The available evidence demonstrates that the use of clopidogrel plus aspirin in people at high risk of cardiovascular disease and people with established cardiovascular disease without a coronary stent is associated with a reduction in the risk of myocardial infa rct ion and ischaemic stroke , and an increased risk of major and minor bleeding compared with aspirin alone .
According to GRADE criteria , the quality of evidence was moderate for all outcomes except all-cause mortality ( low quality evidence ) and adverse events ( very low quality evidence )
BACKGROUND Aspirin is the prophylactic antiplatelet drug of choice for people with cardiovascular disease .
Adding a second antiplatelet drug to aspirin may produce additional benefit for people at high risk and people with established cardiovascular disease .
This is an up date to a previously published review from 2011 .
OBJECTIVES To review the benefit and harm of adding clopidogrel to aspirin therapy for preventing cardiovascular events in people who have coronary disease , ischaemic cerebrovascular disease , peripheral arterial disease , or were at high risk of atherothrombotic disease , but did not have a coronary stent .
Aspirin to Prevent Cardiovascular Disease: The Association of Aspirin Dose and Clopidogrel With Thrombosis and Bleeding
Context The optimal aspirin dose for prevention of cardiovascular events is unknown . Contribution This post hoc analysis of CHARISMA trial data suggests no overall differences in efficacy or safety by aspirin dose . However , in the subgroup of patients r and omly assigned to clopidogrel , there was a hint of reduced efficacy and increased harm with higher doses . Caution Patients were not r and omly assigned to aspirin dose . Implication Lower aspirin doses ( 75 to 81 mg/d ) may optimize efficacy and safety for patients requiring aspirin for long-term prevention , especially those taking clopidogrel .  The Editors Aspirin is the most widely used drug worldwide for the prevention of thrombotic cardiovascular events . Of note , the doses of aspirin used most often clinical ly or recommended in guidelines are based not on the results of trials design ed to identify the most efficacious or safest dose , but on a combination of historical precedents and trials in which specific doses of aspirin were m and ated by protocol . This practice has led to a wide range in aspirin doses ( 75 to 325 mg/d ) recommended by the U.S. Food and Drug Administration ( 1 ) for the management of cardiovascular disease in various population s. Although as little as 30 mg of aspirin daily is needed to fully inhibit platelet thromboxane production ( 2 ) , doses more than 10 times higher than this are routinely used in long-term prevention of cardiovascular disease . Because aspirin has been used clinical ly for more than a century and is a mainstay of therapy for patients who have or are at risk for atherosclerotic disease and other common ailments , its risks are often underappreciated . However , given that more than one third of U.S. adults are estimated to take aspirin daily for cardiovascular disease ( 3 ) , even a very small incidence of hemorrhagic complications places a large number of people at risk . Consistent with this is a recent analysis of hospitalizations for adverse drug effects that found aspirin to be one of the most common causal agents ( 4 ) . The gastrointestinal tract is the leading source of bleeding events in  aspirin-treated  patients because of inhibition of gastroprotective prostacyclins , with an excess risk for upper gastrointestinal complications of 5 cases per 1000 aspirin users per year ( 5 ) . Prospect i ve evaluation of  aspirin-treated patients with coronary artery disease identified an incidence of upper gastrointestinal bleeding of 1.5 % per year , with substantial associated morbidity ( 6 ) . Because inhibition of gastric prostacyclin is dose-dependent and not maximal until a daily dose of about 1300 mg is reached ( 4 ) , minimizing the dose of aspirin to that needed to fully inhibit platelet thromboxane production would probably offer the greatest potential benefit with the lowest possible risk . In several observational studies of large prospect i ve trials , lower doses of aspirin ( < 162 mg/d ) have been associated with the lowest incidence of thrombotic events ( 7 , 8) and a trend toward fewer bleeding events ( 8) . These favorable trends in efficacy and safety were confirmed in the CURE ( Clopidogrel in Unstable angina to prevent Recurrent Events ) trial ( 9 ) of dual antiplatelet therapy with clopidogrel plus aspirin versus placebo plus aspirin . On the basis of these results , the design of the CHARISMA ( Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization , Management and Avoidance ) trial ( 10 ) , which r and omly assigned 15603 patients at high risk for atherothrombotic events to clopidogrel or placebo in conjunction with aspirin , m and ated a daily aspirin dose of 75 to 162 mg . We performed a post hoc analysis of associations between investigator-determined daily aspirin dose and thrombotic and hemorrhagic outcomes in the prospect i ve CHARISMA trial . Methods The design , methods , and primary results of the CHARISMA study are reported elsewhere ( 10 ) . In brief , CHARISMA was a multicenter , double-blind , r and omized , placebo-controlled trial of long-term clopidogrel ( 75 mg/d ) treatment versus placebo in patients 45 years or older who had established atherosclerotic disease or were asymptomatic but at high risk because of a combination of risk factors . All patients also received low-dose aspirin therapy , which was limited by protocol to between 75 and 162 mg/d . Patients were excluded if they had an established indication for clopidogrel therapy , such as a recent acute coronary syndrome or stent implantation . Clinical follow-up was done at 1 , 3 , and 6 months and every 6 months thereafter until the end of the trial . The actual dose of aspirin being taken was confirmed at each evaluation . The ethics committee at each of the 768 participating hospitals worldwide , as well as the appropriate national ethics committee for each of the 32 participating countries , review ed and approved the study protocol . All patients provided written informed consent before enrollment . The primary efficacy end point was the first occurrence of myocardial infa rct ion , stroke , or cardiovascular death . The primary safety end point was severe or life-threatening bleeding according to the GUSTO-I ( Global Utilization of Streptokinase and TPA for Occluded coronary arteries ) criteria ( 11 ) : intracerebral bleeding or bleeding result ing in substantial hemodynamic compromise requiring treatment . A secondary safety end point was the combined incidence of severe or life-threatening bleeding or moderate bleeding by the GUSTO-I criteria , with moderate defined as bleeding requiring transfusion but not result ing in hemodynamic compromise ( 11 ) . Of note , patients believed to be at high risk for bleeding were excluded from enrollment .  Aspirin dose was not r and omized ; rather , it was selected at the discretion of the treating physician . We prospect ively divided patients into 3 major groups according to clear demarcations in aspirin dose at baseline : less than 100 mg/d , represented almost entirely by doses of either 75 or 81 mg/d ; 100 mg/d ; and greater than 100 mg/d , represented by either 150 or 162 mg/d . We evaluated the relative efficacy and safety of the different doses of aspirin among all patients , and we evaluated the efficacy and safety end points between the treatment ( clopidogrel ) versus placebo groups by aspirin dose category . Statistical Analysis We performed all data analyses on the intention-to-treat population . We performed hypothesis tests by using 2-sided tests at the 5 % significance level . Baseline characteristics were compared by using chi-square tests for discrete variables and t tests for continuous variables . We calculated cumulative KaplanMeier estimates of the event rates and assessed differences in the unadjusted rates of primary efficacy and safety end points across the aspirin groups by using a 2-sided log-rank test . We used log-rank weights to compute a test for trend across aspirin dose categories . We estimated the treatment effect , measured by the hazard ratio and its 95 % CI , by using the Cox proportional hazards model . Multivariable modeling was performed to determine whether aspirin dose was independently associated with the primary efficacy and safety outcomes after controlling for potentially confounding factors . Because patients could have had more than 1 efficacy or safety event , we defined the time to the primary efficacy end point as the first occurrence of myocardial infa rct ion , stroke , or cardiovascular death . We defined the time to the primary safety end point as the first occurrence of severe or life-threatening bleeding according to the GUSTO-I criteria ( 11 ) . We selected variables for inclusion in the models on the basis of differences in baseline characteristics among patients in the 3 aspirin dose categories or their clinical relevance to the outcomes . Covariates included in the multivariable model for the primary efficacy end point were the continuous variables of age , weight , and systolic blood pressure and the categorical variables of sex ; race or ethnicity ( white or Hispanic vs. other ) ; hypertension ; hypercholesterolemia ; history of congestive heart failure ; previous myocardial infa rct ion ; previous stroke ; previous transient ischemic attack ; diabetes mellitus ; atrial fibrillation ; peripheral arterial disease ; diabetic nephropathy ; current smoking ; primary ( vs. secondary ) prevention and past use of statins , nitrates , and antiplatelet agents other than aspirin . We developed models with and without inclusion of interaction terms for r and omized treatment assignment by aspirin dose category . Adjustment variables in the multivariable model for the primary safety end point ( GUSTO-I severe or life-threatening bleeding ) included age and weight as continuous variables and the categorical variables of stable angina with multivessel disease , sex , race or ethnicity ( white or Hispanic vs. other ) , history of congestive heart failure , previous myocardial infa rct ion , previous stroke , previous transient ischemic attack , diabetes mellitus , atrial fibrillation , peripheral arterial disease , diabetic nephropathy , hypertension , hypercholesterolemia , primary prevention ( vs. secondary ) , and current smoking . We developed models with and without inclusion of interaction terms for r and omized treatment assignment by daily aspirin dose category . To adjust for geographical region without estimating its effect , we used region ( categorized as United States , Canada , Western Europe , Eastern Europe , Latin America , Asia and Australia , or Africa ) as a stratification variable in models for both end points . We assessed the interaction of  aspirin dose and r and omized treatment in both models . We calculated and tested the difference between the maximum likelihood ratios with and without 2 interaction terms ( r and omized treatment assignment by daily aspirin dose of 100 mg and greater than 100 mg ) . We assessed proportional hazards by multiplying each covariate by the log of the time to the event . A Wald test was performed to test the linear hypotheses of the regression coefficients . The proportional
The available evidence demonstrates that the use of clopidogrel plus aspirin in people at high risk of cardiovascular disease and people with established cardiovascular disease without a coronary stent is associated with a reduction in the risk of myocardial infa rct ion and ischaemic stroke , and an increased risk of major and minor bleeding compared with aspirin alone .
According to GRADE criteria , the quality of evidence was moderate for all outcomes except all-cause mortality ( low quality evidence ) and adverse events ( very low quality evidence )
BACKGROUND Aspirin is the prophylactic antiplatelet drug of choice for people with cardiovascular disease .
Adding a second antiplatelet drug to aspirin may produce additional benefit for people at high risk and people with established cardiovascular disease .
This is an up date to a previously published review from 2011 .
OBJECTIVES To review the benefit and harm of adding clopidogrel to aspirin therapy for preventing cardiovascular events in people who have coronary disease , ischaemic cerebrovascular disease , peripheral arterial disease , or were at high risk of atherothrombotic disease , but did not have a coronary stent .