Aspirin Wars
1996; Lippincott Williams & Wilkins; Volume: 27; Issue: 4 Linguagem: Inglês
10.1161/01.str.27.4.585
ISSN1524-4628
AutoresRobert G. Hart, Michael Harrison,
Tópico(s)Inflammatory mediators and NSAID effects
ResumoHomeStrokeVol. 27, No. 4Aspirin Wars Free AccessResearch ArticleDownload EPUBAboutView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticleDownload EPUBAspirin Wars The Optimal Dose of Aspirin to Prevent Stroke Robert G. Hart and Michael J.G. Harrison Robert G. HartRobert G. Hart From the Department of Medicine (Neurology), University of Texas Health Science Center, San Antonio, Texas (R.G.H.), and the Reta Lila Weston Institute of Neurological Studies, University College London Medical School, London, England (M.J.G.H.). and Michael J.G. HarrisonMichael J.G. Harrison From the Department of Medicine (Neurology), University of Texas Health Science Center, San Antonio, Texas (R.G.H.), and the Reta Lila Weston Institute of Neurological Studies, University College London Medical School, London, England (M.J.G.H.). Originally published1 Apr 1996https://doi.org/10.1161/01.STR.27.4.585Stroke. 1996;27:585–587In 1899, Farbenfabriken Bayer introduced acetylsalicylic acid (brand name, aspirin) for the treatment of fever and rheumatism, assuring consumers that it had no effect on the heart.1 At that time, the more commercially promising product of this respected pharmaceutical firm was the recently synthesized heroin, successfully marketed as a cough suppressant and for colic of infants.1 Times have changed.Interestingly, the clinical antithrombotic effects of aspirin were not widely recognized until the 1970s.2 Aspirin reduces the risk of myocardial infarct, ischemic stroke, and vascular death for many patients.3 In this issue of Stroke, Patrono and Roth4 argue persuasively that the optimal dose of aspirin to prevent stroke is the same as that to prevent myocardial infarction and need not exceed 75 mg/d. Their conclusion is based on careful scrutiny of existing clinical data and on the maximal inhibition of platelet thromboxane synthesis by low doses of aspirin,5 the presumed major mediator of the clinical antithrombotic effect of aspirin.The strongest clinical support for their contention comes from two randomized trials that directly compared different doses of aspirin in patients with transient ischemic attack (TIA) or minor ischemic stroke.67 These well-executed trials showed that an aspirin dose of 283 mg/d is unlikely to be more than 5% better than 30 mg/d7 and that 1200 mg/d is unlikely to be more than 25% better than 300 mg/d6 for stroke prevention, with small nonsignificant trends favoring the lower doses. Some have argued that recruits to these trials were not typical of patients with advanced cerebrovascular disease, either because of young age (mean age of 60 years in one study6 ) or because of their benign natural history (stroke rates of 3.2% per year when given placebo6 and about 3% per year given aspirin7 ), but there is no compelling evidence that such differences influence the relationship between aspirin dose and its efficacy. Considering the extreme limits of the 95% confidence intervals from these two trials, a 30% difference in aspirin efficacy between doses of 30 mg and 1300 mg is possible.67 We have little confidence in indirect comparisons of aspirin dose and efficacy for stroke prevention,8 since it is likely that the relative efficacy of aspirin for stroke prevention varies between patient populations with different spectra of stroke mechanisms independent of aspirin dose, confounding indirect comparisons.9 In short, the best existing clinical evidence supports the concept that 75 mg/d aspirin is effective for stroke prevention and that higher doses may offer no additional protection.However, there are some loose ends. In the double-blind Dutch TIA Trial, epistaxis and minor nongastrointestinal bleeding occurred twice as often in patients given 283 mg/d versus 30 mg/d aspirin (P<.01).7 This finding, while not directly relevant to stroke prevention, suggests a dose-related difference in in vivo antithrombotic effect, albeit of unclear mechanism and unconfirmed. A double-blind comparison of 300 mg/d to 1200 mg/d showed no difference in nongastrointestinal bleeding.6 Anecdotal clinical observations suggest that higher doses of aspirin may confer greater benefit in high-risk patients with cerebrovascular disease.810 The optimal laboratory method correlating platelet aggregation with in vivo efficacy is unclear, and several studies report that higher doses of aspirin are sometimes required to fully suppress in vitro platelet aggregation induced by varying types and concentrations of stimuli,111213 although the relevance to stroke prevention and reproducibility are open to question, as pointed out by Patrono and Roth.4 That different doses of aspirin differentially influence atherogenesis1415 or mediate stroke prevention by mechanisms unrelated to platelet thromboxane inhibition1617 has been suggested but not rigorously assessed. Confidence that the beneficial effect of aspirin for stroke prevention is exclusively mediated by the currently characterized antiplatelet effects would be arrogance, as the unknown can surely be expected to loom larger than the known in clinical medicine.A critical element of the aspirin-dose controversy is the link between dose and the absolute rate of serious toxicity. When considering major hemorrhage in aspirin-treated patients, the rate of such bleeding in untreated patients of similar age and with similar comorbidities must also be accounted for (0.5% to 1.0% per year; Table). The absolute rate of major bleeding during aspirin therapy is likely age-related.24 Most major hemorrhages during aspirin therapy are gastrointestinal and directly related to dose,2829 explained by the antithrombotic effect of aspirin amplified by a dose-related erosive effect on enteric mucosa. The risk of intracranial hemorrhage is probably doubled by aspirin to absolute rates of 0.2% to 0.3% per year for elderly stroke-prone patients, with no apparent relation to aspirin dose.692030 The absolute rates of major hemorrhage have varied substantially in trials of stroke-threatened patients (Table), with incremental increases of 0.3% to 0.7% per year in patients given aspirin in various doses. About 20% of major hemorrhages in patients taking aspirin are fatal.672224 In the only direct comparison of 30 mg/d to 283 mg/d, there were only small absolute increases in major hemorrhage (0.3% per year [95% confidence interval, 0% to 0.8% per year]) and fatal bleeding (0.15% per year) that were not statistically significant.7 Thus, in absolute terms, the incremental increase in major hemorrhage with higher doses of aspirin is small, although many patients are unable to sustain high-dose aspirin because of minor side effects.2731 Enteric coating reduces gastrointestinal toxicity and appears to inhibit thromboxane synthesis in a manner similar to equal doses of uncoated preparations, despite altered pharmacokinetics and dynamics.32333435363738394041Even if a 30% increase in aspirin efficacy exists with higher doses42 (translating into a 26% relative risk reduction in stroke by the higher dose versus approximately 20% by the lower dose), about 275 patients would need to be treated with the higher dose to prevent one additional stroke each year for TIA patients who have a 6% annual rate of stroke. For patients with a higher intrinsic stroke rate of 10% per year, 150 patients would need to be given the higher dose to prevent one stroke per year, offset by about one additional major hemorrhage. Seemingly, "all doses of aspirin are equally ineffective"43 when considering therapy for individual patients. On the other hand, from a public health perspective, even a modest increase in the efficacy of aspirin by dose could prevent or postpone tens of thousands of strokes yearly with a net savings in healthcare costs.Are further clinical trials comparing different doses of aspirin for stroke prevention warranted, at present? Yes, but… . Other antiplatelet regimens, alone or including aspirin, and other antithrombotic agents would seem to have a greater potential efficacy versus different doses of aspirin, yet they will not likely match the low cost and low predictable toxicity of aspirin for stroke prevention. In our view, better understanding of mediators of the potential benefit of high-dose aspirin and more and better studies of differing doses of aspirin on surrogate markers1112131415 should precede large-scale, randomized trials. Such trials might best involve high-risk patients, for whom modest differences in the relative risk reduction of stroke with different doses of aspirin would be clinically important, if verified, and detectable with feasible sample sizes. Furthermore, it would be useful to define the relative efficacy of aspirin and of different doses of aspirin for specific pathogenetic subgroups (intracranial small-vessel disease, ulcerated carotid plaques, cardiac valvular abnormalities) rather than lumping together all patients with TIA and minor ischemic stroke of diverse mechanisms.For now, what is the "optimal" dose of aspirin to prevent ischemic stroke? Surveys indicate that 300 to 325 mg is most often prescribed (by 45% to 61% of physicians around the world) and that lower doses (by 35% to 51%) are used much more often than higher ones (by 4%).4445 Phenomenologically, it seems unlikely that a dose of aspirin (5 grains) formulated nearly 100 years ago for analgesia should be the optimal one for stroke prevention. The cumulative weight of existing clinical evidence favors low-dose (75 mg/d) aspirin, as advocated by Patrono and Roth.4 Depending on how much importance one attaches to the "loose ends" described above, the lowest effective dose associated with a negligible increase in serious side effects is also reasonable, favoring 300 to 325 mg/d enteric-coated aspirin. Patients at special risk for gastrointestinal bleeding should receive the lowest proven effective dose; patients at particularly high risk for ischemic stroke would benefit most if higher doses offer more protection. In our view, it is not yet time to declare a final victor in the aspirin-dose war.48 Table 1. Major Hemorrhage During Aspirin Therapy: Recent Studies in Stroke-Prone Patients1StudyMean Age, yRates of Major Hemorrhage, %/y2Placebo30-100 mg/d300-325 mg/d325 mg/d, Enteric-Coated900-1500 mg/dAFI18691.0…………Canadian19…0.7………0.0SALT2067±0.4±1.1………Dutch TIA7±66…1.01.3……UK-TIA6600.1…0.53…0.83Swedish2168±0.7………±1.0SPAF I22670.6……0.7…EAFT23730.3…0.3……SPAF II2470………1.1…TASS2563…………0.6Coté et al26660.3……0.3…Minar et al2766…0.0……0.5AFI indicates Atrial Fibrillation Investigators; SALT, Swedish Aspirin Low-Dose Trial; SPAF, Stroke Prevention in Atrial Fibrillation; EAFT, European Atrial Fibrillation Trial; and TASS, Ticlopidine Aspirin Stroke Study.1Additionally, the US Physicians Health Study found various types of major and minor bleeding increased by 1.2- to 2.0-fold with use of 325 mg buffered aspirin every other day. The absolute rate of major bleeding was low (about 0.15% per year), likely due to the young age and the general good health of the participants and the run-in period to exclude aspirin intolerance.2As criteria for major bleeding in each study varied, these figures are for general comparison only. Those subjects requiring hospitalization with blood transfusion and those with intracranial bleeding or permanent residual disability are included here, when determinable.3Enteric-coated aspirin was used for part of the study.We thank Ruth McBride for statistical assistance, Robert Talbert (San Antonio, Tex) and Peter Koudstaal (Rotterdam, Netherlands) for critical reading of the manuscript (but they do not necessarily endorse the views expressed) and Michelle Lewis for able secretarial work.FootnotesCorrespondence to Robert G. Hart, MD, Department of Medicine (Neurology), University of Texas Health Science Center, 7703 Floyd Curl Dr, San Antonio, TX 78284-7883. 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