Fujimoto, DO, FAAFP Chief Medical Officer United Healthcare
Ray Mummery, MD, CMCE Chief Medical Officer Dimension Health
Howard Garber, MD, MPH Medical Director Johns Hopkins Health Care
Barbara Nabrit-Stephens, MD, MBA Medical Director United Healthcare
Uwe G. Goehlert, MD, MSC, MPH, MBA Principle Goehlert & Associates
Tim Newman, MD Medical Director FirstEnergy
Linda Ash-Jackson, MD Medical Director Hometown Health Paul Bluestein, MD Chief Medical Officer Connecticare
Steven E. Goldberg, MD, MBA Vice President of Medical Affairs Coventry Health Care of Kentucky Humberto Guerra-Garcia, MD, MPH, FACP Chief Medical Officer MMM Healthcare, Inc./PMC Medicare Choice Puerto Rico
Denis Oâ€™Connell, MD Medical Director Blue Cross Blue Shield of North Carolina Arik Olson, MD, MBA Senior Medical Director CHOICE Health Plans Gary Owens, MD Principle Gary Owens Associates
6 Journal of Managed Care Medicine | Vol. 17, No. 2 | www.namcp.org
Kevin Roache, MD, MMM, CPE, FACPE Vice President Medical Affairs Peoples Health, Inc. Mark R. Rosenberg, MD, PhD President/CEO Behavioral Health Management Joseph Schappert, MD Chief Medical Officer PAML Christine M. Seals, MD Medical Director Umpqua Health Alliance
William D. Strampel, DO, FACOI Dean, College of Osteopathic Medicine Michigan State University Prentiss Taylor, MD Corporate Medical Director Advocate At Work at Advocate Health Care Pamella Thomas, MD,MPH, FACOEM Consulting Medical Director Wellness Health & Productivity Strategies Robert A. Ziff, MD, MBA, FACS, CPE East Central Region Medical Director, Senior Products Humana
A Closer Look at Targeted Therapies in Metastatic Colorectal Cancer Bassel F. El-Rayes, MD For a CME/CEU version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.
Summary The discovery of key regulators in cancer cell growth has led to the development of targeted therapies in many cancers, including colorectal cancer. Five targeted therapies are now approved for use in metastatic colorectal cancer (mCRC). These therapies modestly increase overall survival and progression-free survival in a heavily pretreated patient population. Key Points • Targeted therapy combined with chemotherapy is the standard of care in mCRC. • EGFR inhibitors are beneficial in patients without KRAS mutations. • VEGF inhibitors are beneficial in both KRAS mutated and wild-type patients. • There are no head-to-head trials to identify the most effective or safest targeted therapy. • The choice of targeted therapy in mCRC depends both on underlying mutations and previous therapy. • Data support continuing antiangiogenic therapies beyond progression.
The discovery of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF), two key regulators of tumor cell growth, survival, metastasis, and angiogenesis, has led to the development of targeted biologic therapies for colorectal cancer. Five targeted therapies have been approved for use in metastatic colorectal cancer (mCRC) in combination with chemotherapy. Bevacizumab (Avastin®), ziv-aflibercept (Zaltrap®), and regorafenib (Stivarga®) all target VEGF. Cetuximab (Erbitux ®) and panitumumab (Vectibix ®) are EGFR inhibitors. Bevacizumab was the first VEGF inhibitor approved by the FDA. In the trials used to get this agent approved, the addition of bevacizumab to chemotherapy improved overall survival (OS) by 4.4 months compared with placebo in mCRC (20.3 months vs 15.6 months).1 There is still an improve-
ment in survival even out to two years. There are data to support combining bevacizumab with single agent, doublet, or triplet chemotherapy. Thus, depending on the patient’s ability to tolerate chemotherapy, bevacizumab still adds survival benefit. There are also data demonstrating benefits of continuing bevacizumab even when the patient’s cancer has progressed.2,3 Aflibercept is a fusion protein of key domains from human VEGF receptors 1 and 2 with constant region (Fc) of human immunoglobulin G.4 It blocks all human VEGF-A isoforms, VEGF-B, and placental growth factor (PlGF).5 It binds VEGF-A and PlGF more tightly than native receptors. Because it has a different mechanism of action than bevacizumab, it hits more targets, which may be a possible benefit. In the main study used for FDA approval, afliber-
www.namcp.org | Vol. 17, No. 2 | Journal of Managed Care Medicine 7
Exhibit 1: Regorafenib Mechanism of Action7-9
Inhibition of proliferation KIT PDGFR RET
Inhibition of tumor microenvironment signaling
Inhibition of neoangiogenesis
PDGFR- Î˛ FGFR
KIT = V-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog RET = rearranged during transfection proto-oncogene PDGFR = platelet-derived growth factor receptor FGFR = fibroblast growth factor receptor VEGFR = vascular endothelial growth factor receptor TIE2 = TEK tyrosine kinase, endothelial
cept was studied in combination with FOLFIRI (leucovorin, 5-fluorouracil (5-FU), and irinotecan (Camptosar). Addition of afilbercept increased OS by a median of 1.4 months.6 The hazard ratio (HR) was 0.82 so the people who received aflibercept had a 20 percent lower likelihood of death during the trial. It also increased progression-free survival by 2.2 months. It had similar effects whether patients were previously treated with bevacizumab or not (PFS difference 2.8 months, OS difference 0.8 months). Addition of this agent to standard chemotherapy does result in higher rates of certain adverse effects including hypertension, hemorrhage, proteinuria, and thromboembolic events, which are common adverse effects of VEGF inhibition. It has not been compared to bevacizumab in a trial. Regorafenib is another new targeted therapy approved for mCRC. This is an oral multikinase inhibitor that targets multiple areas of tumor growth including VEGF (Exhibit 1).7-9 Regorafenib has been studied in combination with best supportive care in patients with mCRC who have progressed after standard therapy.10 The target population for this study were those with disease progression during or within three months after last administration of or intolerance to approved standard therapies, which had to include fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, and cetuximab or
panitumumab. This was a very treatment-resistant study group. Addition of regorafenib improved OS by median 1.4 months and PFS by 0.2 months. The most common adverse effects of this agent are hand-foot skin reaction, rash, fatigue, hypertension, diarrhea, and voice change. Voice changes occur in about 30 percent of patients treated with VEGF inhibiting agents. Certain genetic mutations have been identified in colorectal cancer. One of these is in the KRAS (VKi-ras2 Kirsten rat sarcoma viral oncogene homolog) gene. The protein product of the normal KRAS gene performs an essential function in normal tissue signaling, and the mutation of a KRAS gene is an essential step in the development of many cancers. Since KRAS can be used to predict outcomes of therapy, patients should be tested for KRAS mutations before treatment. The story with KRAS mutation and response to therapy is different for the VEGF and EGFR inhibitors. KRAS mutation status does not have an impact on VEGF inhibitor efficacy but does for the EGFR inhibitors. Cetuximab and panitumumab block the EGFR receptor. Around 40 percent of patients with colorectal cancer have KRAS mutations that bypass the EGFR receptor. In patients with these mutations, there is no benefit of adding an EGFR inhibi-
8 Journal of Managed Care Medicine | Vol. 17, No. 2 | www.namcp.org
Exhibit 2: KRAS as Biomarker for Panitumumab Response in mCRC15 PFS in Patients with Mutant KRAS
1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0
Median PFS BSC + Pan BSC Alone
12.3 weeks 7.3 weeks
HR = 0.45; P < 0.0001
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52
Proportion with PFS
Proportion with PFS
PFS in Patients with Wild-Type KRAS 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0
Median PFS BSC + Pan BSC Alone
7.4 weeks 7.3 weeks
HR = 0.99
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52
Exhibit 3: How Best to Use the Targeted Agents KRAS Wild-Type Disease • First Line – Oxaliplatin-based regimen: Bevacizumab plus XELOX or FOLFOX – Irinotecan-based regimen: Bevacizumab plus FOLFIRI or EFGR I plus FOLFIRI • Second Line and Beyond – FOLFIRI/ EGFRI in first line • FOLFOX/Bevacizumab • Third line: Regorafenib – FOLFIRI/Bev in first line • Second/Third line - FOLFOX/Bev - Irinotecan/EGFR 1 • Fourth line: Regorafenib – FOLFOX/ Bev in first line • Second line - FOLFIRI/Bev - FOLFIRI/Aflibercept • Third line: Irinotecan/EGFRI • Fourth line: Regorafenib KRAS Mutated Disease • First Line – FOLFIRI/Bev – FOLFOX/Bev • Second Line – FOLFOX/Bev in first line • FOLFIRI/Bev • FOLFIRI/Aflibercept – FOLFIRI/Bev in first line • FOLFOX/Bev • Third Line – Regorafenib Bev = bevacizumab; XELOX = capecitabine/oxaliplatin; EGFRi = endothelial growth factor inhibitor; FOLFIRI = 5-FU/leucovorin/irinotecan; FOLFOX = 5-FU/leucovorin/oxaliplatin
tor in those with KRAS mutation.11-15 As shown in Exhibit 2, EGFR inhibitors provide significant benefit in those with wild-type KRAS and no benefit in those with mutant KRAS.15 There are many different options for managing
mCRC with combinations of chemotherapy and targeted agents and, in some cases, monotherapy with targeted agents. Exhibit 3 shows the treatment options for first-line and subsequent lines of therapy dependent on KRAS status.
www.namcp.org | Vol. 17, No. 2 | Journal of Managed Care Medicine 9
Targeted therapy combined with chemotherapy has become the standard of care in mCRC. There are now several antiangiogenic therapies that target VEGF, but it is not known which is best because they have not been compared head-to-head. There are data to support continuing them beyond progression. EGFR inhibitors provide benefit for patients who do not have KRAS mutations. Importantly, KRAS mutation status does not impact antiangiogenic therapy outcome. There is a need for better biomarkers to decide on how best to select the targeted agents.
6. Van Cutsem E, Tabernero J, et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol. 2012;30(28):3499-506. 7. Wilhelm SM, Dumas J, Adnane L, et al. Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int J Cancer. 2011;129(1):245-55. 8. Mross K, Frost A, Steinbild S, et al. A phase I dose-escalation study of regorafenib (BAY 73-4506), an inhibitor of oncogenic, angiogenic, and stromal kinases, in patients with advanced solid tumors. Clin Cancer Res. 2012;18(9):2658-67. 9. Strumberg D, Schultheis B. Regorafenib for cancer. Expert Opin Investig Drugs. 2012;21(6):879-89.
Bassel F. El-Rayes, MD is an Associate Professor of Hematology and
10. Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for
Oncology at Winship Cancer Institute at Emory University in Atlanta,
previously treated metastatic colorectal cancer (CORRECT): an international,
2013;381(9863):303-12. 11. LiĂ¨vre A, Bachet JB, Boige V, et al. KRAS mutations as an independent
1. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan,
prognostic factor in patients with advanced colorectal cancer treated with ce-
fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med.
tuximab. J Clin Oncol. 2008;26(3):374-9.
12. De Roock W, Piessevaux H, De Schutter J, et al. KRAS wild-type state
2. Bennouna J, Sastre J, Arnold D, et al. Continuation of bevacizumab after first
predicts survival and is associated to early radiological response in metastatic
progression in metastatic colorectal cancer (ML18147): a randomised phase 3
colorectal cancer treated with cetuximab. Ann Oncol. 2008;19(3):508-15.
trial. Lancet Oncol. 2014;14(1):29-37.
13. Di Fiore F, Blanchard F, Charbonnier F, et al. Clinical relevance of KRAS
3. Kubicka S, Greil R, AndrĂŠ T, et al. Bevacizumab plus chemotherapy contin-
mutation detection in metastatic colorectal cancer treated by cetuximab plus
ued beyond first progression in patients with metastatic colorectal cancer previ-
chemotherapy. Br J Cancer. 2007;96(8):1166-9.
ously treated with bevacizumab plus chemotherapy: ML18147 study KRAS
14. Khambata-Ford S, Garrett CR, Meropol NJ, et al. Expression of epiregulin
subgroup findings. Ann Oncol. 2013;24(9):2342-9.
and amphiregulin and K-ras mutation status predict disease control in meta-
4. Holash J, Davis S, Papadopoulos N, et al. VEGF-Trap: a VEGF blocker with
static colorectal cancer patients treated with cetuximab. J Clin Oncol.
potent antitumor effects. Proc Natl Acad Sci U S A. 2002;99(17):11393-8.
5. Tew WP, Gordon M, Murren J, et al. Phase 1 study of aflibercept adminis-
15. Amado RG, Wolf M, Peeters M, et al. Wild-type KRAS is required for
tered subcutaneously to patients with advanced solid tumors. Clin Cancer Res.
panitumumab efficacy in patients with metastatic colorectal cancer. J Clin On-
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Current and Emerging Treatment Options in the Management of Relapsed/Refractory Myeloma Melissa Alsina, MD
Summary Multiple myeloma (MM) is an incurable plasma cell malignancy, which causes significant morbidity due to organ damage and bone tissue destruction. Many effective treatments are available that prolong survival and improve the quality of life of patients with this disease. Despite the availability of novel therapeutics, MM still evolves into a refractory phase and most patients die of progressive disease. Key Points • Multiple myeloma is incurable. • Relapsed/refractory MM can be treated with multiple lines of treatment, but the response declines with each subsequent treatment. • Two new agents were recently FDA approved for relapsed/refractory MM. • Additional agents are on the horizon.
Multiple myeloma (MM) is a cancer of the plasma cell characterized by excessive numbers of abnormal plasma cells in the bone marrow. There is overproduction of intact monoclonal immunoglobulins (IgG, IgA, IgD, or IgE) or BenceJones protein (free antibody light chains). There is usually overproduction of one immunoglobulin or light chains. After lymphoma, MM is the second most common hematologic cancer. Approximately 20,000 new cases and 10,650 deaths from MM occurred in the United States in 2010.1 It is slightly more common in men than in women and occurs with a higher incidence in African Americans versus Caucasians (2:1). The median age at diagnosis is 69 years for men and 71 for women.2 Seventy-five percent of men are older than 70 years of age at diagnosis and 79 percent of women are older than 70. In 80 percent of patients, the initial symptom of MM is bone pain. Many patients will be seen by health care providers for back pain or other type of pain and be treated for arthritis. Other clinical fea-
tures of MM include constitutional symptoms such as weakness, fatigue, and weight loss; anemia; renal disease, and frequent infections.3 These patients can have neutropenia, hypercalcemia, and hyperviscosity. Myeloma cells secrete osteoclast-activating factors which lead to unopposed bone resorption and hypercalcemia. Neurologic dysfunction can occur with spinal cord or nerve root compression. There are three major categories of plasma cell dyscrasias - monoclonal gammopathy of undetermined significance (MGUS), smoldering myeloma, and multiple myeloma. Exhibit 1 shows the diagnostic criteria for these categories.4-6 Patients with MGUS have abnormal production of plasma cells but have no symptoms or end-organ damage. MGUS is very common, being seen in more than 10 percent of patients over 70 years of age. Patients with MGUS are followed once a year because 25 percent of them will develop myeloma at some point. Patients with smoldering myeloma are not currently treated but are followed with labs every three months. Studies of smoldering myelo-
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Exhibit 1: Diagnostic Criteria for Myeloma 4-6
< 3 g/dL spike
> 3 g/dL spike and/or
In serum and/or urine
Monoclonal plasma cells in bone marrow, %
> 1 CRAB* feature
*C: Calcium elevation (> 11.5 mg/L or ULN) R: Renal dysfunction (serum creatinine > 2 mg/dL) A: Anemia (Hb < 10 g/dL or 2 g < normal) B: Bone disease (lytic lesions or osteoporosis)
Exhibit 2: Risk Categories7-10 Risk Factors
Standard Risk (Expected OS: 6-7 years)
High Risk (Expected OS: 2-3 years)
t (11; 14) t(6; 14)
del(17p) t(4; 14)* t(14; 16)
Low (, 3.5 mg/L)
High (> 5.5 mg/L)
High (> 3%)
Isotype Gene expression profile
*Patients with t(4;14), β2-M < 4 mg/L, and Hb ≥ 10 g/dL may have intermediate-risk disease. FISH = Fluorescence in situ hybridization: Hb = hemoglobin: OS = overall survival: PCLI = plasma cell labeling index: del = deletion
ma treatment are ongoing; therefore, this standard of care may change. Patients with high numbers of plasma cells in the bone marrow, myeloma protein (M) spike, or end-organ involvement (CRAB, see Exhibit 1) are considered to have multiple myeloma and are treated. Various factors can predict prognosis and impact of therapy with MM. The most important are the cytogenetic abnormalities of the plasma cells in the bone marrow. Myeloma can also be categorized as standard or high risk based on these predictive factors (Exhibit 2).7-10 Those with high-risk disease have a significantly shorter expected overall survival (2 to 3 years versus 6 to 7 years). Even with newer
therapies, the survival of patients with high-risk disease has not been significantly impacted. The treatment of MM has evolved significantly over the last 50 years. In the 1960s, MM was treated with oral melphalan and prednisone. Bone marrow transplants were used beginning in the 1980s. The 1990s brought high-dose chemotherapy and autologous stem cell transplants, which was the first regimen to show a difference in progression-free survival. Novel agents that included proteasome inhibitors (bortezomib) and immunomodulatory agents (thalidomide, lenalidomide) came into use in the early 2000s. Increased survival in MM patients during the years 1965 to 2004 was due to the evolution of
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Exhibit 3: Natural History of MM
M Protein (g/L)
50 MGUS or smoldering myeloma
therapeutic options. However, MM is not curable. Relapses are inevitable, with patients going through several lines of therapy before reaching the relapsed/refractory stage. The natural history of treated MM is shown in Exhibit 3. The first therapy used is going to have the most impact on prognosis; once the patient relapses from the first therapy, the response is less profound and shorter. Effectiveness continues to decline with each relapse. The management of relapsed/refractory disease has changed dramatically over the last 10 years with many new agents being introduced. There are several considerations in selecting therapy for relapsed/refractory disease. Types of previous therapy, response to previous therapy, patient characteristics and other prognostic factors all must be considered. Patient characteristics that can affect therapy selection include age, current albumin and platelet levels, and kidney function. Up to 50 percent of patients with MM have renal dysfunction. Between 20 and 30 percent of patients have concomitant renal failure. Extensive bone disease will also impact chosen therapy. Differences between biochemical relapse and symptomatic relapse need to be considered. Patients with asymptomatic rise in M protein (biochemical relapse) can be observed to determine the rate of rise and nature of the relapse. Because treatment options are limited and response declines with each treatment, therapy should be reserved for those with symptomatic disease, with some exceptions. Patients with known aggressive or high-risk disease should be considered for salvage, even in the setting of bio-
chemical relapse. Presence of CRAB criteria (see Exhibit 1) are an indication to treat in the relapse setting. Lenalidomide in combination with dexamethasone, bortezomib, and bortezomib in combination with pegylated liposomal doxorubicin have been studied in relapsed/refractory MM. All improve progression-free survival (PFS) and overall survival (OS) compared with dexamethasone alone, but the response typically lasts less than a year.11-15. Any of these regimens can be used for treating relapsed/refractory disease. Two new therapies have recently been approved for relapsed/ refractory MM. Carfilzomib (Kyprolis速) is a proteasome inhibitor like bortezomib. Proteasome is an enzyme complex that plays a critical role in the degradation of many proteins involved in cell cycle regulation, apoptosis and angiogenesis. Since these pathways are fundamental for cell survival and proliferation, particularly in cancer cells, the inhibition of proteasome leads to cell death. Carfilzomib is approved for patients who progress within 60 days of last therapy and have received more than two therapies including bortezomib and an immunomodulatory agent. About 20 percent of exposed patients will respond to this agent, and the response lasts four to eight months. Median overall survival in a heavily pretreated population was 15.6 months.16 Even in patients with unfavorable cytogenetics/FISH markers, there is a similar response to this agent compared with patients without those markers. Higher response rates (78%) can be seen when carfilzomib is combined with lenalidomide
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Exhibit 4: Proposed Guidelines for Management of Peripheral Neuropathy18 Severity of PN Signs/Symptoms
Modification of Dose and Regimen
Grade 1 (paresthesia, weakness, and/or loss of reflexes without pain or loss of function)
Reduce current bortezomib dose by 1 level (1.3 - 1.0 - 0.7 mg/m2). For patients receiving a twice-weekly schedule, change to a once-per-wk schedule using the same dose. For patients with prior PN, consider starting with 1.3 mg/m2 once per wk
Grade 1 with pain or grade 2 (no pain but interfering with basic activities of daily living)
For patients receiving twice-weekly bortezomib, reduce current dose by 1 level or change to a once-per-wk schedule using the same dose For patients receiving bortezomib on a once-per-wk schedule, reduce current dose by 1 level, OR consider temporary discontinuation; upon resolution (grade â‰¤ 1), restart once-per-wk dosing at lower dose level in cases of favorable benefitto-risk ratio
Grade 2 with pain, grade 3 (limiting self-care and activities of daily living), or grade 4
â€˘ Subcutaneous bortezomib causes less peripheral neuropathy
and dexamethasone. Additionally, this agent is being evaluated as first-line therapy. Even though carfilzomib is in the same class as bortezomib, it does not cause neuropathy to the same extent. Peripheral neuropathy occurred in 14 percent of patients enrolled in clinical trials with carfilzomib compared with 46 percent with bortezomib. In the trials with carfilzomib, there were several patient deaths related to cardiovascular disease. Underlying cardiovascular disease should be assessed before patients are given this agent. Pomalidomide (Pomalyst ÂŽ) is the other agent recently approved for relapsed/refractory MM. It is an oral immunomodulatory agent related to lenalidomide and thalidomide. These three immunomodulatory agents exert their anticancer effects in several ways, including angiogenesis inhibition, immunomodulation, impeding cytokine production, and interaction with the bone marrow and tumor microenvironment. When pamalidomide is given in heavily pretreated patients in combination with dexamethasone, about 34 percent will respond with a median PFS of 4.7 months.17 Adverse effects are primarily hematologic. There are ongoing studies using it in combination and in earlier settings. When treating a patient with MM initially, the goal is complete response. The goal in treating a relapsed patient is quality of life. Thus, there are several adverse effects of the agents used in MM that will need to be managed in order to allow patients
to continue therapy and maintain quality of life. As previously mentioned, bortezomib frequently causes neuropathy. Exhibit 4 provides some guidelines for adjusting the dose to minimize the impact of the neuropathy.18 Thromboembolic events are a well-known complication of immunomodulatory therapy, occurring in approximately 2 to 4 percent of patients with these agents alone and in up to 12 to 26 percent in patients treated with one in combination with dexamethasone. Patients receiving these agents need to be evaluated for risk factors and should receive prophylaxis (Exhibit 5).19 Cytopenias (neutropenia, anemia, thrombocytopenia) are also common with these agents. Dose reductions, use of erythropoiesisstimulating agents or granulocyte colony-stimulating factors, and even stopping therapy may be necessary to manage. Humoral-mediated as well as cell-mediated immunity is compromised in myeloma patients receiving treatment. Immunocompromised patients are at risk of developing herpes zoster (VZV) infection. Bortezomib and carfilzonib therapy are associated with a significant risk of herpes zoster infection.20 Acyclovir and other antiviral prophylaxis are effective at preventing VZV infection in patients treated with proteasome inhibitors for MM (with or without corticosteroids).21 Thus, prophylaxis should be given to all patients receiving these agents. Novel therapies and combinations are under study
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Exhibit 5: Risk Assessment for VTEs in Patients with MM Receiving Immunomodulatory Agents19 • VTE prophylaxis for individual risk factors or myeloma-related risk factors (eg, hyperviscosity) - If ≤ 1 risk factor present, aspirin 81-325 mg/day - If ≥ 2 risk factors present, LMWH (equivalent to enoxaparin 40 mg/day) or full-dose warfarin (target INR: 2-3) • VTE prophylaxis for myeloma therapy–related risk factors (eg, high-dose dexamethasone, doxorubicin, multiagent chemotherapy) - LMWH (equivalent to enoxaparin 40 mg/day) or full-dose warfarin (target INR: 2-3) INR = international normalized ratio: LMWH = low–molecular-weight heparin: MM = multiple myeloma: VTE = venous thromboembolism.
to find additional alternatives for relapsed/refractory MM.22 Ixazomib is another oral proteasome inhibitor in investigational trials. Preliminary data show decent response rates in the relapsed/refractory population and as first- line therapy. Another investigational agent is oprozomib, a structural analog of carfilzomib. A 22 percent overall response rate was seen in an early trial of this agent. Histone deacetylase inhibitors (vorinostat, romidepsin, panobinostat) and numerous monoclonal antibodies are also under study for treating MM.
the International Myeloma Working Group. Br J Haematol. 2003;121(5):749-57. 5. Kyle RA, Therneau TM, Rajkumar SV, et al. A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med. 2002;346(8):564-9. 6. Durie BG, Kyle RA, Belch A, et al. Myeloma management guidelines: a consensus report from the Scientific Advisors of the International Myeloma Foundation. Hematol J. 2003;4(6):379-98. 7. Dispenzieri A, Rajkumar SV, Gertz MA, et al. Treatment of newly diagnosed multiple myeloma based on Mayo Stratification of Myeloma and Risk-adapted Therapy (mSMART): consensus statement. Mayo Clin Proc. 2007;82(3):323-41. 8. Fonseca R, Bergsagel PL, Drach J, et al. International Myeloma Working Group molecular classification of multiple myeloma: spotlight review. Leuke-
A new treatment paradigm utilizing novel therapy combinations targeting both the tumor cell and its microenvironment has already markedly improved overall response, complete response, progressionfree survival, and overall survival in multiple myeloma. Unfortunately, the disease is still incurable. The future is to determine the markers that will determine which patients will respond best to which therapy and what are the best therapies in the relapsed/refractory setting. Future molecularly-based, rationally designed combination therapies will hopefully achieve durable complete responses in the majority of patients.
9. Kyle RA, Rajkumar SV. Treatment of multiple myeloma: a comprehensive review. Clin Lymphoma Myeloma. 2009;9(4):278-88. 10. Munshi NC, Anderson KC, Bergsagel PL, et al. Consensus recommendations for risk stratification in multiple myeloma: report of the International Myeloma Workshop Consensus Panel 2. Blood. 2011;117(18):4696-700. 11. Weber DM, Chen C, Niesvizky R, et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med. 2007;357(21):2133-42. 12. Dimopoulos M, Spencer A, Attal M, et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med. 2007;357(21):2123-32. 13. Richardson PG, Sonneveld P, Schuster M, et al. Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial. Blood. 2007;110(10):3557-60. 14. Orlowski RZ, Nagler A, Sonneveld P, et al. Randomized phase III study of
Melissa Alsina, MD is Head of the Myeloma Clinical Program at the H.
pegylated liposomal doxorubicin plus bortezomib compared with bortezomib
Lee Moffitt Cancer Center in Tampa, FL.
alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J Clin Oncol. 2007;25(25):3892-901.
15. Taverna C, Voegeli J, Trojan A, et al. Effective response with bortezomib
1. Cancer facts and figures 2010. American Cancer Society; 2010.
retreatment in relapsed multiple myeloma—a multicentre retrospective survey
2. Altekruse SF, Kosary CL, Krapcho M, et al (eds). SEER Cancer Statistics
in Switzerland. Swiss Med Wkly 2012;142:w13562.
Review, 1975-2007, National Cancer Institute. Bethesda, MD.
16. Siegel DS, Martin T, Wang M, et al. A phase 2 study of single-agent carfil-
3. Smith A, Wisloff F, Samson D, et al. Guidelines on the diagnosis and manage-
zomib (PX-171-003-A1) in patients with relapsed and refractory multiple my-
ment of multiple myeloma 2005. Br J Haematol. 2006;132(4):410-51.
eloma. Blood. 2012;120(14):2817-25.
4. International Myeloma Working Group. Criteria for the classification of
17. Richardson PG, Siegel D, Baz R, et al. Phase 1 study of pomalidomide
monoclonal gammopathies, multiple myeloma and related disorders: a report of
MTD, safety, and efficacy in patients with refractory multiple myeloma who
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have received lenalidomide and bortezomib. Blood. 2013;121(11):1961-7.
events among bortezomib-treated patients in the phase III APEX study. J Clin
18. Richardson PG, Delforge M, Beksac M, et al. Management of treatment-
21. Vickrey E, Allen S, Mehta J, Singhal S. Acyclovir to prevent reactivation of
varicella zoster virus (herpes zoster) in multiple myeloma patients receiving
19. Palumbo A, Rajkumar SV, Dimopoulos MA, et al. Prevention of thalidomide-
bortezomib therapy. Cancer. 2009;115(1):229-32.
and lenalidomide-associated thrombosis in myeloma. Leukemia. 2008;22(2):414-23.
22. McBride A, Ryan PY. Proteasome inhibitors in the treatment of multiple
20. Chanan-Khan A, Sonneveld P, Schuster MW, et al. Analysis of herpes zoster
myeloma. Expert Rev Anticancer Ther. 2013;13(3):339-58.
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Current Immunization Updates for the Management and Prevention of Influenza Kevin Sherin MD, MBA, MPH, FACPM For a CME/CEU version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.
Summary Influenza vaccination is recommended for everyone, but current vaccination rates are significantly below target goals of 80 to 90 percent of the population. Because influenza represents a major public health concern, strategies for targeting underimmunized groups and settings are needed. Additionally, more effective vaccines are needed to further reduce the health impact of this disease. Key Points • Although universally recommended, overall influenza vaccination rates remain around 40 percent. • Patients are much more likely to get vaccinated when health care providers recommend and offer the vaccination. • Two groups to focus on for increasing coverage are pregnant women and health care providers. • Recommending and offering flu vaccinations at routine visits for pregnancy should be standard. • Programs to increase vaccination rates among health care providers need to tar get areas of underutilization – long-term care facilities, assistants/aides, and administrative/non-clinical support staff. • Improved influenza vaccines with proven efficacy in high-risk groups are needed.
In the 1800s, Hermann Pidoux, a physician during the early tuberculosis days in France, said, “Epidemics are the lives of diseases.” Is there any disease other than influenza for which this is more truthful? It has been with us for hundreds and hundreds of years, arriving each year, sometimes predictably, and changing too frequently. For all of its many characteristics, the virus has not only “lived” for hundreds of years; it has flourished and has always provided public health a formidable challenge, and will likely continue to do so. Today, more than 500 infectious diseases are known to occur in humans; yet, in the United States, public health officials recommend routine childhood or adult vaccinations for only 17 of these diseases. For only one of these diseases is there a recommendation for universal annual vaccination - influenza. The current vaccination recommendations
for all diseases can be found at the Advisory Committee on Immunization Practices (ACIP) website (www.cdc.gov/vaccines/acip/index.html). Several different influenza (flu) vaccines are available and are reformulated each year for those strains expected to be prevalent in the U.S. during the flu season (November to April). There are now four different intramuscular versions and one intranasal (live, attenuated quadrivalent [FluMist ®]). The four intramuscular injectable types are inactivated trivalent standard and high-dose, inactivated quadrivalent [Fluarix ®], cell culture-based inactivated trivalent [Flucelvax ®], and recombinant hemagglutinin trivalent [FluBlok®]. The ACIP guidelines are updated yearly with the dosing, mercury content, and indications for each available vaccine. Although universally recommended, flu vaccination coverage is lacking. Exhibit 1 provides early
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Exhibit 1: Flu Vaccination Coverage by Age Group - Early 2012-2013 Season (National Immunization Survey and National Internet Flu Survey)1
November 2011 %* + 95% Cl†
November 2011 %* + 95% Cl
Overall (> 6 months)
36.3 + 1.3
36.5 + 1.0
Children ( 6 months to 17 years)
36.7 + 3.3
39.9 + 3.0
Adults (> 18 years)
36.2 + 1.3
35.2 + 2.4
Exhibit 2: Place of Vaccination for Children and Adults - Early 2012-2013 Flu Season (National Immunization Survey and National Internet Flu Survey)1
Other medically-Related Place‡ Pharmacy or Store
Other Non-Medical Place§
season vaccination coverage estimates for 2012-2013 and 2011-2012. In the 2012-2013 season, fewer than 40 percent of children and adults were vaccinated by early to mid November.1 Vaccination rates vary among different age and ethnic groups. From 2011-2012 to 2012-2013, there was a decrease in coverage in both the 50 to 64 age group and the 18 to 64-year-old age group. There were only two early season differences between the race/ethnicity groups: Non-Hispanic white adults (37.4%) had higher coverage than Hispanic adults (29.5%). Non-Hispanic other or multiple race adults (37.2%) had higher coverage than Hispanic
adults (29.5%).1 As shown in Exhibit 2, the most common place where people get vaccinated against flu is the doctor’s office.1 Alternate sites, such as pharmacies and the workplace, are common for adults but not children. The Healthy People 2020 goals for flu vaccinations are very ambitious – 80 to 90 percent; therefore, the health system has a long way to go to achieve these goals.2 Racial and ethnic disparities remain among adults when compared with non-Hispanic whites. Continued efforts to increase vaccination coverage among adults in other racial and ethnic groups are necessary to decrease these disparities. Immuniza-
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tion programs should work with leaders in African American, Hispanic, and American Indian and Alaska Native communities to ensure all members have access to and receive flu vaccinations. Patients are much more likely to get vaccinated when health care providers strongly recommend their patients get vaccinated. Standing orders, client reminder and recall systems, and provider reminders are also important strategies proven to increase vaccinations. Two groups to focus on for increasing coverage are pregnant women and health care providers. Coverage of pregnant women has varied over the recent past seasons. Before the 2009 season, flu vaccination levels among pregnant women were below 30 percent. In the 2009 to 2010 flu season, seasonal vaccinations increased to 47 percent; this increase was likely the result of publicity about a flu epidemic. More recent rates have ranged from 44 to 47 percent early in the flu season.3 This is significantly below the Healthy People 2020 flu vaccination target of 80 percent for pregnant women. Younger pregnant women (18 to 24 years) were less likely to be vaccinated (41.1%) than pregnant women 25 to 49 years (50.2%). In the 2012 season, coverage was 57.4 percent among Hispanic women, higher than the coverage for non-Hispanic other women (46.0%), non-Hispanic white women (44.6%), and non-Hispanic black women (41.2%). Vaccination coverage among pregnant women with less than a college degree (42.5%) was lowest, followed by pregnant women with a college degree (49.9%), and women with more than a college degree (61.5%). Women with an additional high-risk condition besides pregnancy that increases the risk of severe influenza had higher vaccination coverage (53.8%) than women with no other high-risk conditions (40.7%). Targeting younger, less educated women specifically might be beneficial in increasing vaccination rates during pregnancy. As with other groups, vaccination coverage was highest (73.5%) when the women received both a recommendation and an offer for vaccination from their doctor or other medical professional. During the 2012 to 2013 season, most women (97.7%) reported visiting a doctor or other medical professional at least once since July 1, 2012; among these women, 46.1 percent reported receiving an offer for influenza vaccination from the provider, 18.6 percent received only a recommendation, and 35.2 percent received neither an offer nor a recommendation for flu vaccination. The most common place reported for receiving their flu vaccination was in the offices of an obstetrician/gynecologist or midwife during pregnancy (49.9%). Thus, recommending and offering flu vaccinations at routine visits for
pregnancy should be standard. There are many reasons why women do not get vaccinated. The most common reason reported for not receiving a flu shot, and definitely not intending to receive a flu shot, was safety concerns by 43.4 percent of unvaccinated pregnant women. The safety concerns included safety for the unborn child, safety risk to self, concern about side effects, lack of trust in the vaccine, and concern that the vaccine would result in the flu. The second most common reason was concern about the efficacy of the flu vaccine/severity of the flu (31.0%). Health reasons, psychosocial reasons, and other reasons were less frequently reported (15.5%, 3.8%, and 5.5%, respectively). Only 0.7 percent of women reported tangible barriers such as the lack of medical insurance or cost, lack of time, unavailability of the vaccine, and lack of knowledge of where to get the vaccine or who to contact as a main reason for not receiving a flu shot. Surveys have shown that the recommendation of a doctor or other medical professional is a strong predictor of vaccination during pregnancy. If more pregnant women receive both a recommendation and offer of a flu vaccination from their doctor or other medical professional, vaccination coverage should increase. Health care providers should continue to offer flu vaccine to pregnant women throughout the flu season. Health care providers and immunization programs should provide pregnant women with accurate information on the risk of the flu to pregnant women and their baby and the benefits and safety of influenza vaccination for the mother and the baby. Unless contraindicated, all health care professionals (HCPs) should be vaccinated annually against influenza. In a vaccine coverage survey of HCPs in 2012, early season coverage was 62.9 percent, which was similar to previous seasons.4 Flu vaccination coverage was higher among pharmacists (88.7%), physicians (83.8%), nurses (81.5%), nurse practitioners and physician assistants (73.3%), and other clinical professionals (76.9%) compared to assistants or aides (43.4%) and administrative/nonclinical support staff (54.5%). Flu vaccination coverage increased from midseason 2010-2011 to midseason 2012-2013; the coverage increased among physicians from 75.5 to 83.8 percent and among nurses from 61.5 to 81.5 percent. Coverage varied by work setting and was higher among HCPs working in hospitals (83.4%) compared to other work settings and lowest among HCPs working in long-term care facilities (48.7%). Coverage among HCPs working in hospitals was higher than HCPs working in other work settings in the November
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Exhibit 3: Online Resources • The Community Guide.org • Vaccinefinder.gov • The Program Manager’s Page -http://www.cdc.gov/vaccines/program-mgrs.htm • The Immunization Action Coalition -http://www.immunize.org/ • The Association of Immunization Managers -http://www.immunizationmanagers.org/ • CDC’s Partners and Related Websites -http://www.cdc.gov/vaccines/partners.htm
Exhibit 4: The Compelling Need for Game-Changing Influenza Vaccines Recommendations5 • Game-changing flu vaccines are urgently needed. • Scientifically sound estimates of influenza vaccines’ efficacy must be the cornerstone of policy recommendations • Any pandemic influenza vaccine should demonstrate high efficacy and effectiveness for different pandemic epidemiologic patterns. • A newly designed model adapted specifically to the development and licensure of novel-antigen influenza vaccines must be implemented • The US government should assume a primary leadership role in moving the global influenza vaccine enterprise forward • An internationally accepted standard for evaluating influenza vaccine efficacy and effectiveness should be used for calculating cost effectiveness of influenza vaccines.
2011 and November 2010 surveys. Protecting themselves from flu was the most common reason reported by vaccinated HCPs for receiving the influenza vaccination (47.2%). Employer requirement for flu vaccination and protecting friends, family, and patients from flu were each the reported reason in 15.5 and 11.4 percent, respectively. Among unvaccinated HCPs who reported that they did not intend to get a flu vaccination this year, the most commonly reported reason was that they do not want a vaccination. Other reasons included not thinking that influenza vaccinations work, being allergic to the vaccine, fear of getting sick or side effects from the vaccination, and not thinking that an influenza vaccination was needed. While overall flu vaccination coverage estimates among HCPs working in hospital settings, and among pharmacists, physicians, nurse practitioners, physician assistants, and nurses across all work set-
tings are nearing the Healthy People 2020 target goal of 90 percent, flu vaccination coverage levels among other categories of HCPs and among HCPs working in long-term care facilities and other work settings remain substantially lower. Clinical care groups should be commended for high vaccination levels. Additional efforts need to be focused on improving vaccination coverage among assistants or aides and administrative/non-clinical support staff and in long-term care facilities and work settings other than hospitals and physician offices/ambulatory care settings. Continued efforts are needed to ensure all HCPs are vaccinated as soon as possible during each flu season. There are many different resources available to help increase vaccination coverage. Exhibit 3 lists several online resources that provide valuable information. The Community Guide provides information regarding programs to promote coverage, including
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supporting materials and reviews of programs used to increase coverage in a variety of settings. Vaccinefinder.gov contains “Health Map” locater for finding providers of adult flu shots. Various community groups or health care organizations can become a flu prevention partner with the CDC. Organizations can promote flu vaccination within their communities, coordinate or host flu vaccination clinics, and increase awareness about the importance and benefits of annual flu vaccination. Beyond increasing vaccination rates, there are several other issues with flu vaccination that need to be addressed by the health care community. In 2012, Dr. Michael T. Osterholm and colleagues from the Center for Infectious Disease and Research at University of Minnesota published an exhaustive review of virtually all aspects of influenza vaccine production, policy, and technology dating back to 1936.5 This review made several recommendations (Exhibit 4).5 Their primary points were that current influenza vaccines are not very effective and that new vaccines that have superior proven effectiveness compared with current vaccines are urgently needed. These new vaccines must demonstrate increased effectiveness for populations at increased risk for severe influenza morbidity and mortality, but with a similar or better safety profile to current influenza vaccines. The review points out many barriers to developing game- changing vaccines. Additionally, the review points out that pandemic influenza remains a clear and compelling
threat to our national security .Commensurate prioritization and an unprecedented, coordinated effort among government, academia, and the private sector will be required to mitigate this threat. Conclusion
Influenza epidemics and pandemics remain a major public health concern. Reaching the ambitious Healthy People 2020 goals of 80 to 90 percent vaccination rates for influenza will require targeting groups that currently have lower vaccination rates or where vaccination is most important. In addition to increasing vaccination rates, there is a need for new and improved vaccines and studies to prove the effectiveness of these vaccines. Kevin Sherin, MD, MBA, MPH, FACPM is Director of the Florida Department of Health in Orange County, FL.
References 1. CDC. Flu Vaccination Coverage, United States, 2012-13 Influenza Season. Available at http://www.cdc.gov/flu/fluvaxview/coverage-1213estimates.htm. 2. Helathy People 2020 Goals. Available at healthypeople.gov 3. Influenza Vaccination Coverage Among Pregnant Women — United States, 2012–13 Influenza Season. MMWR Morb Mortal Wkly Rep. 2013;62(38);787-792 4. Influenza Vaccination Coverage Among Health-Care Personnel — United States, 2012–13 Influenza Season. MMWR Morb Mortal Wkly Rep. 2013;62(38);781-6. 5. Osterholm MT, Kelley NS, Manske JM, et al. The Compelling Need for Game-Changing Influenza Vaccines. An Analysis of the Influenza Vaccine Enterprise and Recommendations for the Future. Available at: www.cidrap.umn.edu.
www.namcp.org | Vol. 17, No. 2 | Journal of Managed Care Medicine 21
Emerging Treatment Strategies for ACS Management: Improving Patient Outcomes Frederick Korley, MD For a CME/CEU version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.
Summary Targeting platelet activation and aggregation is an important component of acute coronary syndrome (ACS) management. Numerous new agents that target platelets have been approved, but the risks of bleeding with these agents must be balanced against their benefits. Practice guidelines provide evidence-based recommendations for managing antiplatelet therapy, both short term and long term. Key Points • Aspirin is the base of antiplatelet regimens and is continued indefinitely if tolerated. • Additional antiplatelet agents that target platelet activation and aggregation are available. • Dual antiplatelet therapy is indicated in most cases after an acute event or cardiovascular procedure for ACS. • Patients who have a history of stroke or transient ischemic attack (TIA), age greater than 75 years, or weight less than 60 kg are at higher risk for bleeding with the newer P2Y12 inhibitors and thus should receive clopidogrel.
Acute coronary syndrome (ACS) leads to more than a million hospitalizations annually.1 In 2010, there were 813,000 myocardial infarctions (MIs) and 322,000 cases of unstable angina. The distinguishing feature is that some heart muscle has died with a myocardial infarction (MI). In unstable angina, there is a blockage, but the heart still has blood flow. Of the MIs, 29 to 38 percent were ST segment elevation MIs (STEMI) and the remainder were non-ST segment elevation MIs (NSTEMI). Although there are a lot of ACS cases each year, much has improved. Fewer people are dying compared with the past. Additionally, there has been a significant decrease in the incidence of STEMI [48.5% (1999) to 24% (2008)]. These improvements have occurred because people are aware of the symptoms of a heart attack, and they go to the emergency room sooner. In addition, clinicians are doing a better job with prevention. Using evidence-based guidelines, STEMI, NSTEMI,
and unstable angina are all treated slightly differently. With STEMI, it is important to return blood flow to the heart as soon as possible; the goal is to get the patient to the cardiac catheterization lab within 90 minutes of diagnosis. With NSTEMI and unstable angina, treatment is not quite as urgent. Treatment may be surgical or medical. One important aspect of ACS management is antiplatelet therapy. Antiplatelet therapy prevents platelets from contributing to blood clot formation at the site of atherosclerotic plaque rupture, which is the initiating event leading to ACS. Plaque rupture caused by percutaneous coronary intervention (PCI) also triggers the platelet response. Both events initiate a platelet response that starts with the adhesion of platelets to the vessel wall, followed by the activation and then aggregation of platelets. Antiplatelet therapy either blocks activation or aggregation (Exhibit 1). Aspirin is the oldest antiplatelet agent, and it blocks
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Exhibit 1: Mechanisms of Action: Antiplatelet Agents
Thromboxane A 2 P2X1
Abciximab Eptifibatide Tirofiban
activation. It should be administered to patients with ACS as soon as possible after hospital presentation and continued indefinitely in patients who tolerate it. Mortality benefit in ACS is not dose-dependent but bleeding risk goes up with increasing dosage. Daily doses should be 325 mg or less. Because aspirin only blocks one area of platelet activation, other antiplatelet agents were developed. Ticlopidine (Ticlid®) was the first agent developed to target another site of activation – purinergic receptor 12 (P2Y12). The P2Y12 protein is found mainly, but not exclusively, on the surface of blood platelets, and is an important regulator in blood clotting. It is a chemoreceptor for adenosine diphosphate (ADP). Although effective, hematologic complications including neutropenia and thrombotic thrombocytopenic purpura have limited the use of ticlopidine. Clopidogrel (Plavix ®) is an irreversible inhibitor of ADP and P2Y12 binding. Many studies have shown that adding clopidogrel to aspirin reduces mortality and cardiovascular events in ACS populations. For example, in the CURE trial, clopidogrel in combination with aspirin was shown to have a benefit over aspirin alone in reducing death from cardiovascular causes, non-fatal MI, and stroke.2 Some patients treated with clopidogrel have resistance to therapy and have a higher rate of stent thrombosis or an MI. Clopidogrel has to be converted to an active metabolite to be effective. Clopidogrel nonresponders have lower concentrations of the active metabolite. Factors associated with clopidogrel resistance are obesity, advanced age, and polymorphism of cytochrome P-450 system. Clopido-
Ticlopidine Clopidogrel Prasugrel Ticagrelor
g g re
grel is converted by CYP2C19. Patients can be either poor, moderate, or normal metabolizers through the CYP2C19 enzyme systems. Polymorphisms in this enzyme occur in one-third of Caucasians and half of Asian Americans. Options for those who are resistant include double daily dose or switching to a different agent. The next iteration of antiplatelet therapy was prasugrel (Effient ®). This agent has the same mechanism of action as clopidogrel but does not require metabolism to be active. Thus, it is effective in patients with poor CYP2C19 metabolizer status. Prasugrel was compared with clopidogrel in a study which included patients with unstable angina/ NSTEMI scheduled for PCI.3 In this trial, there was a lower rate of the primary outcome with prasugrel, but the trial used a 300 mg clopidogrel loading dose, which is half of the currently recommended dose. The largest benefit with prasugrel was in nonfatal MI, urgent revascularization, and stent thrombosis, but there was a slightly higher rate of bleeding in the prasugrel group. There may have been more similar bleeding and efficacy rates with a higher loading dose of clopidogrel. The subgroup with a higher risk of bleeding from prasugrel included those with history of stroke or transient ischemic attack (TIA), age greater than 75 years, or weight less than 60 kg. Essentially, prasugrel is better for people going for PCI than clopidogrel if they do not have the three mentioned risk factors for bleeding. Ticagrelor (Brilinta®) is the latest addition to the P2Y12 inhibitors. It has been compared to clopidogrel.4 In terms of the primary outcome, ticagrelor
www.namcp.org | Vol. 17, No. 2 | Journal of Managed Care Medicine 23
Exhibit 2: Choice of P2Y12 Inhibitors 5
Antithrombolic trialists meta-analysis
CV Death, MI or Stroke CURE
12 Patients %
Clopidogrel + Aspirin Prasugrel + Aspirin
Risk reduction Residual risk
Placebo + Aspirin
N = 135,640
N = 12,562
N = 13,608
N = 18,624
Exhibit 3: ACCF/AHA 2012 NSTEMI/Unstable Angina Guidelines 6 2012 Focused Update Recommendations Class I Before PCI: • Clopidogrel (Level of Evidence: B); or • Ticagrelor† (Level of Evidence: B); or • An IV GP Iib/IIIa inhibitor (Level of Evidence: A)IV eptifibatide and tirofiban are preferred GP IIB/IIIa (Level of Evidence: B) At the time of PCI: • Clopidogrel if not started before PCI (Level of Evidence: A); or • Prasurgrel (level of Evidence B); or • Ticagrelor† (Level of Evidence: B); or • An IV GP IIb/IIIa inhibitor (Level of Evidence: A)
was better. There was less procedural bleeding with ticagrelor because P2Y12 inhibition is reversible with this agent but spontaneous bleeding is more common in ticagrelor. Benefits applied whether PCI was performed or not. This agent reversibly inhibits P2Y12. Reversibility is a disadvantage for noncompliant patients, as this agent has twice-daily dosing. Exhibit 2 shows a comparison of the oral P2Y12 inhibitors.5 The reductions in events are very similar. The one major difference is ticagrelor has been shown effective in people not having PCI. The 2012 American College of Cardiology Foundation/
American Heart Association update of the guidelines for unstable angina/NSTEMI recommend prasugrel only after PCI decision and ticagrelor can be used in all comers.6 These medications should be given two hours before the procedure. Caution must be used because of bleeding risk in certain subgroups – prior stroke/TIA, age greater than 75, or weight less than 60 kg. Clopidogrel may be a better choice in those with these risk factors. An intravenous antiplatelet agent with a very short half-life (3 to 5 minutes) that is under development is cangrelor. It is currently being evaluated for ap-
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proval by the FDA. The antiplatelet effect of this agent is immediate and platelet activity is restored within one hour after cessation of infusion. There have been three trials with this agent. The first two did not show a benefit over clopidogrel but the third did.7 The difference appears to be that this agent was decreasing instant thrombosis but patients were having periprocedural MIs. The difference may have been as a result of the changes in troponin related to the procedure and not a true MI. The third study used the newest definition of periprocedural MI, which accounts for spurious increases in troponin. The study enrolled both ACS and stable angina patients with scheduled stent or PCI. The IV agent was given before and during the procedure. Clopidogrel was given as a loading dose at the end of the procedure. Use of this reversible agent during procedures did reduce events, but there was a higher rate of bleeding in the cangrelor group. The bleeding rate was not statistically significantly different between the two treatment groups. The final part of the platelet pathway is aggregation. Abciximab (Reopro®), eptifibatide (Integrilin®), and tirofiban (Aggrastat®) are glycoprotein (GP) IIb/IIIa inhibitors which prevent aggregation. In a meta-analysis of the data on these agents, adding one of these to aspirin decreases events with a small increase in bleeding risk.7 No studies have compared them with P2Y12 inhibitors and none have looked at all three together. These are also intravenous agents whose effect is reversed when the infusion stops. As shown in Exhibit 3, these are alternatives to the PGY inhibitors.6 After an ACS event, patients will be continued on dual antiplatelet therapy for at least one month and likely out to one year. The choice will be guided by what therapy the patient received for ACS.
Dual antiplatelet therapy reduces ischemic events in patients with ACS. However, there is increased risk of bleeding with combination therapy. There is significant evidence for combining aspirin with one of any of the other available antiplatelet agents during acute event management and with the oral P2Y12 inhibitors for post event risk reduction. Therapy is guided by the patient’s risk profile and the practice guidelines. Frederick Korley, MD is an Assistant Professor of Emergency Medicine at Johns Hopkins Hospital in Baltimore, MD.
References 1. Go AS et al. Heart disease and stroke statistics--2013 update: a report from the American Heart Association. Circulation. 2013;127(1):e6-e245. 2. Yusuf S et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345:494-502. 3. Wiviott SD, Braunwald E, McCabe CH, et al; for the TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357:2001-15. 4. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045-57. 5. Fintel DJ. Oral antiplatelet therapy for atherothrombotic disease: overview of current and emerging treatment options. Vasc Health Risk Manag. 2012;8:77-89. 6. 2012 Writing Committee Members, Jneid H, Anderson JL, et al. 2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/Non-ST-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2012;126:875-910. 7. Bhatt DL, Stone GW, Mahaffey KW, et al. Effect of platelet inhibition with cangrelor during PCI on ischemic events. N Engl J Med. 2013;368(14):1303-13. 8. Boersma E, Harrington RA, Moliterno DJ, et al. Platelet glycoprotein IIb/ IIIa inhibitors in acute coronary syndromes: a meta-analysis of all major randomised clinical trials. Lancet. 2002;359:189-98.
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New Developments in the Treatment and Management of Multiple Sclerosis Myla D. Goldman, 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 Therapy for multiple sclerosis (MS) continues to evolve. Available disease-modifying therapies target the inflammatory process of this disease and are only effective for relapsing-remitting MS. Clinicians have a wide range of oral and injectable medications to select from, each of which has advantages and disadvantages. Key Points • There are effective medications to reduce relapses in relapsing-remitting MS. • These agents reduce the annualized relapse rate at least 30 percent. • Comparative effectiveness is difficult to determine because of lack of sufficient comparative trials among all the agents.
Multiple sclerosis (MS) is a chronic inflammatory condition of the central nervous system (CNS) induced by an environmental trigger in a genetically susceptible person with CNS lesions disseminated in time and space without an alternative explanation. It is the most common, nontraumatic cause of disability in young adults. There are an estimated 400,000 MS patients in the United States. It is more common in women at a two to one ratio. Onset is typically between ages 20 to 40. The etiology of MS is unknown but is thought to be a combination of an environmental trigger in a susceptible person. Genetics definitely plays a role; a much higher rate of MS is seen in identical twins compared to non-identical twins or siblings (20 to 30% vs 2 to 5%). Given that there is not a 100 percent rate in identical twins, genetics is not the only reason someone develops MS. Only 20 percent of people with MS have a family member with the disease, thus 80 percent of the cases are considered sporadic. Environmental exposures play a role. In-
fectious agent exposure, smoking, geographical distance from the equator, and sunlight exposure (vitamin D) have all been implicated in the development of this disease. MS has three components – inflammation, demyelination, and neuron loss. The diagnosis requires a multifocal CNS process (dissemination in space) and relapses or progression by history or new lesions on MRI (dissemination in time).1,2 There are people who have one episode of symptoms such as optic neuritis and never develop MS. Thus, patients have to have symptoms of multiple CNS lesions which recur or worsen over time. The disease can be classified into several categories: Radiologically Isolated Syndrome (RIS), Clinically Isolated Syndrome, Relapsing-Remitting MS, Secondary-Progressive MS, Primary-Progressive MS, and Primary-Progressive with Relapses. RIS is the newest identified type, with classic MS findings on an MRI without any CNS manifestations. Many people get MRI scans for some reason other than
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Exhibit 1: MS Disease Classification3
Time Secondary-Progressive (following relapsing remitting)
MS symptoms and findings classic for MS are identified. Someone with RIS is followed over time to see if they develop overt MS. CIS is an isolated symptomatic event without enhancing lesions on MRI and is also a precursor to overt MS. Once someone has lesions on MRI and symptoms, they are considered to have MS. Exhibit 1 illustrates the four presentations of MS.3 The disease is expressed clinically and subclinically. Clinically, people have symptomatic relapses, residual symptoms between relapse, and disability accrual. Subclinically, changes in the CNS can be seen on MRI. Acute damage in the brain from the disease appears as enhancing lesions. Chronically, several measures can be monitored to assess the long-term damage of MS, including T2 lesion burden, T1 “black holes”, and atrophy. Some people have a relapse and get 100 percent better and others don’t get all the way better. Even when the neurons get repaired, the repair does not appear to be optimal. Neurons can also die off over time, resulting in brain atrophy. As shown in Exhibit 2, early in the disease process there are a lot of relapses, even more events on MRI, and inflammation. It is thought that for every clinical relapse there are as many as 10 active CNS events that can be seen on MRI (subclinical disease). Over time, there can be fewer relapses and less inflammation but increasing CNS deterioration and accumulating disability. All of the current disease-modifying medications work during the inflammatory phase.
MS is a costly disease. The direct health care costs are estimated at $10 billion annually. This is an average of $47,000 per patient per year and $12,000 for a relapse event. The indirect health care costs are also significant. Total annual indirect costs are estimated at $5,769 versus $1,417 for people without MS. MS patients have a mean of almost 30 disability days annually. The annual disability cost for an employer with an employee with MS is $3,858 compared to $414 for those without MS.4 Disability from MS is significant and increases over time. After having the disease for five years, about 10 percent of patients will be wheelchair bound.5 At 25 years, over 50 percent will be. So for someone diagnosed at 20, they may be wheelchair bound at 45. As disability increases, there is a significant drop-off in employment. There are numerous ways to measure disability and track it over time. One way is to measure how fast someone can walk. Walking ability is directly related to the ability to conduct activities of daily living. In one study, the timed 25-foot walk (T25FW) of 6 to 7.99 seconds was associated with a change in occupation due to MS, occupational disability, walking with a cane, and with needing “some help” with instrumental activities of daily living; time greater than 8 seconds was associated with collecting Supplemental Security Income and government health care, walking with a walker, and with the inability to do instrumental activities of daily living.6 The goal of treatment in MS is to prevent re-
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Exhibit 2: Natural History of Relapsing MS Clinical and MRI Measures Brain Volume Relapses and Impairment
MRI T2 Burden of Disease (BOD) MRI Activity Preclinical
5 - 10
15 - 20+
Disease Duration (years)
Exhibit 3: Agents to Reduce Risk of Relapse in MS
Dimethyl Fumarate (Tecfidera)
120 Ă 240 mg PO twice daily
0.5mg PO daily
Glateramer Acetate (Copaxone)
20mg SQ daily
Interferon-beta 1a (Avonex)
30mcg IM weekly
Interferon-beta 1a (Rebif)
22 or 44mcg SQ three times weekly
Interferon-beta 1b (Betaseron, Extavia)
250mcg SQ every other day
12mg/m2IV q3M; Max dose140mg/m2
Worsening RRMS, SPMS, PRMS
300mg IV every 4 weks
7 or 14 mg PO daily
lapses, subclinical events, and progressive disability. Preventing relapses is done with one of the disease-modifying medications listed in Exhibit 3. All the agents but mitoxantrone are only approved for relapsing forms of MS. Mitoxantrone has fallen out of favor due to delayed blood dyscrasias and cardiac issues. Natalizumab (TysabriÂŽ) is an agent that has generated a great deal of press and was temporarily removed from the U.S. market, but is now avail-
able. It is a monoclonal antibody, which essentially works by preventing lymphocytes from crossing the blood-brain barrier. This agent is effective in reducing relapses and damage on MRI but can rarely cause a major adverse effect - progressive multifocal leukoencephalopathy (PML). As of April 2013, 347 total PML cases out of 112,181 patients treated with natalizumab worldwide have been reported.7 The mortality in those cases has been 23 percent. Natalizumab-associated
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PML has improved survival compared with PML in other populations. Residual disability from PML has been mild in 13 percent, moderate in 50 percent, and severe in 37 percent. PML is a reactivation of JC virus inducing a lytic infection of oligodendrocytes, resulting in demyelination. The factors leading to viral activation are not fully understood but risk factors for PML include JC virus positivity, duration of natalizumab therapy, and previous immune suppressive therapy. Eighty percent of adults harbor JC virus, thus people have to be screened for positivity before starting natalizumab. Presenting symptoms can include impaired cognition, cortical blindness, hemiparesis, and seizure (17%). Although some of these symptoms could also suggest a MS relapse, seizures do not usually occur as part of a relapse. Thus, new onset seizures in a patient on natalizumab should be assumed to be PML until proven otherwise. Treatment of PML involves discontinuing natalizumab and three to five plasma exchange treatments. Immune Reconstitution Inflammatory Syndrome (IRIS) can occur and is the primary reason for mortality with PML. This is treated with highdose intravenous corticosteroids. There have been several oral therapies approved for MS. Fingolimod (Gilenya速 ), a sphingosine1-phosphate receptor agonist/modulator, was the first oral therapy approved. This agent blocks the egress of lymphocytes out of the lymph nodes. It results in a 50 percent reduction in annualized relapse rate compared with interferons or glatiramer.8 The most common adverse effects with this agent are asymptomatic bradycardia, headache, elevated liver function tests, and reversible macular edema. Thirty-one deaths thought to be secondary to fingolimod therapy have occurred in the 32,000 patients treated to date. Several of these deaths appeared to be cardiovascular related. The FDA now recommends an electrocardiogram be done at baseline and six hours after the first dose. Some sites do a 23-hour cardiac monitoring on patients with known underlying cardiovascular disease or sleep apnea. Teriflunomide (Aubagio速) was the second oral agent approved for MS. This is the active metabolite of leflunomide, an agent approved several years ago for rheumatoid arthritis. Teriflunomide appears to work by blocking pyrimidine synthesis and decreasing antigen presenting cell activity. It results in a 31 percent relative reduction in annualized relapse rate compared with placebo.9 The adverse effects of concern with this agent are hepatotoxicity and teratogenicity. Dimethyl fumarate (Tecfidera速 ) is the most re-
cent oral agent to reach the market. A different formulation of this (Fumaderm) has been used in Germany to treat severe psoriasis. The mechanism of action in MS is uncertain, but it has effects on T- and B-cells in the immune system and on dendritic, endothelial and glial cells in the CNS. The most common adverse effects are headache, mild infections, gastrointestinal symptoms, increased liver function tests, and flushing. In trials of this agent, there was a 44 to 53 percent reduction in ARR over two years compared to placebo and a 29 percent reduction versus glatiramer.10,11 Three cases of PML thought to be related to the psoriasis product have been reported. No cases have been reported in 2,600 patients using the MS approved formulation for up to four years. Although there are 10 effective disease-modifying treatments for MS, there are definitely limitations with current therapies. One limitation is the cost of these agents which can be significant. Another limitation is the partial effectiveness; none of them prevent every relapse. Additionally, significant adverse effects can occur. For individual agents, the optimal dose of most is uncertain. The biggest challenge in choosing therapy is that comparative efficacy of all the agents is unknown. The oral agents have been compared with some of the injectable agents and the injectables have been compared with each other. The interferons and glatiramer appear to have similar efficacy, resulting in a 30 percent reduction in ARR in the randomized double blind- trials. More recent open-label trials have shown higher rates of reduction, but this may be the effect of less severe disease in the study subjects or the lack of blinding. Fingolimod and dimethyl fumarate lead to a lower annualized relapse rate compared to interferons or glatiramer, but these oral agents have not been compared to each other. Teriflumonide appears to have a similar efficacy to the injectable agents. None of the oral agents have been compared to natalizumab, which appears to be most effective in reducing ARR. Thus, clinicians have an array of effective medications, but the optimal order in which the agents should be used is unknown. Conclusion
Although a devastating disease, there are effective disease- modifying medications for MS. Although not ideal, the use of disease-modifying therapy can reduce annual relapses around 30 percent and maybe more with some of the newer oral agents. It is hoped that in the near future there will be better data to help clinicians select the most effective agent at the most effective dose for a given patient.
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Myla D. Goldman, MD, MS is Director of the James Q. Miller Multiple
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Sclerosis Clinic at the University of Virginia in Charlottesville.
References 1. McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol. 2001;50(1):121-7. 2. Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69(2):292-302. 3. Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology. 1996;46(4):907-11. 4. Mathis AS. Managed care aspects of managing multiple sclerosis. Am J Manag Care. 2013;19(2 Suppl):S28-34. 5. Richards RG, Sampson FC, Beard SM, Tappenden P. A review of the natural history and epidemiology of multiple sclerosis: implications for resource allocation and health economic models. Health Technol Assess. 2002;6(10):1-73 6. Goldman MD, Motl RW, Scagnelli J, et al. Clinically meaningful performance benchmarks in MS: timed 25-foot walk and the real world. Neurology. 2013;81(21):1856-63. 7. Vermersch P, Kappos L, Gold R, et al. Clinical outcomes of natalizumabassociated
■ Provide leadership to a team of clinical support
staff focused on prompt and targeted care coordination for our plan members
2011;76(20):1697-704. 8. Bergvall N, Makin C, Lahoz R, et al. Comparative effectiveness of fingolimod versus interferons or glatiramer acetate for relapse rates in multiple sclerosis: a ret-
■ Function as a resource for network providers and
internal staff, helping to pinpoint services and benefits that promote optimal member health outcomes
rospective US claims database analysis. Curr Med Res Opin. 2013;29(12):1647-56. 9. O’Connor P, Wolinsky JS, Confavreux C, et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med. 2011;365(14):1293-303. 10. Gold R, Kappos L, Arnold DL, et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012;367(12):1098-107.
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Closing Performance Gaps in the Diagnosis and Management of Osteoporosis Andrea J. Singer, MD, FACP, CCD 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 several performance gaps in the diagnosis and management of osteoporosis. Improving recognition and treatment are both needed. Once patients are started on therapy, they need support and education to continue medications for at least five years to decrease fracture risk. Collaborative models of care that focus on those at most risk for osteoporosis and its complications can be used to close the gaps. Key Points • Osteoporosis is underdiagnosed and undertreated. • Adherence and persistence are major issues with osteoporosis treatment. • Recognizing the risk factors for osteoporosis is the first step to increasing diagnosis. • National groups are working to close the performance gaps.
Osteoporosis, reduced bone strength leading to increased risk of fractures, is a significant health problem, particularly as our population ages. Nine million Americans have osteoporosis and more than 48 million are at risk because they have osteopenia (low bone mineral density).1,2 The consequences of osteoporosis are enormous. There are more than two million osteoporotic fractures per year. One of every two women aged 50 or older will have a fracture before her death. These fractures lead to disability and increased mortality at an estimated cost of $17 billion (2005).4 Vertebral fracture is the most common osteoporotic fracture and indicates a high risk for future fractures. Twenty-six percent of women with a vertebral fracture will fracture again within one year.5 Only one-third of vertebral fractures are symptomatic and diagnosed at the time they occur; the other two-thirds are “silent”. Red flags for vertebral frac-
tures are height loss, postural changes (kyphosis), and new or worsening back pain. Approximately 20 to 30 percent of women and 50 percent of men with osteoporosis have secondary factors causing or contributing to their bone loss.1,3 The rate may be even higher in healthy premenopausal women and men under 50 with osteoporosis and fractures (44 to 90%). In one study of 173 “healthy,” osteoporotic women aged 46 to 87 evaluated for secondary osteoporosis, 44 percent were found to have underlying disease.6 The most common secondary factors were vitamin D deficiency (20%), hypercalciuria (10%), malabsorption (including celiac disease, 7%) and hyperparathyroidism (3%). There are three major performance gaps in osteoporosis management: under-identification, undertreatment, and poor adherence/persistence with therapy. Many patients who meet guidelines for
www.namcp.org | Vol. 17, No. 2 | Journal of Managed Care Medicine 31
Exhibit 1: Clinical Risk Factors for Osteoporosis1,3 Lifestyle-Related Risk Factors
Other Significant Factors
Alcohol (3 or more drinks per day)
Prior fracture without major trauma
Aluminum ingestion (antacids)
Clinical risk factors
Excessive vitamin A intake
Age > 65
Family history of osteoporosis or fractures
High caffeine intake High sodium (salt) intake Immobilization Inadequate physical activity Low calcium intake Smoking
Early menopause Secondary osteoporosis Height loss or kyphosis Risk factors for falling Patient’s reliability, understanding, and willingness to accept intervention
Thinness (body weight <127 pounds) Vitamin D deficiency
bone density testing are not tested, particularly those with fractures. A significant number of those diagnosed with osteoporosis are not treated adequately to reduce risk of future fractures. Even when treatment is started, there are issues with patients taking medication accurately and for a long duration. The first step toward identifying osteoporosis is recognizing clinical risk factors that identify an increased risk of low bone mass and fractures (Exhibit 1).1,3 Those at risk for osteoporosis are then screened to determine their bone mass (Exhibit 2).1,7 Guidelines established by the World Health Organization (WHO) in 1998 designated four diagnostic categories for osteoporosis.8 A normal BMD is represented by a T-score greater than or equal to –1.0 on BMD testing. Osteopenia (low bone mass) is a T-score between –1.0 and –2.5. T-scores less than or equal to -2.5 indicate osteoporosis. Severe (established) osteoporosis is a T-score less than or equal to –2.5 and the presence of one or more fragility fractures. In studies of populations, the lower the T-score, the higher the risk for fracture. Once it is determined that a patient has decreased BMD, a decision whether to treat must be made. In those with osteopenia, assessing risk for fracture in the given patient needs to be done in order to make this decision. One commonly used method is the fracture risk assessment (FRAX). The tool is available online at http://www.shef.ac.uk/FRAX and is included in some BMD result printouts. FRAX provides a quantitative risk estimate based on BMD and an assessment of other key factors in treatment-
naïve patients between 40 and 90 years. For patients with osteopenia, FRAX provides an estimate of a 10-year probability of major osteoporotic fracture (hip, spine, proximal humerus, distal forearm) and 10-year probability of hip fracture. Fracture probability can be used with treatment guidelines to determine when treatment should be recommended. Exhibit 3 lists the benefits and limitations of FRAX. The National Osteoporosis Foundation (NOF) guidelines recommend considering pharmacological treatment in postmenopausal women and men greater than or equal to 50 years of age with hip or vertebral fracture, T-score less than -2.5 at femoral neck or lumbar spine, or T-score between -1.0 and -2.5 and 10-year probability of hip fracture greater than or equal to 3 percent or 10-year probability of major osteoporotic fracture greater than or equal to 20 percent.1 The judgment of a clinician and/or patient preferences may indicate treatment for people with 10-year fracture probabilities above or below these levels. The mainstays of osteoporosis treatment have been bisphosphonates. The American Association of Clinical Endocrinologists (AACE) guidelines recommend the use of alendronate, risedronate, zoledronic acid or denosumab as the first line of therapy in postmenopausal women.3 The other available agents have less data or more significant adverse effects and thus should be reserved for those who do not respond to or cannot take one of the first-line agents. Exhibit 4 lists some considerations in selecting medications to treat osteoporosis.9,10
32 Journal of Managed Care Medicine | Vol. 17, No. 2 | www.namcp.org
Exhibit 2: Indications for BMD Testing1,7 Criterion
65 years and older
70 years and older
Based on Risk Factors
• Postmenopausal, < 65 with 1+ risk factor(s)
50-70 years with 1+ risk factors
• Perimenopausal with specific risk factor* associated with increased fracture risk • Postmenopausal, discontinuing estrogen Regardless of Gender
• Fragility fracture (adulthood/ after age 50) • Comorbid high-risk condition or exposure to high-risk medication associated with low bone mass or bone loss • Anyone being considered for pharmacologic therapy
*Low body weight, prior low-trauma fracture or high risk medication
Exhibit 3: FRAX Benefits and Limitations Benefits
• Validated in large cohort of ~60,000 patients • Combined use of BMD and clinical risk factors improves case finding • Quantitative estimation of fracture risk – more comprehensible to patients • Applicability to men and women worldwide • Can be used with economic modeling to determine cost-effective intervention thresholds
• Limited to 4 ethnicities in US (Caucasian, African-American, Hispanic, Asian) • Dichotomous input for continuous variables • Discordantly low spine BMD cannot be used • Not all risk factors can be incorporated • No provision for nonskeletal risk factors (falling) • May underestimate or overestimate fracture risk
The benefits and risks of treating osteoporosis need to be considered. If 1,000 women are treated with bisphosphonates for five years, 35 to 50 nonvertebral fractures and 50 to 115 vertebral fractures would be prevented.11 With those benefits, come some risks. Five atypical femur fractures would result from that treatment. Thus, the risk of an AFF is low compared to the risk of common osteoporotic fractures. Osteonecrosis of the jaw is another rare adverse effect of bisphosphonates. The prevalence is one in 10,000 to less than one in 100,000 patient-years in patients treated for osteoporosis.12 Overall the risk-benefit ratio for use of bisphosphonates for fracture reduction in osteoporotic patients is favorable. Adherence (taking every day) and persistence (tak-
ing for extended period of time) are critical components of successful management of osteoporosis. One study examined two claims databases of patients older than 45 years of age who received alendronate or risedronate from 1999 to 2003.13 The 35,537 eligible patients were evaluated for six months before the prescription and during 24 months of follow-up. Endpoints included total, vertebral, and nonvertebral osteoporotic fractures, persistence (no gap in refills for more than 30 days during the two-year follow-up), and refill compliance (medication possession ratio [MPR] of greater than or equal to 80%). All three fracture types were significantly lower in adherent and persistent patients. Fifty-seven percent of patients were nonadherent with bisphosphonates
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Exhibit 4: Individualizing Osteoporosis Therapy 9,10 Therapy
Potential Patient Characteristics
• Older patients • Patients at high risk for fracture/hip fracture • IV for those who cannot tolerate oral agents • IV for easier dosing regimen or those with compliance issues, nursing home patients (but consider/evaluate renal function)
• Patients at high risk for fracture/hip fracture • Patients who cannot tolerate oral bisphosphonates • Patients with decreased kidney function • Nursing home patients • Desire for easier dosing regimen or those with compliance issues
• Younger woman at low risk for hip and non-vertebral fractures • Postmenopausal woman who cannot tolerate other therapies
• Patients at high risk for fracture
• Unable or unwilling to take other agents
and 80 percent were nonpersistent with bisphosphonates. Virtually no treatment benefit was obtained when the MPR was less than 50 percent. The probability of fracture remains relatively stable around 11 percent with refill compliance up to 50 percent. The fracture rate with 100 percent refill compliance was approximately 8 percent. In this study, there was a pronounced fracture reduction at a refill compliance of 75 percent (Exhibit 5).13 Thus, patients treated for osteoporosis need to take their medication at least 75 percent of the time to have significant fracture risk benefit. This study had a very high rate of nonpersistence at two years. Other studies show that up to 50 percent of patients who start osteoporosis medications are no longer taking them one year after they are prescribed.14 Numerous strategies can be used to improve adherence. Targeted patient education on fracture risk, consequences of fracture, and benefits and risks of treatment should be provided. Patients also need to be involved in the decision-making when selecting treatment. There are numerous dosage forms of bisphosphonates that can be used which some patients might find helpful in improving their adherence. Regular contact with health care providers can provide the support necessary to maintain therapy. Bisphosphonates alone are not going to provide optimal fracture risk reduction. There are some universal prevention and treatment strategies that apply to everyone with both osteopenia and osteoporosis. Adequate calcium and vitamin D are necessary to build quality bone when osteoporosis medications are given. Both NOF and AACE recommend 1200
mg of elemental calcium daily.1,3 Vitamin D recommendations vary. NOF suggest 800 to 1000 IU/day to achieve a target 25-hydroxy vitamin D level of 30 ng/mL.1 AACE recommends 1000 to 2000 IU/ day and maintaining a level of 30 to 50 ng/mL.3 Weight-bearing exercise and muscular strengthening exercises can be helpful in maintaining bone mass and reducing risk of fracture. All patients with low bone mass should be counseled on fracture risk reduction. They should avoid high-impact activities, activities that increase the risk of falling, and forward or sideward trunk flexion because of increased load on the spine. Fall prevention is an important part of fracture risk reduction. This may require gait and balance training, minimizing medications known to increase fall risk, and making home safety modifications. Lastly, smoking cessation and avoidance of excessive alcohol intake are two other ways to prevent additional bone loss. As indicated in the Surgeon General’s Report, data points to a real gap between what is known about bone health and the application of that knowledge to patient care.2 Studies done prior to the Report show that physicians frequently failed to diagnose and treat osteoporosis, even in elderly patients who had suffered a fracture. In one study of four well-established Midwestern health systems, only one-eighth to one-quarter of patients who had a hip fracture were tested for their bone density, fewer than a quarter were given calcium and vitamin D supplements, and fewer than one-tenth were treated with effective antiresorptive drugs.15 Other pre-report studies found low usage rates for testing and
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Exhibit 5: Clinical Consequences of Poor Compliance and Persistence13
Probability of Fracture
0.12 Pronounced fracture reduction at 0.75
0.11 0.10 0.09 0.08 0.07
Medication Possession Ratio (MPR)* Data on 35,537 patients from 2 claims databases *Medication Possession Ratio (MPR) is a measure of refill compliance using the percentage of time a medication was available to the patient.
treatment among high-risk populations, including BMD testing (which ranged from 3 to 23%), calcium and vitamin D supplementation (11 to 44 %) and antiresorptive therapy (12 to 16 %). Thus, most health care providers do not consider osteoporosis in their patients, even after a fracture. When health care providers do suggest therapy, it often does not conform to evidence–based recommendations. One of the key difficulties in osteoporosis and post-fracture patient care is the fragmented U.S. health care system, which makes it difficult to coordinate patient care across hospitals, medical offices, and multiple medical specialties in the community. In fact, only 23 percent of women over age 67 who have suffered a hip or other type of fracture are tested or treated for osteoporosis, and 25 percent of patients who break their hip die within the first year. Medicare spends more than $5 billion annually to treat fractures among seniors, yet the majority of patients are released without being evaluated for osteoporosis – the underlying disease which may have led to the fracture. The post-fracture care gap can be significantly reduced though implementation of a systematic approach to secondary fracture prevention, a fracture liaison service (FLS), which ensures that every patient age 50 and above who presents with a fracture undergoes osteoporosis assessment. These programs recognize that patients who have fractured are at highest risk of future fractures. A FLS model of care is a coordinated preventive care model which operates under the supervision of bone health specialists and collaborates with the patient’s primary care physician. Post-fracture care is organized through a
coordinator, generally a nurse or other allied health professional. Patients with recent fractures are tracked via a population registry. There are processes and timelines established for patient assessment and follow-up. FLS programs have been shown to greatly reduce the number of secondary fractures and have achieved cost savings by identifying and appropriately treating post-fracture patients.16,17 The National Bone Health Alliance (NBHA) is working to close the gaps in care. NBHA is a publicprivate partnership launched in 2010 that brings together the expertise and resources of its member organizations to collectively undertake the following initiatives: promote bone health and prevent disease; improve diagnosis and treatment of bone disease; and enhance bone research, surveillance and evaluation. The NBHA’s 52 member organizations, along with liaisons representing the Centers for Disease Control and Prevention, National Aeronautics and Space Administration, National Institutes of Health and the U.S. Food and Drug Administration, are working together to bring about a shared vision to improve the overall health and quality of life of all Americans by enhancing their bone health. Working with CECity and NOF, the NBHA recently announced a study to assess hospital use of proven fracture liaison service models across communities, utilizing a cloud-based computer platform. Conclusion
Osteoporosis is a common disease with serious clinical consequences due to fractures, but it can be prevented and treated. There are easily available, effective clinical tools to diagnosis osteoporosis, assess
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fracture risk, and identify patients for pharmacological therapy. Pharmacological agents can reduce fracture risk, but they need to be taken consistently for a period of time to adequately reduce risk. Treatment decisions for each patient should be individualized considering the balance of expected benefit and potential risks. Critical issues in closing the gaps in osteoporosis require changing health care provider, patient, and health systems behavior. Also required in closing the gaps is identifying, evaluating, and initiating evidence-based care for osteoporosis and low bone density after a fragility fracture, along with primary fracture prevention. A multidisciplinary approach can be used to improve collaboration and care.
a vertebral fracture. Osteoporos Int. 2005;16(1):78-85. 6. Tannenbaum C, Clark J, Schwartzman K, et al. Yield of laboratory testing to identify secondary contributors to osteoporosis in otherwise healthy women. J Clin Endocrinol Metab. 2002;87(10):4431-7. 7. Baim S, Binkley N, Bilezikian JP, et al. Official Positions of the International Society for Clinical Densitometry and executive summary of the 2007 ISCD Position Development Conference. J Clin Densitom. 2008;11(1):75-91. 8. World Health Organization. Guidelines for Preclinical Evaluation and Clinical Trials in Osteoporosis. Geneva, Switzerland: WHO; 1998:5-6. 9. Silverman S, Christiansen C. Individualizing osteoporosis therapy. Osteoporos Int. 2012;23(3):797-809. 10. Miller PD, Derman RJ. What is the best balance of benefits and risks among anti-resorptive therapies for postmenopausal osteoporosis? Osteoporos Int. 2010;21(11):1793-802. 11. Shane E, Burr D, Ebeling PR, et al. Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone
Andrea J. Singer, MD, FACP, CCD is an Associate Professor of Medi-
and Mineral Research. J Bone Miner Res. 2010;25(11):2267-94.
cine, Obstetrics, and Gynecology and the Director of Bone Densitom-
12. Khosla S, Burr D, Cauley J, et al. Bisphosphonate-associated osteonecrosis
etry Program at Medstar Georgetown University Hospital. She is also a
of the jaw: report of a task force of the American Society for Bone and Mineral
Clinical Director for the National Osteoporosis Foundation.
Research. J Bone Miner Res. 2007;22(10):1479-91.
fracture rates in North America and Europe. Am J Med. 2009;122(2
13. Siris E, Selby P, Saag K, et al. Impact of osteoporosis treatment adherence on
1. National Osteoporosis Foundation. Clinicianâ€™s Guide to Prevention and
Treatment of Osteoporosis. 2013.
14. Solomon DH, Avorn J, Katz JN, et al. Compliance with osteoporosis medi-
2. US Department of Health and Human Services. Bone Health and Osteopo-
cations. Arch Intern Med. 2005;165(20):2414-9.
rosis: A Report of the Surgeon General. Rockville, MD: US Department of
15. Harrington JT, et al. Hip fracture patients are not treated for osteoporosis: a
Health and Human Services, Office of the Surgeon General, 2004.
call to action. Arthritis Rheum. 2002;47(6):651-4.
3. Watts NB, Bilezikian JP, Camacho PM, et al. American Association of Clinical
16. Solomon DH, Patrick AR, Schousboe J, Losina E. The Potential Economic
Endocrinologists Medical Guidelines for Clinical Practice for the diagnosis and
Benefits of Improved Post-Fracture Care: A Cost-Effectiveness Analysis of a
treatment of postmenopausal osteoporosis. Endocr Pract. 2010;16 Suppl 3:1-37.
Fracture Liaison Service in the US Health Care System. J Bone Miner Res. 2014
4. Burge R, Dawson-Hughes B, Solomon DH, et al. Incidence and economic
burden of osteoporosis-related fractures in the United States, 2005-2025. J Bone
17. Eisman JA, Bogoch ER, Dell R, et al. Making the first fracture the last
Miner Res. 2007;22(3):465-75.
fracture: ASBMR task force report on secondary fracture prevention. J Bone
5. Lindsay R, Burge RT, Strauss DMl. One year outcomes and costs following
Miner Res. 2012;27(10):2039-46.
36 Journal of Managed Care Medicine | Vol. 17, No. 2 | www.namcp.org
Overcoming Challenges in the Management of Obesity: A Closer Look at Emerging Therapeutic Options Tirissa J. Reid, MD For a CME/CEU version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.
Summary Obesity continues to be an epidemic issue in the United States. Managing this issue requires a stepwise approach that always includes lifestyle changes. Two new antiobesity treatments were approved by the FDA recently, which adds to the possible long-term treatment options. Bariatric surgery is a last step option for many patients but is an effective option. Key Points • The treatment of obesity should be managed using a stepwise approach, starting with lifestyle changes and progressing to medications and surgery. • Concomitant medications causing weight gain should be substituted with therapeutic alternatives that cause weight loss or are weight neutral, whenever possible. • Obesity is a chronic disease requiring long-term therapy. • Bariatric surgery is not a cure, but it can take weight off and keep it off, improve most obesity-related conditions, reduce the risk of premature death, and improve quality of life. • Medication therapy can be considered for weight regain after bariatric surgery.
Obesity is defined as an excess of fat. For practical reasons, since precise measurement of body fat in every patient is not practical, body mass index is used as a surrogate measure to evaluate obesity. Body mass index is calculated by dividing weight in kilograms by height in meters squared; a BMI greater than or equal to 30 kg/m 2 is classified as obese. Obesity can further be divided into Class I (BMI of 30-34.9), Class II (35-39.9) and Class III (greater than or equal to 40 kg/m 2 ). Class III obesity is often referred to as morbid obesity. Since BMI is a surrogate measure for obesity, clinical judgment must be used when applying it to patients and planning to treat them; for instance, a bodybuilder may have a BMI greater than 30, but the increase in weight is mainly due to increased muscle and not fat. Since 1990, the prevalence of obesity in the U.S.
has dramatically increased. In 1990, no state had a prevalence of obesity greater than 15 percent. Ten years later, in 2000, about half of the states had an obesity prevalence of 15 to 19 percent. The others had 20 to 24 percent prevalence. More recently, in 2010, every state had a prevalence of obesity greater than 20 percent and about a third of states already had a prevalence greater than 30 percent. There are numerous medical complications of obesity. These include sleep apnea, coronary artery disease, stroke, diabetes, dyslipidemia, hypertension, and nonalcoholic fatty liver disease. Nonalcoholic steatohepatitis is the third most common cause for liver transplantation, after hepatitis and alcoholic liver disease; it is predicted to become the number one cause for liver transplantation within the next decade. Treating obesity is not a matter of vanity, but a way to prevent or control some of these associ-
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Exhibit 1: A Guide to Selecting Treatment1 Body Mass Index (BMI) (kg/m2) Treatment
25 - 26.9
27 - 29.9
30 - 34.9
35 - 39.9
Diet, physical activity, behavior therapy
Yes with comorbidity
Yes with comorbidity
Yes with comorbidity
Yes with comorbidity
*Yes alone indicates that the treatment is indicated regardless of the presence or absence of comorbidities. The solid arrow signifies the point at which therapy is initiated. *** The FDA has approved use of LAGB for patients with BMI > 30 who also have at least one condition linked to obesity, such as heart disease or diabetes.
ated diseases which are shortening the life expectancy for many Americans and costing us millions to treat once they progress to later stages and cause significant disability. Importantly, before starting any weight loss program, a review of the patient’s medication list should be done to identify any medications that are contributing to weight gain and whether these can be replaced with a medication with similar therapeutic effect that does not cause weight gain. Some of the most commonly used medications that are well known to cause weight gain are corticosteroids, tricyclic antidepressants, selective serotonin reuptake inhibitors, the atypical antipsychotic agents, and gabapentin. Medications used to treat diabetes can also affect weight. Many patients gain weight when placed on insulin, sulfonylureas, or thiazolidinediones. The non-sulfonylurea secretagogues (repaglinide [Prandin®] and nateglinide [Starlix ®]), as well as the dipeptidyl peptidase inhibitors (sitagliptin [ Januvia®] and alpha-glucosidase inhibitors like acarbose are weight neutral. Metformin tends to cause weight loss or be weight neutral. The glucagon like peptide (GLP-1) agonists, exenatide [Byetta®] and liraglutide [Victoza®], delay gastric emptying, promote satiety and reduce appetite which leads to weight loss. This loss will be 1.5 to 2.3 kg after four to six months. Pramlintide [Symlin®], which is used in conjunction with mealtime insulin in those with type 1 and 2 diabetes, also delays gastric emptying and results in weight loss [mean loss of 6 lbs in 6 months]. The weight effect of various medica-
tions must be considered in selecting treatments for chronic disease. Weight loss treatment is indicated for 1) obese individuals and 2) overweight individuals with one or more indicators of increased CVD risk (e.g., diabetes, prediabetes, hypertension, dyslipidemia, elevated waist circumference) or other obesity-related comorbidities (Exhibit 1).1 A patient’s readiness to change should be assessed prior to initiating therapy. If they don’t want to lose weight, counseling on weight maintenance can be provided. However, if the patient is in agreement regarding the need for weight loss, the guidelines recommend lifestyle changes for everyone who is overweight. Pharmacotherapy can be considered for people with a BMI between 27 and 30 if a comorbidity is present, and for anyone with a BMI of 30 and above. Weight loss surgery can be considered for patients with a BMI of 35 to 40 in the presence of comorbidities, and for anyone with a BMI greater than 40 who has failed other treatments. In 2012, the FDA approved the use of the lap-band for patients with a BMI between 30 and 35 with a weight-related comorbidity. The updated guidelines do not address this patient group. These treatments should be used in a stepwise fashion. A patient who has a BMI greater than 30 shouldn’t be treated with pharmacotherapy if diet, physical activity and behavior therapies have not been tried. Lifestyle changes must be the cornerstone of any weight-loss program if patients are to have any hope of not just losing weight, but of maintaining their
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weight loss. Lifestyle changes include behavior therapy, diet and exercise. Behavior therapy includes the use of several techniques, such as self-monitoring, stimulus control, reinforcement, and stress management. Self-monitoring includes recording food intake, exercise, and body weight on a regular basis. Stimulus control helps patients identify and change cues that are associated with poor eating and exercise habits. For example, if a patient is able to recognize that eating while watching television results in the intake of large quantities of food, they are encouraged to separate these activities. Reinforcement for positive changes includes social support networks or planned non-food rewards for reaching goals or for sticking to a healthy regimen. Stress management techniques help patients respond to setbacks regarding weight goals or personal stressors in ways other than engaging in emotional eating. A psychotherapist with a focus on eating disorders should be recommended. Dietary advice most important for weight loss is that a calorie deficit has to be created. Patients can choose a plan that is based on their own food preferences. Patients can be offered a few meal plan options to get them started. Meal replacements or pre-packaged food plans offer the most structure, allowing the patient to focus on other behaviors, such as how to incorporate exercise into their routine, instead of thinking about which groceries they need to buy and which meals to cook. These plans are also great for portion and calorie control. Simple calorie counting is another option. Some patients prefer to have a specific meal plan worked out for them. Referral to a nutritionist can be very helpful. Keeping a food diary is not mandatory, but is often very helpful for patients to become aware of their true dietary intake and especially valuable in weight maintenance. With weight loss, there is an increase in the hormone ghrelin, often referred to as the hunger hormone, and it is natural to slowly increase the quantity of food consumed. This may be noted much more quickly if a patient is keeping a food diary and measuring quantities. A trial comparing various popular diets found that adherence rates were low for all diets, ranging from 50 to 65 percent and there was modest weight loss in all groups at one year, in the range of 4 to 7 lbs.2 The most interesting finding was that the degree of weight loss and improvement of cardiac risk markers was found to be associated, not with any specific type of diet, but with increased levels of dietary adherence. What this study tells us is, as far as weight loss, the most important issue isn’t the macronutrient composition, but patient adherence. Exercise is the third component of lifestyle chang-
es to help with weight loss. Exercise is especially important for weight maintenance. Once a person loses weight, there are several hormonal and metabolic changes which occur that tend to make individuals regain a portion or all of the weight they have lost. For example, their metabolism slows down and their muscles become about 20 percent more efficient, so they are burning fewer calories than before for the same amount of exercise. Because they are carrying around less weight, even the calories that were previously burned doing routine daily activities will be less. In fact, this change in energy expenditure can be significant, with people burning about 8 kcal/ day less for each pound of weight lost; so a person who loses 25 pounds will burn 200 calories less per day than before the weight loss. To prevent weight regain, they must either decrease their caloric intake by 200 calories or increase their exercise to burn off an additional 200 calories each day. With exercise, it is important to have the patient start slowly and build from there. It may take months to reach their activity goal. Thirty minutes of moderate-intensity aerobic activity at least five days a week (150 min/week) is recommended to reduce chronic disease risk. To help manage body weight and prevent weight gain in adulthood, 60 minutes of moderate physical activity is recommended most days of the week (300 min/week). In people who have lost weight, 60 to 90 minutes of moderate physical activity most days of the week (350 min/week) is needed to prevent weight regain. Strength training on two or more days a week for 20 minutes or more each session is also recommended. If lifestyle changes aren’t enough to get the patient to goal, the use of antiobesity medications can be considered. The noradrenergic agents have been used for many years for weight loss but are approved only for short-term use (approximately 3 months). These agents, such as phentermine, work by causing a decrease in appetite. Studies of the use of these agents show they result in 2 to 10 kg weight loss over placebo. Adverse effects are common and include insomnia, dry mouth, constipation, palpitations, and hypertension. While the short-term use of medication may assist with weight loss, once the medication is stopped, patients will have difficulty maintaining the weight loss and will soon regain most, if not all, of it. Medications currently available for long-term therapy of obesity include orlistat, approved in 1999, lorcaserin [Belviq®], and phentermine/topiramate [Qsymia®]. Both lorcaserin and phentermine/topiramate were FDA approved last year. Orlistat [Alli®, lower dose OTC; Xenical®, high-
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Exhibit 2: Lorcaserin Effectiveness at One Year8 Weight Loss at One Year 60 Patients (%)
Lorcaserin (N = 1,538)
Placebo (N = 1,499)
P < 0.001
P < 0.001
20 10 0
> 10% Weight Loss
> 5% Weight Loss
er dose prescription product] is a medication that blocks the absorption of about 30 percent of ingested fat. It does this by acting on two key enzymes of the digestive system - gastric and pancreatic lipases. These lipases break down fat molecules in the digestive tract that would otherwise be too large to pass as nutrients through the intestinal wall into the bloodstream. Orlistat interacts with these lipases and prevents them from acting on the fat molecules, which then remain whole and exit the body as waste. Approximately 70 percent of those on orlistat lose greater than or equal to 5 percent of their baseline weight within one year.3-5 Only 50 percent of patients with diabetes lose the same amount.6 Nearly 40 percent of patients were able to lose 10 percent or greater weight loss. The 10 percent weight-loss goal occurred in only 20 percent of the patients with diabetes.6 Importantly, it is well known that just a 7 to 8 percent weight loss can cause significant metabolic changes and decrease the risk for diabetes and cardiovascular disease, thus orlistat is an effective option. The biggest issue with orlistat is its adverse effects. These adverse effects relate to the mechanism of action, in that blocking the absorption of fat means that the fat will need to be excreted. This may result in oily spotting, flatulence and fecal urgency or incontinence. The severity of these adverse effects increases with an increase in fat intake, so to some degree there is an element of negative conditioning involved with this medication. Because of these effects, many patients are reluctant to even try it. It is important to educate patients that this medication is to be used in conjunction with a low-fat diet. Contraceptive pills and fat-soluble vitamins, like A, D and E, may not be absorbed as effectively and patients who take cyclosporine, levothyroxine
or warfarin may need the dosages of their medication adjusted. The FDA modified the labeling of orlistat based on 13 cases of severe liver injury out of 40 million patients who had used the medication worldwide between 1999 and 2009. The causal relationship is unclear because many of the patients had other conditions or were taking other medications which could also cause liver injury. Patients with pre-existing liver damage should not receive orlistat. As for managing adverse effects associated with orlistat, the most important tip is to choose the right patient and advise them to maintain a low-moderate fat diet. For those who still experience gastrointestinal adverse effects, they can increase the fiber in their diet, either with dietary fiber or by adding a fiber supplement such as Metamucil. Lorcaserin is a recently FDA approved medication for weight loss. Lorcaserin is a serotonin (5HT) 2C selective receptor agonist which does not appear to affect cardiac values. Fenfluramine, a nonselective serotonin receptor agonist, was pulled from the market after it was found to cause valvulopathies, likely due to binding to 5HT-2B serotonin receptors in the heart. Lorcaserin is thought to bind to 5-HT2C receptors in the hypothalamus, activating anorexigenic pro-opiomelanocortin neurons, which ultimately promotes weight loss by inducing a feeling of satiety and reducing food intake.7 As shown in Exhibit 2, about 20 percent of treated patients lost 10 percent or more of their baseline weight at one year compared with about 7 percent in the placebo group.8 The most common adverse effects were headaches, dry mouth, fatigue, nausea, vomiting and dizziness. The third FDA approved long-term medication for obesity is an extended-release combination of
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Percent weight loss
Exhibit 3: Phentermine/topiramate Efficacy at 2 years10
Percentage of subjects (%) Placebo (n = 227)
PHEN/TPM CR 7.5/46 (n = 153)
phentermine and topiramate. Phentermine increases norepinephrine release and, to a lesser extent, dopamine release, which suppresses the appetite and increases the heart rate secondary to increasing levels of catecholamines. The exact mechanism for weight loss with topiramate is unknown, but it does cause a decrease in appetite with subsequent weight loss. Some animal studies suggest increased energy expenditure and decreased energy efficiency may also contribute to weight loss with topiramate monotherapy.9 In a study of high and low doses of the combination, subjects experienced 10 to 11 percent median weight loss at two years compared with just two percent loss in the placebo group.10 Exhibit 3 shows the percentages of subjects who achieved 5 and 10 percent body weight losses.10 The effects of this combination on progression from prediabetes to diabetes have been studied. The annual incidence rate for the progression to diabetes in the placebo group was 3.7 percent.10 Those receiving low-dose phentermine/topiramate had half the rate of progression to diagnosed diabetes; while those on the higher dose had one fourth the rate of progression to diabetes compared with placebo. This medication also resulted in significant improvements in lipid values. Thus, not only are patients losing weight but they also have decreased metabolic risk with the use of this combination. The most common adverse effects are dry mouth, dizziness, constipation, insomnia, dysgeusia and paresthesias. Since topiramate is a carbonic anhydrase inhibitor, it decreases the serum concentrations of bicarbonate and potassium, which increases the risk of hypokalemia and nephrolithiasis. The biggest concern with the phentermine/topiramate combination is the risk of birth defects. Topiramate can cause cleft palate in babies born to mothers us-
PHEN/TPM CR 15/92 (n = 295)
ing the medication. To try to mitigate this problem, phentermine/topiramate was approved with a Risk Evaluation and Mitigation Strategy (REMS) program which requires negative pregnancy tests for all female patients before the initiation of therapy and monthly thereafter, requires counseling to use effective birth control, and requires distribution through authorized pharmacies. Obviously, weight loss achieved through the use of any medication can help lessen the severity of diabetes, hyperlipidemia and the progression of cardiovascular disease, but there may be some cases where the use of a specific medication is preferred. Since orlistat blocks the absorption of fat, itâ€™s a good choice for obese patients who also have hyperlipidemia, since it leads to a decrease in lipid parameters greater than what is seen with an equivalent amount of weight loss without the medication. None of the three obesity medications has been shown to improve glycemic control by any mechanism other than through weight loss, although a trial with phentermine/topiramate is being conducted to see if it can gain approval as a therapy to treat diabetes, since a decrease in hemoglobin A1C was noted in earlier trials. At this time, for patients with diabetes, orlistat, phentermine/topiramate, and lorcaserin are all good choices, as one would expect that weight loss by any method would improve glycemic control. In summary, the treatment guidelines include recommendations for initiating pharmacotherapy when weight goals are difficult to achieve or maintain through diet and physical activity. In other words, pharmacotherapy shouldnâ€™t be implemented instead of diet and physical activity, but when lifestyle changes are not effective. Medications need to be administered for the long term to be effective. At
www.namcp.org | Vol. 17, No. 2 | Journal of Managed Care Medicine 41
the very least, the intermittent use of medicine must be considered for the long term. There are several other promising combination obesity medications currently in trials, including the combination of bupropion with naltrexone and the combination of zonisamide and bupropion. Using a combination of medications allows different pathways in the appetite/metabolic system to be targeted, which will hopefully lead to greater efficacy and allow the individual medications to be used at lower doses, decreasing the risk of adverse effects. The other nonpharmacologic therapy for obesity is bariatric surgery, which is last in the stepwise progression of obesity therapy. The three most common types of bariatric surgery performed in the U.S. are the adjustable gastric band, Roux-en-Y gastric bypass and sleeve gastrectomy. Gastric banding is a restrictive procedure, which works by placing a hollow, doughnut-shaped tube around the upper portion of the stomach connected to an access port placed in the abdomen for easy access post-op. This tube is then filled with saline to restrict the amount of food that can enter the stomach and it also reduces the size of the stomach, allowing it to hold less food. This results in patients feeling full faster and eating less. Generally, patients lose up to 40 to 45 percent of their excess body weight by two years post-op. This surgery requires frequent follow-up with the surgeon to monitor weight and increase or decrease the amount of saline in the tube to maximize weight loss and minimize complications like frequent vomiting and reflux. Sleeve gastrectomy is another restrictive procedure where the surgeon removes approximately 80 percent of the stomach, which then takes on the shape of a tube or â€œsleeve.â€? The remaining portion of the stomach can hold a very small volume of 100-150ml (3 to 4 ounces). Since patients are only able to consume much smaller quantities of food, they lose weight. Forty to 70 percent of excess body weight is lost with this procedure. Patients who get a sleeve gastrectomy usually lose a greater amount than those undergoing gastric banding, which is also a restrictive procedure. Roux-en-Y-gastric bypass (RYGB) is both restrictive and malabsorptive. A small gastric remnant is created to restrict the quantity of food a patient can ingest, and a Y limb connects the jejunum to the new gastric pouch, so that food bypasses the duodenum. Thus, fewer calories and nutrients are absorbed. Patients generally lose 50 to 75 percent of their excess weight with this procedure, but are at greater risk of vitamin and mineral deficiencies due to the decreased absorption area for nutrients. The greatest loss occurs with gastric bypass, with a
mean weight loss of 32 percent of total body weight at five years and the least amount lost is in the gastric band group, with 17 percent of total body weight loss at five years.11 In addition to substantial amounts of weight loss with bariatric surgery, there are also positive benefits on several weight-related disorders. Only the results for remission of comorbidities after RYGB are reviewed here. In patients with hypertension, 50 percent have complete resolution with the remainder having a decrease in the number and dosage of medications required for control.12,13 With sleep apnea, 40 percent have complete resolution and 70 percent of the rest have a minimal number of apneic episodes nightly. Positive changes in hyperlipidemia and a decrease in acute phase reactants result in a significantly decreased risk for CVD after bariatric surgery. Many patients also report overall improved quality of life as well as decreased disability. The most striking result seen with bariatric surgery is the rate of remission of type 2 diabetes. Initial reports were of resolution of type 2 diabetes in 70 to 84 percent of patients, which is much higher than remission rates seen in patients losing equivalent amounts of weight by caloric restriction. However, more rigorous, recent studies show that remission is sustained at 10 years in 36 to 42 percent of people. It is still impressive to have a 36 percent resolution rate of diabetes 10 years after a single intervention and those who do not remit frequently require fewer medications to control their disease. It is currently unclear why bariatric surgery results in such pronounced remission rates for type 2 diabetes, but the mechanisms are being explored by several groups. One possible theory is that the remission rates are related to changes in incretin excretion. Incretins, like GLP-1, are secreted after glucose is ingested and result in the secretion of insulin. GLP1 levels are significantly higher in bypass patients compared with patients who undergo banding or overweight controls. Higher levels of GLP-1 result in more efficient glucose disposal. Some other differences have been found in ghrelin levels and other gastrointestinal hormones, but none fully explains the differences in diabetes remission rates. Regardless of the mechanism, bariatric surgery has proven a valuable tool for weight loss in patients with type 2 diabetes. Lest anyone begins to think that bariatric surgery is the magic bullet for obesity and its related comorbidities, many patients experience weight recidivism after bypass surgery. After RYGB, it is normal for patients to continue losing weight for 12 and 18 months and then quite normal to have a small amount of weight regain. This is about 5 to 10 per-
42 Journal of Managed Care Medicine | Vol. 17, No. 2 | www.namcp.org
cent over the next six months, after which there is weight stabilization. For a RYGB to be considered a success, at five years, a patient must have lost and maintained a 50 percent decrease or greater of their excess body weight. About 30 percent of patients experience significant weight regain post-op. There are even greater rates of weight recidivism after gastric banding in the range of 50 percent. With 30 to 50 percent of all bariatric patients experiencing significant weight regain after bariatric surgery, there is still a role for lifestyle changes and pharmacotherapy in these patients.14 Antiobesity medications should be considered in those who regain significant weight after a bariatric procedure.
for the Management of Overweight and Obesity in Adults . A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. Circulation. 2013;00:000–000. 2. Dansinger ML, Gleason JA, Griffith JL, et al. Comparison of the Atkins, Ornish, Weight Watchers, and Zone diets for weight loss and heart disease risk reduction: a randomized trial. JAMA. 2005;293(1):43-53. 3. Hill JO, Hauptman J, Anderson JW, et al. Orlistat, a lipase inhibitor, for weight maintenance after conventional dieting: a 1-y study. Am J Clin Nutr. 1999;69(6):1108-16. 4. Davidson MH, Hauptman J, DiGirolamo M, et al. Weight control and risk factor reduction in obese subjects treated for 2 years with orlistat: a randomized controlled trial. JAMA. 1999;281(3):235-42. 5. Sjöström L, Rissanen A, Andersen T, et al. Randomised placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients. European Multicentre Orlistat Study Group. Lancet. 1998;352(9123):167-72.
6. Hollander PA, Elbein SC, Hirsch IB, et al. Role of orlistat in the treatment of
The treatment of obesity should be managed using a stepwise approach, starting with lifestyle changes and progressing to medications and surgery, if appropriate and necessary. Concomitant medications being used should be assessed for contributing to weight gain and substituted with therapeutic alternatives which cause weight loss or are weight neutral, whenever possible. Obesity is a chronic disease requiring long-term therapy, so if medications are used, patients and providers should plan to use them long-term. For appropriate candidates, surgery can provide durable weight loss and remission of obesity-related comorbidities; however, if patients experience weight regain, medication therapy can be considered.
obese patients with type 2 diabetes. A 1-year randomized double-blind study. Diabetes Care. 1998;21(8):1288-94. 7. Sargent BJ, Henderson AJ. Targeting 5-HT receptors for the treatment of obesity. Curr Opin Pharmacol. 2011;11(1):52-8. 8. Smith SR, Weissman NJ, Anderson CM, et al. Multicenter, placebo-controlled trial of lorcaserin for weight management. N Engl J Med. 2010;363(3):245-56. 9. Smith SM, Meyer M, Trinkley KE. Phentermine/topiramate for the treatment of obesity. Ann Pharmacother. 2013;47(3):340-9. 10. Garvey WT, Ryan DH, Look M, et al. Two-year sustained weight loss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweight adults (SEQUEL): a randomized, placebo-controlled, phase 3 extension study. Am J Clin Nutr. 2012;95(2):297-308. 11. Buchwald H, Avidor Y, Braunwald E, et al. Bariatric surgery: a systematic review and meta-analysis. JAMA. 2004;292(14):1724-37. 12. Sjöström L. Bariatric surgery and reduction in morbidity and mortality: experiences from the SOS study. Int J Obes (Lond). 2008;32 Suppl 7:S93-7.
Tirissa J. Reid, MD is an Assistant Professor in the Division of Endocri-
13. Sjöström L, Lindroos AK, Peltonen M, et al. Lifestyle, diabetes, and cardio-
nology at the Weight Control Center at Columbia University Medical
vascular risk factors 10 years after bariatric surgery. N Engl J Med.
Center and Bariatric Clinic at Harlem Hospital in New York.
2004;351(26):2683-93. 14. Choban PS, Jackson B, Poplawski S, Bistolarides P. Bariatric surgery for
morbid obesity: why, who, when, how, where, and then what? Cleve Clin J Med.
1. Jensen MD, Ryan DH, Apovian CM, et al. 2013 AHA/ACC/TOS Guideline
www.namcp.org | Vol. 17, No. 2 | Journal of Managed Care Medicine 43
Chemotherapy-Induced Nausea and Vomiting (CINV): Perceptions, Mechanisms, and Treatment Guidelines Charles Loprinzi, MD For a CME/CEU version of this article, please go to www.namcp.org/cmeonline.htm, and then click the activity title.
Summary Chemotherapy-induced nausea and vomiting (CINV) has a significant impact on quality of life and is a dreaded adverse effect of cancer treatment. As the understanding of the underlying pathophysiology of this process has evolved, so has treatment. There are numerous effective options for preventing both acute and delayed CINV. Following the evidence-based guidelines will significantly reduce the incidence of this feared adverse effect. Key Points • CINV can be acute, delayed, or anticipatory. • In controlling CINV, the strategy is prevention rather than treatment. • Therapy is guided by the emesis potential of the chemotherapy being given. • The most effective combination for preventing acute CINV is serotonin receptor antagonists and dexamethasone. • Guidelines provide specifics on agents to use that provide both acute and delayed coverage.
Chemotherapy-induced nausea and vomiting (CINV) may be classified as acute (beginning within the first 24 hours after chemotherapy), delayed (beginning more than 24 hours after chemotherapy), or anticipatory (beginning before acute chemotherapy-related symptoms would be expected to occur). Some data suggest the delayed phase may begin as early as 16 hours after chemotherapy administration. Although mild nausea and vomiting may be discomforting, more severe cases of nausea and vomiting may result in dehydration, malnutrition, and electrolyte imbalance. These conditions can affect quality of life, the desire to continue with antitumor therapy, and survival.1,2 Studies have demonstrated that nausea and vomiting secondary to chemotherapy impair a patient’s ability to complete household tasks, enjoy meals, and maintain activities of daily living and recreation.3,4 Patient- and treatment-related risk factors exist for developing chemotherapy-induced nausea and vom-
iting. Patient-related risk factors include younger age, female gender, and no prior history of alcohol use. Treatment-related risk factors include high emetogenicity (compared with moderate or low emetogenicity) of the chemotherapy agent and high drug dose.5,6 Exhibit 1 shows the definitions of the emetic risk groups for chemotherapy.7,8 Algorithms that account for these risks have been developed to classify the acute emetogenicity of chemotherapy agents. This classification system serves as a framework for the development of antiemetic treatment guidelines and the design of clinical trials. Nausea and vomiting are two of the most concerning adverse effects of chemotherapy.9-12 Unfortunately, even in the era of modern antiemetic therapy, health care providers can underestimate the impact of CINV on patients. In an international prospective observational study of 298 patients from 14 oncology practices performed in 2001 to 2002, 97 percent of patients received a 5-HT3 receptor
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Exhibit 1: The Four Emetic Risk Groups of Chemotherapeutic Drugs (ASCO/MASCC/NCCN)7,8
Risk in nearly all patients (> 90%)
Risk in 30% to 90% of patients
Risk in 10% to 30% of patients
Fewer than 10% at risk
antagonist and 78 percent received a corticosteroid prior to receipt of moderately or highly emetogenic chemotherapy (78% received moderately emetogenic regimens).13 Given the emetogenic potential of the regimens, all the patients should have received both agents. Physicians and nurses overestimated the efficacy of antiemetic treatment for the majority of patients. The greatest discrepancy between predicted and actual nausea and emesis occurred for the delayed period, with physicians and nurses underestimating the incidence of delayed nausea/vomiting by nearly 30 percent. Of interest, even with treatment with antiemetics, 35 percent of patients experienced acute nausea and more than 50 percent experienced delayed nausea.13 CINV appears to occur via two different mechanismsâ€”one is located in the central nervous system (central) and the other is mediated in the GI tract (peripheral).14 The central mechanism is hypothesized to occur by activation of the chemotherapy trigger zone (CTZ) by a chemotherapeutic agent. The CTZ is found within the area postrema of the brain, which lacks a blood-brain barrier and can be accessed through either the blood or cerebrospinal fluid. Once activated, the CTZ releases multiple neurotransmitters, which in turn activate the brain stem vomiting center. The peripheral mechanism is postulated to occur by a chemotherapeutic agent causing local GI irritation and damage to the GI mucosa, which results in the release of neurotransmitters. This then activates receptors in the GI tract, which are mediated by afferent fibers of the vagus nerve. The activated vagal afferent fibers send signals to the brain stem vomiting centers. In both instances, the neurotransmitters may act independently or in combination to induce vomiting. The evolution of antiemetic agents during the past 20 years parallels advances in understanding the neuropharmacology of emesis and which neurotransmitters are involved. In the early 1960s, phenothiazines became the first class of agents demonstrated to reduce emesis associated with fluorouracil by targeting the neurotransmitter dopamine and
the D2 receptor. During the late 1970s, the introduction of cisplatin provided stimulus for further antiemetic research because the inevitable side effects of nausea and vomiting threatened the use of this effective agent. Beginning in the 1980s, highdose metoclopramide provided a new antiemetic option. The value of combination regimens for improving antiemetic efficacy was recognized and our understanding of the pathophysiology of emesis significantly improved. In addition, predictive variables were identified, including such treatmentrelated factors as the inherent emetogenicity of the chemotherapeutic agent and patient-related factors as well. The first serotonin (5-HT3) receptor antagonist launched in 1991 and continued research led to its combined use with dexamethasone for improved results. This regimen became the standard of care. The extensive research regarding 5-HT3 receptor antagonists also clarified the existence and persistence of delayed nausea and vomiting following chemotherapy and helped fuel development of agents active on other neurotransmitters and receptor systems, such as substance P and neurokinin one (NK1) receptors. Prior to the use of 5-HT3 receptor antagonists, dopamine antagonists (especially metoclopramide) were used to treat emesis from highly emetogenic chemotherapy regimens. Use of dopamine antagonists is limited by antidopaminergic side effects, including extrapyramidal reactions, anxiety, and depression. The effectiveness of metoclopramide, which is due to both antidopaminergic and antiserotonergic actions, led to the development of 5-HT3 receptor antagonists specifically for the treatment of emesis. Cannabinoids (dronabinol) are effective in patients receiving moderately emetogenic chemotherapy, although serious side effects (including dysphoria, hallucinations, sedation, and disorientation) limit their use. Steroids also have an antiemetic effect. A metaanalysis was performed to identify randomized evidence of the efficacy of dexamethasone in protecting against acute and delayed nausea and vomiting
46 Journal of Managed Care Medicine | Vol. 17, No. 2 | www.namcp.org
Exhibit 2: Palonosetron vs Ondansetron in MEC – Complete Response: Acute and Delayed Emesis18
Complete Response (No Emesis, No Rescue) (% of Patients)
Palonosetron 0.25 mg IV (n = 189) Ondansetron 32 mg IV (n = 185)
*p < 0.025 (Fisher’s exact test) * 81.0
* 69.3 55.1
40 20 0
Acute: 0-24 (Day 1)
Delayed: 24-120 (Days 2-5)
Overall: 0-120 (Days 1-5)
Time (hr) No concomitant dexamethasone pretreatment
in patients who received highly or moderately emetic chemotherapy. A search of 1200 citations revealed 32 studies that included 42 pertinent comparisons in a total population of 5,613 patients. Results of the meta-analysis revealed that dexamethasone was superior to placebo or to no treatment for complete protection from acute and delayed emesis and nausea. One in six patients treated with dexamethasone avoided emesis completely.15 Four 5-HT3 receptor antagonists are approved for use in the United States for chemotherapy-induced emesis: palonosetron (Aloxi®), ondansetron (Zofran®), dolasetron (Anzemet®), and granisetron (Kytril®). Clinical studies have shown that a regimen containing a 5-HT3 receptor antagonist is highly effective in preventing acute vomiting, but demonstrates variable efficacy for delayed events. Based on the vast accumulated literature to date, the primary mechanism of action for 5-HT3 receptor antagonists is thought to be blockade of 5-HT3 receptor activation mediated by serotonin release in the gut.16,17 The 5-HT3 agents are similar in efficacy with the possible exception of palonosetron which appears to have improved efficacy for delayed CINV. The extended plasma half-life of palonosetron, combined with its high binding affinity for the serotonin receptor, may contribute to its prolonged effect. During the acute, delayed, and overall time intervals, significantly more patients treated with palonosetron 0.25 mg achieved a complete response (CR) compared with those treated with ondansetron (p<0.025). CR rates for palonosetron 0.75 mg were numerically higher than ondansetron during the acute (73.5%), delayed (64.6%), and overall (58.7%) time intervals
(Exhibit 2).18 Treatment with palonosetron 0.25 mg resulted in significantly more patients nausea-free on days three, four, and five compared with ondansetron. Nausea-free rates for palonosetron 0.75 mg were significantly higher than ondansetron on days four (70.9%) and five (81.0%). Another meta-analysis evaluated 30 randomized studies comparing 5-HT3 antagonists with conventional antiemetics in patients receiving moderately and highly emetogenic chemotherapy. In 11 of these trials, 5-HT3 antagonists used as single agents were compared to combination therapy with 5-HT3 antagonists plus dexamethasone. Combination therapy with dexamethasone was superior to treatment with a 5-HT3 antagonist alone in 10 of 11 trials.19 Based on extensive research and as reflected in guidelines, 5-HT3 antagonists are first-line treatments for emesis associated with chemotherapy and are most effective when combined with dexamethasone. Relatively new treatment options for CINV are the NK-1 antagonists, with aprepitant (Emend®) as the only agent in this class with FDA approval. As single agents, NK-1 antagonists are less effective than serotonin receptor antagonists in preventing acute emesis. However, when combined with serotonin receptor antagonists, they appear to be effective in delayed emesis.20 The discovery of substance P was first reported in 1931. This neurotransmitter plays an integral role in relaying noxious sensory information to the brain. As a modulator of nociception, it is involved in several physiologic activities, including the vomiting reflex. Substance P, which belongs to the group of peptides known as neurokinins, exerts its effect by
www.namcp.org | Vol. 17, No. 2 | Journal of Managed Care Medicine 47
Exhibit 3: Aprepitant in Patients Receiving Cisplatin: Complete Response Rates from Two Trials21
% of Patients
Aprepitant (n = 520) Standard (n = 523)
* 68 52
40 20 0
Acute: 0-24 (Day 1)
Delayed: 24-120 (Days 2-5)
Overall: 0-120 (Days 1-5)
Time (hr) Complete response (CR): no emesis and no rescue medication. *p < 0.001
Exhibit 4: ASCO 2011 Antiemetic Consensus Guidelines23 Emetic Risk Group
Risk (% of Patients)
5-hT3 + DEX + aprepitant or fosprepitant
DEX + aprepitant (if aprepitant used for acute)
30% - 90%
Palonoseetron* + DEX
Oral DEX (preferred) 5-hT3 (alternate)
10% - 30%
Single 8-mg dose of dexamethasone before chemotherapy
No preventive measures
No preventive measures
No preventive measures
DEX, dexamethasone; AC, anthracycline-cyclophosphamide. *If no palonosetron available, substitute first-generation 5-hT 3RA (granisetron or ondansetron). Limited evidence supports adding aprepitant If aprepitant used, any 5-hT 3 antagonist is OK.
binding to the NK1 receptor. High concentrations of substance P/NK1 receptors are located in brain regions implicated in the emetic reflex, such as the nucleus tractus solitarius and area postrema. Unlike 5-HT3 receptor antagonists that work primarily at a peripheral site, the primary mechanism of NK1 receptor antagonists appears to be central. Several clinical trials have demonstrated that the most effective use of a NK1 receptor antagonist is with a 5-HT3 receptor antagonist and a corticosteroid. Exhibit 3 shows the combined efficacy data from two studies of aprepitant.21 The combination of a
5-HT3 receptor antagonist plus dexamethasone is the cornerstone of therapy, and aprepitant adds to symptom control in the acute and delayed phases after highly emetic chemotherapy. Fosaprepitant (Emend速) is an intravenous form of aprepitant that can be given as a single dose, which produces equivalent results to a three-day oral regimen of aprepitant.22 The only differences between these two regimens are the possible adverse effects of the intravenous injection and possibly a lower cost with the injectable form. Phlebitis can occur in addition to pain on infusion.
48 Journal of Managed Care Medicine | Vol. 17, No. 2 | www.namcp.org
In controlling emesis, the strategy is prevention rather than treatment. Thus, the goal is to prevent CINV from occurring if at all possible. Evidencebased guidelines are available to guide therapy.8,23,24 Exhibit 4 shows the recommended regimens by emetogenic type of chemotherapy from the updated ASCO guidelines.23 The Multinational Association of Supportive Care in Cancer and European Society of Medical Oncology (MASCO/ESMO) guidelines are very similar.24 The only difference between these two guidelines are for acute prevention with low emetogenic risk. The MASCO/ESMO guidelines recommend dexamethasone, a 5-HT3 receptor antagonist, or a dopamine receptor antagonist (metoclopramide). Conclusion
perceptions of the side effects of cancer chemotherapy in 1993. Ann Oncol. 1996;7(2):189-95. 11. de Boer-Dennert M, de Wit R, Schmitz PI, et al. Patient perceptions of the side-effects of chemotherapy: the influence of 5HT3 antagonists. Br J Cancer. 1997;76(8):1055-61. 12. Lindley C, McCune JS, Thomason TE, et al. Perception of chemotherapy side effects cancer versus noncancer patients. Cancer Pract. 1999;7(2):59-65. 13. Grunberg SM, Hansen M, Deuson RR, et al. Incidence of chemotherapyinduced nausea and emesis after modern antiemetics. Cancer. 2004;100:2261-8. 14. Berger AM, Clark-Snow RA. In: Cancer: Principles and Practice of Oncology. Lippincott Williams & Wilkins: 2001 15. Ioannidis JPA, Hesketh PJ, Lau J. Contribution of dexamethasone to control of chemotherapy-induced nausea and vomiting: a meta-analysis of randomized evidence. J Clin Oncol. 2000;18:3409-22. 16. Endo T, Minami M, Hirafuji M, et al. Neurochemistry and neuropharmacology of emesis - the role of serotonin. Toxicology. 2000;153(1-3):189-201. 17. Hesketh PJ, Van Belle S, Aapro M, et al. Differential involvement of neu-
The key to treating CINV is to prevent it from ever occurring. Preventive regimens are selected based on the emetogenic potential of the chemotherapy being given and patient-related factors. The available evidence-based guidelines should be used to select therapy.
rotransmitters through the time course of cisplatin-induced emesis as revealed by therapy with specific receptor antagonists. Eur J Cancer. 2003;39(8):1074-80. 18. Gralla R, Lichinitser M, Van Der Vegt S, et al. Palonosetron improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: results of a double-blind randomized phase III trial comparing single doses of palonosetron with ondansetron. Ann Oncol. 2003;14:1570-7.
Charles Loprinzi, MD is the Regis Professor of Breast Cancer Research
19. Jantunen IT, Kataja VV, Muhonen TT. An overview of randomised studies
at the Mayo Clinic College of Medicine in Rochester, MN.
comparing 5-HT3 receptor antagonists to conventional anti-emetics in the prophylaxis of acute chemotherapy-induced vomiting. Eur J Cancer. 1997;33:66-74.
20. Hesketh PJ. Potential role of NK1 receptor antagonists in chemotherapy-
1. ASHP Commission on Therapeutics. ASHP therapeutic guidelines on the
induced nausea and vomiting. Support Care Cancer. 2001;9:350-354.
pharmacologic management of nausea and vomiting in adult and pediatric pa-
21. Warr D, Gralla RJ, Hesketh PJ, et al. The oral NK1 antagonist aprepitant for
tients receiving chemotherapy or radiation therapy or undergoing surgery. Am J
the prevention of chemotherapy induced nausea and vomiting: 2 randomized,
Health Syst Pharm. 1999;56:729-64.
double-blind, placebo controlled trials. Proc Am Soc Clin Oncol. 2003;22:726.
2. Hesketh PJ. Comparative review of 5-HT3 receptor antagonists in the treat-
ment of acute chemotherapy-induced nausea and vomiting. Cancer Invest.
22. Grunberg S, Chua D, Maru A, et al. Single-dose fosaprepitant for the pre-
vention of chemotherapy-induced nausea and vomiting associated with cisplatin
3. Lindley CM, Hirsch JD, O’Neill CV, et al. Quality of life consequences of
therapy: randomized, double-blind study protocol--EASE. J Clin Oncol.
chemotherapy-induced emesis. Qual Life Res. 1992;1:331-40.
4. O’Brien BJ, Rusthoven J, Rocchi A, et al. Impact of chemotherapy-associat-
23. Basch E, Prestrud AA, Hesketh PJ, et al. Antiemetic Use in Oncology: Up-
ed nausea and vomiting on patients’ functional status and on costs: survey of five
dated Guideline Recommendations from ASCO. Am Soc Clin Oncol Educ Book.
Canadian centres. Can Med Assoc J. 1993;149:296-302.
5. Gregory RE, Ettinger DS. 5-HT3 receptor antagonists for the prevention of
24. Roila F, Herrstedt J, Aapro M, et al. Guideline update for MASCC and
chemotherapy-induced nausea and vomiting. A comparison of their pharmacol-
ESMO in the prevention of chemotherapy- and radiotherapy-induced nausea
ogy and clinical efficacy. Drugs. 1998;55:173-89.
and vomiting: results of the Perugia consensus conference. Ann Oncol. 2010;21
6. Hesketh PJ, Kris MG, Grunberg SM, et al. Proposal for classifying the acute
emetogenicity of cancer chemotherapy. J Clin Oncol. 1997;15:103-9. 7. Antiemetic Subcommittee of the Multinational Association of Supportive Care in Cancer (MASCC). Prevention of chemotherapy- and radiotherapy-induced emesis: results of Perugia Consensus Conference. Ann Oncol. 1998;9(8):811-9. 8. NCCN Clinical Practice Guidelines in Oncology. Antiemesis. Version 1.2013. Available at www.nccn.org. 9. Coates A, Abraham S, Kaye SB, et al. On the receiving end--patient perception of the side-effects of cancer chemotherapy. Eur J Cancer Clin Oncol. 1983;19(2):203-8. 10. Griffin AM, Butow PN, Coates AS, et al. On the receiving end. V: Patient
www.namcp.org | Vol. 17, No. 2 | Journal of Managed Care Medicine 49
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product comprising not less than 96% EPA. For more information about Vascepa visit www.vascepa.com. For more information about Amarin visit www.amarincorp.com.
Ambry Genetics Booth 125
Ambry Genetics is a CLIA-certified laboratory with a clinical diagnostics and a genomic services division. Ambry is a leader in (NGS) technology and offers cost effective testing solutions for more than three hundred genetic tests. The clinical division is focused on using NGS multi-gene panels and whole-exome sequencing. Cancer menus include BRCAinclusive NGS-panels (BRCAplus, BreastNext, OvaNext, PancNext and CancerNext). Additional NGS panels test genes implicated in hereditary ovarian, uterine, colorectal, pancreatic, renal and other cancers. Visit: www.ambrygen.com
American Regent Booth 223
American Regent, Inc., a subsidiary of Luitpold Pharmaceuticals, Inc., is the leading IV iron manufacturer and distributor in the
U.S. In addition to Venofer ® (iron sucrose injection, USP), American Regent now offers Injectafer ® (ferric carboxymaltose injection), available in 750 mg/15 mL single-use vials. Luitpold Pharmaceuticals also brings you Betamethasone Sodium Phosphate and Betamethasone Acetate Injectable Suspension, USP, the only AB-rated generic equivalent to Celestone® Soluspan®†, and SPRIX® (ketorolac tromethamine) Nasal Spray. Visit Booth 223 to learn more!
Bako Integrated Physician Solutions Booth 222
Bako Integrated Physician Solutions is a physician lead provider of anatomic and clinical pathology services tailored to meet the needs of podiatric and primary care physicians. We are the nation’s only turn-key solution for high quality anatomic pathology services and corresponding office-dispensed therapeutics. Our experts boast training in dermatopathology, bone and soft tissue pathology, and cytology. Founded in 2008, Bako’s state-of-the-art laboratory is based in Alpharetta, GA.
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Today’s healthcare system is an incredibly complex matrix, connecting patients, providers, payers, and products. At Lilly, we are continually looking for innovative ways to connect the right medicines to the right patients and build better connections across the continuum of care. With a 130-year tradition of innovation and collaboration, we are committed to creating better connections to help diagnose and treat chronic diseases such as diabetes, depression, or osteoporosis. It’s our way of connecting the dots and working together for better health.
MH85706 0713 Printed in USA. ©2013, Lilly USA. All rights reserved.
Spring Managed Care Forum: Guide to Conference Supporters We are contracted with all major national health plans.
Bayer Healthcare Pharmaceuticals Booth 219
Bayer HealthCare is one of the world’s leading, innovative companies in the healthcare and medical products industry, and combines the activities of the Animal Health, Consumer Care, Medical Care, and Pharmaceuticals divisions. As a specialty pharmaceutical company, Bayer HealthCare provides products for Cardiopulmonary, Hematology, Neurology, Oncology, Dermatology and Women’s Healthcare.
bioTheranostics Booth 224
bioTheranostics, Inc., is the leading solution provider for metastatic cancer management, leveraging its unique expertise in gene expression profiling to develop a growing array of molecular diagnostic tests for cancer patients. The company operates a CLIA-certified, CAP-accredited diagnostic laboratory to perform its proprietary tests under the bioT3 Metastatic Cancer Solution brand: CancerTYPE ID®, CancerTARGET ID, and CancerTREATMENT ID. It also offers the Breast Cancer IndexSM, which quantifies risk of recurrence of estrogen receptor-positive, lymph node-negative breast cancer.
Bioventus Booth 300
Bioventus, a global leader in active orthopedic healing, is a biologics company that delivers clinically proven, cost-effective products that help people heal quickly and safely.
CardioDx Booth 326
CardioDx®, Inc., is a cardiovascular genomic diagnostics company located in Palo Alto, CA. As a pioneer in the field of cardiovascular genomic diagnostics, the company is committed to developing clinically validated tests that empower clinicians to better tailor care to each individual patient. Corus CAD is a blood test that can safely, accurately and conveniently help clinicians assess whether or not a patient’s symptoms are due to obstructive CAD. The test is simple, convenient
and most importantly is the only sex-specific test for the diagnosis of obstructive coronary artery disease that accounts for critical biological differences between men and women.
Crescendo Biosciences Sponsor
Crescendo Bioscience, Inc., is a molecular diagnostics company dedicated to developing and commercializing quantitative blood tests for rheumatoid arthritis (RA) and other autoimmune diseases, located in South San Francisco, CA. Crescendo Bioscience develops quantitative, objective, blood tests to provide rheumatologists with deeper clinical insight to help enable more effective management of patients with autoimmune and inflammatory diseases.
Eisai Booth 207
Eisai Inc. is the U.S. pharmaceutical operation of Eisai Co. Ltd., a research-based human healthcare (hhc) company that discovers, develops and markets products throughout the world. Eisai’s areas of commercial focus include neurology, gastrointestinal disorders and oncology/critical care.
Exact Sciences Corporation Booth 109
Exact Sciences is a molecular diagnostics company focused on colorectal cancer. The company has exclusive intellectual property protecting its non-invasive, molecular screening technology for the detection of colorectal cancer. Stool-based DNA (sDNA) technology is included in the colorectal cancer screening guidelines of the American Cancer Society and the U.S. Multi-Society Task Force on Colorectal Cancer. For more information, please visit the company’s website at www. exactsciences.com.
Express Scripts Booth 218
Express Scripts Specialty Benefit Services offers the industry’s most comprehensive range of specialty health solutions to improve care for patients and reduce waste for plan sponsors. Through the application of behavioral sciences, a specialized clinical approach, and actionable data we
enable better decisions which yield healthier outcomes. To optimize care and maximize savings, we manage specialty medications across both the pharmacy and medical benefits. For more information, visit us at www. specialtybenefitservices.com.
First Call Pharmacy Booth 119
First Call IV Pharmacy is a leading provider of home infusion and high-tech specialty pharmacy services throughout America. We are ACHC accredited with a staff of professionals having combined homecare experience rivaling anyone in the business. Offering true national coverage and customer service second to none, we can provide services for your patients in any location – we specialize in those challenging cases in tough to reach rural areas. Importantly, we offer this comprehensive coverage and top-notch service at a level cheaper than most in-network rates. Should your home infusion patient require additional nursing or therapy services, you can tap into the wealth of resources provided by our network of over 3,000 full service home health agencies across the country. Make one call to our centralized intake center and speak to one of our customer service professionals today for help with your next home infusion case. No matter how challenging the case, we will make the process as easy and seamless as possible, getting your patient home quickly with all of their home infusion needs met. We are truly your “First Call” for the best in home infusion services. Remember, regardless of location or time, First Call IV Pharmacy is always where you need us to be. National Central Intake – (800) 877-5705
Genomic Health Booth 211
Genomic Health, Inc. is the world’s leading provider of genomic-based diagnostic tests that address both the overtreatment and optimal treatment of early stage cancer - one of the greatest issues in healthcare today. The company is applying its world-class scientific and commercial expertise and infrastructure to lead the translation of massive amounts of genomic data into clinically-actionable results for treatment planning throughout the
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PURSUING A LIFE WITHOUT BLEEDS one person at a time
Our pursuit will continue until a life without bleeds is a reality for all. OUR PROMISE TO YOU CAN BE SEEN IN EVERYTHING WE DO. For more than 60 years, Baxter has consistently pursued advancements in the treatment of bleeding conditions. Through our leading investments in research, vast array of programs and support, and people who are dedicated to serving you every day, we partner with you on your life’s journey to strive toward our vision. We have a bold vision for the future of bleeding conditions: “A Life Without Bleeds.” We’re passionate about this vision – it inspires us, motivates us, and deﬁnes us. Baxter is dedicated to doing everything we can to help make your life better by delivering cutting-edge treatments and an extensive selection of critical resources. We have more than 10 ongoing clinical trials, including those in hemophilia A, hemophilia B, inhibitors, von Willebrand disease, and acquired hemophilia A. For people with bleeding conditions, the future has never been brighter. Our proven past, the advancements we’re making today, and our passion for the future fuel the Baxter promise: Our relentless pursuit continues until a life without bleeds is a reality for all. This promise to you can be seen in everything we do, and this is what makes us the company we are.
Baxter and Nava are registered trademarks of Baxter International Inc. © Copyright 2014 Baxter Healthcare Corporation. All rights reserved. USBS/MG1/13-0088
Learn more about Baxter resources and support at www.NAVA.Baxter.com
Spring Managed Care Forum: Guide to Conference Supporters cancer patient’s journey, from screening and surveillance, through diagnosis, treatment selection and monitoring.
Genoptix Medical Laboratory Booth 324
Genoptix® Medical Laboratory is a part of the Novartis Pharmaceuticals Division. We are focused on developing and commercializing evidence-driven diagnostic tests to improve physicians’ ability to optimize patient outcomes. Our vision is to become the leading provider of diagnostic testing and services, helping to redefine the shape of personalized medicine. Through our integrated approach to case management, we ensure that each patient receives the individualized attention that she or he deserves. www.genoptix.com
Gilead Sciences Booth 206 and Sponsor
Gilead Sciences, Inc. is a research-based biopharmaceutical company that discovers, develops and commercializes innovative medicines in areas of unmet medical need. With each new discovery and experimental drug candidate, we seek to improve the care of patients suffering from life-threatening diseases around the world. Gilead’s therapeutic areas of focus include HIV/AIDS, hepatitis, serious respiratory, cardiovascular, metabolic conditions, cancer and inflammation.
GlaxoSmithKline Booth 306
GSK Care Management Solutions offers award-winning educational resources to help people achieve their health goals, and for organizations to build targeted, populationbased care management initiatives. Educational and self-coaching resources include online patient tools in multiple languages, over 1,000 health-literate guides/mobile applications and quick access to NCQA* certified care management programs.
Glooko Booth 127
Glooko offers an FDA 510(k) cleared diabetes management system focused on making glucose data accessible to both patients, cli-
nicians, and payers. The system includes the Glooko MeterSync Cable and App - when combined, these tools allow glucose data to be directly transferred from a meter onto a mobile device. The mobile apps integrate into the existing Glooko diabetes management web dashboards, that enable clinicians and care management teams to remotely monitor and identify at-risk patients.
HMP Communications Sponsor
First Report ®Managed Care (firstreportnow. com) is a managed markets print and online brand that circulates to more than 21,000 health plan CEOs, hospital formulary committee members, HMO pharmacists, health plan medical directors and pharmacy directors, large employer decision-makers, and state prison facility managers. The editorial mission is focused on delivering news that affects managed market providers. First Report Managed Care reports on dozens of scientific and managed care conferences throughout the world.
InSightec Booth 302
InSightec, the pioneer and global leader in MRgFUS technology was founded in 1999. MR guided Focused Ultrasound combines two well-known technologies to create a breakthrough therapy. High intensity focused ultrasound waves precisely heat and destroy targeted tissue non-invasively combined with MRI provides precision anatomical visualization, and real time thermal feedback for treatment monitoring and guidance. ExAblate® is FDA approved for the treatment of symptomatic uterine fibroids and pain palliation of bone metastases. Learn more at www.us.insightec.com.
Iroko Pharmaceuticals Booth 308
Iroko is a global specialty pharmaceutical company dedicated to advancing the science of analgesia. At Iroko, we are using proprietary SoluMatrix Fine Particle Technology™ to develop new lower dose drug products, based on existing NSAIDs. For more information, visit www.iroko.com.
Medical Review Institute of America Booth 121
MRIoA provides specialty matched physician review services for fully insured and self insured benefit administrators. MRIoA is the premier provider of specialty matched review services since 1983. MRIoA is a URAC accredited and NCQA certified company; and has developed a national network of active practicing board certified physicians with over 122 different specialties. MRIoA can assist with Health, Pharmacy, Workers Comp, Disability, Allied Specialty, Initial/Pre-cert Medical Director, and Dental reviews.
Myriad Genetic Laboratories Booth 312
Myriad Genetics is a leading molecular diagnostic company dedicated to making a difference in patient’s lives through the discovery and commercialization of transformative tests to assess a person’s risk of developing disease, guide treatment decisions and assess risk of disease progression and recurrence.
Natera Booth 210
Natera Inc. is a genetic testing company that specializes in analyzing microscopic quantities of DNA for reproductive health indications. The mission of the company is to help families conceive and deliver. In pursuit of that mission, Natera operates a CLIA-certified laboratory in San Carlos, CA, providing a host of preconception and prenatal genetic testing services primarily to OBGYN physicians and in-vitro fertilization centers.
NovaSom Booth 314
NovaSom, Inc. is a leader in sleep apnea diagnostic testing, with the AccuSom. The clinically validated AccuSom is the only home sleep test that provides 24/7 patient support with the wireless transmission of test results, reducing the time between diagnosis and therapy initiation. OSA diagnosis and treatment is key in addressing co-morbidities such as diabetes, hypertension, heart disease, obesity, stroke, and overall mortality risk.
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For over 150 years Bayer has been developing high-tech materials that contribute to an active, modern lifestyle and state-ofâ€“the-art diagnostics technology that advances human health care. When a company is this committed to advancing science you see its employees making remarkable contributions to the greater good. For example, our employees participate in Making Science Make SenseÂŽ, our award winning initiative to advance science literacy. They volunteer in hundreds of classrooms and reach thousands of students each year. Bayer believes thereâ€™s no better place to fulfill our mission to help shape the future and develop innovations that benefit humankind. www.BayerUS.com
Spring Managed Care Forum: Guide to Conference Supporters Novartis Pharmaceuticals Booth 208
Novartis Pharmaceuticals is dedicated to discovering, developing, manufacturing and marketing prescription drugs that help meet our customers’ medical needs and improve their quality of life. Please visit the Novartis exhibit where our representatives will be available to discuss our products.
Novo Nordisk Booth 107/213 and Sponsor
Novo Nordisk is a global healthcare company with nearly a century of innovation and achievement in diabetes care. United in our passion for helping people, with extensive therapeutic expertise, Novo Nordisk will continue its heritage of innovations in diabetes care to fulfill patient and healthcare provider needs. To learn more, visit NovoNordisk-US.com.
PerkinElmer Booth 111
PerkinElmer is a global company committed to healthier pregnancies, healthier babies and healthier families. NTD Labs and Signature Genomics provide one source for genetic screening and diagnostic testing by providing a well-rounded selection of services to support your genetic testing needs. We are happy to now offer non-invasive prenatal testing (NIPT) through our partnership with Verinata Health. Visit PerkinElmer at booth #111.
Rapid Pathogen Screening Booth 215
Rapid Pathogen Screening, Inc. (RPS) is a biotechnology company that manufactures and sells rapid point-of-care diagnostic tests. AdenoPlus is the only CLIA-waived, reimbursable in-office test that detects all known serotypes of adenoviral conjunctivitis, commonly called pink eye.
SI-Bone Booth 221
SI-BONE, Inc. is the leading sacroiliac (SI) joint medical device company dedicated to the development of tools for diagnosing and treating patients with low back issues related to SI joint disorders. The company is manu-
facturing and marketing a minimally invasive surgical (MIS) technique for the treatment of SI joint pathology.
Salix Pharmaceuticals Booth 212/214
Salix Pharmaceuticals is a specialty pharmaceutical company dedicated to acquiring, developing and commercializing brand name, prescription pharmaceutical products used in the treatment of a variety of gastrointestinal diseases. Salix’s strategy is to identify, acquire late-stage proprietary pharmaceutical products having an existing base of safety and efficacy data in humans for the treatment of gastrointestinal disease, to apply the Company’s regulatory, product development, sales and marketing expertise to commercialize these products.
Sanofi Pasteur Booth 220
Sanofi Pasteur Inc. provides pediatric, adult, and travel vaccines for diseases such as diphtheria, tetanus, pertussis, polio, Haemophilus influenzae type b, influenza, rabies, typhoid fever, yellow fever, and meningococcal disease. To learn more about our products visit our exhibit.
Sequenom Center for Molecular Medicine Booth 318
Sequenom Center for Molecular Medicine® (Sequenom CMM), a CAP accredited and CLIA-certified molecular diagnostics laboratory, has developed a broad range of laboratory tests with a focus on prenatal and ophthalmological diseases and conditions. Branded under the names MaterniT21™ PLUS, Heredi-T™, SensiGene®, and Retna-
Gene™, these molecular genetic laboratory tests provide early patient management information for obstetricians, geneticists, maternal fetal medicine specialists, retina specialists and ophthalmologists. Sequenom CMM is changing the landscape in genetic disorder diagnostics using proprietary cutting edge technologies.
Torax Medical Booth 225
Torax Medical, Inc. develops products
designed to treat chronic diseases related to defective sphincter muscles. Our technology platform, Magnetic Sphincter Augmentation (MSA), employs a small implant comprised of interlinked titanium beads with magnetic cores. The magnetic attraction between the beads augments the existing sphincter’s barrier function to prevent reflux or incontinence. The company products include LINX Reflux Management System for the treatment of GERD and FENIX Continence Restoration System for the treatment of fecal incontinence.
Uroplasty Booth 226
Uroplasty provides transformative treatment options for voiding dysfunctions. Urgent ® PC is a low-risk, office-based treatment for OAB that delivers exceptional results. Response rates are 60-80%, clinically significant and durable. Now included in the AUA/SUFU OAB guideline. Macroplastique® is a predictable, permanent, proven bulking agent indicated for adult female SUI. Efficacy, safety and durability are supported by over 15 years of global experience. Uroplasty - Changing care to change lives.
VITAS Innovative Hospice Care Booth 115
Vitas is the nation’s leading provider of end of life care, bringing palliative and hospice care to more than 75,000 patients a year in 20 states throughout the country. With more than 350 health plan partners, Vitas offers managed care organizations a dedicated intake team, education for clinicians and data-sharing to augment the highest quality care available for patients with advanced illnesses. See vitas.com for further information or call 800-873-5198.
VIVUS, Inc. Booth 320
VIVUS is a biopharmaceutical company dedicated to the development and commercialization of novel therapeutic products addressing obesity, diabetes, sleep apnea and sexual health. Qsymia is approved as an adjunct to diet and exercise for chronic weight management in adults who are obese or overweight with at least one weight-related comorbidity.
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Spring Managed Care Forum: Guide to Conference Supporters Valued Relationships, Inc. (VRI) Booth 203
With 25 years of experience, VRI is one of the largest providers of tele-health monitoring, monitored medication dispensing, and medical alert systems in the country. VRI’s solutions support patient self-management and health plan LTSS that enable seniors and the at-risk to maintain their independence, avoid long-term care facilities, disease and care management operations that enable the chronically ill and those with complex medical needs to avoid preventable ER use, hospitalization, and hospital readmission.
Verinata Health, an Illumina Company
WelldyneRx Booth 123
Illumina is a leading developer, manufacturer, and marketer of life science tools and integrated systems for the analysis of genetic variation and function. Illumina offers the non-invasive verifi® prenatal test (formerly offered by Verinata Health, Inc.) in their CLIA-certified, CAP-accredited clinical services laboratory, to detect chromosome abnormalities and aberrations with improved resolution for consistent and dependable results. For more information, visit http:// www.verifitest.com.
WellDyneRx® offers customized pharmacy benefit management solutions that provide clients with lower costs and increased flexibility, giving them a strategic business advantage. We empower our clients with the tools and resources they need to optimize their benefits plans, and we ensure the highest levels of customer service and member satisfaction.
COUNTLESS EYES AT RISK
Acute conjunctivitis, commonly called pink eye, affects 6 million people in the U.S. each year.1 Help stop the spread of disease and reduce unnecessary antibiotics with AdenoPlus®, a point-of-care test to help diagnose acute conjunctivitis. References:  O’Brien TP, Jeng BH, McDonald M, Raizman MB. Acute Conjunctivitis: truth and misconceptions. Curr Med Res Opin 2009;25(8):1953-1961.  FDA Section 510k number (K1107 22) for RPS Adeno Detector Plus™; March 15, 2011.  Udeh BL, Schneider JE, Ohsfeldt RL. Cost-effectiveness of a point-of-care test for adenoviral conjunctivitis. Am J Med Sci 2008;336(3):254-64.
Rapid: results in 10 minutes Accurate: 90% sensitivity, 96% specificity2 Lower costs associated with conjunctivitis by 40%3 Reduce repeat office visits Reduce unnecessary antibiotic use Reduce spread of disease Overall cost savings of $467 million annually3
Visit Booth 215 at the Spring Managed Care Forum for a Product Demonstration. ©2014 Rapid Pathogen Screening, Inc. All Rights Reserved.
AdenoPlus.com +1.941.556.1850, info@RPSdetectors.com RPS 1-2 Page advSpManCareForum2.indd 1
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