A Randomised Controlled Trial of Triple Antiplatelet Therapy (Aspirin, Clopidogrel and Dipyridamole) in the Secondary Prevention of Stroke: Safety, Tolerability and Feasibility A comparative study of dual versus monoantiplatelet therapy in patients with acute large-artery atherosclerosis stroke. Design of the blockade of the glycoprotein IIb/IIIa receptor to avoid vascular occlusion (BRAVO) trial. Protocol for Cilostazol Stroke Prevention Study for Antiplatelet Combination (CSPS.com): a randomized, open-label, parallel-group trial 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 randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE) 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 adds no benefit but bleeding risk in patients with recent lacunar stroke. Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) Trial: Rationale and design Antiplatelet therapy with aspirin, clopidogrel, and dipyridamole versus clopidogrel alone or aspirin and dipyridamole in patients with acute cerebral ischaemia (TARDIS): a randomised, open-label, phase 3 superiority trial Rationale and design of the dual antiplatelet therapy study, a prospective, multicenter, randomized, double-blind trial to assess the effectiveness and safety of 12 versus 30 months of dual antiplatelet therapy in subjects undergoing percutaneous coronary intervention with either drug-eluting stent  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. Impact of dual antiplatelet therapy on outcomes among aspirin-resistant patients following coronary artery bypass grafting. New antiplatelet therapies in development. Comparative Safety and Tolerability of Clopidogrel and Aspirin The secondary prevention of stroke according to cytochrome P450 2C19 genotype in patients with acute large-artery atherosclerosis stroke Clopidogrel and Aspirin in Acute Ischemic Stroke and High‐Risk TIA
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 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 BACKGROUND Platelets play a key role in the pathogenesis of atherosclerosis , thrombosis , and acute coronary and cerebrovascular syndromes . Inhibition of platelet function by acetylsalicylic acid ( aspirin ) has been shown to reduce the incidence atherothrombotic events in patients with coronary , cerebrovascular , or peripheral vascular disease .  Thienopyridine agents , however , including ticlopidine and clopidogrel , inhibit the adenosine diphosphate receptor and have modestly superior effects compared with aspirin on reduction of death , myocardial infa rct ion , and stroke among a broad group of patients with vascular disease . More effective antithrombotic agents are still required to treat patients at high risk for recurrent vascular events . METHODS Lotrafiban , a selective , nonpeptide antagonist of the human platelet fibrinogen receptor ( glycoprotein [ GP ] IIb/IIIa [ alphaIIb/beta3 integrin ] ) , blocks the binding of fibrinogen to the GP IIb/IIIa receptor , which is the final common pathway of platelet aggregation . Lotrafiban at doses of up to 50 mg twice daily was well-tolerated in a 12-week , double-blind , placebo-controlled , dose-ranging study in patients with recent myocardial infa rct ion , unstable angina , transient ischemic attack , or stroke when added to aspirin therapy . On the basis of these results , a dosing regimen was selected for the phase III Blockage of the Glycoprotein IIb/IIIa Receptor to Avoid Vascular Occlusion ( BRAVO ) trial based on pharmacodynamics and drug tolerability . In the pivotal BRAVO study , lotrafiban therapy is being evaluated in patients who have had a recent myocardial infa rct ion , unstable angina , transient ischemic attack , or ischemic stroke , or who present at any time after a diagnosis of peripheral vascular disease combined with either cardiovascular or cerebrovascular disease . RESULTS The efficacy evaluation will be based on a composite end point of clinical events ( death by any cause , myocardial infa rct ion , stroke , recurrent ischemia requiring hospitalization , or urgent ischemia-driven revascularization ) .  The target enrollment is 9200 patients worldwide . Approximately 700 centers will participate and will be distributed within 30 countries across North America , Europe , Australia , and Asia 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 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 BACKGROUND Many clinical trials have evaluated the benefit of long-term use of antiplatelet drugs in reducing the risk of clinical thrombotic events .  Aspirin and ticlopidine have been shown to be effective , but both have potentially serious adverse effects .  Clopidogrel , a new thienopyridine derivative similar to ticlopidine , is an inhibitor of platelet aggregation induced by adenosine diphosphate . METHODS CAPRIE was a r and omised , blinded , international trial design ed to assess the relative efficacy of clopidogrel ( 75 mg once daily ) and aspirin ( 325 mg once daily ) in reducing the risk of a composite outcome cluster of ischaemic stroke , myocardial infa rct ion , or vascular death ; their relative safety was also assessed . The population studied comprised subgroups of patients with atherosclerotic vascular disease manifested as either recent ischaemic stroke , recent myocardial infa rct ion , or symptomatic peripheral arterial disease . Patients were followed for 1 to 3 years . FINDINGS 19,185 patients , with more than 6300 in each of the clinical subgroups , were recruited over 3 years , with a mean follow-up of 1.91 years . There were 1960 first events included in the outcome cluster on which an intention-to-treat analysis showed that patients treated with clopidogrel had an annual 5.32 % risk of ischaemic stroke , myocardial infa rct ion , or vascular death compared with 5.83 % with aspirin . These rates reflect a statistically significant ( p = 0.043 ) relative-risk reduction of 8.7 % in favour of clopidogrel ( 95 % Cl 0.3 - 16.5 ) . Corresponding on-treatment analysis yielded a relative-risk reduction of 9.4 % . There were no major differences in terms of safety . Reported adverse experiences in the clopidogrel and aspirin groups judged to be severe included rash ( 0.26 % vs 0.10 % ) , diarrhoea ( 0.23 % vs 0.11 % ) , upper gastrointestinal discomfort ( 0.97 % vs 1.22 % ) , intracranial haemorrhage ( 0.33 % vs 0.47 % ) , and gastrointestinal haemorrhage ( 0.52 % vs 0.72 % ) , respectively . There were ten ( 0.10 % ) patients in the clopidogrel group with significant reductions in neutrophils ( < 1.2 x 10(9)/L ) and 16 ( 0.17 % ) in the aspirin group . INTERPRETATION Long-term administration of clopidogrel to patients with atherosclerotic vascular disease is more effective than aspirin in reducing the combined risk of ischaemic stroke , myocardial infa rct ion , or vascular death . The overall safety profile of clopidogrel is at least as good as that of medium-dose aspirin 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 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 Ischemic stroke and other vascular outcomes occur in 10–20 % of patients in the three-months following a transient ischemic attack or minor ischemic stroke , and many are disabling . The highest risk period for these outcomes is the early hours and days immediately following the ischemic event . Aspirin is the most common antithrombotic treatment used for these patients . Aim The aim of POINT is to determine whether clopidogrel plus aspirin taken < 12 h after transient ischemic attack or minor ischemic stroke symptom onset is more effective in preventing major ischemic vascular events at 90 days in the high-risk , and acceptably safe , compared with aspirin alone . Design POINT is a prospect i ve , r and omized , double-blind , multicenter trial in patients with transient ischemic attack or minor ischemic stroke . Subjects are r and omized to clopidogrel  ( 600 mg loading dose followed by 75 mg/day )  or matching placebo  , and all will receive  open-label aspirin 50–325 mg/day , with a dose of 162 mg daily for five-days followed by 81 mg daily strongly recommended . Study Outcomes The primary efficacy outcome is the composite of new ischemic vascular events — ischemic stroke , myocardial infa rct ion , or ischemic vascular death — by 90 days . The primary safety outcome is major hemorrhage , which includes symptomatic intracranial hemorrhage . Discussion Aspirin is the most common antithrombotic given to patients with a stroke or transient ischemic attack , as it reduces the risk of subsequent stroke . This trial expects to determine whether more aggressive antithrombotic therapy with clopidogrel plus aspirin , initiated acutely , is more effective than aspirin alone Summary Background Intensive antiplatelet therapy with three agents might be more effective than guideline treatment for preventing recurrent events in patients with acute cerebral ischaemia . We aim ed to compare the safety and efficacy of intensive antiplatelet therapy ( combined aspirin , clopidogrel , and dipyridamole ) with that of guideline -based antiplatelet therapy . Methods We did an international , prospect i ve , r and omised , open-label , blinded-endpoint trial in adult participants with ischaemic stroke or transient ischaemic attack ( TIA ) within 48 h of onset . Participants were assigned in a 1:1 ratio using computer r and omisation to receive loading doses and then 30 days of intensive antiplatelet therapy ( combined aspirin 75 mg , clopidogrel 75 mg , and dipyridamole 200 mg twice daily ) or guideline -based therapy ( comprising either clopidogrel alone or combined aspirin and dipyridamole ) . R and omisation was stratified by country and index event , and minimised with prognostic baseline factors , medication use , time to r and omisation , stroke-related factors , and thrombolysis . The ordinal primary outcome was the combined incidence and severity of any recurrent stroke ( ischaemic or haemorrhagic ; assessed using the modified Rankin Scale ) or TIA within 90 days , as assessed by central telephone follow-up with masking to treatment assignment , and analysed by intention to treat . This trial is registered with the IS RCT N registry , number IS RCT N47823388 . Findings 3096 participants ( 1556 in the intensive antiplatelet therapy group , 1540 in the guideline antiplatelet therapy group ) were recruited from 106 hospitals in four countries between April 7 , 2009 , and March 18 , 2016 . The trial was stopped early on the recommendation of the data monitoring committee . The incidence and severity of recurrent stroke or TIA did not differ between intensive and guideline therapy ( 93 [ 6 % ] participants vs 105 [ 7 % ] ; adjusted common odds ratio [ cOR ] 0·90 , 95 % CI 0·67–1·20 , p=0·47 ) . By contrast , intensive antiplatelet therapy was associated with more , and more severe , bleeding ( adjusted cOR 2·54 , 95 % CI 2·05–3·16 , p<0·0001 ) . Interpretation Among patients with recent cerebral ischaemia  , intensive antiplatelet therapy did not reduce the incidence and severity of recurrent stroke or TIA , but did significantly increase the risk of major bleeding . Triple antiplatelet therapy should not be used in routine clinical practice . Funding National Institutes of Health Research Health Technology Assessment Programme , British Heart Foundation BACKGROUND Dual antiplatelet therapy with aspirin and thienopyridines ( clopidogrel or prasugrel ) is required after placement of coronary stents to prevent thrombotic complications . Although current clinical practice guidelines recommend 12-month treatment after drug-eluting stent placement , even longer duration s may prevent thrombotic events . STUDY DESIGN The Dual Antiplatelet Therapy ( DAPT ) Study is comparing the benefits and risks of 12 versus 30 months of dual antiplatelet therapy in preventing stent thrombosis or major adverse cardiovascular and cerebrovascular events in subjects undergoing percutaneous coronary intervention ( PCI ) for the treatment of coronary artery obstructive lesions . The DAPT Study is a multicenter , international , r and omized , double-blind , placebo-controlled trial that will enroll 15,245 subjects treated with drug-eluting stent ( DES ) and 5,400 subjects treated with bare-metal stents ( BMS ) .  All subjects will receive 12 months of open-label thienopyridine treatment in addition to aspirin . After 12 months , subjects who are free from death , myocardial infa rct ion , or stroke ( MACCE ) , repeat revascularization , and GUSTO ( Global Use of Strategies to Open Occluded Coronary Arteries ) moderate or severe bleeding events will be r and omized to receive either 18 additional months of thienopyridine ( clopidogrel or prasugrel ) ( 30 month DAPT arm ) or placebo ( 12 month DAPT arm ) plus aspirin . Co primary end points are MACCE and stent thrombosis . The primary safety end point is GUSTO moderate or severe bleeding . CONCLUSIONS This r and omized trial is design ed to define the relative safety and effectiveness of 12 versus 30 months of dual antiplatelet therapy across the broad spectrum of patients receiving coronary stents 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 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 PURPOSE The efficacy and safety of new antiplatelet therapies , as well as antiplatelet therapies in development , are review ed . SUMMARY Variability in the response to treatment with aspirin has been recognized for more than 40 years . Thienopyridine antiplatelet agents are now a st and ard pharmacologic component in the management of patients undergoing percutaneous coronary intervention ( PCI ) and stent placement . However , investigators have recently described wide inter-individual variability in the level of platelet inhibition following treatment with the thienopyridine clopidogrel , with a small number of patients classified as " non-responders " or " resistant . " Such variability in response is likely to have important clinical implication s , because antiplatelet therapy plays a key role in the prevention and treatment of cardiovascular disease , For example , recent studies have demonstrated that diminished response to clopidogrel may be associated with increased cardiac events after PCI . Even with larger-than-approved loading doses , clopidogrel requires several hours to reach a steady-state effect , and therapy must be discontinued for several days prior to surgery in order to avoid major bleeding events . Clinical trials of prasugrel , a new oral thienopyridine with a more rapid onset of platelet inhibition , have demonstrated significant reductions in adverse cardiovascular outcomes and stent thrombosis ; however , there is an increased risk for major bleeding events with prasugrel in some subgroups of the study population s. These limitations have led to development of agents that may potentially overcome such clinical challenges . AZD6140 , a novel , potent oral P2Y12 antagonist , demonstrated more effective platelet inhibition versus clopidogrel in a large r and omized trial of patients with acute coronary syndrome . However , patients taking AZD6140  reported dyspnea significantly more frequently than those taking clopidogrel . Cangrelor , a novel intravenous P2Y(12 ) receptor antagonist with a rapid onset of action and complete reversibility of platelet inhibition within 20 - 50 minutes of administration , may offer advantages over currently approved antiplatelet therapies . A new oral antiplatelet thrombin-receptor antagonist , TRA-SCH 530348 , is in early clinical trials . Unlike currently available drugs , TRA-SCH 530348 effectively prevents thrombin-induced activation of platelets . CONCLUSION Each new class of antiplatelet therapies has the potential for specific benefits and adverse effects in clinical use Objective The objective of this study was to provide a comprehensive comparison of the long term safety and tolerability of clopidogrel , a new adenosine diphosphate ( ADP ) receptor antagonist that inhibits platelet activation induced by ADP , and aspirin ( acetylsalicylic acid ) . Patients and Methods The study population comprised 19 185 patients with symptomatic atherosclerosis manifested as recent ischaemic stroke , recent myocardial infa rct ion or symptomatic peripheral arterial disease . Patients were r and omised to receive  clopidogrel 75 mg/day or aspirin 325 mg/day  for a minimum of 1 year and a maximum of 3 years . Results Compared with aspirin , clopidogrel reduced the combined risk of ischaemic stroke , myocardial infa rct ion or vascular death by 8.7 % ( p = 0.043 ) . The incidence of early permanent discontinuations of the study drug due to adverse events was almost identical in both treatment groups ( 11.94 % for clopidogrel vs 11.92 % for aspirin ) . Reported neutropenia was similar in the clopidogrel and aspirin groups ( 0.10 vs 0.17 % , respectively ) with corresponding rates ( 0.05 vs 0.04 % , respectively ) for severe neutropenia . Thrombocytopenia was identical in the clopidogrel and aspirin groups ( 0.26 % ) , with the rates of severe thrombocytopenia being 0.19 vs 0.10 % , respectively . None of these observed differences was statistically significant . The overall incidence of haemorrhagic events did not differ statistically significantly between treatment groups ( 9.27 % for clopidogrel vs 9.28 % for aspirin ; p = 0.98 ) . There was a trend towards a lower incidence of intracranial haemorrhage in the clopidogrel group ( 0.31 % ) compared with the aspirin group ( 0.42 % ) . Any reported gastrointestinal haemorrhage was significantly less frequent with clopidogrel ( 1.99 % ) than with aspirin ( 2.66 % ) [ p < 0.002 ] . The corresponding data for severe gastrointestinal bleeding were 0.49 vs 0.71 % ; p < 0.05 . Overall , there were significantly fewer gastrointestinal adverse events with clopidogrel than with aspirin ( 27.1 vs 29.8 % ; p < 0.001 ) , with less abdominal pain , dyspepsia , constipation , or peptic , gastric , or duodenal ulceration with clopidogrel .  Diarrhoea was significantly more common in the clopidogrel group ( 4.46 vs 3.36 % ; p < 0.001 ) , although the incidence of severe diarrhoea ( 0.23 vs 0.11 % ) was low and was not significantly different between groups . There were significantly more patients with rash in the clopidogrel group ( 6.0 % ) compared with the aspirin group ( 4.6 % ) [ p < 0.001 ] . However , these events were generally mild and transient in nature . Conclusion Given the favourable benefit/risk ratio , clopidogrel represents a clinical ly important advance in the treatment of patients with manifest atherosclerotic disease Purpose To investigated the effectiveness of antiplatelet agents for the secondary prevention of stroke according to CYP2C19 genotype in patients with ischemic stroke ( IS ) . Methods Between August 2009 and December 2011 , 570 acute IS patients with acute large-artery atherosclerosis were r and omly assigned to receive either combined clopidogrel and aspirin for the first 30 day , and clopidogrel thereafter ( clopidogrel group , n=284 ) or aspirin monotherapy ( aspirin group , n=286 ) . CYP2C19 genotypes were measured and masked until the end-of- study . The primary outcome was a composite of IS , transient ischemic attack ( TIA ) , myocardial infa rct ion ( MI ) , and death . Results During the 5 years follow-up , the primary outcome occurred in 105 patients ( 18.4 % ) ( 71 had IS , 10 had TIA , 12 had MI , and 12 died ) . There were no significant differences in the primary outcome between clopidogrel group and aspirin group ( 16.5 % vs. 20.3 % ) or between carriers of the CYP2C19 reduced-function alleles and noncarriers ( 21.8 % vs.15.7 % ) . In patients with aspirin therapy , CYP2C19 polymorphism was not associated with the primary outcome . However , in patients treated with clopidogrel , carriers of at least one CYP2C19 reduced-function allele had a 3-fold higher adjusted risk for primary outcome compared with noncarriers ( 95 % confidence interval , 1.23 to 8.74 ) . Conclusions Among IS patients treated with clopidogrel  , carriers of a reduced-function CYP2C19 allele had a significantly higher rate of adverse vascular events than did noncarriers . It should avoid prescribing clopidogrel to these patients with known CYP2C19 polymorphisms BACKGROUND Combination antiplatelet therapy with clopidogrel and aspirin may reduce the rate of recurrent stroke during the first 3 months after a minor ischemic stroke or transient ischemic attack ( TIA ) . A trial of combination antiplatelet therapy in a Chinese population has shown a reduction in the risk of recurrent stroke . We tested this combination in an international population . METHODS In a r and omized trial , we assigned patients with minor ischemic stroke or high‐risk TIA to receive either clopidogrel at a loading dose of 600 mg on day 1 , followed by 75 mg per day , plus aspirin ( at a dose of 50 to 325 mg per day ) or the same range of doses of aspirin alone . The dose of aspirin in each group was selected by the site investigator . The primary efficacy outcome in a time‐to‐event analysis was the risk of a composite of major ischemic events , which was defined as ischemic stroke , myocardial infa rct ion , or death from an ischemic vascular event , at 90 days . RESULTS A total of 4881 patients were enrolled at 269 international sites . The trial was halted after 84 % of the anticipated number of patients had been enrolled because the data and safety monitoring board had determined that the combination of clopidogrel and aspirin was associated with both a lower risk of major ischemic events and a higher risk of major hemorrhage than aspirin alone at 90 days . Major ischemic events occurred in 121 of 2432 patients ( 5.0 % ) receiving clopidogrel plus aspirin and in 160 of 2449 patients ( 6.5 % ) receiving aspirin plus placebo ( hazard ratio , 0.75 ; 95 % confidence interval [ CI ] , 0.59 to 0.95 ; P=0.02 ) , with most events occurring during the first week after the initial event . Major hemorrhage occurred in 23 patients ( 0.9 % ) receiving clopidogrel plus aspirin and in 10 patients ( 0.4 % ) receiving aspirin plus placebo ( hazard ratio , 2.32 ; 95 % CI , 1.10 to 4.87 ; P=0.02 ) . CONCLUSIONS In patients with minor ischemic stroke or high‐risk TIA , those who received a combination of clopidogrel and aspirin had a lower risk of major ischemic events but a higher risk of major hemorrhage at 90 days than those who received aspirin alone . ( Funded by the National Institute of Neurological Disorders and Stroke ; POINT Clinical Trials.gov number , NCT00991029 .
Compared with aspirin , thienopyridines significantly reduced gastrointestinal adverse effects .
However , thienopyridines increased the odds of skin rash and diarrhoea , ticlopidine more than clopidogrel .
Allocation to ticlopidine , but not clopidogrel , significantly increased the odds of neutropenia .
The thienopyridine derivatives are at least as effective as aspirin in preventing serious vascular events in patients at high risk , and possibly somewhat more so .
However , the size of any additional benefit is uncertain and could be negligible .
Clopidogrel has a more favourable adverse effects profile than ticlopidine and so is the thienopyridine of choice .
BACKGROUND Aspirin is the most widely studied and prescribed antiplatelet agent for preventing serious vascular events , reducing the odds of such events among high vascular risk patients by about a quarter .
Thienopyridine derivatives inhibit platelet activation by a different mechanism and so may be more effective .
OBJECTIVES To determine the effectiveness and safety of thienopyridine derivatives ( ticlopidine and clopidogrel ) versus aspirin for preventing serious vascular events ( stroke , myocardial infa rct ion ( MI ) or vascular death ) in patients at high risk , and specifically in patients with a previous TIA or ischaemic stroke .