Osteoarthritis: Improving Clinical Performance in Managing Pain and Mobility

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1 SYLLABUS AND COURSE GUIDE Release Date: December 22, 2010 Credit Expiration Date: December 22, 2011 MMV Osteoarthritis: Improving Clinical Performance in Managing Pain and Mobility A Free, One-Hour CME/AAFP WEBCAST Activity Based Off of a Live Symposium Held During the GAFP 2010 Annual Scientific Assembly and Exhibition (free account activation and log-in required) FACULTY: Byron L. Cryer, MD University of Texas Southwestern Medical School Dallas, TX Gary Ruoff, MD Westside Family Medical Center Michigan State University-Kalamazoo Kalamazoo, MI Questions? Call CME Outfitters at 877.CME.PROS. This continuing education activity is provided by CME Outfitters, LLC, gratefully acknowledges an educational grant from AstraZeneca Pharmaceuticals in support of this CE activity and an unrestricted educational grant from Mallinckrodt, a Covidien company. The recipient may make a request to the sender not to send any future faxes and failure to comply with the request within 30 days is unlawful. To opt out from future faxes go to enter PIN# 11105, or call , or fax back to

2 INFORMATION FOR PARTICIPANTS Statement of Need A progressive, osteodegenerative condition, osteoarthritis (OA) is a major cause of skeletal pain and chronic disability. The pain of OA often makes the mechanics of mobility (e.g., walking and climbing stairs) difficult or virtually impossible, thus impairing quality of life in patients. Further, it is the most common reason for adult hip and knee replacement. There are a variety of pharmacological and nonpharmacological treatment modalities for OA, yet no modality is universally effective. This unmet need is underscored by results of a treatment satisfaction survey in which 73% of 2,000 primary care physicians and 63% of 30,000 patients reported inadequate pain relief with current treatment regimens. 1 Many patients pain can be controlled with acetaminophen, but if pain persists, oral NSAIDs (in the form of a traditional agent or a COX-2 inhibitor) may be a necessary next step in managing joint pain. It is well recognized that traditional NSAIDs and COX-2 inhibitors are associated with gastrointestinal (GI) side effects and can lead to life-threatening complications. Evidence-based guidelines recommend coadministration of NSAIDs with a proton pump inhibitor (PPI) or misoprostol, yet few who are at risk for upper GI complications receive preventive, gastroprotective agents. 2 This webcast presents expert faculty who will address both pharmacological and nonpharmacological treatment options that integrate strategies to minimize risk and improve outcomes for patients with OA. 1 Crichton B, Green M. GP and patient perspectives on treatment with non-steroidal anti-inflammatory drugs for the treatment of pain in osteoarthritis. Curr Med Res Opin 2002;18: Goldstein JL, Howard KB, Walton SM, McLaughlin TP, Kruzikas DT. Impact of adherence to concomitant gastroprotective therapy on nonsteroidal-related gastroduodenal ulcer complications. Clin Gastroenterol Hepatol 2006;4: Activity Goal To improve physician competence in the awareness and application of validated guidelines in the management of osteoarthritis. Learning Objectives At the end of this CE activity, participants should be able to: Develop multimodal OA pain treatment strategies that are based on best-available clinical evidence and individualized to the patient. Document evidence that you assessed for gastrointestinal and cardiovascular risk factors in patients with OA pain in whom you are considering prescribing an NSAID. In patients taking an NSAID to control OA pain, recommend GI protective strategies to appropriate candidates. Target Audience Family practice physicians, primary care physicians, and other healthcare professionals with an interest in managing patients with osteoarthritis. Financial Support CME Outfitters, LLC, gratefully acknowledges an educational grant from AstraZeneca Pharmaceuticals in support of this CE activity and an unrestricted educational grant from Mallinckrodt, a Covidien company. CREDIT INFORMATION CME Credit (Physicians) CME Outfitters, LLC is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. CME Outfitters, LLC designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit. Physicians should only claim credit commensurate with the extent of their participation in the activity. Note to Physician Assistants: AAPA accepts Category I credit from AOACCME, Prescribed credit from AAFP, and AMA Category I CME credit for the PRA from organizations accredited by ACCME. 2

3 AAFP Credit (Family Physicians) This activity, Osteoarthritis: Improving Clinical Performance in Managing Pain and Mobility, has been reviewed and is acceptable for up to 1 Prescribed credit(s) by the American Academy of Family Physicians. AAFP accreditation begins December 15, Term of approval is for one year(s) from this date, with option for yearly renewal. AMA/AAFP Equivalency: AAFP Prescribed credit is accepted by the American Medical Association as equivalent to AMA PRA Category 1 Credit toward the AMA Physician s Recognition Award. When applying for the AMA PRA, Prescribed credit earned must be reported as Prescribed, not as Category 1. All other clinicians will either receive a CME Attendance Certificate or may choose any of the types of CE credit being offered. CREDIT REQUIREMENTS Successful completion of this CE activity includes participating in the live or recorded activity, reviewing the course materials, and following the instructions below within 30 days of completion of the activity: To complete your credit request form, activity evaluation, and post-test online, and print your certificate or statement of credit immediately (70% pass rate required), please visit (requires free account activation). There is no fee for participation in this activity. The estimated time for completion is 60 minutes. Questions? Please call 877.CME.PROS. FACULTY BIOS & DISCLOSURES Byron L. Cryer, MD Dr. Cryer is the John C. Vanatta Professor of Medicine in the Department of Internal Medicine, Division of Digestive and Liver Diseases and an Associate Dean at the University of Texas Southwestern Medical Center. Dr. Cryer is certified in Internal Medicine with a subspecialty in Gastroenterology. His clinical interests are in general gastroenterology, specifically, acid-peptic diseases of the upper gastrointestinal tract. Dr. Cryer is a graduate of Harvard University in Cambridge, Massachusetts. He received his medical degree in 1986 from Baylor College of Medicine in Houston, Texas, where he also completed his internal medicine residency training. Dr. Cryer completed his gastroenterology fellowship training at the University of Texas Southwestern Medical Center in Dr. Cryer is a member of the American Gastroenterological Association and former Associate Chair of the Esophagus, Stomach, and Duodenum section of the American Gastroenterological Association. Dr. Cryer s primary research has been in the pathogenesis of peptic ulcer disease. His research focus has been clinically oriented in that he has exclusively studied the pathophysiology of these processes in humans. Dr. Cryer s recent investigations have explored the mechanism of gastrointestinal toxicity of nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, clopidogrel within the stomach and duodenum, mechanisms of other drug induced injury within the upper GI tract and Helicobacter pylori. Gary Ruoff, MD Dr. Ruoff earned his medical degree from the Stritch School of Medicine, Loyola University, Chicago, Illinois, and presently serves as Director of Clinical Research at the Westside Family Medical Center in Kalamazoo, Michigan. He is also Clinical Professor of Family Practice at Michigan State University College of Medicine in East Lansing. Dr. Ruoff s main research interest is pain therapy and management, including headache and acute and chronic pain arising from the musculoskeletal and neurogenic systems. Dr. Ruoff is actively involved in teaching students, residents and physicians, and serves on several advisory boards for pain and pain therapy. He has authored over 80 articles, abstracts and monographs, and received numerous awards for his research work. 3

4 Disclosure Declaration It is the policy of CME Outfitters, LLC, to ensure independence, balance, objectivity, and scientific rigor and integrity in all its CE activities. Faculty must disclose to the participants any significant relationships with commercial companies whose products or devices may be mentioned in faculty presentations, or with the commercial supporter of this CE activity. CME Outfitters, LLC, has evaluated, identified, and attempted to resolve any potential conflicts of interest through a rigorous content validation procedure, use of evidence-based data/ research, and a multidisciplinary peer review process. The following information is for participant information only. It is not assumed that these relationships will have a negative impact on the presentations. Dr. Cryer has disclosed that he receives research/grants from PLx Pharma. He serves as a consultant to AstraZeneca Pharmaceuticals LP, Horizon Therapeutics, Inc., NicOx, Inc., Pfizer Inc., PLx Pharma, and Sucampo Pharmaceuticals, Inc. Dr. Ruoff has no disclosures to report. Jeffrey Helfand, DO, MS (peer/content reviewer) has no disclosures to report. Unlabeled Use Disclosure Faculty of this CME activity may include discussions of products or devices that are not currently labeled for use by the FDA. The faculty have been informed of their responsibility to disclose to the audience if they will be discussing off-label or investigational uses (any uses not approved by the FDA) of products or devices. CME Outfitters, LLC, the faculty, AstraZeneca Pharmaceuticals, and Mallinckrodt, a Covidien company, do not endorse the use of any product outside of the FDA labeled indications. Medical professionals should not utilize the procedures, products, or diagnosis techniques discussed during this activity without evaluation of their patient for contraindications or dangers of use. Activity Slides The slides that are presented in this activity are available for download and printout at the CME Outfitters website: Activity slides may also be obtained via fax or by calling 877.CME.PROS. 4

5 Abbreviation List BMI COX-2 Coxib CV EULAR GI GPA H2RA MSM MUCOSA Body mass index Cyclooxygenase-II Cyclooxygenase inhibitor Cardiovascular European League Against Rheumatism Gastrointestinal Gastroprotective agent Histamine2-receptor antagonist Methylsulfonylmethane Misoprostol Ulcer Complications Outcomes Safety Assessment NO-NSAID Nitric oxide-donating non-steroidal anti-inflammatory drug NSAID OA PC-NSAID PPI PUBs RCT ROM SAMe TENS TID UGI UK US VAS VIGOR Non-steroidal anti-inflammatory drug Osteoarthritis Phosphatidylcholine-associated nonsteroidal anti-inflammatory drug Proton-pump inhibitor Perforations, ulcers and bleeds Randomized, controlled trial Range of motion S-adenosylmethionine Transcutaneous electrical nerve stimulation Three times daily Upper gastrointestinal United Kingdom United States Visual Analogue Scale Vioxx Gastrointestinal Outcomes Research 5

6 Osteoarthritis: Improving Clinical Performance in Managing Pain and Mobility Byron L. Cryer, MD Gary Ruoff, MD Multi-Modal Treatment Strategies for Patients with Osteoarthritis Gary Ruoff, MD Westside Family Medical Center Michigan State University-Kalamazoo Gary Ruoff, MD Disclosures Research/Grants: None Speakers Bureau: None Consultant: None Stockholder: None Other Financial Interest: None Advisory Board: None Pathophysiology of OA Most commonly affects hands and weight-bearing joints Involves all joint tissue cartilage, bone, synovium, ligaments, muscle Process is both biochemical and biomechanical Emerging evidence suggests symptoms and disease progression related to inflammation Atlman R, Ruoff G, et al. J Family Practice 2009;58:1-9. 6

7 Treatment Goals for OA Reduction of joint pain and stiffness Maintain and improve joint mobility Reduce physical disability and handicap Improve health-related quality of life Limit progression of joint damage Educate patients about the nature of the disorder and long-term management Zhang W, et al. Osteoarthritis Cartilage 2008;16: When OA is Suspected, Accurately Identify the Affected Joint Comprehensive examination should include: 1 Joint pain on manipulation Muscle strength and ligament stability Body weight and BMI Postural alignment during standing and walking Typically, x-rays provide little information for initial diagnosis 40% of patients with radiographic evidence of OA are asymptomatic 2 1. Atlman RD, Ruoff G, et al. J Family Practice 2009;58: Altman RD. Semin Arthritis Rheum 1991;20: Select Therapy-Based Pain Characteristics Weight-bearing joint Weight reduction Exercise Lifestyle modification Medication Non-weight-bearing joint Medication Splints Heat 8. Do Therapy Trials in a Systematic Fashion Start with acetaminophen Use NSAIDs at the lowest possible dose for shortest possible duration Choose NSAID based on safety profile Topical NSAIDs (diclofenac gel) and capsaicin can be effective adjuncts Intra-articular injections with corticosteroids can be used in patients with moderate to severe pain not responding to oral analgesics/anti-inflammatory agents Zhang W, et al. Osteoarthritis Cartilage 2008;16:

8 7. Don t Forget About Non-Pharmacological Options Weight reduction Range of motion exercises Muscle strengthening Heat Aquatic therapy Physical therapy Orthotics Walking aids 6. Patient Education Important Aspect of Long-Term Strategy Lifestyle modification Pain management Side effects Take medication as prescribed Take with food full meal Co-administration with PPI Zhang W, et al. Osteoarthritis Cartilage 2008;16: Use of Weak Opioids Can Be Considered for Refractory Pain Evidence that opioids have demonstrated efficacy in OA pain 18 placebo-controlled RCTs with 3,244 patients showed a moderate effect size for reduction in pain intensity weeks Pooled effect sizes for opioids vs. placebo were and respectively Long-term safety in OA not determined Avouac J, et al. Osteoarthritis Cartilage 2007;15: What If Oral Medications Don t Manage Pain? Intra-articular corticosteroid injections Intra-articular injections of hyaluronic acid Knee/hip replacement Joint fusion Transcutaneous electrical nerve stimulation (TENS) Zhang W, et al. Osteoarthritis Cartilage 2008;16:

9 3. Know What Medications/ Supplements Your Patients May Be Reading About Drug-drug interactions related to: Nutritional supplements Glucosamine Chondroitin Alternative/herbal medicines SAMe (S-adenosylmethionine) MSM (methylsulfonylmethane) Flavocoxid Marketed as a medical food for the management of OA Atlman R, Ruoff G, et al. J Family Practice 2009;58:1-9. Differences in Pain Intensity Measured on Visual Analogue Scale (VAS) Between Experimental Interventions and Placebo Over Time Difference in means on 10 cm VAS Chondroitin Glucosamine Combination Months No. of trials No. of patients Wandel S, et al. Br Med J 2010;341:bmj.c4675. Placebo superior Clinical equivalence Supplement superior 2. When Prescribing NSAIDs, Perform a GI and CV Risk Assessment NSAIDs can cause serious GI complications such as peptic ulcer, perforations, and bleeds (PUBS) 1 Risk increases with age, concurrent use of other medications, and probably duration of use EULAR advises: COX-2 and NSAIDs are contraindicated in patients with ischemic heart disease or stroke 2 Caution in patients with risk factors for heart disease hypertension, hyperlipidemia, diabetes, smoking 2 1. Always Carefully Consider Implementing a Gastroprotection Strategy in Patients with OA on NSAIDs Use of misoprostol or a proton pump inhibitor (PPI) for gastroprotection is recommended 1. Tramer MR, et al. Pain 2000;85: Zhang W, et al. Osteoarthritis Cartilage 2008;16: Zhang W, et al. Osteoarthritis Cartilage 2008;16:

10 Assessing Risk When Making Treatment Choices for Patients with Osteoarthritis Byron L. Cryer, MD University of Texas Southwestern Medical School Dallas VA Medical Center Byron L. Cryer, MD Disclosures Research/Grants: PLx Pharma Speakers Bureau: None Consultant: AstraZeneca Pharmaceuticals LP; Horizon Therapeutics, Inc.; NicOx, Inc.; Pfizer Inc.; PLx Pharma; Sucampo Pharmaceuticals, Inc. Stockholder: None Other Financial Interest: None Advisory Board: None Incidence and Prevalence of NSAID-Associated GI Complications More than 60 million Americans are NSAID users 1 1% to 2% of users have clinically significant upper GI events Endoscopic studies indicate that gastric or duodenal ulcers develop in approximately 15% to 30% of patients using NSAIDs 2 Estimates of mortality vary widely from 3,200 to higher than 16,500 deaths per year in the United States 1 1. Cryer B. Am J Gastroenterol 2005;100: Laine L. Gastroenterology 2001;120: Gastrointestinal Side Effects Induced by Nonselective NSAIDs No Lesion 70% to 85% Complications 1% to 2% Graham DY, et al. Ann Intern Med 1993;119: Langman MJ, et al. Lancet 1994;343: Larkai EN, et al. J Clin Gastroenterol 1989;11: Silverstein FE, et al. Ann Intern Med 1995;123: Ulcers 15% to 30% Dyspepsia occurs in 25% to 50% of patients with or without complications 10

11 Mortality Rate per Million People Mortality Associated with NSAID/Aspirin Use 153 Spain 253 UK 443 US Peptic Ulcer Disease and NSAIDs The major cause of peptic ulcer disease in Amsterdam has changed from H. pylori to NSAIDs Cause of Peptic Ulcers H. pylori NSAIDs % 20-30% 47% 53% Lanas A, et al. Am J Gastroenterol 2005;100: Ramsoekh D, et al. Clin Gastroenterol Hepatol 2005;3: Risk Factors for Serious GI Adverse Events with NSAIDs Prior Bleed Anticoag/NSAID Use Corticosteroid Use Low-Dose NSAID High-Dose NSAID Age Age Age ( ) ( ) ( ) ( ) ( ) ( ) Relative Risk 1. García-Rodriguez LA. Lancet 1994;343: Shorr RI. Arch Intern Med 1993;153: Piper JM, et al. Ann Intern Med 1991;114: Gutthann SP, et al. Epidemiology 1997;8: ( ) ( ) 2 Age (Years) > Risk for GI Complications Begins at an Earlier Age in Men * Male patients had an onset of GI complications at an earlier age than women * Adapted from Lanas A, et al. Am J Gastroenterol 2005;100: Females Males Patients with GI Complications (%) 11

12 Relative Risk High Risk of Upper GI Bleeding Is Maintained During NSAID Use Increased risk appears at start of therapy and is maintained during use Nonuse Days of NSAID Use Hernández-Díaz S, et al. Arch Intern Med 2000;160: Probability of UGI Complication The Risk of NSAID-Associated Upper GI Complications is Constant Over Time MUCOSA Trial 1 NSAIDs (N = 4,439) Days on Study Cumulative Incidence (%) Silverstein FE, et al. Ann Intern Med 1995;123: Bombardier C, et al. N Engl J Med 2000;343: VIGOR Trial 2 Naproxen (N = 4,029) Months of Follow-Up GI Safety Profiles of Available Agents Relative Risk: Current Use vs. Nonuse Relative Risk 7 NSAID risk varies 6.3 Aspirin and ibuprofen have higher risk than non-nsaids* 6 Aspirin > Ibuprofen > Acetaminophen Reducing the Risk * Statistical significance was not reported García-Rodríguez LA, et al. Epidemiology 2001;12: Hernández-Díaz S, et al. Arch Intern Med 2000;160: de Abajo FJ, et al. BMC Clin Pharmacol 2001;1:1. 12

13 Reducing the Risk of GI Complications with NSAIDs Identify risk factors Use of gastroprotective drugs Safer NSAIDs Options for Patients with GI Risk Who Need NSAIDs NSAID plus gastroprotective agent Misoprostol PPI Histamine 2 -receptor antagonist (H 2 RA) high dose COX-2 inhibitor Non-NSAID pharmacologic therapy Acetaminophen Tramadol Narcotics Zhang W, et al. Osteoarthritis Cartilage 2008:16: Relative GI Safety of Different Anti- Inflammatory Therapies: Overview Therapy Safety Profile All nonselective Increased risk of serious GI NSAIDs events Different formulations No reduction in serious GI of nonselective NSAIDs toxicity Different routes of No reduction in serious GI NSAID administration toxicity Gastroprotection Reduction in serious GI co-therapy toxicity but compliance issues NSAIDs that Reduction in serious GI specifically inhibit toxicity but possible increase COX-2 in cardiovascular adverse effects Gastroprotection Strategies Use lowest effective NSAID dose Misoprostol Proton pump inhibitors H 2 -receptor antagonists (high dose) Zhang W, et al. Osteoarthritis Cartilage 2008:16:

14 Prevention of NSAID-Induced Ulcers Systematic Review of 41 RCTs Intervention Misoprostol 800 μg Misoprostol 400 μg PPI H 2 RA (standard dose) Relative Risk vs. Placebo (95% Confidence Interval) 0.17 ( ) 0.42 ( ) 0.40 ( ) 0.73 ( ) H 2 RA (double dose) 0.44 ( ) Unmet Medical Needs in Improving GI Safety of OA Treatments Problems with Adherence 0.0 Favors Co-Therapy Favors Placebo Rostom A, et al. Cochrane Database Systematic Review 2002;4. Adherence to Evidence-Based Guidelines for Safe Prescription of NSAIDs in High-Risk* Patients Adherence (%) Risk Factor 2 Risk Factors 3 Risk Factors N = 303,787 veterans prescribed NSAIDs in 2002 * Included age 65 years, concurrent corticosteroid or anticoagulant use, history of peptic ulcer, and high average daily dose of NSAIDs Abraham NS, et al. Gastroenterology. 2005;129: Utilization of Gastroprotective Strategies Among New NSAID Users 1 GI Risk Factor 0.1% 2.5% 86.6% 10.8% COX-2 inhibitor alone COX-2 inhibitor + GPA 2 GI Risk Factors 0.2% 4% 81.2% NSAID + GPA GPA = gastroprotective agent Sturkenboom MC, et al. Rheumatology 2003;42(Suppl 3):iii23-iii31. No gastroprotection 14.7% 14

15 Nonadherence Is Associated with Decreased Relative Effectiveness Annualized 0.4 rates of upper GI events per patient-year Goldstein JL, et al. Clin Gastroenterol Hepatol 2006;4: R 2 = Adherence (%) Potential New Safer NSAIDs Being Studied Combination products PPI H 2 RA NO-NSAIDs PC-NSAIDs Pro-drugs (e.g., naproxen) Lipoxygenase/COX inhibitors Recent Guidelines The Heart Is More Important than the Stomach Chan FKL, et al. Am J Gastroenterol 2008;103:

16 A patient requires regular NSAID treatment High Naproxen is preferred Assessment of GI risk High* Avoid NSAIDs Naproxen + PPI/ misoprostol if NSAID is necessary Assessment of CV risk Average Naproxen if not on aspirin Naproxen + PPI/ misoprostol if on aspirin Chan FKL, et al. Am J Gastroenterol 2008;103: Average Any NSAIDs Assessment of GI risk High* Nonselective NSAID + PPI/ misoprostol or Coxib + PPI/ misoprostol** Average Nonselective NSAID alone* Summary PPIs, high-dose H 2 RA, misoprostol, and COX-2 selective inhibitors decrease upper GI ulcers due to traditional, nonselective NSAIDs (RCT evidence) Fixed-dose combination therapy may increase patient compliance with GI risk reduction strategies Patients with the highest GI risk may require more than one risk-reducing strategy such as COX-2 selective inhibitor plus a PPI Clinicians must balance GI and CV issues when choosing NSAID therapy RCT = randomized controlled trial Patient History Patient Case Vignette 61-year-old Obese Woman with Right Knee Pain 61-year-old obese woman presents to family physician with right knee pain Weight: 225 lbs Height: 5 6 BMI: 34 kg/m 2 Right knee pain has lasted 2 months, but has intensified over past 2 weeks necessitating the visit 16

17 Physical Examination Range of motion (ROM) exam Assess for ROM at hip and knees Decreased internal and external rotation of the hip Reduced flexion and extension Slight swelling of right knee No evidence of joint swelling in hands or feet Self-reported pain 9 out of 10 Treatment Plan Diagnosis: OA of the right knee History of ulcer at 25 years old so initiate acetaminophen 500 mg/day TID Recommend non-pharmacological interventions Weight reduction Heat Exercise Follow-Up Visit 3 Months Later No change in weight or BMI No improvement with acetaminophen Continued decreased flexion and extension of right knee Pain mostly unchanged, measured at 8 of 10 Clinical Considerations GI history If prescribe NSAID, should you also prescribe a proton pump inhibitor (PPI)? Educate patient about importance of taking NSAID with food Needed weight loss Counsel patient that little as 10 lb reduction in weight can improve pain scores 17

18 Follow-Up Visit 3 Months Later Weight reduced 15 lbs to 210 lbs BMI reduced to 32 kg/m 2 ROM remains limited Pain score reduced to 6 of 10 What Next? 18

19 Strategies for Treatment Selection in Patients with OA Gary Ruoff, MD Bibliography Altman RD. Classification of disease: osteoarthritis. Semin Arthritis Rheum 1991;20(Suppl 2): Atlman R, Kuritzky L, Ruoff G. Improving long-term management of osteoarthritis: strategies for primary care physicians. J Family Practice 2009;58(Suppl):S17-S24. Avouac J, Gossec L, Dougados M. Efficacy and safety of opioids for osteoarthritis: a meta-analysis of randomized controlled trials. Osteoarthritis Cartilage 2007;15: Tramer MR, Moore RA, Reynolds DJ, McQuay HJ. Quantitative estimation of rare adverse events which follow a biological progression: a new model applied to chronic NSAID sue. Pain 2000;85: Wandel S, Juni P, Tendal B, et al. Effects of glucosamine, chondroitin, or placebo in patients with osteoarthritis of hip or knee: network meta-analysis. BMJ 2010;341:c4675. Zhang W, Moskowitz RW, Nuki G, et al. OARSI recommendations for the management of hip and knee osteoarthritis, Part II: OARSI evidence-based, expert consensus guidelines. Osteoarthritis Cartilage 2008;16:

20 Bibliography Assessing Risk When Making Treatment Choices for Patients with Osteoarthritis Byron L. Cryer, MD Abraham NS, El-Serag HB, Johnson ML, et al. National adherence to evidence-based guidelines for the prescription of nonsteroidal anti-inflammatory drugs. Gastroenterology 2005;129: Bombardier C, Laine L, Reicin A, et al.; VIGOR Study Group. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med 2000;343: Chan FK, Abraham NS, Scheiman JM, Laine L; First International Working Party on Gastrointestinal and Cardiovascular Effects of Nonsteroidal Anti-inflammatory Drugs and Anti-platelet Agents. Management of patients on nonsteroidal anti-inflammatory drugs: a clinical practice recommendation from the First International Working Party on Gastrointestinal and Cardiovascular Effects of Nonsteroidal Anti-inflammatory Drugs and Anti-platelet Agents. Am J Gastroenterol 2008;103: Cryer B. NSAID-associated deaths: the rise and fall of NSAID-associated GI mortality. Am J Gastroenterol 2005;100: de Abajo FJ, García Rodríguez LA. Risk of upper gastrointestinal bleeding and perforation associated with low-dose aspirin as plain and enteric-coated formulations. BMC Clin Pharmacol 2001;1:1. García Rodríguez LA, Hernández-Díaz S. Relative risk of upper gastrointestinal complications among users of acetaminophen and nonsteroidal anti-inflammatory drugs. Epidemiology 2001;12: García Rodríguez LA, Jick H. Risk of upper gastrointestinal bleeding and perforation associated with individual non-steroidal anti-inflammatory drugs. Lancet 1994;343: Erratum in: Lancet 1994;343:1048. Goldstein JL, Howard KB, Walton SM, McLaughlin TP, Kruzikas DT. Impact of adherence to concomitant gastroprotective therapy on nonsteroidal-related gastroduodenal ulcer complications. Clin Gastroenterol Hepatol 2006;4: Graham DY, White RH, Moreland LW, et al. Duodenal and gastric ulcer prevention with misoprostol in arthritis patients taking NSAIDs. Misoprostol Study Group. Ann Intern Med 1993;119: Gutthann SP, García Rodríguez LA, Raiford DS. Individual nonsteroidal antiinflammatory drugs and other risk factors for upper gastrointestinal bleeding and perforation. Epidemiology 1997;8: Hernández-Díaz S, Rodríguez LA. Association between nonsteroidal anti-inflammatory drugs and upper gastrointestinal tract bleeding/perforation: an overview of epidemiologic studies published in the 1990s. Arch Intern Med 2000;160: Laine L. Approaches to nonsteroidal anti-inflammatory drug use in the high-risk patient. Gastroenterology 2001;120: Lanas A, Perez-Aisa MA, Feu F, et al; Investigators of the Asociación Española de Gastroenterología (AEG). A nationwide study of mortality associated with hospital admission due to severe gastrointestinal events and those associated with nonsteroidal antiinflammatory drug use. Am J Gastroenterol 2005;100: Langman MJ, Weil J, Wainwright P, et al. Risks of bleeding peptic ulcer associated with individual non-steroidal anti-inflammatory drugs. Lancet 1994;343: Erratum in: Lancet 1994;343:1302. Larkai EN, Smith JL, Lidsky MD, Sessoms SL, Graham DY. Dyspepsia in NSAID users: the size of the problem. J Clin Gastroenterol 1989;11: Piper JM, Ray WA, Daugherty JR, Griffin MR. Corticosteroid use and peptic ulcer disease: role of nonsteroidal anti-inflammatory drugs. Ann Intern Med 1991;114: Ramsoekh D, van Leerdam ME, Rauws EA, Tytgat GN. Outcome of peptic ulcer bleeding, nonsteroidal anti-inflammatory drug use, and Helicobacter pylori infection. Clin Gastroenterol Hepatol 2005;3: Rostom A, Dube C, Wells G, et al. Prevention of NSAID-induced gastroduodenal ulcers. Cochrane Database Syst Rev 2002;(4):CD Shorr RI, Ray WA, Daugherty JR, Griffin MR. Concurrent use of nonsteroidal anti-inflammatory drugs and oral anticoagulants places elderly persons at high risk for hemorrhagic peptic ulcer disease. Arch Intern Med 1993;153: Silverstein FE, Graham DY, Senior JR, et al. Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1995;123: Sturkenboom MC, Burke TA, Dieleman JP, Tangelder MJ, Lee F, Goldstein JL. Underutilization of preventive strategies in patients receiving NSAIDs. Rheumatology (Oxford) 2003;42(Suppl 3):iii23-iii31. Zhang W, Moskowitz RW, Nuki G, et al. OARSI recommendations for the management of hip and knee osteoarthritis, part II: OARSI evidence-based, expert consensus guidelines. Osteoarthritis Cartilage 2008:16: