The coronary risk of cyclo-oxygenase-2 inhibitors in patients with a previous myocardial infarction
J M Brophy*, L E Lévesque and B Zhang
Department of Epidemiology and Biostatistics, McGill University Health Centre, McGill University, Montréal, Canada
Background: Cyclo-oxygenase-2 selective inhibitors have been associated with cardiovascular side effects, but previous studies have generally excluded people with previous myocardial infarction, thereby limiting our knowledge of their cardiotoxicity in this population.
Objectives: To determine whether a history of myocardial infarction modified the risk of acute myocardial infarction associated with the use of various non-steroidal anti-inflammatory drugs (NSAIDs).
Methods: A population-based cohort of 122 079 elderly people with and without previous myocardial infarction newly treated with an NSAID between 1 January 1999 and 30 June 2002 were identified using the computerised health databases of Québec, Canada. A nested-case–control approach was used for the analysis, with controls matched by cohort entry and age. Current users of NSAIDs, those whose last prescription overlapped with the index date, were compared with those who were not exposed to NSAIDs in the year preceding the event. Rate ratios of acute myocardial infarction were estimated using conditional logistic regression and adjusted for potential confounders.
Results: Users of rofecoxib, both with and without previous myocardial infarction, were at increased risk of myocardial infarction, with a trend for greater risk among those with a previous event (rate ratio (RR) 1.59, 95% confidence interval (CI) 1.15 to 2.18 v RR 1.23, 95% CI 1.05 to 1.45; p = 0.14 for interaction). By contrast, celecoxib was only associated with an increased risk in people with previous myocardial infarction (RR 1.40, 95% CI 1.06 to 1.84 v RR 1.03, 95% CI 0.88 to 1.20; p = 0.04 for interaction). The available power was insufficient to reliably assess risks among patients with previous myocardial infarction treated with other NSAIDs, dose–response relationships or interaction with aspirin.
Conclusions: Although only rofecoxib use was associated with an increased risk of myocardial infarction in those without a previous event, both rofecoxib and celecoxib were associated with an excess risk of acute myocardial infarction for current users with a history of myocardial infarction. A large randomised trial is required to more completely and reliably assess the cardiovascular safety of celecoxib and traditional NSAIDs in this population of high-risk patients.
Abbreviations: Cox-2, cyclo-oxygenase-2; NSAID, non-steroidal anti-inflammatory drug
Heart 2007;93:189-194
© 2007 by BMJ Publishing Group Ltd & British Cardiovascular Society
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Aspirin versus acetaminophen: a comparative view.
I read with great interest the recently published EULAR recommendations for the management of early arthritis.(1) In this regard, I would like to add a few words of comment concerning the use of analgesics in patients with cardiovascular (CV) and gastrointestinal (GI) risk factors. In my opinion the rational choice for such patients is the use of aspirin combined with a proton-pump inhibitor.
First, both coxibs and traditional NSAIDs should not be prescribed in patients at higher CV risk. On the contrary, there is good evidence that analgesic doses of aspirin (up to 1500mg) are associated with protection from CV events.(2,3) Furthermore, aspirin dose or its higher lifetime use is not significantly associated with hypertension(4) or renal toxicity.(5,6) Importantly, a recent meta- analysis of 24 randomised controlled trials found no evidence of dose- responsiveness for bleeds over a wide range of doses (50 to 1500 mg/day).(7) Indeed, aspirin in doses commonly used in practice, seems to have an excellent safety profile.(8)
Second, recent evidence suggest that not only NSAIDs but also acetaminophen can raise cardiovascular risk.(9) High acetaminophen use may also increase the risk of hypertension(4) and a decrease of renal function.(5) Interestingly, increased acetaminophen use has now been linked to increased prevalence of asthma and chronic obstructive pulmonary disease, and with lowered lung function.(10) Surprisingly, a recent case-control study showed that acetaminophen (>2 g per day) was ssociated with a greater risk of GI perforation or bleed(11) and one cohort study reported a dose-response relationship between acetaminophen and dyspepsia.(12) It appears that regular use of acetaminophen is also associated with symptoms of severe diverticular disease, particularly bleeding.(13)
Lastly, compelling evidence suggests that both aspirin and other NSAIDs are superior to acetaminophen for improving moderate-to-severe painin patients with osteoarthritis(14,15,16) and rheumatoid arthritis.(17) Likewise, in acute pain states aspirin provides significant and more rapid analgesia than acetaminophen.(18)
References
1. Combe B, Landewe R, Lukas C, Bolosiu HD, Breedveld F, Dougados M, et al. EULAR recommendations for the management of early arthritis: report of a task force of the European Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis 2007;66:34-45. Epub 2006 Jan 5.
2. Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324:71-86.
3. Johnson ES, Lanes SF, Wentworth CE 3rd, Satterfield MH, Abebe BL, Dicker LW.A metaregression analysis of the dose-response effect of aspirin on stroke. Arch Intern Med 1999;159:1248-53.
4. Forman JP, Stampfer MJ, Curhan GC. Non-narcotic analgesic dose andrisk of incident hypertension in US women. Hypertension 2005;46:500-7.
5. Curhan GC, Knight EL, Rosner B, Hankinson SE, Stampfer MJ. Lifetime nonnarcotic analgesic use and decline in renal function in women. Arch Intern Med 2004;164:1519-24.
6. Dubach UC, Rosner B, Sturmer T. An epidemiologic study of abuse of analgesic drugs. Effects of phenacetin and salicylate on mortality and cardiovascular morbidity (1968 to 1987) N Engl J Med 1991;324:155-60.
7. Derry S, Loke YK. Risk of gastrointestinal haemorrhage with long term use of aspirin: meta-analysis. BMJ 2000;321:1183-7.
8. Fries JF, Ramey DR, Singh G, Morfeld D, Bloch DA, Raynauld JP. A reevaluation of aspirin therapy in rheumatoid arthritis. Arch Intern Med 1993;153:2465-71.
9. Chan AT, Manson JE, Albert CM, Chae CU, Rexrode KM, Curhan GC, et al. Nonsteroidal antiinflammatory drugs, acetaminophen, and the risk of cardiovascular events. Circulation 2006;113:1578-87.
10. McKeever TM, Lewis SA, Smit HA, Burney P, Britton JR, Cassano PA. The association of acetaminophen, aspirin, and ibuprofen with respiratory disease and lung function. Am J Respir Crit Care Med 2005;171:966-71.
11. Garcia Rodriguez LA, Hernandez-Diaz S. Relative risk of upper gastrointestinal complications among users of acetaminophen and nonsteroidal anti-inflammatory drugs. Epidemiology 2001;12:570-6.
12. Rahme E, Pettitt D, LeLorier J. Determinants and sequelae associated with utilization of acetaminophen versus traditional nonsteroidal antiinflammatory drugs in an elderly population. Arthritis Rheum 2002;46:3046-54.
13. Aldoori WH, Giovannucci EL, Rimm EB, Wing AL, Willett WC. Use of acetaminophen and nonsteroidal anti-inflammatory drugs: a prospective study and the risk of symptomatic diverticular disease in men. Arch Fam Med 1998;7:255-60.
14. Lee C, Straus WL, Balshaw R, Barlas S, Vogel S, Schnitzer TJ. A comparison of the efficacy and safety of nonsteroidal antiinflammatory agents versus acetaminophen in the treatment of osteoarthritis: a meta-analysis. Arthritis Rheum 2004;51:746-54.
15. Towheed TE, Maxwell L, Judd MG, Catton M, Hochberg MC, Wells G. Acetaminophen for osteoarthritis. Cochrane Database Syst Rev 2006;(1):CD004257.
16. Zhang W, Jones A, Doherty M. Does paracetamol (acetaminophen) reduce the pain of osteoarthritis? A meta-analysis of randomised controlled trials. Ann Rheum Dis 2004;63:901-7.
17. Wienecke T, Gotzsche PC. Paracetamol versus nonsteroidal anti-inflammatory drugs for rheumatoid arthritis. Cochrane Database Syst Rev 2004;(1):CD003789.
18. Seymour RA, Hawkesford JE, Sykes J, Stillings M, Hill CM. An investigation into the comparative efficacy of soluble aspirin and solid paracetamol in postoperative pain after third molar surgery. Br Dent J 2003;194:153-7.
Michal R. Pijak,
Assistant Professor and Consultant in Internal Medicine, Rheumatology and Clinical Immunology
Department of Internal Medicine, Slovak Medical University, Bratislava, Slovakia
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