This report is based on research conducted by the Oregon Evidence-based Practice Center (EPC) under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (Contract No. 290-02-0024). The findings and conclusions in this document are those of the authors, who are responsible for its contents; the findings and conclusions do not necessarily represent the views of AHRQ. Therefore, no statement in this article should be construed as an official position of the Agency for Healthcare Research and Quality or of the U.S. Department of Health and Human Services.
This report is intended as a reference and not as a substitute for clinical judgment. Anyone who makes decisions concerning the provision of clinical care should consider this report in the same way as any medical reference and in conjunction with all other pertinent information.
This report may be used, in whole or in part, as the basis for development of clinical practice guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied.
Comparative Effectiveness Review Number 4
Comparative Effectiveness and Safety of Analgesics for Osteoarthritis
Comparative Effectiveness Review Number 4
Comparative Effectiveness and Safety of Analgesics for Osteoarthritis
Prepared for: Agency for Healthcare Research and Quality U.S. Department of Health and Human Services 540 Gaither Road Rockville, MD 20850 www.ahrq.gov
Contract No. 290-02-0024
Prepared by: Oregon Evidence-based Practice Center
Investigators Roger Chou, M.D. Mark Helfand, M.D. Kim Peterson, M.S. Tracy Dana, M.L.S. Carol Roberts, B.S.
AHRQ Publication No. 06-EHC009-EF September 2006
This document is in the public domain and may be used and reprinted without permission except those copyrighted materials noted for which further reproduction is prohibited without the specific permission of copyright holders.
None of the investigators has any affiliations or financial involvement that conflicts with the material presented in this report.
Suggested citation: Chou R, Helfand M, Peterson K, Dana T, Roberts C. Comparative Effectiveness and Safety of Analgesics for Osteoarthritis. Comparative Effectiveness Review No. 4. (Prepared by the Oregon Evidence-based Practice Center under Contract No. 290-02-0024.) Rockville, MD: Agency for Healthcare Research and Quality. September 2006. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.
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Preface
The Agency for Healthcare Research and Quality (AHRQ) conducts the Effective Health Care Program as part of its mission to organize knowledge and make it available to inform decisions about health care. As part of the Medicare Prescription Drug, Improvement, and Modernization Act of 2003, Congress directed AHRQ to conduct and support research on the comparative outcomes, clinical effectiveness, and appropriateness of pharmaceuticals, devices, and health care services to meet the needs of Medicare, Medicaid, and the State Children’s Health Insurance Program (SCHIP).
AHRQ has an established network of Evidence-based Practice Centers (EPCs) that produce Evidence Reports/Technology Assessments to assist public- and private-sector organizations in their efforts to improve the quality of health care. The EPCs now lend their expertise to the Effective Health Care Program by conducting Comparative Effectiveness Reviews of medications, devices, and other relevant interventions, including strategies for how these items and services can best be organized, managed, and delivered.
Systematic reviews are the building blocks underlying evidence-based practice; they focus attention on the strength and limits of evidence from research studies about the effectiveness and safety of a clinical intervention. In the context of developing recommendations for practice, systematic reviews are useful because they define the strengths and limits of the evidence, clarifying whether assertions about the value of the intervention are based on strong evidence from clinical studies. For more information about systematic reviews, see www.effectivehealthcare.ahrq.gov/reference/purpose.cfm.
AHRQ expects that Comparative Effectiveness Reviews will be helpful to health plans, providers, purchasers, government programs, and the health care system as a whole. In addition, AHRQ is committed to presenting information in different formats so that consumers who make decisions about their own and their family’s health can benefit from the evidence.
Transparency and stakeholder input are essential to the Effective Health Care Program. Please visit the Web site (www.effectivehealthcare.ahrq.gov) to see draft research questions and reports or to join an e-mail list to learn about new program products and opportunities for input. Comparative Effectiveness Reviews will be updated regularly.
iii Acknowledgments
We would like to acknowledge with appreciation the members of the Technical Expert Panel for their advice and consultation. In addition, we would also like to acknowledge Eric Johnson, Ph.D., for reviewing this manuscript.
Technical Expert Panel
Vibeke Strand, M.D. Adjunct Clinical Professor Division of Immunology, Stanford University Portola Valley, CA Expertise: Rheumatology
Kenneth Saag, M.D., M.Sc. UAB Center for Education and Research on Therapeutics (CERTs) of Musculoskeletal Disorders Birmingham, AL Expertise: Rheumatology
Leslie J. Crofford, M.D. UK Hospital, University of Kentucky Lexington, KY Expertise: Rheumatology
Michel Boucher, B.Pharm., M.Sc. Canadian Coordinating Office for Health Technology Assessment Ottawa, Ontario Expertise: Pharmacology
Lara Maxwell Coordinator, Cochrane Musculoskeletal Group Institute of Population Health University of Ottawa Ottawa, Ontario Expertise: Rheumatology
AHRQ Contacts
Beth A. Collins Sharp, Ph.D., R.N. Carmen Kelly, Pharm.D., R.Ph. Director Task Order Officer Evidence-based Practice Center Program Evidence-based Practice Center Program Center for Outcomes and Evidence Center for Outcomes and Evidence Agency for Healthcare Research and Quality Agency for Healthcare Research and Quality Rockville, MD Rockville, MD
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Contents
Executive Summary ...... 1
Chapter 1. Introduction...... 17 Scope and Key Questions ...... 19
Chapter 2. Methods...... 23 Topic Development...... 23 Search Strategy ...... 23 Study Selection ...... 23 Data Extraction ...... 24 Quality Assessment...... 24 Assessing Research Quality...... 24 Assessing Research Applicability...... 24 Rating a Body of Evidence ...... 25 Data Synthesis...... 25 Effectiveness Versus Efficacy ...... 25 Data Presentation ...... 25
Chapter 3. Results ...... 27 Overview...... 27 Key Question 1a. What are the Comparative Benefits and Harms of Treating Osteoarthritis with Oral Medications or Supplements?...... 27 Benefits: Effectiveness and Efficacy ...... 27 Safety: Serious Gastrointestinal and Cardiovascular Events...... 30 Other Adverse Events Associated with Selective and Non-Selective NSAIDs ...... 61 Key Question 1b. How Do these Benefits and Harms Change with Dosage and Duration of Treatment, and What is the Evidence that Alternative Dosage Strategies, such as Intermittent Dosing and Drug Holidays, Affect the Benefits and Harms of Oral Medication Use? ...... 73 Key Question 2. Do the Comparative Benefits and Harms of Oral Treatments for Osteoarthritis Vary for Certain Demographic and Clinical Subgroups? ...... 75 Demographic Subgroups Include Age, Sex, and Race ...... 75 Co-Existing Diseases Include History of Previous Bleeding Ulcer due to NSAIDs; Hypertension, Edema, Ischemic Heart Disease, and Heart Failure ...... 76 Concomitant Anticoagulant or Aspirin Use...... 77 Key Question 3. What Are the Comparative Effects of Co-Prescribing of H2-Antagonists, Misoprostol, or Proton Pump Inhibitors (PPIs) on the Gastrointestinal Harms Associated with NSAID Use?...... 80 Key Question 4. What Are the Comparative Benefits and Harms of Treating Osteoarthritis with Oral Medications as Compared with Topical Preparations?...... 81 Topical NSAIDs – Efficacy...... 81 Topical NSAIDs – Safety ...... 84 Topical Salicylates (Including Capsaicin) ...... 85
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Chapter 4. Summary and Discussion...... 87 Discussion...... 92
Chapter 5. Future Research ...... 97
Addendum ...... 99
References...... 101
Tables
Table 1. One year risk of GI bleeding due to NSAID ...... 18 Table 2. Comparison of rofecoxib and celecoxib in flare-ups of chronic osteoarthritis of the knee...... 29 Table 3. Head to head efficacy comparisons at 6 weeks (mean change from baseline)...... 30 Table 4. Re-analysis of the CLASS and VIGOR Trials ...... 35 Table 5. CV events in trials of rofecoxib versus non-selective NSAIDs: meta-analyses...... 39 Table 6. CV events in trials of rofecoxib versus placebo: meta-analyses ...... 41 Table 7. CV events in trials of celecoxib: meta-analysis of 15 trials in patients with arthritis ...... 42 Table 8. CV events in trials of celecoxib: meta-analysis of 41 trials ...... 42 Table 9. MI’s in trials of celecoxib: meta-analysis of 31 trials in patients with arthritis ...... 43 Table 10. MI’s in trials of celecoxib: meta-analysis of trials of at least 6 weeks duration with published or publicly available data ...... 44 Table 11. CV events in trials of celecoxib: meta-analysis of 41 trials of at least 4 weeks duration ...... 44 Table 12. Serious GI events in observational studies ...... 46 Table 13. Cardiovascular events in observational studies ...... 48 Table 14. Baseline rates of MI, upper GI bleed, and congestive heart failure (CHF) and risk associated with selective and non-selective NSAIDs in an Ontario cohort of elderly persons...... 51 Table 15. Effects of selective or non-selective NSAIDs on number of serious adverse events ...... 51 Table 16. Myocardial infarction in trials of valdecoxib for chronic pain: meta-analysis of 19 trials ...... 52 Table 17. Cardiovascular events in trials of valdecoxib versus placebo: meta-analysis of 14 trials ...... 53 Table 18. Relative Risk (95% CI) of UGIB for NSAIDs vs. non-use...... 57 Table 19. Rate Ratios (95% CI): COX 2 inhibitor relative to NSAID ...... 58 Table 20. Risk of myocardial infarction associated with naproxen in recent observational studies not included in the Juni meta-analysis ...... 59 Table 21. Risk of myocardial infarction associated with non-selective, non-naproxen NSAIDs...... 60
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Table 22. Toxicity Index Scores from ARAMIS database studies...... 66 Table 23. Tolerability profile of COX-2’s vs. NSAIDs in meta-analysis and systematic reviews ...... 67 Table 24. Pain relief in systematic reviews of acetaminophen versus NSAID ...... 68 Table 25. Adverse events in systematic reviews of acetaminophen versus NSAID ...... 69 Table 26. Incidence of hypertension in the Nurses’ Health Study and Physicians’ Health Study according to use of acetaminophen or NSAIDs...... 71 Table 27. Response rates in the Glucosamine/chondroitin Arthritis Intervention Trial (GAIT) ...... 73 Table 28. Celecoxib in patients with bleeding ulcer history...... 76 Table 29. Placebo-controlled trials of gastroprotective agents...... 80 Table 30. Head-to-head trials of gastroprotective agents ...... 81 Table 31. Head-to-head trials of topical versus oral NSAID for osteoarthritis ...... 82 Table 32. Clinical success rates in recent placebo-controlled trials of topical NSAIDs ...... 83 Table 33. Adverse events from a trial comparing topical to oral diclofenac...... 85 Table 34. Summary of findings with strength of evidence...... 87
Figures
Figure 1. Clinical success in trials comparing a topical versus an oral NSAID ...... 83 Figure 2. Withdrawal due to adverse events in trials comparing a topical to an oral NSAID ...... 84
Appendixes
Appendix A. Pharmacokinetics, Indications and Dosing of Included Drugs ...... 118 Appendix B. Cycloxygenase Selectivity of NSAIDs ...... 123 Appendix C. Comparable NSAID Dose Levels ...... 124 Appendix D. Exact Search Strings...... 125 Appendix E. Quality Assessment Methods ...... 130 Appendix F. Evidence Tables...... 133
vii Executive Summary
Background
Osteoarthritis is a chronic condition involving degeneration of cartilage within the joints. It is the most common form of arthritis and is associated with pain, substantial disability, and reduced quality of life. About 6 percent of U.S. adults aged 30 years or older have symptomatic osteoarthritis of the knee, and 3 percent have symptomatic osteoarthritis of the hip. Osteoarthritis increases with age: the incidence and prevalence increase two- to tenfold from age 30 to 65 and continue to increase after age 65. The total costs for arthritis, including osteoarthritis, may be greater than 2 percent of the gross domestic product, with more than half of these costs related to work loss. Common oral medications for osteoarthritis include nonsteroidal antiinflammatory drugs (NSAIDs) and acetaminophen. Patients with osteoarthritis also use over-the-counter supplements not regulated by the U.S. Food and Drug Administration (FDA) as pharmaceuticals, including glucosamine and chondroitin, as well as topical agents. Opioid medications are also used for selected patients with refractory, chronic pain but are not recommended for first-line treatment of osteoarthritis and therefore not included in this review. Each class of medication or supplement is associated with a unique balance of risks and benefits. In addition, efficacy and safety may vary for individual drugs within a class. Nonpharmacologic interventions (such as physical therapy, weight reduction, and exercise) also help improve pain and functional status in patients with osteoarthritis. A challenge in treating osteoarthritis is deciding which medications will provide the greatest symptom relief with the fewest serious adverse effects. NSAIDs decrease pain, inflammation, and fever by blocking cyclo-oxygenase (COX) enzymes. Understanding of the pharmacology of NSAIDs continues to evolve, but it is now thought that most NSAIDs block three different COX isoenzymes, known as COX-1, COX-2, and COX-3. COX-1 protects the lining of the stomach from acid. COX-2 is found in joint and muscle, and mediates effects on pain and inflammation. By blocking COX-2, NSAIDs reduce pain compared to placebo in patients with arthritis, low back pain, minor injuries, and soft tissue rheumatism. However, NSAIDs that also block the COX-1 enzyme (also called “nonselective NSAIDs”) can cause gastrointestinal bleeding. In the United States, there are an estimated 16,500 annual deaths due to NSAID-induced gastrointestinal complications, a higher death rate than that for cervical cancer or malignant melanoma. Theoretically, NSAIDs that block only the COX-2 enzyme (also called “coxibs,” “COX-2 selective NSAIDs,” or “selective NSAIDs”) should be safer with regard to gastrointestinal bleeding, but they also appear to be associated with increased rates of serious cardiovascular and other adverse effects. Less is known about COX-3, which is found in the cerebral cortex and cardiac tissue and appears to be involved in centrally mediated pain. For this report, we defined the terms “selective NSAIDs” or “COX-2 selective NSAIDs” as drugs in the “coxib” class (celecoxib, rofecoxib, valdecoxib, etoricoxib, lumiracoxib). We defined “partially selective NSAIDs” as other drugs shown to have partial in vitro COX-2 selectivity (etodolac, nabumetone, meloxicam). Aspirin differs from other NSAIDs because it irreversibly inhibits platelet aggregation, and the salicylic acid derivatives (aspirin and salsalate)
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were considered a separate subgroup. We defined “nonaspirin, nonselective NSAIDs” or simply “nonselective NSAIDs” as “all other NSAIDs.” This report summarizes the available evidence comparing the benefits and harms of analgesics in the treatment of osteoarthritis.
Oral agents include: • Aspirin • Ketorolac • Aacetaminophen • Lumiracoxib1 • Celecoxib • Meclofenamate sodium • Choline magnesium trisalicylate • Mefenamic acid • Chondroitin • Meloxicam • Diclofenac • Nabumetone • Diflunisal • Naproxen • Etodolac • Oxaprozin • Etoricoxib1 • Piroxicam • Fenoprofen • Rofecoxib1 • Flurbiprofen • Salsalate • Glucosamine • Sulindac • Ibuprofen • Tenoxicam1 • Indomethacin • Tiaprofenic acid1 • Ketoprofen • Tolmetin • Ketoprofen ER • Valdecoxib1 1 These drugs are currently not approved by the FDA for use in the United States (etoricoxib, lumiracoxib, tenoxicam, tiaprofenic acid) or have been withdrawn from the market (rofecoxib and valdecoxib).
Questions addressed in this report are:
1. What are the comparative benefits and harms of treating osteoarthritis with oral medications or supplements? How do these benefits and harms change with dosage and duration of treatment, and what is the evidence that alternative dosage strategies, such as intermittent dosing and drug holidays, affect the benefits and harms of oral medication use? (Note: The only benefits considered under this question are improvements in osteoarthritis symptoms from long-term use. Evidence of harms associated with NSAID use include long-term studies of these drugs for treating osteoarthritis or rheumatoid arthritis and for cancer prevention.
2. Do the comparative benefits and harms of oral treatments for osteoarthritis vary for certain demographic and clinical subgroups of patients?
● Demographic subgroups include age, sex, and race.
● Coexisting diseases include hypertension, edema, ischemic heart disease, heart failure; peptic ulcer disease; history of previous bleeding due to NSAIDs.
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● Concomitant medication use includes anticoagulants.
3. What are the comparative effects of coprescribing of H2-antagonists, misoprostol, or proton pump inhibitors (PPIs) on the gastrointestinal harms associated with NSAID use? 4. What are the comparative benefits and harms of treating osteoarthritis with oral medications as compared with topical preparations? Topical preparations include: capsaicin, diclofenac, ibuprofen, ketoprofen, and salicylate.
A summary of the findings is shown in Table A.
Conclusions
Oral NSAIDs
Benefits: improvements in osteoarthritis symptoms
• Nonselective NSAID vs. another nonselective NSAID