Clopidogrel added to aspirin adds no benefit but bleeding risk in patients with recent lacunar stroke. Net Clinical Benefit of Adding Clopidogrel to Aspirin Therapy in Patients With Atrial Fibrillation for Whom Vitamin K Antagonists Are Unsuitable A Randomised Controlled Trial of Triple Antiplatelet Therapy (Aspirin, Clopidogrel and Dipyridamole) in the Secondary Prevention of Stroke: Safety, Tolerability and Feasibility Unstable angina, stroke, myocardial infarction and death in aspirin non‐responders. A prospective, randomized trial. The ASCET (ASpirin non‐responsiveness and Clopidogrel Endpoint Trial) design Clopidogrel added to aspirin versus aspirin alone in secondary prevention and high-risk primary prevention: rationale and design of the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial. A comparative study of dual versus monoantiplatelet therapy in patients with acute large-artery atherosclerosis stroke. Impact of dual antiplatelet therapy on outcomes among aspirin-resistant patients following coronary artery bypass grafting. Prophylactic Add-on Antiplatelet Therapy in Chronic Kidney Disease With Type 2 Diabetes Mellitus: Comparison Between Clopidogrel and Low-dose Aspirin Dual antiplatelet drug resistance in patients with acute coronary syndrome. Rationale and design of a randomized, double-blind trial comparing the effects of a 3-month clopidogrel-aspirin regimen versus aspirin alone for the treatment of high-risk patients with acute nondisabling cerebrovascular event. A Cost-Effectiveness Analysis of Combination Antiplatelet Therapy for High-Risk Acute Coronary Syndromes: Clopidogrel plus Aspirin versus Aspirin Alone Protocol for Cilostazol Stroke Prevention Study for Antiplatelet Combination (CSPS.com): a randomized, open-label, parallel-group trial An analysis of mortality rates with dual-antiplatelet therapy in the primary prevention population of the CHARISMA trial. A randomized trial to compare the safety of rivaroxaban vs aspirin in addition to either clopidogrel or ticagrelor in acute coronary syndrome: The design of the GEMINI-ACS-1 phase II study. Antiplatelet profiles of the fixed-dose combination of extended-release dipyridamole and low-dose aspirin compared with clopidogrel with or without aspirin in patients with type 2 diabetes and a history of transient ischemic attack: a randomized, single-blind, 30-day trial. Design and rationale for the Effects of Ticagrelor and Clopidogrel in Patients with Peripheral Artery Disease (EUCLID) trial. Clopidogrel Plus Aspirin Prevents Early Neurologic Deterioration and Improves 6-Month Outcome in Patients With Acute Large Artery Atherosclerosis Stroke
Patients with transient ischemic attack or ischemic stroke have a high risk of recurrent stroke .  Antiplatelet therapy has shown efficacy in secondary stroke prevention and is recommended by guidelines .1–3 In patients without cardiac source of embolism  aspirin , clopidogrel or the combination of aspirin and dipyridamole is recommended . In cardiology , the combination of aspirin and clopidogrel was superior to aspirin monotherapy in the prevention of vascular events after acute coronary syndrome4 but carried a higher bleeding risk . In patients with atrial fibrillation the combination of aspirin plus clopidogrel was superior to aspirin alone in preventing strokes,5 but was again associated with a significant higher risk of major bleeds . In early secondary stroke prevention after transient ischemic attack or minor stroke combination , antiplatelet therapy seems to be superior to monotherapy , but larger r and omized trials are needed.6,7 Combination antiplatelet therapy carries a consistent higher risk of major bleeding complications than monotherapy . Therefore , the possible benefit of a reduction in vascular events has to be balanced against the bleeding risk , especially in stroke patients . In the Management of Atherothrombosis with Clopidogrel in High-risk patients ( MATCH ) trial , aspirin plus clopidogrel was investigated against aspirin monotherapy in high-risk patients with recent transient ischemic attack or ischemic stroke.8 Similar to the Secondary Prevention of Small Subcortical Strokes ( SPS3 ) trial , patients with a cardiac source of embolism and significant carotid stenosis requiring surgery were excluded . About 50 % of patients were categorized to have small vessel disease with suspected lacunar strokes , but in contrast to the SPS3 trial , BACKGROUND Adding clopidogrel to aspirin therapy reduces stroke in patients with atrial fibrillation ( AF ) but increases hemorrhage . OBJECTIVE To quantify the net benefit of adding clopidogrel to aspirin therapy , accounting for differences in clinical significance between ischemic and hemorrhagic events . DESIGN Observational cohort study to assign the relative weighting of events and post hoc analysis of r and omized trial data to assess net benefit of dual antiplatelet therapy in the ACTIVE ( Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events ) clinical trials . SETTING Global r and omized clinical trial . PATIENTS 10,041 patients with AF , 7554 of whom were not c and i date s for warfarin therapy .  MEASUREMENTS Ischemic events ( ischemic stroke or myocardial infa rct ion ) and hemorrhagic events ( hemorrhagic stroke or subdural or extracranial bleeding ) , weighted by the hazard ratio for death ( or death or disability ) after an event relative to death ( or death or disability ) after ischemic stroke . The net clinical benefit of dual antiplatelet therapy in the ACTIVE A trial participants was defined as the sum of weighted event incidence with dual antiplatelet therapy subtracted from the sum of weighted event incidence on control treatment , expressed as ischemic stroke equivalents prevented per 100 patients years . RESULTS Adding clopidogrel to aspirin therapy prevented 0.57 ischemic stroke equivalent ( 95 % CI , -0.12 to 1.24 ) per 100 patient-years of treatment when weighted by hazard for death after ischemia or hemorrhage and 0.67 ischemic stroke equivalent ( CI , -0.03 to 1.18 ) when weighted by death or disability after ischemia or hemorrhage . LIMITATION No attempt was made to relate deaths used for weighting to events ; disability data were missing for more than one half of patients . CONCLUSION Adding clopidogrel to aspirin therapy result ed in a modest net benefit among patients with AF for whom warfarin was unsuitable . The benefit would probably be clinical ly relevant for some patients , but estimates could not exclude the possibility of either no benefit or very small harm in this population . PRIMARY FUNDING SOURCE Bristol-Myers Squibb and sanofi-aventis Background Aspirin , dipyridamole and clopidogrel are effective in secondary vascular prevention . Combination therapy with three antiplatelet agents might maximise the benefit of antiplatelet treatment  in the secondary prevention of ischaemic stroke . Methodology /Principal Findings A r and omised , parallel group , observer-blinded phase II trial compared the combination of aspirin , clopidogrel and dipyridamole with aspirin alone .  Adult patients with ischaemic stroke or transient ischaemic attack ( TIA ) within 5 years were included . The primary outcome was tolerability to treatment assessed as the number of patients completing r and omised treatment . Recruitment was halted prematurely after publication of the ESPRIT trial ( which confirmed that combined aspirin and dipyridamole is more effective than aspirin alone ) . 17 patients were enrolled : male 12 ( 71 % ) , mean age 62 ( SD 13 ) years , lacunar stroke syndrome 12 ( 71 % ) , median stroke/TIA onset to r and omisation 8 months . Treatment was discontinued in 4 of 9 ( 44 % ) patients receiving triple therapy vs. none of 8 taking aspirin ( p = 0.08 ) . One recurrent stroke occurred in a patient in the triple group who was noncompliant of all antiplatelet medications . The number of patients with adverse events and bleeding complications , and their severity , were significantly greater in the triple therapy group ( p<0.01 ) . Conclusions / Significance Long term triple antiplatelet therapy was asociated with a significant increase in adverse events and bleeding rates , and their severity , and a trend to increased discontinuations . However , the patients had a low risk of recurrence and future trials should focus on short term therapy in high risk patients characterised by a very recent event or failure of dual antiplatelet therapy . Trial Registration Controlled-Trials.com IS RCT Background —Aspirin is widely used as an antiplatelet drug in patients with coronary heart disease . Despite documented clinical benefit , many patients on aspirin  still experience severe cardiovascular events . Several laboratory reports have shown lack of platelet inhibition in 5–40 % of aspirin‐treated patients , and the term aspirin resistance has been introduced . The clinical relevance of these laboratory findings is , however , still unknown . New antiplatelet drugs have been developed , and the adenosin diphosphate ( ADP ) receptor inhibitor clopidogrel has at least the same efficacy as aspirin with an acceptable safety profile . Laboratory methods for determination of platelet reactivity and treatment efficacy have been complicated and time consuming . New method ologies , like the PFA‐100 ® system , have made such analyses more suitable for clinical use . Design —In the ASCET study , 1000 patients with documented coronary heart disease will be r and omized to either continued treatment with aspirin 160 mg/d or change to clopidogrel 75 mg/d after initial determination of their platelet reactivity while on aspirin treatment . Clinical endpoints will be recorded for at least 2 years and related to the initial aspirin response BACKGROUND Clopidogrel is a more potent antiplatelet agent than aspirin , result ing in greater clinical efficacy in patients with atherothrombotic disease . Furthermore , the combination of clopidogrel plus aspirin has been demonstrated to be superior to aspirin alone in the treatment of patients with acute coronary syndromes and after coronary stenting . Whether dual antiplatelet therapy is superior to aspirin monotherapy for high-risk primary prevention and secondary prevention is unknown . METHODS AND RESULTS The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization , Management , and Avoidance ( CHARISMA ) study was design ed to evaluate the efficacy and safety of clopidogrel plus aspirin versus placebo plus aspirin in patients with established coronary , cerebral , or peripheral arterial disease or in patients with multiple risk factors for atherothrombosis who have not yet sustained an ischemic event . This r and omized , international , multicenter , double-blinded , placebo-controlled study has finished enrolling patients worldwide . A total of 15,603 patients will be followed long term . The primary end point will be the composite of vascular death , myocardial infa rct ion , or stroke . Rates of severe bleeding will also be compared between the two arms of the study . CONCLUSIONS This large-scale trial of patients at high risk for atherothrombotic events will allow determination of the value of a strategy of adding clopidogrel to the current st and ard of care , including low-dose aspirin , for a wide spectrum of patients with atherothrombosis BACKGROUND Antiplatelet drugs are recommended for patients with acute noncardioembolic stroke . However , few r and omized clinical trials have investigated the safety and efficacy of dual antiplatelet therapy for these patients . The aim of this study was to evaluate the effects of treatment with clopidogrel and aspirin ( combination therapy ) and aspirin alone ( monotherapy ) on neurologic deterioration , platelet activation , and other short-term outcomes in patients with acute large-artery atherosclerosis stroke . MATERIAL S AND METHODS Altogether 574 patients with acute ( ≤2 days ) large-artery atherosclerosis stroke were r and omly assigned to receive either combined clopidogrel and aspirin or aspirin alone . Platelet aggregation and platelet-leukocyte aggregation studies were performed at days 1 and 30 . Primary outcomes including recurrent ischemic stroke , neurologic deterioration , periphery vascular events , and myocardial infa rct ion were monitored . Safety endpoints were hemorrhagic episodes and death . RESULTS The prevalence of neurologic deterioration and recurrent ischemic stroke were lower in patients in the combination therapy group than in those of the monotherapy group ( 3.52 % versus 9.78 % and 1.76 % versus 6.29 % , respectively ) . At day 30 of treatment , the platelet aggregations and platelet-leukocyte aggregates were lower in patients who were treated with clopidogrel and aspirin than in patients given aspirin alone ( P < .001 ) . CONCLUSIONS For patients with acute large-artery atherosclerosis stroke , treatment with clopidogrel and aspirin for 1 month provided significantly greater inhibition of platelet activity  than aspirin alone . Thus , dual therapy can be safer and more effective in reducing ischemic stroke recurrence and neurologic deterioration Coronary artery bypass grafting is pivotal in the contemporary management of complex coronary artery disease . Interpatient variability to antiplatelet agents , however , harbors the potential to compromise the revascularization benefit by increasing the incidence of adverse events . This study was design ed to define the impact of dual antiplatelet therapy ( dAPT ) on clinical outcomes among aspirin-resistant patients who underwent coronary artery surgery .  We r and omly assigned 219 aspirin-resistant patients according to multiple electrode aggregometry to receive clopidogrel ( 75 mg ) plus aspirin ( 300 mg ) or aspirin-monotherapy ( 300 mg ) . The primary end point was a composite outcome of all-cause death , nonfatal myocardial infa rct ion , stroke , or cardiovascular hospitalization assessed at 6 months postoperatively . The primary end point occurred in 6 % of patients assigned to dAPT and 10 % of patients r and omized to aspirin-monotherapy ( relative risk 0.61 , 95 % confidence interval 0.25 to 1.51 , p = 0.33 ) . No significant treatment effect was noted in the occurrence of the safety end point . The total incidence of bleeding events was 25 % and 19 % in the dAPT and aspirin-monotherapy groups , respectively ( relative risk 1.34 , 95 % confidence interval 0.80 to 2.23 , p = 0.33 ) . In the subgroup analysis , dAPT led to lower rates of adverse events in patients with a body mass index > 30 kg/m(2 ) ( 0 % vs 18 % , p < 0.01 ) and those < 65 years ( 0 % vs 10 % , p = 0.02 ) . In conclusion , the addition of clopidogrel in patients found to be aspirin resistant after coronary artery bypass grafting did not reduce the incidence of adverse events , nor did it increase the number of recorded bleeding events . dAPT did , however , lower the incidence of the primary end point in obese patients and those < 65 years Background : Chronic kidney disease ( CKD ) coexisting with type 2 diabetes mellitus ( DM ) leads to coronary artery disease . The present study compares clopidogrel and low-dose aspirin as prophylactic therapy against coronary events in patients with CKD with diabetes . Methods : Total 80 patients of CKD with type 2 DM were r and omized and allocated to clopidogrel and aspirin groups to receive the drug at a dose of 75 mg and 150 mg once daily respectively for 8 weeks as add-on therapy . Main outcome was change in blood pressure , metabolic parameters , renal function , inflammatory biomarkers , platelet aggregability and ( UKPDS ) United Kingdom Prospect i ve Diabetes Study risk scoring . Results : Significant decrease in blood pressure ( P < 0.01 ) , total cholesterol ( P = 0.02 ) , LDL ( P < 0.01 ) , triglyceride ( P < 0.01 ) and a better glycemic control ( P < 0.01 ) was found in clopidogrel group . Renal markers and electrolytes have been improved in clopidogrel group but in aspirin group there was deterioration ( 2.5 % ) of creatinine clearance . Clopidogrel group has shown a significant decrease in hsCRP ( P < 0.01 ) , UKPDS risk scoring ( P < 0.01 ) and better anti-aggregatory effect . Conclusions : Clopidogrel has prophylactic role in CKD with type 2 DM due to better control of metabolic parameters , renal function and inflammatory burden in comparison to aspirin AIMS AND OBJECTIVES Antiplatelet therapy is a cornerstone in the management of the atherosclerotic vascular disease . Aspirin and clopidogrel are the two most commonly used antiplatelet drugs in its management . Recently , there has been a concern about the development of resistance to one or both antiplatelet agents with potentially devastating consequences . In this study we tried to assess the in vitro resistance to antiplatelet agents in patients presenting with acute coronary syndrome ( ACS ) . MATERIAL S AND METHODS 144 patients presenting with ACS , who were not on any antiplatelet therapy prior to hospital admission were evaluated in this study . Baseline clinical data was obtained before giving the oral loading dose of aspirin and clopidogrel . Patients received a loading dose of 325 mg of aspirin and 300 mg of clopidogrel followed by a daily dose of 150 mg . of aspirin and 75 mg.of clopidogrel . After 7 days of dual antiplatelet therapy , platelet aggregation pattern was analyzed using optical aggregometer ( chrono-log ) . Response to  aspirin  and  clopidogrel  was assessed by interaction with collagen ( 2microg/ml ) and Adenosine diphosphate ( ADP ) ( 10micro/ml ) respectively . The results were analyzed . Response to doubling the dose of antiplatelet agents  was also observed in 6 aspirin resistant patients , 12 clopidogrel resistant patients and in 6 patients resistant to the effect of dual antiplatelet agents . RESULTS There were 22 patients ( 15.27 % ) who showed poor response to  aspirin  , 28 patients ( 19.44 % ) to clopidogrel ( primary non-responder ) and 18 patients ( 12.5 % ) showed a primary non-responsiveness to both the antiplatelet agents in the usual doses . After dose doubling , all 6 aspirin resistant patients showed adequate response but 4 out of 12 clopidogrel resistant patients showed inadequate response . CONCLUSIONS This pilot study brings out a disquieting picture of 12.5 % patients suffering from ACS showing resistance to the antiplatelet effects of both aspirin and clopidogrel in the conventional dose . A long-term prospect i ve r and omized controlled trial is required to give an insight into this problem and its clinical consequences BACKGROUND Acute nondisabling cerebrovascular events are common and often portend a disabling stroke . Aspirin is the only antiplatelet agent to have been studied in patients presenting acutely with a cerebrovascular event , but the effect is modest and is reduced by a small increased risk of intracerebral hemorrhage . Treatment with the combination of clopidogrel and aspirin might be beneficial when taken soon after a transient ischemic attack ( TIA ) or minor stroke . The CHANCE trial is a r and omized , double-blind , multicenter , placebo-controlled trial to test an aggressive antiplatelet regimen in acute minor stroke or TIA . DESIGN The study will r and omize 5,100 Chinese patients with acute TIA or minor stroke to receive a 3-month regimen of clopidogrel initiated with a loading dose of 300 mg followed by 75 mg/d , combined with aspirin 75 mg/d during the first 21 days , or a 3-month regimen of aspirin 75 mg/d alone . The primary efficacy end point is percentage of patients with any stroke ( ischemic or hemorrhage ) at 3 months . Study visits will be performed on the day of r and omization , at day 21 , and at day 90 . SUMMARY CHANCE will determine whether clopidogrel combined with aspirin can prevent more strokes after acute minor stroke or TIA compared with aspirin alone-with an acceptable risk profile Context In patients with unstable angina , combination therapy with clopidogrel plus aspirin has been shown to be more effective than aspirin alone in preventing myocardial infa rct ion , stroke , or cardiovascular death , but the cost-effectiveness of such therapy has yet to be determined . Contribution When the authors used a societal perspective and lifetime time horizon , combination therapy increased quality -adjusted life span at a cost that was within the traditionally accepted limits of cost-effectiveness . Caution s Data are not yet available to determine whether combination therapy for longer than 1 year remains cost-effective , due to the uncertainty of the relationship between long-term efficacy and risk for hemorrhage . The Editors The Clopidogrel  in Unstable Angina to Prevent Recurrent Events ( CURE ) trial demonstrated that clopidogrel plus aspirin was superior to aspirin alone in preventing the composite outcome of myocardial infa rct ion , stroke , or cardiovascular death in the year following an acute coronary syndrome or nonQ-wave myocardial infa rct ion ( 1 ) . Although combination therapy is recommended for such patients for at least 1 month , the optimal duration is less clear ( 2 ) . In addition , the cost of clopidogrel complicates the decision to combine it with aspirin . Adding clopidogrel to aspirin is financially unattractive if done in all patients with coronary disease ( 3 ) but may be cost-effective in high-risk patients , for whom clopidogrel offers more substantial absolute risk reduction . To assess the cost-effectiveness of clopidogrel plus aspirin relative to aspirin alone in high-risk patients with coronary artery disease and to explore the optimal duration of therapy , we constructed a decision analytic Markov model comparing these treatment strategies after an acute coronary syndrome as defined in CURE . Methods We performed a cost-effectiveness analysis using a Markov model ( 4 ) ( DATA 4.0 , TreeAge Software , Inc. , Williamstown , Massachusetts ) . We analyzed a reference case assuming a societal perspective ( 5 ) and a lifetime time horizon ( 6 ) . Our analysis was based on the CURE trial , a r and omized comparison of 3 to 12 months of therapy with clopidogrel plus aspirin or aspirin alone to prevent cardiovascular death , myocardial infa rct ion , or stroke in 12562 patients with an acute coronary syndrome ( 1 ) . We discounted costs and utilities at 3 % annually and determined lifetime costs , quality -adjusted life expectancy , and the incremental cost-effectiveness ratio . Sensitivity analyses included 1-way analyses on all data inputs ; probabilistic sensitivity analysis ; evaluation of varying duration of combination therapy , including potential loss of efficacy over time ; and consideration of population s with varying risk . Target Population The target population was analogous to that of the CURE trial ( 1 ) : patients with an acute coronary syndrome characterized by electrocardiographic changes or elevated serum cardiac markers in association with chest pain . Patients who had prolonged ST-segment elevation , who had undergone revascularization in the previous 3 months , who were at risk for severe bleeding or heart failure , or who had been treated with oral anticoagulants or glycoprotein IIb/IIIa inhibitors in the preceding 3 days were excluded . On the basis of the average age of CURE patients , we considered a 64-year-old as our base case and explored other ages in sensitivity analysis . We compared treatment costs and clinical outcomes for 2 types of antiplatelet therapy : 1 ) aspirin alone , 325 mg/d , and 2 ) clopidogrel , 75 mg/d , plus aspirin , 325 mg/d , for 1 year , followed by aspirin monotherapy . Model Structure In our model , we included vascular events : myocardial infa rct ion , stroke , vascular death and revascularization , intracerebral and gastrointestinal hemorrhagic events , and clopidogrel-associated thrombotic thrombocytopenic purpura . We included age-related mortality , correcting for events explicitly included in the model . We did not directly include procedures or outcomes , such as congestive heart failure , that CURE did not specifically address ( 1 ) . We indirectly accounted for the cost of such events by using age-adjusted annual health care costs ( 7 ) . This assumes equal probability of such events in each arm of the analysis . We allowed for multiple events , including multiple events of a particular type , within a given monthly cycle . We created Markov states for conditions that changed quality of life , annual cost , or probability of future events . For events with temporary decrements in quality of life , we assessed a utility toll proportional to the duration of hospitalization required ( 8) . We also modeled each combination of 2 events . When more than 2 events occurred , we used the Markov state that combined the 2 events with the lowest utility ( Figure 1 ) . Figure 1 . Schematic representation of the decision model . Model Inputs Probabilities We derived probabilities for vascular and hemorrhagic events over the first year of our analysis from the CURE trial ( 1 ) . Rates of cardiovascular outcomes were highest in the month immediately following the acute coronary syndrome ( 1 ) . To account for temporal variation in risk , we calculated probabilities for the first month separately from those for subsequent months . Beyond the time frame of the CURE trial , we empirically calculated declining probability functions for myocardial infa rct ion , cardiovascular death , and revascularization on the basis of proportional decline in risk over time in survivors of nonQ-wave myocardial infa rct ion ( 9 ) . We assumed that all bleeding events , other than intracerebral hemorrhage , were gastrointestinal . Because intracerebral hemorrhage was equally likely for the 2 treatment strategies ( 1 ) , all of the excess bleeding in the clopidogrel plus aspirin arm was attributed to gastrointestinal causes . The rate of thrombotic thrombocytopenic purpura associated with clopidogrel was derived from an observational study ( 10 , 11 ) . We represented uncertainty in event rates through distributions based on the number of events that occurred and the number of patient-years at risk . We obtained age-specific mortality from life tables ( 12 ) and corrected for death rates of events explicitly included in our model ( Table ) . Table . Model Inputs Efficacy of Combination Therapy Despite the variation in risk , the relative efficacy of clopidogrel plus aspirin did not vary between the first and subsequent months ( 1 ) . In modeling beyond the time frame of the CURE trial , we assumed in our base case that efficacy remained constant , on the basis of data for clopidogrel monotherapy ( 13 ) . We explored waning efficacy over time in sensitivity analysis . We used 3 variables to describe loss of efficacy , duration of constant efficacy ( 1 year to lifetime ) , duration of efficacy deterioration ( 1 to 10 years ) , and the extent of efficacy decline relative to  aspirin monotherapy ( none to complete loss ) . Costs We derived costs for each event and for chronic care of disabled patients from the literature . For medications , we used the average wholesale price in the United States as our base value ( 35 ) and considered prices negotiated by a large-volume purchaser in constructing the price range . Acute care costs for clinical events represent the direct costs of all medical care incurred during hospitalization . Chronic care costs represent direct expenditures for medications , procedures , and nursing care specific to the condition in question and were assessed for each month in the Markov state . For Markov states representing survival after either severe stroke or intracerebral hemorrhage and another event , we assumed 20 % of the long-term cost of the additional condition to account for overlapping therapy . We accounted for other health care costs by using age-adjusted annual health expenditures ( 7 ) . We up date d costs to 2002 U.S. dollars with a gross domestic product deflator ( 44 ) and generated log-normal distributions for each estimate for use in sensitivity analyses ( Table ) . Utilities We used published population -based utilities , representing either time-tradeoff or st and ard-gamble techniques . For Markov states representing 2 events , we combined utilities with multiplication ( 8) . For events and procedures that did not result in durable changes in the health state of the individual , we used disutility tolls based on the average duration of hospitalization ( 8) . We modeled uncertainty in utility estimates by calculating distributions based on the range of utility estimates in the literature ( Table ) . Sensitivity Analyses To assess the degree to which variation in any variable altered our results , we performed 1-way sensitivity analyses for each model input by analyzing the results at both extremes of its 95 % CI . In evaluating patients of different ages , we adjusted both age-related mortality and estimates of annual health care cost accordingly . To better underst and the distribution of the cost-effectiveness ratio for clopidogrel plus aspirin and the potential value of further research , we performed probabilistic sensitivity analysis using Monte Carlo simulation ( 45 , 46 ) . In each of 1000 simulations , the value for each model input was r and omly selected from its distribution . We constructed a cost-effectiveness acceptability curve by calculating the average net monetary benefit for each strategy in each simulation over cost-effectiveness thresholds ranging from no additional expenditure for the least expensive therapy to $ 100000 for each quality -adjusted life-year ( QALY ) gained . We then determined the proportion of simulations for which clopidogrel plus aspirin result ed in the greater net monetary benefit at each cost-effectiveness threshold . We also assessed varying the duration of  clopidogrel therapy from 1 month to 1 year in monthly increments . We considered prolonged therapy , up to patient lifetime , in yearly increments , simultaneously assessing potential decline in the efficacy of clopidogrel . To better Rationale and aims Monotherapy with antiplatelet agents is only modestly effective in secondary prevention of ischemic stroke ( IS ) , particularly in patients with multiple risk factors such as cervicocephalic arterial stenosis , diabetes , and hypertension . While dual antiplatelet therapy ( DAPT ) with aspirin and clopidogrel reduced IS recurrence , particularly in the early stages after IS , it increased the risk of bleeding . Compared with aspirin , cilostazol prevented IS recurrence without increasing the incidence of serious bleeds . In patients with intracranial arterial stenosis , no significant increase in bleeding events was observed for DAPT with cilostazol and aspirin , compared to that for aspirin monotherapy . DAPT involving cilostazol may therefore be safer than conventional DAPT . These findings prompted us to conduct the Cilostazol Stroke Prevention Study for Antiplatelet Combination ( CSPS.com ; Clinical Trials.gov identifier : NCT01995370 ) to evaluate the safety and efficacy of DAPT involving cilostazol for secondary IS prevention , in comparison with that of antiplatelet monotherapy . Design The CSPS.com is a multicenter , r and omized , open-label , parallel-group trial . A total of 4000 high-risk patients with noncardioembolic IS will be r and omized 8–180 days after onset to receive aspirin or clopidogrel monotherapy , or DAPT with cilostazol and aspirin or clopidogrel for at least one-year . Study outcomes The primary outcome is IS recurrence . Secondary outcomes are composite occurrences of any stroke , death from any cause , myocardial infa rct ion , vascular death , and other vascular events . Discussion The CSPS.com is expected to provide evidence indicating whether secondary IS prevention in high-risk patients can be improved by using DAPT involving cilostazol AIMS To examine the unanticipated , excess mortality observed in patients r and omized to clopidogrel and aspirin vs. aspirin alone  in the prespecified ' asymptomatic ' subgroup of CHARISMA , we investigated whether dual-antiplatelet therapy may be associated with adverse  cardiovascular ( CV )  events in a primary prevention population . METHODS AND RESULTS Of 15 603 patients enrolled , 3284 were initially categorized as asymptomatic with CV risk factors , but 995 had a prior CV event , leaving 2289 patients to represent the primary prevention cohort . This subset was compared with 13 148 symptomatic patients with established vascular disease and both were evaluated for CV death and bleeding . A multivariate analysis analysed predictors of CV death in this group . No post mortem data were available . Compared with aspirin alone , a significant increase in CV death ( P = 0.01 ) was observed in patients receiving dual-antiplatelet therapy in the asymptomatic population . Within the primary prevention cohort , this excess CV death was not significant ( P = 0.07 ) . Multivariate analysis of the primary prevention group showed a trend towards excess CV death ( P = 0.054 ; HR 1.72 ; CI 0.99 - 2.97 ) with dual-antiplatelet therapy ( aspirin plus clopidogrel ) . Other independent predictors of CV death included increasing age , hypertension , atrial fibrillation , and a history of heart failure . There was a non-significant increase in moderate or severe bleeding ( P = 0.218 ) with dual-antiplatelet therapy ; thus , bleeding was an unlikely explanation for the excess event rate . CONCLUSION These findings do not support the use of dual-antiplatelet therapy with clopidogrel and aspirin in a primary prevention population . In this subgroup analysis , CV death occurred more frequently than anticipated . The cause of this apparent harm is not eluci date d , may represent play of chance , but requires further prospect i ve evaluation Dual antiplatelet therapy ( DAPT ) , the combination of aspirin and a P2Y12 inhibitor , given for 12 months remains the st and ard of care after presentation with acute coronary syndrome ( ACS ) because it has been shown to be associated with a significant reduction in ischemic events compared with aspirin monotherapy . The factor Xa inhibitor rivaroxaban was shown to be associated with a significant reduction in the composite of cardiovascular death , myocardial infa rct ion , and stroke , and result ed in a nominal reduction in cardiovascular death , when added to background DAPT in the ATLAS ACS 2-TIMI 51 trial ; however , there was excessive bleeding with this " triple-therapy " approach . The combination of rivaroxaban with P2Y12 inhibition in a " dual-pathway " approach may be an effective therapeutic regimen for the treatment of ACS , given the known importance of P2Y12 inhibition after stenting and intriguing data that the combination of an anticoagulant with clopidogrel after stenting in patients with atrial fibrillation appears an attractive option to this patient population . GEMINI-ACS-1 is a prospect i ve , r and omized , double-dummy , double-blind , active-controlled trial that will assess the safety of dual antithrombotic therapy ( rivaroxaban [ 2.5 mg twice daily ] + P2Y12 inhibitor ) as compared with DAPT ( aspirin [ 100 mg ] + P2Y12 inhibitor ) within 10 days of an ACS event in 3,000 patients . Patients will be r and omized in a 1:1 ratio stratified by intended P2Y12 inhibitor use ( clopidogrel 75 mg daily or ticagrelor 90 mg twice daily ) , with 1500 patients expected in each P2Y12 inhibitor strata . The primary end point is Thrombolysis in Myocardial Infa rct ion clinical ly significant bleeding ( major , minor , or requiring medical attention ) . The exploratory efficacy determination will be a composite of cardiovascular death , myocardial infa rct ion , ischemic stroke , and stent thrombosis . GEMINI-ACS-1 will assess the safety and feasibility of dual antithrombotic therapy with rivaroxaban and a P2Y12 inhibitor compared with conventional DAPT for the treatment for patients with recent ACS BACKGROUND Clopidogrel , aspirin ( ASA ) , and the fixed-dose combination of extended-release dipyridamole and ASA ( ER-DP+ASA ) are widely used in post-stroke regimens . OBJECTIVE This study compared serial changes in multiple biomarkers of platelet activation with ER-DP+ASA and clopidogrel with or without ASA in patients with type 2 diabetes mellitus and a history of transient ischemic attack ( TIA ) . METHODS This was a r and omized , single-blind pilot study conducted at an outpatient center in the United States . Eligible patients were aged 40 years and had a diagnosis of type 2 diabetes and a history of TIA . Patients were allocated to receive ER-DP+ASA 200/25 mg BID , clopidogrel 75 mg/d , or clopidogrel 75 mg/d plus ASA 81 mg/d .  Multiple platelet bio-markers were assessed at baseline , day 15 , and day 30 using aggregometry , cartridge-based platelet function analyzers , and flow cytometry . The primary end point was the change in platelet receptor expression after 30 days of therapy . Compliance and tolerability were monitored by measuring plasma dipyridamole levels and recording all episodes of headache and vomiting . RESULTS The study enrolled 60 consecutive patients ( 20 per treatment arm ) , all of whom completed the study . There were no significant differences between treatment arms , although the  ER-DP+ASA group had a numerically greater mean age , higher proportion of men , and a greater prevalence of vascular disease and smoking compared with the other groups . There were no deaths or serious adverse events during the study , including symptoms attributable to cerebral ischemia , worsening of diabetes , or cerebral or systemic bleeding . Three patients in the ER-DP+ASA group and 1 in the clopidogrel plus ASA group reported headache during the first several days of therapy ; 1 patient in the clopidogrel monotherapy group experienced transitory nausea and vomiting .  ER-DP+ASA was associated with a significantly delayed ( day 30 ) reduction in expression of glyco-protein ( GP ) Ilb/IIIa activity ( P = 0.02 ) , platelet-endothelial cell adhesion molecule 1 ( PECAM-1 ) ( P = 0.03 ) , GP Ib ( P = 0.001 ) , vitronectin ( P = 0.001 ) , P-selectin ( P = 0.001 ) , lysosome-associated membrane protein 1 ( P = 0.001 ) , and cluster of differentiation 40 lig and ( P = 0.01 ) , as well as significant inhibition of the intact ( P = 0.01 ) and cleaved ( P = 0.01 ) epitopes of protease-activated receptor 1 . Clopidogrel monotherapy , on the other h and , was associated with significant inhibition of adenosine diphosphate-induced platelet aggregation ( P = 0.001 ) , closure-time prolongation ( P = 0.01 ) , and reduction in measurements on the rapid platelet function assay-ASA at day 15 ( P = 0.001 ) . Expression of PECAM-1 ( P = 0.03 ) and GP IIb/IIIa activity ( P = 0.01 ) was reduced at day 15 in clopidogrel-treated patients . The addition of ASA to clopidogrel was associated with significant inhibition of collagen-induced platelet aggregation ( P = 0.001 ) and diminished formation of platelet-monocyte microparticles at days 15 ( P = 0.02 ) and 30 ( P = 0.03 ) . CONCLUSIONS In these patients with type 2 diabetes and a history of TIA , patterns of platelet inhibition differed significantly according to whether treatment was with ER-DP+ASA or clopidogrel with or without ASA . The antiplatelet activity of clopidogrel was more potent and occurred earlier ( 15 days ) , whereas ER-DP+ASA was associated with moderate downregulation of multiple activation-dependent platelet receptors that occurred later ( 30 days ) BACKGROUND Despite overwhelming data demonstrating the efficacy of antiplatelet therapy in heart disease and stroke , data in peripheral artery disease ( PAD ) are less compelling . Aspirin has modest evidence supporting a reduction in cardiovascular events in patients with PAD , whereas clopidogrel monotherapy may be more effective in PAD . Ticagrelor , a potent , reversibly binding P2Y12 receptor antagonist , is beneficial in patients with acute coronary syndrome and prior myocardial infa rct ion . The EUCLID trial is design ed to address the need for effective antiplatelet therapy in PAD to decrease the risk of cardiovascular events . STUDY DESIGN EUCLID is a r and omized , double-blind , parallel-group , multinational clinical trial design ed to evaluate the efficacy and safety of ticagrelor compared with clopidogrel for the prevention of major adverse cardiovascular events in subjects with symptomatic PAD . Subjects with established PAD will be r and omized in a 1:1 fashion to ticagrelor 90 mg twice daily or clopidogrel 75 mg daily . The primary end point is a composite of cardiovascular death , myocardial infa rct ion , or ischemic stroke . Other end points address limb events including acute leg ischemia , need for revascularization , disease progression by ankle-brachial index , and quality of life . The primary safety objective is Thrombolysis in Myocardial Infa rct ion-defined major bleeding .  Recruitment began in December 2012 and was completed in March 2014 ; 13,887 patients were r and omized . The trial will continue until at least 1,364 adjudicated primary end points occur . CONCLUSIONS The EUCLID study is investigating whether treatment with ticagrelor versus clopidogrel , given as antiplatelet monotherapy , will reduce the incidence of cardiovascular and limb-specific events in patients with symptomatic PAD Aims : To evaluate the effects of treatments with clopidogrel plus aspirin ( dual therapy ) on early neurological deterioration ( END ) and outcomes at 6 months in patients with acute large artery atherosclerosis ( LAA ) stroke . Methods : A total of 574 patients with LAA stroke were r and omly assigned to receive either dual therapy or aspirin alone ( monotherapy ) . The primary outcome was END . Secondary outcomes included recurrent ischemic stroke ( RIS ) and outcomes at 6 months . Results : The prevalence of END and RIS was lower in patients on dual therapy than in those on monotherapy during the 30 days . At 6 months , dual therapy improved outcomes among older patients and those with symptomatic stenosis in the posterior circulation and basilar artery . Conclusion : Clopidogrel plus aspirin is superior to aspirin alone for reducing END and RIS within 30 days and improves outcomes in certain subgroups at 6 months
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 .