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Summing the risk of NSAID therapy
See Articles page 1621
Reports concluding that chronic use of non-steroidal synthesis of the literature—not complete reliance on anti-infl ammatory drugs (NSAIDs) increases the likelihood single studies that address one outcome—is required to of cardiovascular adverse events have led patients and inform decisionmaking. This stepwise approach is crucial, clinicians to reduce use. It is intriguing to recollect that the because appropriate selection of an NSAID should be cardiotoxicity of NSAIDs (both cyclo-oxygenase-2 [COX-2] driven by assessment of an individual’s cardiovascular selective inhibitors and non-selective dual inhibitors have and gastrointestinal risk, or both, rather than by a been implicated) would not have been revealed if not drug’s reported rate of adverse events in heterogeneous for the push to market novel drugs developed to reduce populations (table).1the well-documented gastrointestinal complications of The importance of individualised risk assessment and this widely used class. While weighing risks and benefi ts its role on a single NSAID-related safety outcome is of interventions is an essential component of clinical exemplifi ed in the study by Frances Chan and colleagues in decisionmaking, it has become increasingly complex to today’s Lancet.3 They report that the twice-daily addition of decide in whom the use of any NSAID—with or without a a proton-pump inhibitor to twice daily celecoxib lowered gastroprotective agent, and with or without concomitant the 13-month recurrence of ulcer bleeding to 0% in the aspirin—is appropriate. In view of the multiplicity, and in combined treatment group compared with 8·9% with many cases rarity, of adverse events, it is unlikely that a celecoxib alone (95% CI for the diff erence, 4·1–13·7). The single mega-trial will adequately address the numerous trial enrolled individuals at highest risk of a gastrointest-safety and eff ectiveness issues. In the meantime, careful inal complication: those with previous gastrointestinal bleeding. While the complete absence of recurrent events No or low NSAID
NSAID gastrointestinal risk
gastrointestinal risk
for those on combination therapy, even in the face of aspirin therapy, is surprising, the fi nding provides clear COX-2 selective inhibitor or non-selective guidance for those individuals at greatest gastrointestinal COX-2 selective inhibitor+proton-pump inhibitor for those with prior gastrointestinal bleeding risk who require an NSAID. The incremental risk-reduction Proton-pump inhibitor irrespective of NSAID of a proton-pump inhibitor in the setting of aspirin and Naproxen if CV risk outweighs gastrointestinal risk a COX-2 inhibitor is consistent with the trials comparing inhibitor if gastrointestinal risk COX-2 selective inhibitor+proton-pump inhibitor of aspirin/NSAID combination for those with previous gastrointestinal bleeding etoricoxib and diclofenac.4 The MEDAL programme combined data from three trials and the fi ndings contrast *Non-selective or selective (low-dose) inhibitor without established aspirin interaction if naproxen is ineff ective.2 with those from several studies showing no signifi cant Misoprostol at full dose (200 μg four times a day) may be substituted for proton-pump inhibitor. Adapted from reference 1.
gastrointestinal safety benefi t of COX-2 inhibitors plus Table: Clinicians guide to anti-infl ammatory therapy in 2007
aspirin over a traditional NSAID-aspirin combination.5,6 www.thelancet.com Vol 369 May 12, 2007
This new information supporting the gastrointestinal questions. As important pieces are added to the puzzle, advantage of a combination of a COX-2 and proton-pump it remains critical to sum the risks using all the parts.
inhibitor should not to be interpreted without careful consideration of competing risks from the cardiovascular *James M Scheiman, A Mark Fendrickperspective. For individuals with documented cardio- Division of Gastroenterology, Department of Internal Medicine, vascular risks, the selection of an NSAID is not University of Michigan School of Medicine, Ann Arbor, MI 48109, USA (JMS); and Departments of Internal Medicine and Health straightforward. Recent position statements,7 supported Management & Policy, University of Michigan Schools of Medicine by collective but not conclusive data,8 suggest that and Public Health, Ann Arbor, Michigan, USA (AMF) naproxen is diff erentiated from other selective and jscheima@umich.edunon-selective agents that may increase cardiovascular JS is a consultant for AstraZeneca, Merck, Novartis, Pfi zer, Pozen, Bayer, GSK, PLx risk. For those with competing cardiovascular and Pharma, NiCox, Horizon Therapeutics, and TAP Pharmaceuticals, and has received speaker’s honoraria from AstraZeneca, Takeda, Santarus, and TAP Pharmaceuticals; gastrointestinal risks, the tradeoff s between reducing MF receives research support from Amgen, Merck and Co, Pfi zer Inc, Johnson and gastrointestinal adverse events (COX-2 inhibitor instead of Johnson, Sanofi , and Aventis Pharmaceuticals, is on a speakers bureau for Pfi zer, AstraZeneca, and TAP, and is a consultant for ActiveHealth Management, a non-selective NSAID) must be explicitly weighed against AstraZeneca Pharmaceuticals, Eli Lilly and Co, GlaxoSmithKline, MedImpact HealthCare Systems Inc, Merck and Co, Pfi zer Inc, Johnson and Johnson, vascular side-eff ects (naproxen Sanofi -Aventis Pharmaceuticals, TAP Pharmaceuticals, and Value Based Benefi ts Inc.
Scheiman, JM., Fendrick AM. Practical approaches to minimizing In addition to individual patients’ characteristics, gastrointestinal and cardiovascular safety concerns with COX-2 inhibitors and
NSAIDs. Arthritis Res Ther 2005; 7 (suppl 4): S23–29.
attention to dose, administration, and duration of NSAID 2 Grosser T, Fries S, Fitzgerald GA. Biological basis for the cardiovascular use should also be considered. Chan and colleagues used consequences of COX-2 inhibition: therapeutic challenges and opportunities.
J Cllin Invest 2006; 116: 4–15.
celecoxib 200 mg twice daily, a dose with established 3 Chan FKL, Wong VWS, Suen BY, et al. Combination of a cyclo-oxygenase-2 inhibitor and a proton-pump inhibitor for prevention of recurrent ulcer cardiovascular risk.9 There is no published evidence that bleeding in patients at very high risk: a double-blind, randomised trial. concomitant aspirin lessens the increased cardiovascular Lancet 2007; 369: 1621–26.
Laine L, Curtis SP, Cryer B, for the MEDAL Steering Committee. Assessment of risk observed with COX-2 selective inhibitors,9,10 A once upper gastrointestinal safety of etoricoxib and diclofenac in patients with daily 400 mg and 200 mg dose of celecoxib seems to osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: a randomised not share this hazard,11,12 at least in patients with average comparison. Lancet 2007; 369: 465–73.
Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with cardiovascular risk. On examination of the existing data, celecoxib vs nonsteroidal anti-infl ammatory drugs for osteoarthritis and NSAID adverse eff ects should not be attributed simply by rheumatoid arthritis: the CLASS study: a randomized controlled trial.
Celecoxib Long-term Arthritis Safety Study. JAMA 2000; 284: 1247–55.
drug classifi cation (ie, COX-2 selective inhibitor or non- Schnitzer TJ, Burmester GR, Mysler E, et al. Comparison of lumiracoxib with selective inhibitors), but instead by the dose and dura tion naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications: of COX-2 inhibition. While the ongoing PRECISION trial, randomised controlled trial. Lancet 2004; 364: 665–74.
Antman EM, Bennett JS, Daugherty A, Furberg C, Roberts H, Taubert KAA. Use in which naproxen, ibuprofen, and celecoxib are being of nonsteroidal antiinfl ammatory drugs: an update for clinicians: a scientifi c compared, will be informative, the lack of a placebo control statement from the American Heart Association. Circulation 2007; published online Feb 26. DOI:10.1161/CIRCULATIONAHA.106.181424.
arm and the years of data collection necessary require 8 Kearney PM, Baigent C, Godwin J, Halls H, Emberson JR, Patrono C. Do timely decisions be made with available data.13 selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal antiinfl ammatory drugs increase the risk of atherothrombosis? Meta-analysis Comment about costs is warranted, because it may not of randomised trials. BMJ 2006; 332: 1302–08.
Solomon SD, McMurray JJ, Pfeff er MA, et al. Cardiovascular risk associated be feasible to recommend the “safest” regimen in every with celecoxib in a clinical trial for colorectal adenoma prevention. circumstance. The cost-eff ectiveness of risk-reducing N Engl J Med 2005; 352: 1071–80.
10 Bresalier RS, Sandler RS, Quan H, et al. Cardiovascular events associated with therapies is intimately related to the patients’ underlying rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 2005; 352: 1092–102.
14 For those at highest gastrointestinal risk, the use of 11 Arber N, Eagle CJ, Spicak J, for the PreSAP Trial Investigators. Celecoxib for the a proton-pump inhibitor and a low-dose COX-2 inhibitor prevention of colorectal adenomatous polyps. N Engl J Med 2006; 355: 885–95.
seems cost eff ective for those without high cardiovascular 12 ADAPT Research Group. Cardiovascular and cerebrovascular events in the randomized, controlled Alzheimer’s Disease Anti-infl ammatory Prevention risk. In those patients in whom the cardiovascular risk Trial (ADAPT). PLoS Clin Trials 2006; 1: e33. http://dx.doi.org/10.1371/journal.
pctr.0010033 (accessed April 19, 2007).
parallels or exceeds gastrointestinal concerns, naproxen 13 PRECISION: Prospective Randomized Evaluation of Celecoxib Integrated with a proton-pump inhibitor is recommended when Safety vs Ibuprofen Or Naproxen. ClinicalTrials.gov Identifi er: NCT00346216. http://clinicaltrials.gov/ct/show/NCT00346216;jsessionid=D55628B7B188 792A5D69CD83784575F1?order=10 (accessed April 25, 2007).
14 Fendrick AM, Bandekar RR, Chernew ME, Scheiman JM. Role of initial NSAID The choice of NSAID remains confusing and contro- choice and patient risk factors in the prevention of NSAID gastropathy: versial in a setting of several important unanswered a decision analysis. Arthritis Rheum 2002; 47: 36–43.
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