Advertisement

Systematic Review and Meta-analysis of Adverse Events of Low-dose Aspirin and Clopidogrel in Randomized Controlled Trials

      Abstract

      Purpose

      We performed a systematic review to define the relative and absolute risk of clinically relevant adverse events with the antiplatelet agents, aspirin and clopidogrel.

      Materials and methods

      Databases were searched for randomized controlled trials of low-dose aspirin (75-325 mg/dayay) or clopidogrel administered for cardiovascular prophylaxis. Relative risks (RR) were determined by meta-analysis of 22 trials for aspirin versus placebo and from single studies for aspirin versus clopidogrel, aspirin versus aspirin/clopidogrel, and clopidogrel versus aspirin/clopidogrel. Absolute risk increase was calculated by multiplying RR increase by the pooled weighted incidence of the control.

      Results

      Aspirin increased the risk of major bleeding (RR=1.71; 95% confidence interval [CI], 1.41-2.08), major gastrointestinal (GI) bleeding (RR=2.07; 95% CI, 1.61-2.66), and intracranial bleeding (RR=1.65; 95% CI, 1.06-5.99) versus placebo. No difference between 75-162.5 mg/day and >162.5-325 mg/day aspirin versus placebo was seen. The absolute annual increases attributable to aspirin were major bleeding: 0.13% (95% CI, 0.08-0.20); major GI bleeding: 0.12% (95% CI, 0.07-0.19), intracranial bleeding: 0.03% (95% CI, 0.01-0.08). No study compared clopidogrel with placebo. One study showed increased major GI bleeding (but not non-GI bleeding endpoints) with aspirin versus clopidogrel (RR=1.45; 95% CI, 1.00-2.10). The absolute annual increase was 0.12% (95% CI, 0.00-0.28).

      Conclusions

      Low-dose aspirin increases the risk of major bleeding by ∼70%, but the absolute increase is modest: 769 patients (95% CI, 500-1250) need to be treated with aspirin to cause one additional major bleeding episode annually. Compared with clopidogrel, aspirin increases the risk of GI bleeding but not other bleeding; however, 883 patients (95% CI, 357-∞) would need to be treated with clopidogrel versus aspirin to prevent one major GI bleeding episode annually at a cost of over 1 million dollars.

      Keywords

      Aspirin is an antiplatelet agent that inhibits platelet thromboxane A2 production and is the most important and widely used drug for the primary and secondary prevention of atherothrombotic disease.
      • Sanderson S.
      • Emery J.
      • Baglin T.
      • Kinmonth A.L.
      Narrative review aspirin resistance and its clinical implications.
      U.S. Preventive Services Task Force
      Aspirin for the prevention of cardiovascular events recommendation and rationale.
      • Pearson T.A.
      • Blair S.N.
      • Daniels S.R.
      • et al.
      American Heart Association Science Advisory and Coordinating Committee
      AHA guidelines for primary prevention of cardiovascular disease and stroke: 2002 update: consensus panel guide to comprehensive risk reduction for adult patients without coronary or other atherosclerotic vascular diseases.
      However, low-dose aspirin used for the prevention and treatment of cardiovascular disease may cause side effects due to its antiplatelet activity, as well as its effects on the gastrointestinal (GI) tract mucosa.
      • Derry S.
      • Loke Y.K.
      Risk of gastrointestinal haemorrhge with long term use of aspirin meta-analysis.
      • Hayden M.
      • Pignone M.
      • Phillips C.
      • Mulrow C.
      Aspirin for the primary prevention of cardiovascular events a summary of the evidence for the U.S. Preventive Services Task Force.
      • Serrano P.
      • Lanas A.
      • Arroyo M.T.
      • Ferreira I.J.
      Risk of upper gastrointestinal bleeding in patients taking low-dose aspirin for the prevention of cardiovascular diseases.
      The relative contribution of these 2 mechanisms to the induction of clinical events is uncertain.
      • Among patients enrolled in long-term controlled trials of antiplatelet agents for cardiovascular prophylaxis, low-dose aspirin increases the risk of major bleeding 2-fold compared with placebo.
      • However, the annual incidence of major bleeding due to low-dose aspirin is modest—only 1.3 patients per thousand higher than what is observed with placebo treatment.
      • Treatment of approximately 800 patients with low-dose aspirin annually for cardiovascular prophylaxis will result in only 1 additional major bleeding episode.
      Clopidogrel is an alternative antiplatelet agent that inhibits adenosine diphosphate (ADP)-induced platelet aggregation through irreversible inhibition of P2 nucleotide receptors on the platelet surface.
      CURE study investigators
      The clopidogrel in unstable angina to prevent recurrent events (CURE) trial programme. Rationale, design, and baseline characteristics including a meta-analysis of the effects of thienopyridines in vascular disease.
      It is commonly used for secondary prevention of atherothrombotic disease in place of low-dose aspirin in patients who have experienced gastrointestinal intolerance to aspirin-related adverse events or with aspirin allergy.
      • Braunwald E.
      • Antman E.M.
      • Beasley J.W.
      • et al.
      ACC/AHA guideline update for the management of patients with unstable angina and non-ST segment elevation myocardial infarction—2002: summary article: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines (Committee on the Management of Patients with Unstable Angina).
      Because clopidogrel and aspirin inhibit platelet aggregation through independent but complementary mechanisms, they also are sometimes used in combination (eg, after coronary stenting or in patients with acute coronary syndrome).
      CURE study investigators
      The clopidogrel in unstable angina to prevent recurrent events (CURE) trial programme. Rationale, design, and baseline characteristics including a meta-analysis of the effects of thienopyridines in vascular disease.
      Like aspirin, clopidogrel may cause adverse bleeding events via its antiplatelet activity. Although clopidogrel has not been considered to be injurious to the GI mucosa, the results of a recent randomized trial assessing recurrent GI bleeding with clopidogrel led the authors of the article and an accompanying editorial to raise this possibility.
      • Chan F.K.
      • Ching J.Y.
      • Hung L.C.
      • et al.
      Clopidogrel versus aspirin and esomeprazole to prevent recurrent ulcer bleeding.
      • Cryer B.
      Reducing the risks of gastrointestinal bleeding with antiplatelet therapies.
      As the population ages and increasing numbers of patients receive antiplatelet agents, knowledge of the potential negative effects of treatment will be crucial to health care providers as they attempt to develop management strategies for patients with cardiovascular disease. We therefore sought to define the risk of bleeding events and other noncardiovascular adverse events with these 2 widely used antiplatelet agents through a systematic review of the literature.
      Although several recent systematic reviews of the GI complications of aspirin are available,
      • Derry S.
      • Loke Y.K.
      Risk of gastrointestinal haemorrhge with long term use of aspirin meta-analysis.
      • Hayden M.
      • Pignone M.
      • Phillips C.
      • Mulrow C.
      Aspirin for the primary prevention of cardiovascular events a summary of the evidence for the U.S. Preventive Services Task Force.
      • Serebruany V.L.
      • Malinin A.I.
      • Eisert R.M.
      • Sane D.C.
      Risk of bleeding complications with antiplatelet agents meta-analysis of 338191 patients enrolled in 50 randomized controlled trials.
      • Weisman S.M.
      • Graham D.Y.
      Evaluation of the benefits and risks of low-dose aspirin in the secondary prevention of cardiovascular and cerebrovascular events.
      • Serebruany V.L.
      • Steinhubl S.R.
      • Berger P.B.
      • et al.
      Analysis of risk of bleeding complications after different doses of aspirin in 192036 patients enrolled in 31 randomized controlled trials.
      their selection criteria and analysis are less clinically relevant than the present review. They include studies with doses outside the range of low-dose aspirin commonly used for cardiovascular prophylaxis (75-325 mg daily),
      • Derry S.
      • Loke Y.K.
      Risk of gastrointestinal haemorrhge with long term use of aspirin meta-analysis.
      • Hayden M.
      • Pignone M.
      • Phillips C.
      • Mulrow C.
      Aspirin for the primary prevention of cardiovascular events a summary of the evidence for the U.S. Preventive Services Task Force.
      • Serebruany V.L.
      • Malinin A.I.
      • Eisert R.M.
      • Sane D.C.
      Risk of bleeding complications with antiplatelet agents meta-analysis of 338191 patients enrolled in 50 randomized controlled trials.
      • Weisman S.M.
      • Graham D.Y.
      Evaluation of the benefits and risks of low-dose aspirin in the secondary prevention of cardiovascular and cerebrovascular events.
      • Serebruany V.L.
      • Steinhubl S.R.
      • Berger P.B.
      • et al.
      Analysis of risk of bleeding complications after different doses of aspirin in 192036 patients enrolled in 31 randomized controlled trials.
      data from studies in which aspirin was given concurrently with anticoagulants,
      • Serebruany V.L.
      • Malinin A.I.
      • Eisert R.M.
      • Sane D.C.
      Risk of bleeding complications with antiplatelet agents meta-analysis of 338191 patients enrolled in 50 randomized controlled trials.
      they exclude studies with duration of less than 12 months
      • Derry S.
      • Loke Y.K.
      Risk of gastrointestinal haemorrhge with long term use of aspirin meta-analysis.
      • Hayden M.
      • Pignone M.
      • Phillips C.
      • Mulrow C.
      Aspirin for the primary prevention of cardiovascular events a summary of the evidence for the U.S. Preventive Services Task Force.
      or include short-term studies in which the length of follow-up may be inadequate to observe rare outcomes;
      • Serebruany V.L.
      • Malinin A.I.
      • Eisert R.M.
      • Sane D.C.
      Risk of bleeding complications with antiplatelet agents meta-analysis of 338191 patients enrolled in 50 randomized controlled trials.
      • Serebruany V.L.
      • Steinhubl S.R.
      • Berger P.B.
      • et al.
      Analysis of risk of bleeding complications after different doses of aspirin in 192036 patients enrolled in 31 randomized controlled trials.
      they do not provide information on clinically important “major” bleeding or other relevant side effects of antiplatelet therapy, and they don’t provide information about bleeding rates based on duration of exposure.
      • Weisman S.M.
      • Graham D.Y.
      Evaluation of the benefits and risks of low-dose aspirin in the secondary prevention of cardiovascular and cerebrovascular events.
      • Serebruany V.L.
      • Steinhubl S.R.
      • Berger P.B.
      • et al.
      Analysis of risk of bleeding complications after different doses of aspirin in 192036 patients enrolled in 31 randomized controlled trials.
      Furthermore, some systematic reviews include studies in which aspirin was administered for a single limited indication, ie, primary cardiovascular prevention
      • Hayden M.
      • Pignone M.
      • Phillips C.
      • Mulrow C.
      Aspirin for the primary prevention of cardiovascular events a summary of the evidence for the U.S. Preventive Services Task Force.
      or secondary cardiovascular prevention.
      • Weisman S.M.
      • Graham D.Y.
      Evaluation of the benefits and risks of low-dose aspirin in the secondary prevention of cardiovascular and cerebrovascular events.
      Although these reviews provide data in specific populations of interest, they may have limited precision for estimating risk because of the limited number of studies included; furthermore, it is not clear that differences in the study populations (eg, primary vs secondary prevention) lead to significant differences in incidences of GI bleeding.
      • Lanas A.
      • Bajador E.
      • Serrano P.
      • et al.
      Nitrovasodilators, low-dose aspirin, other nonsteroidal antiinflammatory drugs, and the risk of upper gastrointestinal bleeding.
      Most importantly, prior meta-analyses provide relative risks, or odds ratios as measures of the effect of aspirin on the development of bleeding. However, information on the absolute increase in incidence with antiplatelet agents and the number of patients who would need to be treated to cause an additional serious adverse event may be more useful information for clinicians. We made these clinically relevant measures a focus of this systematic review.

      Methods

      Search Strategy

      We performed a systematic review of the medical literature for randomized controlled trials of aspirin or clopidogrel administered for the primary or secondary prophylaxis of cardiovascular disease. We searched the PubMed and CENTRAL (Cochrane Central Register of Controlled Trials) computerized bibliographic databases (1966 to December 2004), as well as bibliographies from prior systematic reviews.
      • Derry S.
      • Loke Y.K.
      Risk of gastrointestinal haemorrhge with long term use of aspirin meta-analysis.
      • Hayden M.
      • Pignone M.
      • Phillips C.
      • Mulrow C.
      Aspirin for the primary prevention of cardiovascular events a summary of the evidence for the U.S. Preventive Services Task Force.
      • Serebruany V.L.
      • Malinin A.I.
      • Eisert R.M.
      • Sane D.C.
      Risk of bleeding complications with antiplatelet agents meta-analysis of 338191 patients enrolled in 50 randomized controlled trials.
      Antithrombotic Trialists’ Collaboration
      Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients.
      We did not search for abstracts or attempt to identify unpublished data (eg, pharmaceutical companies, other funding sources, the U.S. Food and Drug Administration). The search of PubMed was performed by combining the MESH headings (“aspirin,” “platelet aggregation inhibitors,” “ticlopidine/analogs and derivatives”), or the substance name or text word “clopidogrel” and the publication type “randomized controlled trials.” This strategy yielded 2835 references. Two searches of CENTRAL were conducted by searching the term “aspirin” and the terms “ticlopidine/analogs and derivatives” or “clopidogrel.” These searches yielded 2900 and 215 references, respectively. The searches were not limited by language. The 2 authors independently screened the titles and abstracts for eligibility. Full articles were retrieved for all titles for which abstracts were not available and for all abstracts that appeared to potentially fulfill the inclusion and exclusion criteria.

      Study Inclusion Criteria

      Population

      Studies of adults assigned to antiplatelet therapy for primary or secondary prevention of cardiovascular disease were included. This included studies in which the stated indication for therapy was for primary prevention in patients without known disease and primary or secondary prophylaxis in patients with coronary artery disease, hypertension, atrial fibrillation, valvular heart disease, postcoronary artery bypass graft surgery, postcoronary artery angioplasty or stent placement, cerebral vascular disease (stroke or transient ischemic attack), operative or nonoperative management of peripheral artery disease, or prophylaxis of deep venous thrombosis.

      Intervention

      Antiplatelet therapy with low-dose aspirin (defined as 75-325 mg/day or 150-325 mg every other day) or clopidogrel was required for inclusion, provided the indication for antiplatelet therapy was primary or secondary prophylaxis of cardiovascular disease.

      Outcome

      Studies were included if they provided information on the following adverse events: bleeding, non-cardiovascular deaths, discontinuations due to adverse events, or symptoms other than bleeding or cardiovascular events.

      Study

      Randomized controlled trials assessing cardiovascular outcomes were included if at least one study arm included low-dose aspirin or clopidogrel and a comparator study arm included placebo, low-dose aspirin (compared with clopidogrel), clopidogrel (compared with aspirin), or combined aspirin and clopidogrel. Because antiplatelet agents commonly are administered long term for cardiovascular prophylaxis and because many side effects may require a longer duration of therapy to develop, trials were included only if the planned duration of therapy was ≥2 months. In addition, because many of the important side effects of antiplatelet agents are uncommon, we included only studies with ≥100 patients in the antiplatelet arm(s) in order to exclude smaller studies with imprecise estimates of uncommon events.

      Data Abstraction and Validity Assessment

      The full texts of all selected articles were reviewed independently by the authors to confirm study eligibility, to assess study quality, and to extract data using a predesigned extraction form. Disagreement between reviewers was resolved by consensus. Trials fulfilling the inclusion criteria were scored for quality using the criteria established by Jadad et al on a scale of 0-5.
      • Jadad A.R.
      • Moore R.A.
      • Carroll D.
      Assessing the quality of reports of randomized clinical trials is blinding necessary?.
      For each treatment arm the total number of patients enrolled and the mean or median length of follow-up (in months) were recorded. If available, the person-years of follow-up also were recorded.
      For each treatment arm we attempted to determine the total number of patients with bleeding originating from any site or unspecified sites (“any bleeding”), GI bleeding, intracranial bleeding (intracerebral, subarachnoid, or subdural), and non-GI/nonintracranial bleeding. For all bleeding categories, we attempted to determine the total number of patients with bleeding of any severity (“all bleeding”), as well as the number with major bleeding, fatal bleeding, and minor bleeding. Bleeding events were classified as major or minor in accordance with a priori definitions established in some studies. For studies lacking such definitions, we defined as “major” those bleeding events that were listed as fatal or required hospitalization or transfusion.
      The primary outcome assessments were any major bleeding, major GI bleeding, or intracranial bleeding. Additional bleeding outcome assessments were any bleeding (irrespective of severity), any fatal bleeding, or any minor bleeding; GI bleeding (irrespective of severity), fatal GI bleeding, or minor GI bleeding; fatal intracranial bleeding; all non-GI/non-intracranial bleeding (irrespective of severity), major non-GI/non-intracranial bleeding, fatal non-GI/non-intracranial bleeding, and minor non-GI/non-intracranial bleeding. Bruising and ecchymoses were excluded from tabulations of minor bleeding (both “any bleeding” and non-GI/non-intracranial bleeding).
      Other non-bleeding outcome assessments included noncardiovascular deaths; GI adverse events (including dyspepsia, diarrhea, and constipation); non-GI adverse events (including rash); and discontinuations of therapy due to all adverse events and GI adverse events.

      Data Analysis

      Individual studies providing head-to-head comparisons of therapies (placebo, low-dose aspirin, clopidogrel, or combined aspirin and clopidogrel) were pooled by meta-analysis. For each study, we calculated the crude proportion of patients with each endpoint using an intent-to-treat analysis of all patients randomized to each study arm. Data pertaining to the number of bleeding events (rather than the number of patients with bleeding) were not included when the provided tabulations suggested that there was more than 1 event per patient (“double-counting”). For each endpoint, meta-analysis was performed when at least 2 studies provided head-to-head comparisons of therapies. A summary relative risk with 95% confidence intervals (CI) was calculated using a random effects model (Review Manager software, Version 4.2.7; Oxford, UK: Cochrane Collaboration). Heterogeneity was calculated using the chi-squared test with n-1 degrees of freedom, where n represented the number of studies contributing to the meta-analysis. Significant heterogeneity was defined as a P value of .10 or less. When only 1 study provided head-to-head comparison for an endpoint, a Fisher’s exact test was used for statistical analysis. For primary endpoints, we also performed a planned subgroup analysis assessing the results for ‘low’ low-dose aspirin (75-162.5 mg daily) and ‘high’ low-dose aspirin (>162.5-325 mg daily) versus placebo.
      For the primary endpoints, we determined the absolute risk increase (ie, the attributable incidence) of bleeding due to low-dose aspirin above the comparator (placebo or clopidogrel). To determine this, we first calculated the bleeding incidence (event per person-month) in patients treated with placebo by dividing the number of placebo-treated patients with the bleeding event by the patient-months of follow-up (where provided) or the crude proportion of placebo-treated patients with the event by the mean or median months of follow-up. Where neither mean nor median follow-up was provided, the study duration was used. A pooled incidence for each bleeding endpoint among patients treated with placebo was then calculated by sample-size weighted pooling. To calculate the absolute risk increase (attributable incidence) of bleeding due to low-dose aspirin above placebo, we multiplied the relative risk increase associated with aspirin versus placebo derived from the meta-analysis by the pooled weighted incidence for the placebo studies in the meta-analysis. When only one study provided a head-to-head comparison, we used the absolute risk difference directly from the study divided by the duration of follow-up to determine the attributable incidence. We then calculated the number needed to harm at 1 year based on these absolute incidence increases.

      Results

      Our searches identified 58 original articles pertaining to 55 randomized controlled trials that met our initial inclusion and exclusion criteria and provided sufficient information to determine the proportion of patients with any of the primary or secondary endpoints.
      CAPRIE Steering Committee
      A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE).
      • Yusuf S.
      • Zhao F.
      • Mehta S.R.
      • et al.
      Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators
      Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation.
      • Diener H.C.
      • Bogousslavsky J.
      • Brass L.M.
      • et al.
      Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH) randomised, double-blind, placebo-controlled trial.
      • Pekdemir H.
      • Cin V.G.
      • Camsari A.
      • et al.
      A comparison of 1-month and 6-month clopidogrel therapy on clinical and angiographic outcome after stent implantation.
      • Steinhubl S.R.
      • Berger P.B.
      • Mann 3rd, J.T.
      • et al.
      Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention a randomized controlled trial.
      Steering Committee of the Physicians’ Health Study Research Group
      Final report on the aspirin component of the ongoing Physicians’ Health Study.
      Preliminary report of the Stroke Prevention in Atrial Fibrillation Study.
      Risk of myocardial infarction and death during treatment with low dose aspirin and intravenous heparin in men with unstable coronary artery disease.
      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.
      Stroke Prevention in Atrial Fibrillation Study. Final results.
      The SALT Collaborative Group
      Swedish Aspirin Low-Dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events.
      The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial final results.
      EAFT (European Atrial Fibrillation Trial) Study Group
      Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke.
      Executive Committee for the Asymptomatic Carotid Atherosclerosis Study
      Endarterectomy for asymptomatic carotid artery stenosis.
      The Stroke Prevention in Atrial Fibrillation Investigators
      Bleeding during antithrombotic therapy in patients with atrial fibrillation.
      Coumadin Aspirin Reinfarction Study (CARS) Investigators
      Randomised double-blind trial of fixed low-dose warfarin with aspirin after myocardial infarction.
      Thrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. The Medical Research Council’s General Practice Research Framework.
      The SYMPHONY Investigators
      Comparison of sibrafiban with aspirin for prevention of cardiovascular events after acute coronary syndromes: a randomised trial. Sibrafiban versus Aspirin to Yield Maximum Protection from Ischemic Heart Events Post-acute Coronary Syndromes.
      Efficacy of oral anticoagulants compared with aspirin after infrainguinal bypass surgery (The Dutch Bypass Oral Anticoagulants or Aspirin Study) a randomised trial.
      Collaborative Group of the Primary Prevention Project
      Low-dose aspirin and vitamin E in people at cardiovascular risk a randomised trial in general practice.
      • Cohen M.
      • Adams P.C.
      • Parry G.
      • et al.
      Antithrombotic Therapy in Acute Coronary Syndromes Research Group
      Combination antithrombotic therapy in unstable rest angina and non-Q-wave infarction in nonprior aspirin users. Primary end points analysis from the ATACS trial.
      • Cote R.
      • Battista R.N.
      • Abrahamowicz M.
      • et al.
      The Asymptomatic Cervical Bruit Study Group
      Lack of effect of aspirin in asymptomatic patients with carotid bruits and substantial carotid narrowing.
      • Culebras A.
      • Rotta-Escalante R.
      • Vila J.
      • et al.
      Triflusal vs aspirin for prevention of cerebral infarction a randomized stroke study.
      • Elwood P.C.
      • Cochrane A.L.
      • Burr M.L.
      • et al.
      A randomized controlled trial of acetyl salicylic acid in the secondary prevention of mortality from myocardial infarction.
      • Fiore L.D.
      • Ezekowitz M.D.
      • Brophy M.T.
      • et al.
      Department of Veterans Affairs Cooperative Studies Program Clinical Trial comparing combined warfarin and aspirin with aspirin alone in survivors of acute myocardial infarction primary results of the CHAMP study.
      • Gavaghan T.P.
      • Gebski V.
      • Baron D.W.
      Immediate postoperative aspirin improves vein graft patency early and late after coronary artery bypass graft surgery. A placebo-controlled, randomized study.
      • Goldman S.
      • Copeland J.
      • Moritz T.
      • et al.
      Saphenous vein graft patency 1 year after coronary artery bypass surgery and effects of antiplatelet therapy. Results of a Veterans Administration Cooperative Study.
      • Gullov A.L.
      • Koefoed B.G.
      • Petersen P.
      • et al.
      Fixed minidose warfarin and aspirin alone and in combination vs adjusted-dose warfarin for stroke prevention in atrial fibrillation Second Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation Study.
      • Gullov A.L.
      • Koefoed B.G.
      • Petersen P.
      Bleeding during warfarin and aspirin therapy in patients with atrial fibrillation: the AFASAK 2 study. Atrial Fibrillation Aspirin and Anticoagulation.
      • Hansson L.
      • Zanchetti A.
      • Carruthers S.G.
      • et al.
      HOT Study Group
      Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension principal results of the Hypertension Optimal Treatment (HOT) randomised trial.
      • Hellemons B.S.
      • Langenberg M.
      • Lodder J.
      • et al.
      Primary prevention of arterial thromboembolism in non-rheumatic atrial fibrillation in primary care randomised controlled trial comparing two intensities of coumarin with aspirin.
      • Herlitz J.
      • Holm J.
      • Peterson M.
      • et al.
      Effect of fixed low-dose warfarin added to aspirin in the long term after acute myocardial infarction; the LoWASA Study.
      • Hurlen M.
      • Abdelnoor M.
      • Smith P.
      • et al.
      Warfarin, aspirin, or both after myocardial infarction.
      • Johnson W.C.
      • Williford W.O.
      Benefits, morbidity, and mortality associated with long-term administration of oral anticoagulant therapy to patients with peripheral arterial bypass procedures a prospective randomized study.
      • Julian D.G.
      • Chamberlain D.A.
      • Pocock S.J.
      A comparison of aspirin and anticoagulation following thrombolysis for myocardial infarction (the AFTER study) a multicentre unblinded randomised clinical trial.
      • Juul-Moller S.
      • Edvardsson N.
      • Jahnmatz B.
      • et al.
      The Swedish Angina Pectoris Aspirin Trial (SAPAT) Group
      Double-blind trial of aspirin in primary prevention of myocardial infarction in patients with stable chronic angina pectoris.
      • Lee T.K.
      • Chan K.W.
      • Huang Z.S.
      • et al.
      ASA Study Group in Taiwan
      Effectiveness of low-dose ASA in prevention of secondary ischemic stroke.
      • Lewis Jr, H.D.
      • Davis J.W.
      • Archibald D.G.
      • et al.
      Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. Results of a Veterans Administration Cooperative Study.
      • Lindblad B.
      • Persson N.H.
      • Takolander R.
      • Bergqvist D.
      Does low-dose acetylsalicylic acid prevent stroke after carotid surgery? A double-blind, placebo-controlled randomized trial.
      • Maresta A.
      • Balducelli M.
      • Cantini L.
      • et al.
      Trapidil (triazolopyrimidine), a platelet-derived growth factor antagonist, reduces restenosis after percutaneous transluminal coronary angioplasty. Results of the randomized, double-blind STARC study. Studio Trapidil versus Aspirin nella Restenosi Coronarica.
      • Matias-Guiu J.
      • Ferro J.M.
      • Alvarez-Sabin J.
      • et al.
      Comparison of triflusal and aspirin for prevention of vascular events in patients after cerebral infarction: the TACIP Study: a randomized, double-blind, multicenter trial.
      • Meijer A.
      • Verheugt F.W.
      • Werter C.J.
      • et al.
      Aspirin versus coumadin in the prevention of reocclusion and recurrent ischemia after successful thrombolysis: a prospective placebo-controlled angiographic study. Results of the APRICOT study.
      • Minar E.
      • Ahmadi A.
      • Koppensteiner R.
      • et al.
      Comparison of effects of high-dose and low-dose aspirin on restenosis after femoropopliteal percutaneous transluminal angioplasty.
      • Mohr J.P.
      • Thompson J.L.
      • Lazar R.M.
      • et al.
      A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke.
      • Petersen P.
      • Boysen G.
      • Godtfredsen J.
      • et al.
      Placebo-controlled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation. The Copenhagen AFASAK study.
      • Posada I.S.
      • Barriales V.
      LASAF Pilot Study Group
      Alternate-day dosing of aspirin in atrial fibrillation.
      • Scrutinio D.
      • Cimminiello C.
      • Marubini E.
      • et al.
      Ticlopidine versus aspirin after myocardial infarction (STAMI) trial.
      • Silagy C.A.
      • McNeil J.J.
      • Donnan G.A.
      • et al.
      Adverse effects of low-dose aspirin in a healthy elderly population.
      • Slattery J.
      • Warlow C.P.
      • Shorrock C.J.
      • Langman M.J.
      Risks of gastrointestinal bleeding during secondary prevention of vascular events with aspirin—analysis of gastrointestinal bleeding during the UK-TIA trial.
      • Taylor D.W.
      • Barnett H.J.
      • Haynes R.B.
      • et al.
      ASA and Carotid Endarterectomy (ACE) Trial Collaborators
      Low-dose and high-dose acetylsalicylic acid for patients undergoing carotid endarterectomy a randomised controlled trial.
      • Taylor R.R.
      • Gibbons F.A.
      • Cope G.D.
      • et al.
      Effects of low-dose aspirin on restenosis after coronary angioplasty.
      • Topol E.J.
      • Easton D.
      • Harrington R.A.
      • et al.
      Randomized, double-blind, placebo-controlled, international trial of the oral IIb/IIIa antagonist lotrafiban in coronary and cerebrovascular disease.
      • Tsuchikane E.
      • Fukuhara A.
      • Kobayashi T.
      • et al.
      Impact of cilostazol on restenosis after percutaneous coronary balloon angioplasty.
      • van Es R.F.
      • Jonker J.J.
      • Verheugt F.W.
      • et al.
      Aspirin and coumadin after acute coronary syndromes (the ASPECT-2 study) a randomised controlled trial.
      • Wallentin L.
      • Wilcox R.G.
      • Weaver W.D.
      • et al.
      Oral ximelagatran for secondary prophylaxis after myocardial infarction the ESTEEM randomised controlled trial.
      • Weber M.A.
      • Hasford J.
      • Taillens C.
      • et al.
      Low-dose aspirin versus anticoagulants for prevention of coronary graft occlusion.
      • Weichert W.
      • Meents H.
      • Abt K.
      • et al.
      Acetylsalicylic acid-reocclusion-prophylaxis after angioplasty (ARPA-study). A randomized double-blind trial of two different dosages of ASA in patients with peripheral occlusive arterial disease.
      • Yasue H.
      • Ogawa H.
      • Tanaka H.
      • et al.
      Japanese Antiplatelets Myocardial Infarction Study (JAMIS) Investigators
      Effects of aspirin and trapidil on cardiovascular events after acute myocardial infarction.
      In these trials there were 75,005 patients treated with low-dose aspirin, 13,401 with clopidogrel, 11,247 with combined aspirin and clopidogrel, and 30,515 with placebo. The characteristics of these clinical trials are provided in the Appendix.
      Twenty-five of these trials were included in this meta-analysis. Two trials included a clopidogrel treatment arm: one trial compared clopidogrel (9599 patients) to low-dose aspirin (9586 patients)
      CAPRIE Steering Committee
      A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE).
      and 1 trial compared clopidogrel (3802 patients) to combined clopidogrel and aspirin (3797 patients).
      • Diener H.C.
      • Bogousslavsky J.
      • Brass L.M.
      • et al.
      Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH) randomised, double-blind, placebo-controlled trial.
      Twenty-four trials included a low-dose aspirin treatment arm: 1 trial compared aspirin with clopidogrel (as above);
      CAPRIE Steering Committee
      A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE).
      1 trial compared aspirin (6303 patients) with combined clopidogrel and aspirin (6259 patients);
      • Yusuf S.
      • Zhao F.
      • Mehta S.R.
      • et al.
      Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators
      Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation.
      and 22 compared aspirin (30496 patients) with placebo (30515 patients).
      Steering Committee of the Physicians’ Health Study Research Group
      Final report on the aspirin component of the ongoing Physicians’ Health Study.
      Preliminary report of the Stroke Prevention in Atrial Fibrillation Study.
      Risk of myocardial infarction and death during treatment with low dose aspirin and intravenous heparin in men with unstable coronary artery disease.
      Stroke Prevention in Atrial Fibrillation Study. Final results.
      The SALT Collaborative Group
      Swedish Aspirin Low-Dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events.
      The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial final results.
      EAFT (European Atrial Fibrillation Trial) Study Group
      Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke.
      Thrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. The Medical Research Council’s General Practice Research Framework.
      Collaborative Group of the Primary Prevention Project
      Low-dose aspirin and vitamin E in people at cardiovascular risk a randomised trial in general practice.
      • Cote R.
      • Battista R.N.
      • Abrahamowicz M.
      • et al.
      The Asymptomatic Cervical Bruit Study Group
      Lack of effect of aspirin in asymptomatic patients with carotid bruits and substantial carotid narrowing.
      • Elwood P.C.
      • Cochrane A.L.
      • Burr M.L.
      • et al.
      A randomized controlled trial of acetyl salicylic acid in the secondary prevention of mortality from myocardial infarction.
      • Gavaghan T.P.
      • Gebski V.
      • Baron D.W.
      Immediate postoperative aspirin improves vein graft patency early and late after coronary artery bypass graft surgery. A placebo-controlled, randomized study.
      • Goldman S.
      • Copeland J.
      • Moritz T.
      • et al.
      Saphenous vein graft patency 1 year after coronary artery bypass surgery and effects of antiplatelet therapy. Results of a Veterans Administration Cooperative Study.
      • Hansson L.
      • Zanchetti A.
      • Carruthers S.G.
      • et al.
      HOT Study Group
      Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension principal results of the Hypertension Optimal Treatment (HOT) randomised trial.
      • Juul-Moller S.
      • Edvardsson N.
      • Jahnmatz B.
      • et al.
      The Swedish Angina Pectoris Aspirin Trial (SAPAT) Group
      Double-blind trial of aspirin in primary prevention of myocardial infarction in patients with stable chronic angina pectoris.
      • Lewis Jr, H.D.
      • Davis J.W.
      • Archibald D.G.
      • et al.
      Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. Results of a Veterans Administration Cooperative Study.
      • Lindblad B.
      • Persson N.H.
      • Takolander R.
      • Bergqvist D.
      Does low-dose acetylsalicylic acid prevent stroke after carotid surgery? A double-blind, placebo-controlled randomized trial.
      • Petersen P.
      • Boysen G.
      • Godtfredsen J.
      • et al.
      Placebo-controlled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation. The Copenhagen AFASAK study.
      • Posada I.S.
      • Barriales V.
      LASAF Pilot Study Group
      Alternate-day dosing of aspirin in atrial fibrillation.
      • Silagy C.A.
      • McNeil J.J.
      • Donnan G.A.
      • et al.
      Adverse effects of low-dose aspirin in a healthy elderly population.
      • Taylor R.R.
      • Gibbons F.A.
      • Cope G.D.
      • et al.
      Effects of low-dose aspirin on restenosis after coronary angioplasty.
      • Yasue H.
      • Ogawa H.
      • Tanaka H.
      • et al.
      Japanese Antiplatelets Myocardial Infarction Study (JAMIS) Investigators
      Effects of aspirin and trapidil on cardiovascular events after acute myocardial infarction.
      • Veen G.
      • Meyer A.
      • Verheugt F.W.
      • et al.
      Culprit lesion morphology and stenosis severity in the prediction of reocclusion after coronary thrombolysis: angiographic results of the APRICOT study. Antithrombotics in the Prevention of Reocclusion in Coronary Thrombolysis.
      Twenty-three of the studies eligible for this meta-analysis had a Jadad score of ≥3, and 19 had a score of ≥4, reflecting good quality study design.

      Meta-analyses: Aspirin versus Placebo

      Meta-analyses of bleeding complications (Table 1) and nonbleeding complications (Table 2) were performed on trials comparing aspirin versus placebo. In nine comparative trials comprising over 53,000 patients, the relative risk of any major bleeding among patients treated with aspirin was 1.71 (95% CI 1.41-2.08) (Table 1, Figure 1). The point estimates of all but one relatively small trial
      Preliminary report of the Stroke Prevention in Atrial Fibrillation Study.
      lay on the same side of unity, and the test for heterogeneity was not significant (P=.47).
      Table 1Bleeding Complications: Meta-analyses of Trials with Direct Comparisons of Aspirin versus Placebo
      EndpointNumber of StudiesReference #Subjects Compared: Aspirin/PlaceboRelative Risk (95% CI)
      Primary bleeding endpoints
       Any major bleeding9
      Steering Committee of the Physicians’ Health Study Research Group
      Final report on the aspirin component of the ongoing Physicians’ Health Study.
      Preliminary report of the Stroke Prevention in Atrial Fibrillation Study.
      Stroke Prevention in Atrial Fibrillation Study. Final results.
      The SALT Collaborative Group
      Swedish Aspirin Low-Dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events.
      EAFT (European Atrial Fibrillation Trial) Study Group
      Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke.
      Thrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. The Medical Research Council’s General Practice Research Framework.
      Collaborative Group of the Primary Prevention Project
      Low-dose aspirin and vitamin E in people at cardiovascular risk a randomised trial in general practice.
      • Hansson L.
      • Zanchetti A.
      • Carruthers S.G.
      • et al.
      HOT Study Group
      Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension principal results of the Hypertension Optimal Treatment (HOT) randomised trial.
      • Juul-Moller S.
      • Edvardsson N.
      • Jahnmatz B.
      • et al.
      The Swedish Angina Pectoris Aspirin Trial (SAPAT) Group
      Double-blind trial of aspirin in primary prevention of myocardial infarction in patients with stable chronic angina pectoris.
      • Meijer A.
      • Verheugt F.W.
      • Werter C.J.
      • et al.
      Aspirin versus coumadin in the prevention of reocclusion and recurrent ischemia after successful thrombolysis: a prospective placebo-controlled angiographic study. Results of the APRICOT study.
      26,673/26,7121.71(1.41-2.08)
        Lower-dose aspirin5
      The SALT Collaborative Group
      Swedish Aspirin Low-Dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events.
      Thrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. The Medical Research Council’s General Practice Research Framework.
      Collaborative Group of the Primary Prevention Project
      Low-dose aspirin and vitamin E in people at cardiovascular risk a randomised trial in general practice.
      • Hansson L.
      • Zanchetti A.
      • Carruthers S.G.
      • et al.
      HOT Study Group
      Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension principal results of the Hypertension Optimal Treatment (HOT) randomised trial.
      • Juul-Moller S.
      • Edvardsson N.
      • Jahnmatz B.
      • et al.
      The Swedish Angina Pectoris Aspirin Trial (SAPAT) Group
      Double-blind trial of aspirin in primary prevention of myocardial infarction in patients with stable chronic angina pectoris.
      14,578/14,6421.84(1.47-2.31)
        Higher-dose aspirin3
      Preliminary report of the Stroke Prevention in Atrial Fibrillation Study.
      Stroke Prevention in Atrial Fibrillation Study. Final results.
      EAFT (European Atrial Fibrillation Trial) Study Group
      Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke.
      • Meijer A.
      • Verheugt F.W.
      • Werter C.J.
      • et al.
      Aspirin versus coumadin in the prevention of reocclusion and recurrent ischemia after successful thrombolysis: a prospective placebo-controlled angiographic study. Results of the APRICOT study.
      1058/10360.89(0.45-1.74)
       Major GI bleeding14
      Steering Committee of the Physicians’ Health Study Research Group
      Final report on the aspirin component of the ongoing Physicians’ Health Study.
      The SALT Collaborative Group
      Swedish Aspirin Low-Dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events.
      The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial final results.
      EAFT (European Atrial Fibrillation Trial) Study Group
      Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke.
      Thrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. The Medical Research Council’s General Practice Research Framework.
      Collaborative Group of the Primary Prevention Project
      Low-dose aspirin and vitamin E in people at cardiovascular risk a randomised trial in general practice.
      • Cote R.
      • Battista R.N.
      • Abrahamowicz M.
      • et al.
      The Asymptomatic Cervical Bruit Study Group
      Lack of effect of aspirin in asymptomatic patients with carotid bruits and substantial carotid narrowing.
      • Elwood P.C.
      • Cochrane A.L.
      • Burr M.L.
      • et al.
      A randomized controlled trial of acetyl salicylic acid in the secondary prevention of mortality from myocardial infarction.
      • Gavaghan T.P.
      • Gebski V.
      • Baron D.W.
      Immediate postoperative aspirin improves vein graft patency early and late after coronary artery bypass graft surgery. A placebo-controlled, randomized study.
      • Hansson L.
      • Zanchetti A.
      • Carruthers S.G.
      • et al.
      HOT Study Group
      Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension principal results of the Hypertension Optimal Treatment (HOT) randomised trial.
      • Juul-Moller S.
      • Edvardsson N.
      • Jahnmatz B.
      • et al.
      The Swedish Angina Pectoris Aspirin Trial (SAPAT) Group
      Double-blind trial of aspirin in primary prevention of myocardial infarction in patients with stable chronic angina pectoris.
      • Lewis Jr, H.D.
      • Davis J.W.
      • Archibald D.G.
      • et al.
      Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. Results of a Veterans Administration Cooperative Study.
      • Meijer A.
      • Verheugt F.W.
      • Werter C.J.
      • et al.
      Aspirin versus coumadin in the prevention of reocclusion and recurrent ischemia after successful thrombolysis: a prospective placebo-controlled angiographic study. Results of the APRICOT study.
      • Silagy C.A.
      • McNeil J.J.
      • Donnan G.A.
      • et al.
      Adverse effects of low-dose aspirin in a healthy elderly population.
      • Slattery J.
      • Warlow C.P.
      • Shorrock C.J.
      • Langman M.J.
      Risks of gastrointestinal bleeding during secondary prevention of vascular events with aspirin—analysis of gastrointestinal bleeding during the UK-TIA trial.
      28,686/28,7192.07(1.61-2.66)
        Lower-dose aspirin6
      The SALT Collaborative Group
      Swedish Aspirin Low-Dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events.
      Thrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. The Medical Research Council’s General Practice Research Framework.
      Collaborative Group of the Primary Prevention Project
      Low-dose aspirin and vitamin E in people at cardiovascular risk a randomised trial in general practice.
      • Hansson L.
      • Zanchetti A.
      • Carruthers S.G.
      • et al.
      HOT Study Group
      Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension principal results of the Hypertension Optimal Treatment (HOT) randomised trial.
      • Juul-Moller S.
      • Edvardsson N.
      • Jahnmatz B.
      • et al.
      The Swedish Angina Pectoris Aspirin Trial (SAPAT) Group
      Double-blind trial of aspirin in primary prevention of myocardial infarction in patients with stable chronic angina pectoris.
      • Silagy C.A.
      • McNeil J.J.
      • Donnan G.A.
      • et al.
      Adverse effects of low-dose aspirin in a healthy elderly population.
      14,778/14,8422.22(1.61-3.06)
        Higher-dose aspirin7
      The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial final results.
      EAFT (European Atrial Fibrillation Trial) Study Group
      Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke.
      • Cote R.
      • Battista R.N.
      • Abrahamowicz M.
      • et al.
      The Asymptomatic Cervical Bruit Study Group
      Lack of effect of aspirin in asymptomatic patients with carotid bruits and substantial carotid narrowing.
      • Elwood P.C.
      • Cochrane A.L.
      • Burr M.L.
      • et al.
      A randomized controlled trial of acetyl salicylic acid in the secondary prevention of mortality from myocardial infarction.
      • Gavaghan T.P.
      • Gebski V.
      • Baron D.W.
      Immediate postoperative aspirin improves vein graft patency early and late after coronary artery bypass graft surgery. A placebo-controlled, randomized study.
      • Lewis Jr, H.D.
      • Davis J.W.
      • Archibald D.G.
      • et al.
      Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. Results of a Veterans Administration Cooperative Study.
      • Meijer A.
      • Verheugt F.W.
      • Werter C.J.
      • et al.
      Aspirin versus coumadin in the prevention of reocclusion and recurrent ischemia after successful thrombolysis: a prospective placebo-controlled angiographic study. Results of the APRICOT study.
      • Slattery J.
      • Warlow C.P.
      • Shorrock C.J.
      • Langman M.J.
      Risks of gastrointestinal bleeding during secondary prevention of vascular events with aspirin—analysis of gastrointestinal bleeding during the UK-TIA trial.
      2871/28432.35(0.98-5.66)
       Intracranial bleeding11
      Steering Committee of the Physicians’ Health Study Research Group
      Final report on the aspirin component of the ongoing Physicians’ Health Study.
      Preliminary report of the Stroke Prevention in Atrial Fibrillation Study.
      Stroke Prevention in Atrial Fibrillation Study. Final results.
      The SALT Collaborative Group
      Swedish Aspirin Low-Dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events.
      The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial final results.
      EAFT (European Atrial Fibrillation Trial) Study Group
      Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke.
      Thrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. The Medical Research Council’s General Practice Research Framework.
      Collaborative Group of the Primary Prevention Project
      Low-dose aspirin and vitamin E in people at cardiovascular risk a randomised trial in general practice.
      • Cote R.
      • Battista R.N.
      • Abrahamowicz M.
      • et al.
      The Asymptomatic Cervical Bruit Study Group
      Lack of effect of aspirin in asymptomatic patients with carotid bruits and substantial carotid narrowing.
      • Hansson L.
      • Zanchetti A.
      • Carruthers S.G.
      • et al.
      HOT Study Group
      Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension principal results of the Hypertension Optimal Treatment (HOT) randomised trial.
      • Juul-Moller S.
      • Edvardsson N.
      • Jahnmatz B.
      • et al.
      The Swedish Angina Pectoris Aspirin Trial (SAPAT) Group
      Double-blind trial of aspirin in primary prevention of myocardial infarction in patients with stable chronic angina pectoris.
      • Meijer A.
      • Verheugt F.W.
      • Werter C.J.
      • et al.
      Aspirin versus coumadin in the prevention of reocclusion and recurrent ischemia after successful thrombolysis: a prospective placebo-controlled angiographic study. Results of the APRICOT study.
      • Slattery J.
      • Warlow C.P.
      • Shorrock C.J.
      • Langman M.J.
      Risks of gastrointestinal bleeding during secondary prevention of vascular events with aspirin—analysis of gastrointestinal bleeding during the UK-TIA trial.
      27,671/27,7121.65(1.12-2.44)
        Lower-dose aspirin5
      The SALT Collaborative Group
      Swedish Aspirin Low-Dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events.
      Thrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. The Medical Research Council’s General Practice Research Framework.
      Collaborative Group of the Primary Prevention Project
      Low-dose aspirin and vitamin E in people at cardiovascular risk a randomised trial in general practice.
      • Hansson L.
      • Zanchetti A.
      • Carruthers S.G.
      • et al.
      HOT Study Group
      Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension principal results of the Hypertension Optimal Treatment (HOT) randomised trial.
      • Juul-Moller S.
      • Edvardsson N.
      • Jahnmatz B.
      • et al.
      The Swedish Angina Pectoris Aspirin Trial (SAPAT) Group
      Double-blind trial of aspirin in primary prevention of myocardial infarction in patients with stable chronic angina pectoris.
      14,578/14,6421.43(0.85-2.42)
        Higher dose aspirin5
      Preliminary report of the Stroke Prevention in Atrial Fibrillation Study.
      Stroke Prevention in Atrial Fibrillation Study. Final results.
      The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial final results.
      EAFT (European Atrial Fibrillation Trial) Study Group
      Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke.
      • Cote R.
      • Battista R.N.
      • Abrahamowicz M.
      • et al.
      The Asymptomatic Cervical Bruit Study Group
      Lack of effect of aspirin in asymptomatic patients with carotid bruits and substantial carotid narrowing.
      • Meijer A.
      • Verheugt F.W.
      • Werter C.J.
      • et al.
      Aspirin versus coumadin in the prevention of reocclusion and recurrent ischemia after successful thrombolysis: a prospective placebo-controlled angiographic study. Results of the APRICOT study.
      • Slattery J.
      • Warlow C.P.
      • Shorrock C.J.
      • Langman M.J.
      Risks of gastrointestinal bleeding during secondary prevention of vascular events with aspirin—analysis of gastrointestinal bleeding during the UK-TIA trial.
      2056/20362.11(0.71-6.28)
      Additional bleeding endpoints
       Any bleeding8
      Steering Committee of the Physicians’ Health Study Research Group
      Final report on the aspirin component of the ongoing Physicians’ Health Study.
      The SALT Collaborative Group
      Swedish Aspirin Low-Dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events.
      The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial final results.
      EAFT (European Atrial Fibrillation Trial) Study Group
      Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke.
      • Hansson L.
      • Zanchetti A.
      • Carruthers S.G.
      • et al.
      HOT Study Group
      Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension principal results of the Hypertension Optimal Treatment (HOT) randomised trial.
      • Juul-Moller S.
      • Edvardsson N.
      • Jahnmatz B.
      • et al.
      The Swedish Angina Pectoris Aspirin Trial (SAPAT) Group
      Double-blind trial of aspirin in primary prevention of myocardial infarction in patients with stable chronic angina pectoris.
      • Petersen P.
      • Boysen G.
      • Godtfredsen J.
      • et al.
      Placebo-controlled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation. The Copenhagen AFASAK study.
      • Silagy C.A.
      • McNeil J.J.
      • Donnan G.A.
      • et al.
      Adverse effects of low-dose aspirin in a healthy elderly population.
      • Slattery J.
      • Warlow C.P.
      • Shorrock C.J.
      • Langman M.J.
      Risks of gastrointestinal bleeding during secondary prevention of vascular events with aspirin—analysis of gastrointestinal bleeding during the UK-TIA trial.
      23,871/23,8651.62(1.30-2.03)
      Heterogeneity: P <.10.
        Lower-dose aspirin5
      The SALT Collaborative Group
      Swedish Aspirin Low-Dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events.
      • Hansson L.
      • Zanchetti A.
      • Carruthers S.G.
      • et al.
      HOT Study Group
      Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension principal results of the Hypertension Optimal Treatment (HOT) randomised trial.
      • Juul-Moller S.
      • Edvardsson N.
      • Jahnmatz B.
      • et al.
      The Swedish Angina Pectoris Aspirin Trial (SAPAT) Group
      Double-blind trial of aspirin in primary prevention of myocardial infarction in patients with stable chronic angina pectoris.
      • Petersen P.
      • Boysen G.
      • Godtfredsen J.
      • et al.
      Placebo-controlled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation. The Copenhagen AFASAK study.
      • Silagy C.A.
      • McNeil J.J.
      • Donnan G.A.
      • et al.
      Adverse effects of low-dose aspirin in a healthy elderly population.
      11,620/11,6371.82(1.53-2.16)
        Higher-dose aspirin2
      The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial final results.
      EAFT (European Atrial Fibrillation Trial) Study Group
      Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke.
      • Slattery J.
      • Warlow C.P.
      • Shorrock C.J.
      • Langman M.J.
      Risks of gastrointestinal bleeding during secondary prevention of vascular events with aspirin—analysis of gastrointestinal bleeding during the UK-TIA trial.
      1214/11941.60(1.09-2.35)
       All GI bleeding11
      Steering Committee of the Physicians’ Health Study Research Group
      Final report on the aspirin component of the ongoing Physicians’ Health Study.
      Risk of myocardial infarction and death during treatment with low dose aspirin and intravenous heparin in men with unstable coronary artery disease.
      The SALT Collaborative Group
      Swedish Aspirin Low-Dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events.
      The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial final results.
      EAFT (European Atrial Fibrillation Trial) Study Group
      Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke.
      Thrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. The Medical Research Council’s General Practice Research Framework.
      • Elwood P.C.
      • Cochrane A.L.
      • Burr M.L.
      • et al.
      A randomized controlled trial of acetyl salicylic acid in the secondary prevention of mortality from myocardial infarction.
      • Hansson L.
      • Zanchetti A.
      • Carruthers S.G.
      • et al.
      HOT Study Group
      Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension principal results of the Hypertension Optimal Treatment (HOT) randomised trial.
      • Meijer A.
      • Verheugt F.W.
      • Werter C.J.
      • et al.
      Aspirin versus coumadin in the prevention of reocclusion and recurrent ischemia after successful thrombolysis: a prospective placebo-controlled angiographic study. Results of the APRICOT study.
      • Petersen P.
      • Boysen G.
      • Godtfredsen J.
      • et al.
      Placebo-controlled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation. The Copenhagen AFASAK study.
      • Silagy C.A.
      • McNeil J.J.
      • Donnan G.A.
      • et al.
      Adverse effects of low-dose aspirin in a healthy elderly population.
      • Slattery J.
      • Warlow C.P.
      • Shorrock C.J.
      • Langman M.J.
      Risks of gastrointestinal bleeding during secondary prevention of vascular events with aspirin—analysis of gastrointestinal bleeding during the UK-TIA trial.
      25,036/25,0241.62(1.25-2.09)
      Heterogeneity: P <.10.
        Lower-dose aspirin6
      Risk of myocardial infarction and death during treatment with low dose aspirin and intravenous heparin in men with unstable coronary artery disease.
      The SALT Collaborative Group
      Swedish Aspirin Low-Dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events.
      Thrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. The Medical Research Council’s General Practice Research Framework.
      • Hansson L.
      • Zanchetti A.
      • Carruthers S.G.
      • et al.
      HOT Study Group
      Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension principal results of the Hypertension Optimal Treatment (HOT) randomised trial.
      • Petersen P.
      • Boysen G.
      • Godtfredsen J.
      • et al.
      Placebo-controlled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation. The Copenhagen AFASAK study.
      • Silagy C.A.
      • McNeil J.J.
      • Donnan G.A.
      • et al.
      Adverse effects of low-dose aspirin in a healthy elderly population.
      12,068/12,0821.73(1.28-2.33)
        Higher-dose aspirin4
      The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial final results.
      EAFT (European Atrial Fibrillation Trial) Study Group
      Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke.
      • Elwood P.C.
      • Cochrane A.L.
      • Burr M.L.
      • et al.
      A randomized controlled trial of acetyl salicylic acid in the secondary prevention of mortality from myocardial infarction.
      • Meijer A.
      • Verheugt F.W.
      • Werter C.J.
      • et al.
      Aspirin versus coumadin in the prevention of reocclusion and recurrent ischemia after successful thrombolysis: a prospective placebo-controlled angiographic study. Results of the APRICOT study.
      • Slattery J.
      • Warlow C.P.
      • Shorrock C.J.
      • Langman M.J.
      Risks of gastrointestinal bleeding during secondary prevention of vascular events with aspirin—analysis of gastrointestinal bleeding during the UK-TIA trial.
      1931/19082.26(1.24-4.14)
       All non-GI/non-intracranial bleeding5
      The SALT Collaborative Group
      Swedish Aspirin Low-Dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events.
      EAFT (European Atrial Fibrillation Trial) Study Group
      Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke.
      • Hansson L.
      • Zanchetti A.
      • Carruthers S.G.
      • et al.
      HOT Study Group
      Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension principal results of the Hypertension Optimal Treatment (HOT) randomised trial.
      • Meijer A.
      • Verheugt F.W.
      • Werter C.J.
      • et al.
      Aspirin versus coumadin in the prevention of reocclusion and recurrent ischemia after successful thrombolysis: a prospective placebo-controlled angiographic study. Results of the APRICOT study.
      • Petersen P.
      • Boysen G.
      • Godtfredsen J.
      • et al.
      Placebo-controlled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation. The Copenhagen AFASAK study.
      10,917/10,8791.72(1.39-2.13)
       Major non-GI/non-intracranial bleeding7
      The SALT Collaborative Group
      Swedish Aspirin Low-Dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events.
      EAFT (European Atrial Fibrillation Trial) Study Group
      Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke.
      Thrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. The Medical Research Council’s General Practice Research Framework.
      • Hansson L.
      • Zanchetti A.
      • Carruthers S.G.
      • et al.
      HOT Study Group
      Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension principal results of the Hypertension Optimal Treatment (HOT) randomised trial.
      • Juul-Moller S.
      • Edvardsson N.
      • Jahnmatz B.
      • et al.
      The Swedish Angina Pectoris Aspirin Trial (SAPAT) Group
      Double-blind trial of aspirin in primary prevention of myocardial infarction in patients with stable chronic angina pectoris.
      • Lindblad B.
      • Persson N.H.
      • Takolander R.
      • Bergqvist D.
      Does low-dose acetylsalicylic acid prevent stroke after carotid surgery? A double-blind, placebo-controlled randomized trial.
      • Meijer A.
      • Verheugt F.W.
      • Werter C.J.
      • et al.
      Aspirin versus coumadin in the prevention of reocclusion and recurrent ischemia after successful thrombolysis: a prospective placebo-controlled angiographic study. Results of the APRICOT study.
      12,975/12,9561.45(0.95-2.20)
       Any fatal bleeding10
      Steering Committee of the Physicians’ Health Study Research Group
      Final report on the aspirin component of the ongoing Physicians’ Health Study.
      Preliminary report of the Stroke Prevention in Atrial Fibrillation Study.
      Stroke Prevention in Atrial Fibrillation Study. Final results.
      The SALT Collaborative Group
      Swedish Aspirin Low-Dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events.
      Collaborative Group of the Primary Prevention Project
      Low-dose aspirin and vitamin E in people at cardiovascular risk a randomised trial in general practice.
      • Cote R.
      • Battista R.N.
      • Abrahamowicz M.
      • et al.
      The Asymptomatic Cervical Bruit Study Group
      Lack of effect of aspirin in asymptomatic patients with carotid bruits and substantial carotid narrowing.
      • Hansson L.
      • Zanchetti A.
      • Carruthers S.G.
      • et al.
      HOT Study Group
      Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension principal results of the Hypertension Optimal Treatment (HOT) randomised trial.
      • Juul-Moller S.
      • Edvardsson N.
      • Jahnmatz B.
      • et al.
      The Swedish Angina Pectoris Aspirin Trial (SAPAT) Group
      Double-blind trial of aspirin in primary prevention of myocardial infarction in patients with stable chronic angina pectoris.
      • Meijer A.
      • Verheugt F.W.
      • Werter C.J.
      • et al.
      Aspirin versus coumadin in the prevention of reocclusion and recurrent ischemia after successful thrombolysis: a prospective placebo-controlled angiographic study. Results of the APRICOT study.
      • Silagy C.A.
      • McNeil J.J.
      • Donnan G.A.
      • et al.
      Adverse effects of low-dose aspirin in a healthy elderly population.
      • Taylor R.R.
      • Gibbons F.A.
      • Cope G.D.
      • et al.
      Effects of low-dose aspirin on restenosis after coronary angioplasty.
      25,497/25,5501.30(0.70-2.42)
       Fatal GI bleeding12
      Steering Committee of the Physicians’ Health Study Research Group
      Final report on the aspirin component of the ongoing Physicians’ Health Study.
      Preliminary report of the Stroke Prevention in Atrial Fibrillation Study.
      Stroke Prevention in Atrial Fibrillation Study. Final results.
      The SALT Collaborative Group
      Swedish Aspirin Low-Dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events.
      The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial final results.
      Thrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. The Medical Research Council’s General Practice Research Framework.
      • Cote R.
      • Battista R.N.
      • Abrahamowicz M.
      • et al.
      The Asymptomatic Cervical Bruit Study Group
      Lack of effect of aspirin in asymptomatic patients with carotid bruits and substantial carotid narrowing.
      • Elwood P.C.
      • Cochrane A.L.
      • Burr M.L.
      • et al.
      A randomized controlled trial of acetyl salicylic acid in the secondary prevention of mortality from myocardial infarction.
      • Hansson L.
      • Zanchetti A.
      • Carruthers S.G.
      • et al.
      HOT Study Group
      Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension principal results of the Hypertension Optimal Treatment (HOT) randomised trial.
      • Juul-Moller S.
      • Edvardsson N.
      • Jahnmatz B.
      • et al.
      The Swedish Angina Pectoris Aspirin Trial (SAPAT) Group
      Double-blind trial of aspirin in primary prevention of myocardial infarction in patients with stable chronic angina pectoris.
      • Meijer A.
      • Verheugt F.W.
      • Werter C.J.
      • et al.
      Aspirin versus coumadin in the prevention of reocclusion and recurrent ischemia after successful thrombolysis: a prospective placebo-controlled angiographic study. Results of the APRICOT study.
      • Silagy C.A.
      • McNeil J.J.
      • Donnan G.A.
      • et al.
      Adverse effects of low-dose aspirin in a healthy elderly population.
      • Slattery J.
      • Warlow C.P.
      • Shorrock C.J.
      • Langman M.J.
      Risks of gastrointestinal bleeding during secondary prevention of vascular events with aspirin—analysis of gastrointestinal bleeding during the UK-TIA trial.
      • Taylor R.R.
      • Gibbons F.A.
      • Cope G.D.
      • et al.
      Effects of low-dose aspirin on restenosis after coronary angioplasty.
      25,964/25,9931.23(0.45-3.41)
       Fatal intracranial bleeding12
      Preliminary report of the Stroke Prevention in Atrial Fibrillation Study.
      Stroke Prevention in Atrial Fibrillation Study. Final results.
      The SALT Collaborative Group
      Swedish Aspirin Low-Dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events.
      The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial final results.
      EAFT (European Atrial Fibrillation Trial) Study Group
      Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke.
      • Cote R.
      • Battista R.N.
      • Abrahamowicz M.
      • et al.
      The Asymptomatic Cervical Bruit Study Group
      Lack of effect of aspirin in asymptomatic patients with carotid bruits and substantial carotid narrowing.
      • Hansson L.
      • Zanchetti A.
      • Carruthers S.G.
      • et al.
      HOT Study Group
      Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension principal results of the Hypertension Optimal Treatment (HOT) randomised trial.
      • Juul-Moller S.
      • Edvardsson N.
      • Jahnmatz B.
      • et al.
      The Swedish Angina Pectoris Aspirin Trial (SAPAT) Group
      Double-blind trial of aspirin in primary prevention of myocardial infarction in patients with stable chronic angina pectoris.
      • Meijer A.
      • Verheugt F.W.
      • Werter C.J.
      • et al.
      Aspirin versus coumadin in the prevention of reocclusion and recurrent ischemia after successful thrombolysis: a prospective placebo-controlled angiographic study. Results of the APRICOT study.
      • Posada I.S.
      • Barriales V.
      LASAF Pilot Study Group
      Alternate-day dosing of aspirin in atrial fibrillation.
      • Silagy C.A.
      • McNeil J.J.
      • Donnan G.A.
      • et al.
      Adverse effects of low-dose aspirin in a healthy elderly population.
      • Slattery J.
      • Warlow C.P.
      • Shorrock C.J.
      • Langman M.J.
      Risks of gastrointestinal bleeding during secondary prevention of vascular events with aspirin—analysis of gastrointestinal bleeding during the UK-TIA trial.
      • Taylor R.R.
      • Gibbons F.A.
      • Cope G.D.
      • et al.
      Effects of low-dose aspirin on restenosis after coronary angioplasty.
      • Yasue H.
      • Ogawa H.
      • Tanaka H.
      • et al.
      Japanese Antiplatelets Myocardial Infarction Study (JAMIS) Investigators
      Effects of aspirin and trapidil on cardiovascular events after acute myocardial infarction.
      13,802/13,7622.52(1.06-5.99)
       Fatal non-GI/non-intracranial bleeding8
      Preliminary report of the Stroke Prevention in Atrial Fibrillation Study.
      Stroke Prevention in Atrial Fibrillation Study. Final results.
      The SALT Collaborative Group
      Swedish Aspirin Low-Dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events.
      Thrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. The Medical Research Council’s General Practice Research Framework.
      • Hansson L.
      • Zanchetti A.
      • Carruthers S.G.
      • et al.
      HOT Study Group
      Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension principal results of the Hypertension Optimal Treatment (HOT) randomised trial.
      • Juul-Moller S.
      • Edvardsson N.
      • Jahnmatz B.
      • et al.
      The Swedish Angina Pectoris Aspirin Trial (SAPAT) Group
      Double-blind trial of aspirin in primary prevention of myocardial infarction in patients with stable chronic angina pectoris.
      • Meijer A.
      • Verheugt F.W.
      • Werter C.J.
      • et al.
      Aspirin versus coumadin in the prevention of reocclusion and recurrent ischemia after successful thrombolysis: a prospective placebo-controlled angiographic study. Results of the APRICOT study.
      • Silagy C.A.
      • McNeil J.J.
      • Donnan G.A.
      • et al.
      Adverse effects of low-dose aspirin in a healthy elderly population.
      • Taylor R.R.
      • Gibbons F.A.
      • Cope G.D.
      • et al.
      Effects of low-dose aspirin on restenosis after coronary angioplasty.
      13,314/13,3350.80(0.26-2.53)
      low asterisk Heterogeneity: P <.10.
      Table 2Non-Bleeding Outcomes: Meta-analysis of Trials with Direct Comparisons of Aspirin versus Placebo
      OutcomeStudiesSubjects Compared Aspirin/PlaceboRelative Risk (95% CI)
      Noncardiovascular deaths16
      Steering Committee of the Physicians’ Health Study Research Group
      Final report on the aspirin component of the ongoing Physicians’ Health Study.
      Preliminary report of the Stroke Prevention in Atrial Fibrillation Study.
      The SALT Collaborative Group
      Swedish Aspirin Low-Dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events.
      The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial final results.
      EAFT (European Atrial Fibrillation Trial) Study Group
      Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke.
      Thrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. The Medical Research Council’s General Practice Research Framework.
      Collaborative Group of the Primary Prevention Project
      Low-dose aspirin and vitamin E in people at cardiovascular risk a randomised trial in general practice.
      • Cote R.
      • Battista R.N.
      • Abrahamowicz M.
      • et al.
      The Asymptomatic Cervical Bruit Study Group
      Lack of effect of aspirin in asymptomatic patients with carotid bruits and substantial carotid narrowing.
      • Hansson L.
      • Zanchetti A.
      • Carruthers S.G.
      • et al.
      HOT Study Group
      Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension principal results of the Hypertension Optimal Treatment (HOT) randomised trial.
      • Juul-Moller S.
      • Edvardsson N.
      • Jahnmatz B.
      • et al.
      The Swedish Angina Pectoris Aspirin Trial (SAPAT) Group
      Double-blind trial of aspirin in primary prevention of myocardial infarction in patients with stable chronic angina pectoris.
      • Lindblad B.
      • Persson N.H.
      • Takolander R.
      • Bergqvist D.
      Does low-dose acetylsalicylic acid prevent stroke after carotid surgery? A double-blind, placebo-controlled randomized trial.
      • Meijer A.
      • Verheugt F.W.
      • Werter C.J.
      • et al.
      Aspirin versus coumadin in the prevention of reocclusion and recurrent ischemia after successful thrombolysis: a prospective placebo-controlled angiographic study. Results of the APRICOT study.
      • Posada I.S.
      • Barriales V.
      LASAF Pilot Study Group
      Alternate-day dosing of aspirin in atrial fibrillation.
      • Silagy C.A.
      • McNeil J.J.
      • Donnan G.A.
      • et al.
      Adverse effects of low-dose aspirin in a healthy elderly population.
      • Slattery J.
      • Warlow C.P.
      • Shorrock C.J.
      • Langman M.J.
      Risks of gastrointestinal bleeding during secondary prevention of vascular events with aspirin—analysis of gastrointestinal bleeding during the UK-TIA trial.
      • Taylor R.R.
      • Gibbons F.A.
      • Cope G.D.
      • et al.
      Effects of low-dose aspirin on restenosis after coronary angioplasty.
      • Yasue H.
      • Ogawa H.
      • Tanaka H.
      • et al.
      Japanese Antiplatelets Myocardial Infarction Study (JAMIS) Investigators
      Effects of aspirin and trapidil on cardiovascular events after acute myocardial infarction.
      28,450/28,4520.92(0.81-1.04)
      Discontinuations due to adverse events
       All events5
      The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial final results.
      EAFT (European Atrial Fibrillation Trial) Study Group
      Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke.
      • Lewis Jr, H.D.
      • Davis J.W.
      • Archibald D.G.
      • et al.
      Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. Results of a Veterans Administration Cooperative Study.
      • Lindblad B.
      • Persson N.H.
      • Takolander R.
      • Bergqvist D.
      Does low-dose acetylsalicylic acid prevent stroke after carotid surgery? A double-blind, placebo-controlled randomized trial.
      • Petersen P.
      • Boysen G.
      • Godtfredsen J.
      • et al.
      Placebo-controlled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation. The Copenhagen AFASAK study.
      • Silagy C.A.
      • McNeil J.J.
      • Donnan G.A.
      • et al.
      Adverse effects of low-dose aspirin in a healthy elderly population.
      2292/22861.16(0.94-1.44)
       GI events7
      Preliminary report of the Stroke Prevention in Atrial Fibrillation Study.
      The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial final results.
      • Cote R.
      • Battista R.N.
      • Abrahamowicz M.
      • et al.
      The Asymptomatic Cervical Bruit Study Group
      Lack of effect of aspirin in asymptomatic patients with carotid bruits and substantial carotid narrowing.
      • Gavaghan T.P.
      • Gebski V.
      • Baron D.W.
      Immediate postoperative aspirin improves vein graft patency early and late after coronary artery bypass graft surgery. A placebo-controlled, randomized study.
      • Lewis Jr, H.D.
      • Davis J.W.
      • Archibald D.G.
      • et al.
      Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. Results of a Veterans Administration Cooperative Study.
      • Lindblad B.
      • Persson N.H.
      • Takolander R.
      • Bergqvist D.
      Does low-dose acetylsalicylic acid prevent stroke after carotid surgery? A double-blind, placebo-controlled randomized trial.
      • Slattery J.
      • Warlow C.P.
      • Shorrock C.J.
      • Langman M.J.
      Risks of gastrointestinal bleeding during secondary prevention of vascular events with aspirin—analysis of gastrointestinal bleeding during the UK-TIA trial.
      • Taylor R.R.
      • Gibbons F.A.
      • Cope G.D.
      • et al.
      Effects of low-dose aspirin on restenosis after coronary angioplasty.
      2527/22861.26(0.94-1.70)
       Non-GI events4
      The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial final results.
      • Cote R.
      • Battista R.N.
      • Abrahamowicz M.
      • et al.
      The Asymptomatic Cervical Bruit Study Group
      Lack of effect of aspirin in asymptomatic patients with carotid bruits and substantial carotid narrowing.
      • Lewis Jr, H.D.
      • Davis J.W.
      • Archibald D.G.
      • et al.
      Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. Results of a Veterans Administration Cooperative Study.
      • Lindblad B.
      • Persson N.H.
      • Takolander R.
      • Bergqvist D.
      Does low-dose acetylsalicylic acid prevent stroke after carotid surgery? A double-blind, placebo-controlled randomized trial.
      • Slattery J.
      • Warlow C.P.
      • Shorrock C.J.
      • Langman M.J.
      Risks of gastrointestinal bleeding during secondary prevention of vascular events with aspirin—analysis of gastrointestinal bleeding during the UK-TIA trial.
      1740/17560.84(0.55-1.28)
      Adverse events
       Dyspepsia5
      Steering Committee of the Physicians’ Health Study Research Group
      Final report on the aspirin component of the ongoing Physicians’ Health Study.
      The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial final results.
      • Gavaghan T.P.
      • Gebski V.
      • Baron D.W.
      Immediate postoperative aspirin improves vein graft patency early and late after coronary artery bypass graft surgery. A placebo-controlled, randomized study.
      • Petersen P.
      • Boysen G.
      • Godtfredsen J.
      • et al.
      Placebo-controlled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation. The Copenhagen AFASAK study.
      • Silagy C.A.
      • McNeil J.J.
      • Donnan G.A.
      • et al.
      Adverse effects of low-dose aspirin in a healthy elderly population.
      • Slattery J.
      • Warlow C.P.
      • Shorrock C.J.
      • Langman M.J.
      Risks of gastrointestinal bleeding during secondary prevention of vascular events with aspirin—analysis of gastrointestinal bleeding during the UK-TIA trial.
      12,510/12,4961.09(0.97-1.22)
       Diarrhea2
      The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial final results.
      • Silagy C.A.
      • McNeil J.J.
      • Donnan G.A.
      • et al.
      Adverse effects of low-dose aspirin in a healthy elderly population.
      • Slattery J.
      • Warlow C.P.
      • Shorrock C.J.
      • Langman M.J.
      Risks of gastrointestinal bleeding during secondary prevention of vascular events with aspirin—analysis of gastrointestinal bleeding during the UK-TIA trial.
      1010/10163.30(1.42-7.66)
       Constipation2
      The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial final results.
      • Silagy C.A.
      • McNeil J.J.
      • Donnan G.A.
      • et al.
      Adverse effects of low-dose aspirin in a healthy elderly population.
      • Slattery J.
      • Warlow C.P.
      • Shorrock C.J.
      • Langman M.J.
      Risks of gastrointestinal bleeding during secondary prevention of vascular events with aspirin—analysis of gastrointestinal bleeding during the UK-TIA trial.
      1010/10161.98(1.14-3.44)
       Rash1
      The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial final results.
      • Slattery J.
      • Warlow C.P.
      • Shorrock C.J.
      • Langman M.J.
      Risks of gastrointestinal bleeding during secondary prevention of vascular events with aspirin—analysis of gastrointestinal bleeding during the UK-TIA trial.
      810/8160.77(0.38-1.58)
      Figure thumbnail gr1
      Figure 1Meta-analysis of major bleeding: aspirin vs placebo.
      To assess major GI bleeding complications we performed a meta-analysis of 14 studies comprising over 57,000 patients. This analysis included the Physicians’ Health Study, in which over 22,000 patients were randomized to aspirin or placebo treatment.
      Steering Committee of the Physicians’ Health Study Research Group
      Final report on the aspirin component of the ongoing Physicians’ Health Study.
      This study did not specify the numbers of patients who developed major GI bleeding but did report the numbers with melena, hematemesis, and transfusion-requiring bleeding. We considered 2 scenarios for tabulating the major GI bleeding episodes for this study. Our primary analysis assumed that the transfusion-requiring bleeding episodes comprised the major GI bleeding episodes (48 for aspirin and 28 for placebo). We also performed a “sensitivity” analysis using a “worst case” scenario that assigned all patients with hematemesis or melena as having major GI bleeding (402 for aspirin and 274 for placebo). This number appears to have included a small number of double-counting (ie, patients with both hematemesis and melena) and likely includes a number of patients who were not hospitalized. It is noteworthy that the meta-analysis by Derry and Loke (which did not assess “major” GI bleeding) used the combination of hematemesis and melena from the Physicians’ Health Study to calculate the GI bleeding proportion.
      • Derry S.
      • Loke Y.K.
      Risk of gastrointestinal haemorrhge with long term use of aspirin meta-analysis.
      In contrast, the meta-analysis of Hayden et al
      • Hayden M.
      • Pignone M.
      • Phillips C.
      • Mulrow C.
      Aspirin for the primary prevention of cardiovascular events a summary of the evidence for the U.S. Preventive Services Task Force.
      used the number of subjects with peptic ulcers to calculate GI bleeding in the Physicians’ Health Study and did not use the reported bleeding events. Based upon our primary analysis, there was a significant increase in major GI bleeding episodes among patients treated with aspirin versus placebo (relative risk [RR] 2.07; 95% CI, 1.61-2.66) (Table 1, Figure 2). When the meta-analysis was recalculated using the “worst case” scenario for the Physicians’ Health Study, the relative risk was lower but remained significant (RR 1.59; 95% CI, 1.39-1.82).
      Figure thumbnail gr2
      Figure 2Meta-analysis of major GI bleeding: aspirin vs placebo.
      Significantly increased risks of intracranial bleeding (RR 1.65; 95% CI, 1.12-2.44) and fatal intracranial bleeding (RR 2.52; 95% CI, 1.06-5.99) were also observed among patients taking aspirin versus placebo in separate meta-analyses (Table 1, Figure 3).
      Figure thumbnail gr3
      Figure 3Meta-analysis of intracranial bleeding: aspirin vs placebo.
      Separate subset analyses of trials comparing low low-dose aspirin versus placebo or high low-dose aspirin with placebo demonstrated overlapping confidence intervals for the relative risks for all bleeding endpoints assessed (Table 1). However, firm conclusions are limited by the relatively small number of patients treated with high low-dose aspirin versus placebo.
      Meta-analysis of 16 trials including almost 57,000 subjects detected no difference in risk of noncardiovascular death among patients treated with aspirin versus placebo (RR 0.92; 95% CI, 0.81-1.04) (Table 2). Few studies that assessed non-bleeding adverse events were available for meta-analysis (Table 2). Based on 5 studies, low-dose aspirin was not associated with a significant increase in dyspepsia versus placebo (RR 1.09; 95% CI, 0.97 – 1.22). Interestingly, 2 relatively small studies detected an increased risk of both diarrhea (RR 3.30; 95% CI, 1.42-7.66) and constipation (RR 1.98; 95% CI, 1.14-3.44) in the same study populations. Meta-analyses of a small number of studies and patients did not detect a significantly increased risk of discontinuations for all adverse events (RR 1.16; 95% CI, 0.94-1.44) or GI adverse events (RR 1.26; 95% CI, 0.94-1.70) among patients taking aspirin versus placebo.
      Based upon the weighted incidence of bleeding among patients treated with placebo in the meta-analyses, we determined the rate of bleeding attributable to aspirin (ie, the absolute increase in annual bleeding incidence for aspirin vs placebo) for the 3 primary bleeding endpoints. Nine studies comparing treatment with aspirin versus placebo provided data pertaining to any major bleeding (Table 1, Figure 1). The median duration of 1 study with 192 patients was 3 months,
      • Veen G.
      • Meyer A.
      • Verheugt F.W.
      • et al.
      Culprit lesion morphology and stenosis severity in the prediction of reocclusion after coronary thrombolysis: angiographic results of the APRICOT study. Antithrombotics in the Prevention of Reocclusion in Coronary Thrombolysis.
      while the mean or median duration of the other 8 studies (53,193 patients) ranged from 15 to 76 months. Among patients given placebo, the weighted incidence of any major bleeding was 0.18% per year. The absolute rate increase with aspirin above placebo was 0.13% per year (95% CI, 0.08-0.20% per year), and the number needed to harm (NNH) at 1 year was 769 (95% CI, 500-1250). Fourteen comparative studies provided data for major GI bleeding (Table 1, Figure 2). The median duration of 2 studies
      • Lewis Jr, H.D.
      • Davis J.W.
      • Archibald D.G.
      • et al.
      Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. Results of a Veterans Administration Cooperative Study.
      • Veen G.
      • Meyer A.
      • Verheugt F.W.
      • et al.
      Culprit lesion morphology and stenosis severity in the prediction of reocclusion after coronary thrombolysis: angiographic results of the APRICOT study. Antithrombotics in the Prevention of Reocclusion in Coronary Thrombolysis.
      (1458 patients) was 3 months, whereas the mean or median duration of the other 12 studies (55,947 patients) ranged from 12 to 76 months. The weighted incidence of major GI bleeding with placebo was 0.12% per year. The absolute rate increase with aspirin above placebo was 0.12% per year (95% CI, 0.07-0.19% per year), and the NNH at 1 year was 833 (95% CI, 526-1429). Eleven comparative studies provided data for intracranial bleeding (Table 1, Figure 3). The median duration of 1 study
      • Veen G.
      • Meyer A.
      • Verheugt F.W.
      • et al.
      Culprit lesion morphology and stenosis severity in the prediction of reocclusion after coronary thrombolysis: angiographic results of the APRICOT study. Antithrombotics in the Prevention of Reocclusion in Coronary Thrombolysis.
      (192 patients) was 3 months, while the average duration of the other 10 studies (55,191 patients) ranged from 15 to 76 months. Among patients allocated to placebo therapy, the weighted incidence of any intracranial bleeding was 0.05% per year. The absolute rate increase with aspirin above placebo was 0.03% per year (95% CI, 0.01-0.08% per year), and the NNH at 1 year was 3333 (95% CI, 1250-10,000).

      Aspirin versus Clopidogrel

      No studies were identified comparing clopidogrel with placebo. A single randomized controlled trial did compare clopidogrel with aspirin 325 mg daily
      CAPRIE Steering Committee
      A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE).
      (Table 3). The relative risks of all GI bleeding (RR 1.34; 95% CI, 1.11-1.61) and major (“severe”) GI bleeding (RR 1.45; 95% CI, 1.00-2.10) were increased in patients taking aspirin, while the risks of all other bleeding endpoints (eg, all major bleeding and intracranial bleeding) and of non-cardiovascular deaths were not significantly increased.
      CAPRIE Steering Committee
      A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE).
      A separate safety report from this study provided additional data on the proportion of patients hospitalized with GI bleeding with aspirin versus clopidogrel: 1.08% vs 0.74%; RR 1.47; 95% CI, 1.09-1.98).
      • Harker L.A.
      • Boissel J.P.
      • Pilgrim A.J.
      • Gent M.
      CAPRIE Steering Committee and Investigators
      Comparative safety and tolerability of clopidogrel and aspirin: results from CAPRIE. Clopidogrel versus aspirin in patients at risk of ischaemic events.
      Aspirin was associated with a small but significant increase in dyspepsia (RR 1.18; 95% CI, 1.05-1.32) and constipation (RR 1.39; 95% CI, 1.18-1.65) but a decreased risk of diarrhea (RR 0.75; 95% CI, 0.65-0.87) and rash (RR 0.77; 95% CI, 0.68-0.86).
      Table 3Trials Comparing Clopidogrel, Aspirin, Combined Aspirin and Clopidogrel, or Placebo
      Aspirin vs. Clopidogrel (CAPRIE Study)
      CAPRIE Steering Committee
      A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE).
      Aspirin vs. Aspirin + Clopidogrel (CURE Study)
      • Yusuf S.
      • Zhao F.
      • Mehta S.R.
      • et al.
      Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators
      Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation.
      • Yusuf S.
      • Mehta S.R.
      • Zhao F.
      • et al.
      Early and late effects of clopidogrel in patients with acute coronary syndromes.
      Clopidogrel vs. Aspirin + Clopidogrel (MATCH Study)
      • Diener H.C.
      • Bogousslavsky J.
      • Brass L.M.
      • et al.
      Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH) randomised, double-blind, placebo-controlled trial.
      AspirinClopidogrelAspirinAspirin + ClopidogrelClopidogrelAspirin + Clopidogrel
      Total enrolled958695996303625938023797
      Outcomen(%)n(%)RR(95% CI)n(%)n(%)RR(95% CI)n(%)n(%)RR(95% CI)
      Any bleeding890(9.28%)890(9.27%)1.00(0.92-1.09)317(5.03%)533(8.52%)0.59(0.52-0.68)110(2.89%)289(7.61%)0.38(0.31-0.47)
      Any major bleeding149 1.55%132(1.38%)1.13(0.90-1.43)169(2.68%)231(3.69%)0.73(0.60-0.88)71(1.87%)169(4.45%)0.42(0.32-0.55)
      Any fatal bleeding27(0.28%)23(0.24%)1.18(0.67-2.05)15(0.238%)11(0.176%)1.35(0.62-2.95)11(0.289%)16(0.421%)0.69(0.32-1.48)
      All GI bleeding255(2.66%)191(1.99%)1.34(1.11-1.61)______
      Major GI bleeding68(0.71%)47(0.49%)1.45(1.00-2.10)47(0.75%)83(1.33%)0.56(0.39-0.80)32(0.84%)93(2.45%)0.34(0.23-0.51)
      Fatal GI bleeding2(0.021%)1(0.010%)2.00(0.18-22.08)______
      Intracranial bleeding47(0.49%)34(0.35%)1.38(0.89-2.15)5(0.08%)7(0.11%)0.71(0.23-2.23)25(0.66%)40(1.05%)0.62(0.38-1.03)
      Fatal intracranial bleeding16(0.167%)16(0.167%)1.00(0.50-2.00)______
      Major non-GI, non-intracranial bleeding40(0.42%)55(0.57%)0.73(0.49-1.09)10(0.16%)12(0.19%)0.83(0.36-1.91)14(0.37%)36(0.95%)0.39(0.21-0.72)
      Noncardiovascular death193(2.01%)210(2.19%)0.92(0.76-1.12)45(0.71%)41(0.66%)1.09(0.71-1.66)80(2.10%)77(2.03%)1.04(0.76-1.41)
      Dyspepsia588(6.10%)501(5.22%)1.18(1.05-1.32)______
      Diarrhea322(3.36%)428(4.46%)0.75(0.65-0.87)______
      Constipation319(3.33%)229(2.38%)1.39(1.18-1.65)______
      Rash442(4.61%)578 6.02%0.77(0.68-0.86)______
      Absolute rate increases are calculated only for endpoints with significant differences. The absolute risk increase in major (“severe”) GI bleeding with aspirin versus clopidogrel was 0.22% (95% CI, 0.00-0.54%) over a mean duration of 1.91 years. The yearly absolute increase in incidence is therefore 0.12% per year (95% CI, 0.00-0.28%), with an NNH at 1 year of 833 (95% CI, 357-∞).

      Aspirin plus Clopidogrel versus Aspirin or Clopidogrel Alone

      One trial comparing aspirin versus combined aspirin and clopidogrel (CURE study)
      • Yusuf S.
      • Zhao F.
      • Mehta S.R.
      • et al.
      Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators
      Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation.
      • Yusuf S.
      • Mehta S.R.
      • Zhao F.
      • et al.
      Early and late effects of clopidogrel in patients with acute coronary syndromes.
      and one study comparing clopidogrel versus combined aspirin and clopidogrel (MATCH study)
      • Diener H.C.
      • Bogousslavsky J.
      • Brass L.M.
      • et al.
      Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH) randomised, double-blind, placebo-controlled trial.
      were identified (Table 3). Both aspirin alone and clopidogrel alone were associated with a reduced risk of any bleeding, any major bleeding, and major GI bleeding compared with combined therapy with aspirin and clopidogrel. Compared with combined aspirin and clopidogrel therapy, the relative risk reduction (RRR) for any major bleeding was greater in the MATCH study with clopidogrel therapy alone (RRR 0.58; 95% CI, 0.45-0.68) than in the CURE study with aspirin therapy alone (RRR 0.27; 95% CI, 0.12-0.40) with non-overlapping confidence intervals. For major GI bleeding the relative risk reduction was also greater in the MATCH study with clopidogrel alone (RRR 0.66; 95% CI, 0.49-0.77) than in the CURE study with aspirin alone (RRR 0.44; 95% CI, 0.20-0.61), although the 95% CIs overlapped between the 2 studies. Combined therapy was not associated with a significantly increased risk of any fatal bleeding or intracranial bleeding in either study, although the number of these events in the 2 trials was small.

      Discussion

      When used for primary or secondary prevention of atherothrombotic disease, low-dose aspirin (75-325 mg/day) increases the risk of any major bleeding, major GI bleeding, and intracranial bleeding 1.7-2.1-fold compared with placebo. Although these reflect significant increases in the relative risks of these major bleeding endpoints, the absolute increases in risk are small. The absolute increased risk of any major bleeding attributable to aspirin is 0.13%/year. Hence, the number of patients that would need to be treated with aspirin instead of placebo for 1 year in order to induce 1 additional major bleeding event is 769 (95% CI, 500-1250). Likewise, the absolute increased risk per year of major GI bleeding with aspirin instead of placebo is 0.12% (NNH=833) and it is 0.03% (NNH=3333) for intracranial bleeding.
      This review did not find evidence of an increased risk of bleeding with “high” low-dose aspirin (>162.5 to 325 mg daily) versus “low” low-dose aspirin (75 to 162.5 mg daily). The higher doses of low-dose aspirin did not result in an increased relative risk of any of the major bleeding endpoints, including intracranial bleeding or the secondary endpoints of any bleeding or all GI bleeding. These findings are consistent with the results of meta-regression analyses by Derry and Loke, which did not find a relationship between the odds ratio for all gastrointestinal bleeding and daily aspirin dose (50-1500 mg/day) among controlled trials of long-term aspirin therapy.
      • Derry S.
      • Loke Y.K.
      Risk of gastrointestinal haemorrhge with long term use of aspirin meta-analysis.
      Only one study in our systematic review included a randomized head-to-head comparison of lower dose (81 mg) and higher dose (325 mg) low-dose aspirin: rates of all GI bleeding (1.1% vs 1.1%) and intracranial hemorrhage (0.6% vs 0.8%) were not significantly different in this 3-month trial in 1417 patients after carotid endarterectomy.
      • Taylor D.W.
      • Barnett H.J.
      • Haynes R.B.
      • et al.
      ASA and Carotid Endarterectomy (ACE) Trial Collaborators
      Low-dose and high-dose acetylsalicylic acid for patients undergoing carotid endarterectomy a randomised controlled trial.
      A double-blind trial of colon neoplasm chemoprevention with 33 months mean follow-up also included a randomized head-to-head comparison of 81 and 325 mg of aspirin.
      • Baron J.A.
      • Cole B.F.
      • Sandler R.S.
      • et al.
      A randomized trial of aspirin to prevent colorectal adenomas.
      The proportions with GI bleeding were not significantly different between the 81 mg group (2/377 [0.5%]) and the 325 mg group (4/372 [1.1%]; 95% CI of the difference=−0.7% to 1.8%).
      Another recent review did conclude that increasing doses of “low-dose” aspirin are associated with an increased risk of bleeding.
      • Serebruany V.L.
      • Steinhubl S.R.
      • Berger P.B.
      • et al.
      Analysis of risk of bleeding complications after different doses of aspirin in 192036 patients enrolled in 31 randomized controlled trials.
      This review pooled cohorts of aspirin users from both randomized controlled trials and nonrandomized cohort studies and calculated the weighted crude proportions of events for doses of aspirin <100 mg, 100-200 mg, and >200 mg. Patients included in this analysis were given aspirin for widely variable durations and disparate indications (sometimes with other anticoagulants or thrombolytic agents that may induce bleeding) and were pooled without adjustment for duration of exposure or for potential confounding factors. Furthermore, studies using aspirin doses up to 1200 mg daily (well above the accepted “low dose” of 325 mg) were included. Limitations of this analysis preclude legitimate conclusions regarding dose effects of aspirin. A systematic review of randomized controlled trials of “lower” low-dose aspirin versus “higher” low-dose aspirin or of these doses versus placebo, as done in our review and meta-analysis, is an appropriate way to examine the potential dose response of low-dose aspirin. Ultimately, larger randomized comparisons are required to definitively determine whether a dose-response is present across the range of low-dose aspirin.
      Aspirin did not increase the risk of noncardiovascular deaths as compared with placebo. Consistent with this observation, the risk among aspirin users of any fatal bleeding, fatal GI bleeding, or fatal non-GI/non-intracranial bleeding was not significantly increased, although there was a significant increased risk of fatal intracranial bleeding (RR 2.52; 95% CI, 1.06-5.99).
      Although low-dose aspirin did appear to increase the risk of dyspepsia, diarrhea, and constipation compared with placebo, discontinuations due to all adverse events or GI adverse events were not significantly increased with aspirin compared with placebo. We caution that conclusions are limited by the relatively small number of studies and patients available for analysis of theses endpoints.
      Conclusions about the risks of clopidogrel therapy are limited by the paucity of trials pertaining to the use of this agent for secondary prevention of atherothrombotic disease.
      CAPRIE Steering Committee
      A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE).
      • Yusuf S.
      • Zhao F.
      • Mehta S.R.
      • et al.
      Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators
      Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation.
      • Diener H.C.
      • Bogousslavsky J.
      • Brass L.M.
      • et al.
      Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH) randomised, double-blind, placebo-controlled trial.
      No trials compared clopidogrel with placebo. Only one eligible trial performed a head-to-head comparison of clopidogrel alone versus aspirin.
      CAPRIE Steering Committee
      A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE).
      This large, well-designed study showed an increase in all GI bleeding (RR 1.34; 95% CI, 1.11-1.61) and major GI bleeding (RR 1.45; 95% CI, 1.00-2.10). However, it did not find a significant increase in the relative risk of any of the other bleeding endpoints or non-cardiovascular death. The absolute increased risk associated with low-dose aspirin therapy versus clopidogrel for major GI bleeding was 0.12%/year; ie, 833 patients would have to be treated with aspirin in place of clopidogrel to cause one additional major GI bleeding episode in 1 year. Assuming an incremental retail cost of $1460 for clopidogrel versus aspirin therapy for 1 year, the cost to prevent one major GI bleeding episode from aspirin in 1 year by substituting clopidogrel therapy would be $1,216,180 (95% CI, $521,220-∞).
      The minimal increased risk of GI bleeding with low-dose aspirin as compared with clopidogrel may appear surprising given the known importance of high-dose aspirin as a causal agent in peptic ulcer disease. However, there has been little study of low-dose aspirin in ulcer pathogenesis. In a randomized, prospective, double-blind endoscopic study of 768 patients ≥50 years of age treated with low-dose enteric aspirin (81 mg daily) versus placebo, the 12-week cumulative incidence of ulcers ≥5 mm was 4.9% (95% CI, 2.7-7.1%) in aspirin-treated patients versus 4.2% (95% CI, 2.1-6.3%) with placebo treatment, suggesting that low low-dose aspirin has little ulcerogenic potential.
      • Laine L.
      • Maller E.S.
      • Yu C.
      • et al.
      Ulcer formation with low-dose enteric-coated aspirin and the effect of COX-2 selective inhibition a double-blind trial.
      Similar to aspirin, clopidogrel may potentiate bleeding complications through its inhibition of platelet aggregation, but it has not been considered to be injurious to the GI mucosa. An 8-day endoscopic study showed no evidence of GI tract mucosal injury with clopidogrel in human volunteers.