This Article Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hart, R. G. Articles by Harrison, M. J.G. Search for Related Content PubMed PubMed Citation Articles by Hart, R. G. Articles by Harrison, M. J.G. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB ACETYLSALICYLIC ACID

(Stroke. 1996;27:585-587.)
© 1996 American Heart Association, Inc.

Articles

Aspirin Wars

The Optimal Dose of Aspirin to Prevent Stroke

Robert G. Hart, MD Michael J.G. Harrison, MD

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.).

Correspondence to Robert G. Hart, MD, Department of Medicine (Neurology), University of Texas Health Science Center, 7703 Floyd Curl Dr, San Antonio, TX 78284-7883.

Key Words: aspirin • platelet aggregation • stroke prevention

	Introduction

Top Introduction References

 
In 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.^{6 7} 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.^{6 7} 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.^{8 10} 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,^{11 12 13} 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 atherogenesis^{14 15} or mediate stroke prevention by mechanisms unrelated to platelet thromboxane inhibition^{16 17} 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,^{28 29} 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.^{6 9 20 30} 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.^{6 7 22 24} 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.^{27 31} 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.^{32 33 34 35 36 37 38 39 40 41}

View this table: [in this window] [in a new window]   Table 1. Major Hemorrhage During Aspirin Therapy: Recent Studies in Stroke-Prone Patients1

Even 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 markers^{11 12 13 14 15} 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%).^{44 45} 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.^{4 8}

	Acknowledgments

 
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.

	References

Top Introduction References

 

1. Mann CC, Plummer ML. The Aspirin Wars: Money, Medicine, and 100 Years of Rampant Competition. Boston, Mass: Harvard Business School Press; 1991.
2. Harrison MJG, Marshall J, Meadows JC. Effect of aspirin in amaurosis fugax. Lancet. 1971;2:743-744. [Medline] [Order article via Infotrieve]
3. Antiplatelet Trialists' Collaboration. Collaborative overview of randomized trials of antiplatelet therapy, I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ. 1994;308:81-106. [Abstract/Free Full Text]
4. Patrono C, Roth GJ. Aspirin in ischemic cerebrovascular disease: how strong is the case for a different dosing regimen? Stroke. 1996;27:756-760. [Abstract/Free Full Text]
5. Patrono C, Ciabattoni G, Patrignani P, Pugliese F, Filabozzi P, Catella F, Davi G, Forni L. Clinical pharmacology of platelet cyclooxygenase inhibition. Circulation. 1985;72:1177-1184. [Abstract/Free Full Text]
6. UK-TIA Study Group. The United Kingdom Transient Ischemic Attack (UK-TIA) aspirin trial: final results. J Neurol Neurosurg Psychiatry. 1991;54:1044-1054. [Abstract]
7. The Dutch TIA Trial Study Group. A comparison of two doses of aspirin (30 mg vs 283 mg a day) in patients after a transient ischemic attack or minor ischemic stroke. N Engl J Med. 1991;325:1261-1266. [Abstract]
8. Dyken ML, Barnett HJM, Easton JD, Fields WS, Fuster V, Hachinski V, Norris JW, Sherman DG. Low-dose aspirin and stroke: `it ain't necessarily so.' Stroke. 1992;23:1395-1399. [Free Full Text]
9. The Steering Committee of the Physicians' Health Study Research Group. Final report on the aspirin component of the ongoing Physicians' Health Study. N Engl J Med. 1989;321:129-135. [Abstract]
10. Bornstein NM, Karepov VG, Aronovich BD, Gorbulev AY, Treves TA, Korczyn AD. Failure of aspirin treatment after stroke. Stroke. 1994;25:275-277. [Abstract]
11. Helgason CM, Tortorici KL, Winkler SR, Penney DW, Schuler JJ, McClelland TJ, Brace LD. Aspirin response and failure in cerebral infarction. Stroke. 1993;24:345-350. [Abstract/Free Full Text]
12. Tohgi H, Konno S, Tamura K, Kimura B, Kawano K. Effects of low-to-high doses of aspirin on platelet aggregability and metabolites of thromboxane A₂ and prostacyclin. Stroke. 1992;23:1400-1403. [Abstract/Free Full Text]
13. Helgason CM, Bolin KM, Hoff JA, Winkler SR, Mangat A, Tortorice KL, Brace LD. Development of aspirin resistance in persons with previous ischemic stroke. Stroke. 1994;25:2331-2336. [Abstract]
14. Ranke C, Hecker H, Creutzig A, Alexander K. Dose-dependent effect of aspirin on carotid atherosclerosis. Circulation. 1993;87:1873-1879. [Abstract/Free Full Text]
15. Furberg CD, Adams HP, Applegate WB, Byington RP, Espeland MA, Hartwell T, Hunninghake DB, Lefkowitz DS, Probstfield J, Riley WA, Young B. Effect of lovastatin on early carotid atherosclerosis and cardiovascular events. Circulation. 1994;90:1679-1687. [Abstract/Free Full Text]
16. Ratnatunga CP, Edmondson SF, Rees GM, Kovacs IB. High-dose aspirin inhibits shear-induced platelet reaction involving thrombin generation. Circulation. 1992;85:1077-1082. [Abstract/Free Full Text]
17. Buchanan MR, Brister SJ. Individual variation of the effects of aspirin on platelet function: implications for the use of aspirin clinically. Can J Cardiol. 1995;11:221-227. [Medline] [Order article via Infotrieve]
18. Atrial Fibrillation Investigators. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Arch Intern Med. 1994;154:1449-1457. [Abstract]
19. Canadian Cooperative Study Group. A randomized trial of aspirin and sulfinpyrazone in the threatened stroke. N Engl J Med. 1978;299:53-59. [Abstract]
20. SALT Collaborative Group. Swedish Aspirin Low-Dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischemic events. Lancet. 1991;338:1345-1349. [Medline] [Order article via Infotrieve]
21. Swedish Cooperative Study Group. High-dose acetylsalicylic acid after cerebral infarction. Stroke.. 1987;18:325-334. [Abstract/Free Full Text]
22. Stroke Prevention in Atrial Fibrillation Investigators. Stroke prevention in atrial fibrillation study: final results. Circulation. 1991;84:528-539.
23. European Atrial Fibrillation Trial Study Group. Secondary prevention in nonrheumatic atrial fibrillation after transient ischaemic attack or minor stroke. Lancet. 1993;342:1255-1262. [Medline] [Order article via Infotrieve]
24. Stroke Prevention in Atrial Fibrillation Investigators. Bleeding during antithrombotic therapy in patients with atrial fibrillation. Arch Intern Med. 1996;156:409-415.[Abstract]
25. Hass WK, Easton JD, Adams HP Jr, Pryse-Phillips W, Molony BA, Anderson S, Kamm B, for the Ticlopidine Aspirin Stroke Study Group. A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients. N Engl J Med. 1989;321:501-507. [Abstract]
26. Coté R, Battista RN, Abrahamowicz M, Langlois Y, Bourque F, Mackey A. Lack of effect of aspirin in asymptomatic patients with carotid bruits and substantial carotid narrowing. Ann Intern Med. 1995;123:649-655. [Abstract/Free Full Text]
27. Minar E, Ahmadi A, Koppensteiner R, Maca T, Stumpflen A, Ugurluoglu A, Ehringer H. Comparison of effects of high-dose and low-dose aspirin on restenosis after femoropopliteal percutaneous transluminal angioplasty. Circulation. 1995;91:2167-2173. [Abstract/Free Full Text]
28. Roderick PJ, Wilkes HC, Meade TW. The gastrointestinal toxicity of aspirin: an overview of randomized controlled trials. Br J Clin Pharmacol. 1993;35:219-226. [Medline] [Order article via Infotrieve]
29. Prichard PJ, Kitchingman GK, Daneshmend TK, Walt RP, Hawkey CJ. Human gastric mucosal bleeding by low-dose aspirin, but not warfarin. BMJ. 1989;298:493-496.
30. Hart RG, Pearce LA. In vivo antithrombotic effect of aspirin: dose versus nongastrointestinal bleeding. Stroke.. 1993;24:138-139. Letter. [Medline] [Order article via Infotrieve]
31. Krupski WC, Weiss DG, Rapp JH, Corson JD, Hobson RW. Adverse effects of aspirin in the treatment of asymptomatic carotid artery stenosis. J Vasc Surg. 1992;16:588-600. [Medline] [Order article via Infotrieve]
32. McGuinness ME, Chaudhuri C, Hart RG, Talbert RL. Pharmacokinetics of enteric-coated aspirin in elderly patients with atrial fibrillation. Pharmacotherapy. 1995;15:109. Abstract.
33. Stampfer MJ, Jakubowski JA, Deykin D, Schafer AI, Willet WC, Hennekans CH. Effect of alternate day regular and enteric-coated aspirin on platelet aggregation, bleeding time and thromboxane A₂ levels in bleeding-time blood. Am J Med. 1986;81:400-404. [Medline] [Order article via Infotrieve]
34. Mohri H, Ohkubo T. Single-dose effect of enteric-coated aspirin on platelet function and thromboxane generation in middle-aged men. Ann Pharmacother. 1993;27:405-410. [Abstract]
35. Thiessen JJ, Grad H, Macleod SM, Spino M. Human platelet response to three salicylate dosage forms. Biopharm Drug Dispos. 1983;4:43-51. [Medline] [Order article via Infotrieve]
36. Siebert DJ, Bochner F, Imhoff DM, Watts S, Lloyd JV, Field J, Gabb BW. Aspirin kinetics and platelet aggregation in man. Clin Pharmacol Ther. 1983;33:367-374. [Medline] [Order article via Infotrieve]
37. Ali M, McDonald JWD, Thiessen JJ, Coates PE. Plasma acetylsalicylate and salicylate and platelet cyclooxygenase activity following plain and enteric-coated aspirin. Stroke.. 1980;11:9-13. [Abstract/Free Full Text]
38. Hawthorne AB, Maluda YR, Cole AT, Hawkey CJ. Aspirin-induced gastric mucosal damage: prevention by enteric-coating and relation to prostaglandin synthesis. Br J Clin Pharmacol. 1991;32:77-83. [Medline] [Order article via Infotrieve]
39. Petroski D. Endoscopic comparison of three aspirin preparations and placebo. Clin Ther. 1993;15:314-320. [Medline] [Order article via Infotrieve]
40. Gow JA, Ebbeling L, Gerrard JM. The effect of regular and enteric-coated aspirin on bleeding time, thromboxane, and prostacyclin. Prostaglandins Leukot Essent Fatty Acids. 1993;49:515-520. [Medline] [Order article via Infotrieve]
41. Cole AT, Filipowicz B, Hyman-Taylor P, Hawkey CJ. Low-dose aspirin: selective inhibition of rectal dialysis thromboxane B₂ in healthy volunteers. Aliment Pharmacol Ther. 1994;8:521-526. [Medline] [Order article via Infotrieve]
42. Matchar DB, McCrory DC, Barnett HJM, Feussner JR. Medical treatment for stroke prevention. Ann Intern Med. 1994;121:41-53. [Abstract/Free Full Text]
43. Algra A, van Gijn J. Aspirin, in any dose above 30 mg, offers only modest protection after cerebral ischemia. J Neurol Neurosurg Psychiatry. In press.
44. Goldstein LB, Bonito AJ, Matchar DB, Duncan PW, DeFriese GH, Oddone EZ, Paul JE, Akin DR, Samasa GP. US National Survey of Physician Practices for the Secondary and Tertiary Prevention of Ischemic Stroke. Stroke.. 1995;26:1607-1615. [Abstract/Free Full Text]
45. Hennerici MG. Aspirin dosage: a never-ending story? Cerebrovascular Dis. 1995;5:308-309.

This article has been cited by other articles:

				R. Hart Review: aspirin reduces the risk for stroke in patients with previous transient ischaemic attack or stroke but does not have a dose-response effect Evid. Based Med., January 1, 2000; 5(1): 9 - 9. [Full Text] [PDF]

				G. W. Albers, R. G. Hart, H. L. Lutsep, D. W. Newell, and R. L. Sacco Supplement to the Guidelines for the Management of Transient Ischemic Attacks : A Statement From the Ad Hoc Committee on Guidelines for the Management of Transient Ischemic Attacks, Stroke Council, American Heart Association Stroke, November 1, 1999; 30(11): 2502 - 2511. [Full Text] [PDF]

				B S P Hellemons, M Langenberg, J Lodder, F Vermeer, H J A Schouten, T. Lemmens, J W van Ree, and J A Knottnerus Primary prevention of arterial thromboembolism in non-rheumatic atrial fibrillation in primary care: randomised controlled trial comparing two intensities of coumarin with aspirin BMJ, October 9, 1999; 319(7215): 958 - 964. [Abstract] [Full Text]

				J. L. Wilterdink and J. D. Easton Dipyridamole Plus Aspirin in Cerebrovascular Disease Arch Neurol, September 1, 1999; 56(9): 1087 - 1092. [Abstract] [Full Text] [PDF]

				E. S. Johnson, S. F. Lanes, C. E. Wentworth III, M. H. Satterfield, B. L. Abebe, and L. W. Dicker A Metaregression Analysis of the Dose-Response Effect of Aspirin on Stroke Arch Intern Med, June 14, 1999; 159(11): 1248 - 1253. [Abstract] [Full Text] [PDF]

				M. M. Bednar and C. E. Gross Antiplatelet Therapy in Acute Cerebral Ischemia Stroke, April 1, 1999; 30(4): 887 - 893. [Abstract] [Full Text] [PDF]

				J. Biller, W. M. Feinberg, J. E. Castaldo, A. D. Whittemore, R. E. Harbaugh, R. J. Dempsey, L. R. Caplan, T. F. Kresowik, D. B. Matchar, J. F. Toole, et al. Guidelines for Carotid Endarterectomy : A Statement for Healthcare Professionals From a Special Writing Group of the Stroke Council, American Heart Association Circulation, February 10, 1998; 97(5): 501 - 509. [Full Text] [PDF]

				F. Masuhr, M. Busch, and K. M. Einhaupl Differences in Medical and Surgical Therapy for Stroke Prevention Between Leading Experts in North America and Western Europe Stroke, February 1, 1998; 29(2): 339 - 345. [Abstract] [Full Text] [PDF]

				J. Biller, W. M. Feinberg, J. E. Castaldo, A. D. Whittemore, R. E. Harbaugh, R. J. Dempsey, L. R. Caplan, T. F. Kresowik, D. B. Matchar, J. F. Toole, et al. Guidelines for Carotid Endarterectomy : A Statement for Healthcare Professionals From a Special Writing Group of the Stroke Council, American Heart Association Stroke, February 1, 1998; 29(2): 554 - 562. [Full Text] [PDF]

				H.J.M. Barnett, M. Kaste, H. Meldrum, and M. Eliasziw Aspirin Dose in Stroke Prevention : Beautiful Hypotheses Slain by Ugly Facts Stroke, April 1, 1996; 27(4): 588 - 592. [Full Text]

This Article Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hart, R. G. Articles by Harrison, M. J.G. Search for Related Content PubMed PubMed Citation Articles by Hart, R. G. Articles by Harrison, M. J.G. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB ACETYLSALICYLIC ACID