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Doi:10.1016/j.amjmed.2005.11.013

The American Journal of Medicine (2006) 119, 198-202 Aspirin to Prevent Heart Attack and Stroke: What’s the
Right Dose?

James E. Dalen, MD, MPH
Professor Emeritus, University of Arizona, Tucson
ABSTRACT
Despite hundreds of clinical trials, the appropriate dose of aspirin to prevent myocardial infarction (MI)and stroke is uncertain. In the US, the doses most frequently recommended are 80, 160, or 325 mg per day.
Because aspirin can cause major bleeding, the appropriate dose is the lowest dose that is effective inpreventing both MI and stroke because these two diseases frequently co-exist. Five randomized clinicaltrials have compared aspirin with placebo or no therapy for the prevention of stroke and MI. These trialsvaried with regard to the dose of aspirin, the duration of treatment, and, most important, the populationsselected for study varied in their baseline risk of stroke and MI. In men, 160 mg/day consistently loweredthe risk of MI. In women, doses of 50 mg, 75, and 100 mg/day did not significantly decrease the risk ofMI; therefore, the appropriate dose in women must exceed 100 mg/day. The appropriate dose for theprimary prevention of stroke in men and women has not been established. Doses of 75 and 100 mg/dayhave been ineffective in men and women. The appropriate dose must be at least 160 mg/day. The lowestdose to prevent recurrent MI or death in patients with stable coronary artery disease (CAD) is 75 mg/day.
In acute MI the lowest dose is 160 mg/day. In patients with a history of stroke or transient ischemic attack(TIA), 50 mg/day has been shown to be effective in men and women. In acute stroke, 160 mg/day iseffective in preventing recurrent stroke or death. The risk of major bleeding with 160 mg/day is the sameas with 80 mg/day: 1 to 2 cases per 1000 patient years of treatment, and the risk of fatal bleeding is thesame with 80 and 160 mg/day. These studies indicate that the most appropriate dose for the primary andsecondary prevention of stroke and MI is 160 mg/day. 2006 Elsevier Inc. All rights reserved.
KEYWORDS: Aspirin; Aspirin toxicity; Stroke prevention; Heart attack prevention; Primary prevention; Secondary
prevention
In 1950, Lawrence Craven, a general practitioner in Glen- The appropriate dose of aspirin should be sufficient to dale, Calif, was the first to report that aspirin may prevent prevent MI, as well as stroke, because these 2 diseases have myocardial infraction (MI), and in 1956 he was the first to the same risk factors and frequently co-exist. Ideally, the report that aspirin may also prevent Now, more appropriate dose would be effective for primary and sec- than 50 years later, after hundreds of clinical trials, it has ondary prevention, in women as well as in men.
been well established that Craven was correct; aspirin canprevent MI and stroke.However, the appropriate dose of THE SEARCH FOR THE LOWEST EFFECTIVE DOSE
aspirin remains uncertain. The dose in clinical trials has Because aspirin has significant side effects; principally ranged from 50 to 1200 mg per day. Craven recommended bleeding, especially gastrointestinal (GI) bleeding, many a dose of 325 mg per day, although he noted that 325 mg 5 clinical trials have sought to determine the lowest effective dose of aspirin to prevent MI and stroke.
The Antithrombotic Trialists’ Collaboration reviewed 287 studies involving 135 000 patients that compared antiplatelet Requests for reprints should be addressed to James E. Dalen, MD, therapy to They concluded that doses of 75 to 325 MPH, University of Arizona, 1840 East River Road, Suite 120, Tucson, AZ mg of aspirin are effective and that there is no additional benefit to doses higher than 325 mg per day. They also noted 0002-9343/$ -see front matter 2006 Elsevier Inc. All rights reserved.
doi:10.1016/j.amjmed.2005.11.013 Aspirin to Prevent Heart Attack and Stroke that 75 to 150 mg/day seems to be as effective as 325 mg and Peto et randomized 5139 presumably healthy British that the effects of doses less than 75 mg were less male doctors (median age 60 years) to 500 mg of aspirin per It is now widely accepted that the optimal dose is 325 day or no aspirin. After 6 years of follow-up, there was no mg/day or However, there is no agreement whether the significant difference in the incidence of MI or stroke in those optimal dose is 80, 160, or 325 mg/day. Because the cost of taking or not taking aspirin. It should be noted that many of CLINICAL SIGNIFICANCE
● There is general agreement that the ap- PRIMARY PREVENTION
average follow-up of 60.2 months,there was a significant 44% reduc- ● In randomized clinical trials, doses of ● In randomized clinical trials, the risk of ● These studies indicate that the most ap- propriate dose of aspirin to prevent myo- included only and the other two included men and In the Hypertension Optimal Treatment (HOT) study, Some studies selected participants with risk fac- 18 790 patients (8831 women) aged 50 or older with hyper- tors for cardiovascular disease or who had tension were randomized to receive 75 mg aspirin or pla- Given the heterogeneity of these trials, the risk of MI and After an average follow-up of 3.8 years, there was a stroke in the participants in these 5 trials varied signifi- nonsignificant decrease in the incidence of stroke in those cantly. Therefore, it is not surprising that the results were receiving The incidence of MI was significantly reduced by 42% in men, whereas there was an insignificantreduction in MI of 19% in In the WHS, 39 876 healthy women aged 45 years or older Primary Prevention Trials: Prevention of MI were randomized to a very low dose of aspirin: 100 mg every other day or After 10 years of follow-up, there wasa significant 17% reduction in stroke in those treated with aspirin. However, the reduction in stroke in women aged 65 and older was not significant. The incidence of MI was not decreased in the total patient population. However, there was a significant 34% decrease in MI in women age 65 or older.
LOWEST DOSE FOR PRIMARY PREVENTION
ASA ϭ aspirin; WHS ϭ Women’s Health Study; HOT ϭ Hypertension Optimal Treatment study; PPP ϭ Primary Prevention Project; PHS ϭPhysician’s Health Study; UK ϭ British physician study.
As shown in the lowest reported dose to prevent myocardial infarction in women, 50 mg/day (100 mg QOD), was reported by the WHS, but it was limited to women aged ‡Stroke data for men and women combined.
65 years or In the total group of women aged 45 and The American Journal of Medicine, Vol 119, No 3, March 2006 older, there was an insignificant 2% increase in myocardial SECONDARY PREVENTION OF MI
infarction. These findings in the WHS were not consistent The Swedish Angina Pectoris Aspirin Trial (SAPAT) ran- with the results in women in other trials. In the HOT trial, domized 2035 patients (977 women) with stable angina a daily dose of 75 mg in women age 50ϩ with hypertension pectoris to aspirin 75 mg/day versus None of the resulted in an insignificant decrease in MI of In the patients had a history of prior MI. All patients also received Primary Prevention 100 mg per day resulted in an sotalol. After a median follow-up of 50 months the inci- insignificant decrease in MI of 31% in men and women dence of MI and sudden death was a significant 34% lower aged 50 years and older who had at least one major cardio- in those treated with aspirin plus sotalol, compared with those receiving sotalol plus placebo. In addition, there was The combined results of these studies indicate that the a 25% reduction in stroke that was not statistically signifi- lowest effective dose of aspirin to prevent MI in women aged 50 or older is more than 100 mg per day.
In a Veterans Administration (VA) study of 1266 men In men, the lowest effective dose to prevent MI was with unstable angina, 325 mg of aspirin daily significantly reported in the HOT Men aged 50 or older with decreased the risk of MI or sudden death by 51% in those hypertension had a significant 42% reduction in MI with a taking In the Relationship between Insulin Sensi- daily dose of 75 mg. However, in the PPP trial 100 mg of tivity and Cardiovascular disease risk (RISC) study of 796 aspirin resulted in a statistically insignificant 31% reduction men with unstable angina, there was a significant 31% in In the U.S. physicians 325 mg of aspirin reduction in MI or sudden death after a daily dose of 75 mg QOD led to a significant 44% reduction in MI in men aged 50 or older. Given these data, the lowest effective dose for In the Second International Study of Infarct Survival the primary prevention of MI in men age 50 and older is 160mg/day.
(ISIS-2) 17 187 patients with acute MI were ran-domized to 165 mg per day of aspirin for 1 month versusplacebo. Recurrent MI was significantly reduced by 45%, LOWEST DOSE FOR PRIMARY PREVENTION
and vascular death was significantly decreased by 23%.
OF STROKE
These studies indicate that the lowest effective dose to As shown in the lowest reported effective dose for prevent MI or sudden death in patients with stable coronary the primary prevention of stroke, 50 mg/day, was reported artery disease (CAD) or unstable angina is 75 mg/day. In by the This dose resulted in a statistically significant patients with acute myocardial infarction (AMI), the lowest reduction in stroke of However, in women aged 65 or effective dose to prevent recurrent MI or death is 160 mg older, a reduction in stroke of 22% was not statistically significant. As with the case of MI, these findings from theWHS are inconsistent with the other primary prevention SECONDARY PREVENTION OF STROKE
trials. In the HOT Trial, 75 mg per day in men and women The European Stroke Prevention Study (ESPS) randomized led to a statistically insignificant decrease in stroke of 6602 patients with a history of stroke or TIA to 1 of 4 In the PPP trial, 100 mg per day led to an insignificant 33% regimens: aspirin 50 mg/day, dipyridamole 400 mg/day, reduction in These studies indicate that the appro- dypridamole plus aspirin, or After 2 years of priate dose of aspirin for the primary prevention of stroke in treatment, the incidence of stroke in those taking aspirin was women aged 50 or older is more than 100 mg per day.
(325 mg and 500 either increased or failed In the Chinese Acute Stroke Trial (CAST), 21 106 with to significantly decrease the incidence of stroke. The appro- acute ischemic stroke were randomized to aspirin, 160 mg/ priate dose of aspirin for the primary prevention of stroke in day or After 4 weeks, the incidence of recurrent stroke or death in those receiving aspirin was a significant Three randomized trials have compared aspirin in doses 10% lower than those receiving placebo.
These 2 studies indicate that aspirin, 50 mg/day, can preventing strokes in patients with atrial fibrillation (AF).
significantly reduce the rate of recurrent stroke in patients The incidence of stroke was reduced in each trial, but the with a history of stroke or TIA. In patients with acute decrease was statistically significant in only one, the Stroke ischemic stroke, 160 mg/day of aspirin can significantly Prevention in Atrial Fibrillation trial (SPAF In the reduce the rate of recurrent stroke or death.
SPAF I trial, 325 mg of aspirin per day resulted in a summarizes the lowest effective dose to signif- significant 42% reduction in stroke as compared with pla- icantly reduce MI and stroke in varying patient populations.
cebo. It should be noted that a trial comparing 150 to 160 The dose varies from 50 to 160 mg/day (with the exception mg of aspirin/day with placebo in patients with AF has not of primary stroke prevention in men, and the prevention of stroke in patients with AF). These findings are consistent These data indicate that the lowest effective dose of with the report of the Antithrombotic Trialists that 75 to 150 aspirin to prevent stroke in patients with AF is 325 mg/day.
Aspirin to Prevent Heart Attack and Stroke Stroke/death in men/women with acute stroke WHS ϭ Women’s Health Study; HOT ϭ Hypertension Optimal Treat- MI ϭ myocardial infarction; AF ϭ atrial fibrillation; CAD ϭ coro- ment study; PPP ϭ Primary Prevention Project; PHS ϭ Physician’s nary artery disease; AMI ϭ acute mycardial infarction; HX ϭ history of; Health Study; UK ϭ British physician study.
randomized controlled studies during 368 750 patient years BLEEDING COMPLICATIONS OF ASPIRIN
of therapy. There were actually more fatal bleeds in the The incidence of peptic ulcer is increased during aspirin placebo patients than in those taking doses of aspirin rang- therapy. In the the incidence in those treated with ing from 100 mg QOD to 500 mg per day. The absence of aspirin was 2.7%, compared with 2.1% in controls. In the an increase in fatal bleeding in these 5 randomized clinical PHS the incidence in those taking aspirin (1.4%) trials is in stark contrast to predictions of excess deaths due was not significantly greater than placebo (1.2%). In the to major GI hemorrhage predicted from epidemiological British Physician the incidence in those taking as- pirin was 2.5% versus 1.6% in the controls . There was noconsistent relationship between the dose of aspirin and the ARE BLEEDING COMPLICATIONS RELATED TO
incidence of peptic ulcer in these studies. The aspirin dose THE DOSE OF ASPIRIN?
in the PHS was 3 times greater than in the WHS, yet the As noted in and there seems to be no relationship incidence of peptic ulcer was lower in the PHS and was not between aspirin dose and the incidence of major bleeding or significantly greater than those taking a fatal bleeding in the 5 primary prevention trials.
The risk of major bleeding, in most cases GI bleeding, is clearly increased with aspirin therapy, as shown in meta-analyses of 287 studies of antiplatelet therapy versus However, the excess risk of major bleeding with aspirin in control in 135 000 patients. The risk of a major extracranial these studies was modest, ranging from 0.19 to 1.6 cases per bleed with daily aspirin doses ranging from Ͻ75 mg to 325 1000 patient-years. This is consistent with the rate of 2 per mg is shown in There was no significant difference 1000 patient-years reported by the Antithrombotic Trial- in the relative risk of a major extracranial bleed in those The excess rate of major bleeding was not related to receiving Ͻ75 mg versus those receiving 160 to 325 mg per the dose of aspirin in these 5 trials. The rate was higher in the HOT which prescribed 75 mg/day, than in the Serebruany et reported a similar meta-analysis of the bleeding complications in 50 randomized controlled trials of indicates the number of patients with fatal bleed- antiplatelet agents involving 338 191 patients. They classi- ing during aspirin therapy compared with placebo in 5 fied major bleeding as intracranial bleeding, overt bleedingwith a decrease in hemoglobin Ͼ5 g/dL, or a decreasedhematocrit Ͼ15%.
Their findings, as shown in are consistent with those of the Antithrombotic There was no signif- icant difference in the incidence of major bleeding between ASA ϭ aspirin; WHS ϭ Women’s Health Study; HOT ϭ Hypertension Optimal Treatment study; PPP ϭ Primary Prevention Project; PHS ϭ Physician’s Health Study; UK ϭ British physician study The American Journal of Medicine, Vol 119, No 3, March 2006 2. Patrano C, Coller B, Fitzgerald GA, et al. Platelet-active drugs: the Incidence of Major Bleeding During Aspirin relationships among dose, effectiveness and side effects. Chest 2004; 3. 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: 4. Ridker PM, Cook NR, Lee IM, et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women.
N Engl J Med 2005;352:1293-1304.
5. Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive those taking Ͻ100 mg versus those taking 100 to 325 mg of blood-pressure lowering and low dose aspirin in patients with hyper- aspirin per day. It should be noted that the incidence of tension: principal results of the hypertension optimal treatment (HOT) minor bleeding was clearly related to aspirin dose. The randomised trial. Lancet 1998;351:1755-1762.
incidence of minor bleeding was 1.8% when the dose was 6. Collaborative Group of the Primary Prevention Project (PPP). Low- dose aspirin and vitamin E in people at cardiovascular risk: a random- less than 100 mg and 6.5% with doses of 100 to 325 mg.
ised trial in general practice. Lancet 2001;357:89-95.
7. Steering Committee of the Physicians’ Health Study Group. Final CONCLUSIONS
report of the aspirin component of the ongoing physicians’ healthstudy. N Engl J Med 1989;321:129-135.
In the U.S., the 3 doses of aspirin most frequently recom- 8. Peto R, Gray R, Collins R, et al. Randomised trial of prophylactic daily mended for the prevention of stroke and MI are 80, 160, and aspirin in British male doctors. BMJ 1988;296:313-316.
325 mg/day. In Europe and other countries, 75, 150, and 9. Kjeldsen SE, Kolloch RE, Leonetti G, et al. Influence of gender and 300 mg/day are commonly recommended. Randomized age on preventing cardiovascular disease by antihypertensive treat-ment and acetylsalicylic acid. The HOT study. J Hypertens 2000;18: clinical trials have shown that the lowest dose, 75 or 80 mg/day, is inadequate for primary prevention of stroke and 10. Diener HC, Cunha L, Forbes C, et al. European stroke prevention MI in men and women and has not been shown to be study 2: dipyridamole and acetylsalicyclic acid in the prevention of adequate in patients with acute stroke or acute MI, as shown stroke. J Neurol Sci 1996;143:1-13.
in Of note, a recent report suggests that a daily dose 11. Peterson P, Boysen G, Godtfredsen J, et al. Placebo-controled, ran- domised trial of warfarin and aspirin for prevention of thromboembolic of 100 mg or less of aspirin may be associated with a higher complications in chronic atrial fibrillation. Lancet 1989;1:175-179.
incidence of aspirin resistance in patients with coronary 12. Stroke Prevention in Atrial Fibrillation Investigators. Stroke preven- tion in atrial fibrillation study: final results. Circulation 1991;84:527- These studies indicate that a daily dose of 160 mg of aspirin (or 325 mg QOD) is adequate to prevent MI and 13. Juul-Moller S, Edvardsson N, Jahnmatz B, et al. Double-blind trial of aspirin in primary prevention of myocardial infarction in patients with stroke in men and women, with 3 exceptions. The dose stable chronic angina pectoris. Lancet 1992;340:1421-1425.
adequate for primary prevention of MI in women and the 14. Lewis HD, Davis JW, Archibald DG, et al. Protective effects of aspirin dose adequate for the primary prevention of stroke in men against myocardial infarction and death in men with unstable angina.
and women are unknown, but in both cases the dose must Results of a Veterans Administration cooperative study. N Engl J Med exceed 100 mg/day. A dose of 325 mg/day is required for 15. The RISC Group. Risk of myocardial infarction and death during the prevention of stroke in patients with AF who are not treatment with low dose aspirin and intravenous heparin in men with candidates for long-term warfarin therapy.
unstable coronary artery disease. Lancet 1990;336:827-830.
The primary risk of taking 160 mg of aspirin/day is the 16. ISIS-2 (Second International Study of infarct Survival) Collaborative same as taking 80 mg/day: an increased risk of major Group. Randomised trial of intravenous streptokinase, oral aspirin, bleeding of 1 to 2 cases per 1000 patient years of treatment.
both, or neither among 17 187 cases of suspected acute myocardial There is no evidence that the risk of major bleeding or infarction: ISIS-2. Lancet 1988;i:349-360.
17. Diener HC, Cunha L, Forbes C, et al. European stroke prevention fatal bleeding with a daily dose of 160 mg/day is greater study. 2. dipyridamole and acetylsalicylic acid in the secondary pre- than with a dose of 80 mg or less. The principal disadvan- vention of stroke. J Neurol Sci 1996;143:1-13.
tage of 160 mg as compared with a daily dose of 80 mg or 18. CAST (Chinese Acute Stroke Trial) Collaborative Group. CAST: less is an increase in minor bleeding.
randomised placebo-controlled trial of early aspirin use in 20 000 The data from these randomized clinical trials indicate patients with acute ischaemic stroke. Lancet 1997;349:1641-1649.
19. Nelson MR, Liew D, Bertram M, et al. Epidemiological modelling or that the optimal dose of aspirin to prevent MI and stroke, ie, routine use of low dose aspirin for the primary prevention of coronary the dose that maximizes efficacy while minimizing toxicity, heart disease and stroke in those aged Ͼ 70. BMJ 2005;330:1306- is 160 mg/day. Of note, this dose is not much different from that suggested by Craven more than 50 years ago; 325 mg 20. Serebruany VL, Malinin AI, Eisert RM, et al. Risk of bleeding com- plications with antiplatelet agents: meta-analysis of 338 191 patientsenrolled in 50 randomized controlled trials. Am J Hematol 2004;75:40-47.
References
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