***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
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    Input: Background —The antiplatelet effect of clopidogrel may be attenuated by short-term coadministration of lipophilic statins . We investigated whether the coadministration of atorvastatin for 5 weeks in patients with acute coronary syndromes ( ACS ) could affect the antiplatelet potency of clopidogrel . Methods and Results —Forty-five hypercholesterolemic patients with the first episode of an ACS were included in the study . Patients were r and omized to receive daily either 10 mg of atorvastatin ( n=21 ) or 40 mg of pravastatin ( n=24 ) . Thirty patients who underwent percutaneous coronary intervention ( PCI ) received a loading dose of 375 mg of clopidogrel , followed by 75 mg/d for at least 3 months . In the remaining 15 patients who refused to undergo PCI , clopidogrel therapy was not administered . Eight normolipidemic patients with the first episode of an ACS were also included and received only clopidogrel . The serum levels of soluble CD40L and the adenosine 5′-diphosphate– or thrombin receptor activating peptide-14–induced platelet aggregation , as well as P-selectin and CD40L surface expression , were studied at baseline ( within 30 minutes after admission ) and 5 weeks later . Neither atorvastatin nor pravastatin significantly influenced the clopidogrel-induced inhibition of platelet activation , nor did clopidogrel influence the therapeutic efficacy of atorvastatin . Conclusions —Atorvastatin does not affect the antiplatelet potency of clopidogrel when coadministered for 5 weeks in ACS patients BACKGROUND Gastrointestinal complications are an important problem of antithrombotic therapy . Proton-pump inhibitors ( PPIs ) are believed to decrease the risk of such complications , though no r and omized trial has proved this in patients receiving dual antiplatelet therapy . Recently , concerns have been raised about the potential for PPIs to blunt the efficacy of clopidogrel . METHODS We r and omly assigned patients with an indication for dual antiplatelet therapy to receive clopidogrel in combination with either omeprazole or placebo , in addition to aspirin . The primary gastrointestinal end point was a composite of overt or occult bleeding , symptomatic gastroduodenal ulcers or erosions , obstruction , or perforation . The primary cardiovascular end point was a composite of death from cardiovascular causes , nonfatal myocardial infa rct ion , revascularization , or stroke . The trial was terminated prematurely when the sponsor lost financing . RESULTS We planned to enroll about 5000 patients ; a total of 3873 were r and omly assigned and 3761 were included in analyses . In all , 51 patients had a gastrointestinal event ; the event rate was 1.1 % with omeprazole and 2.9 % with placebo at 180 days ( hazard ratio with omeprazole , 0.34 , 95 % confidence interval [ CI ] , 0.18 to 0.63 ; P<0.001 ) . The rate of overt upper gastrointestinal bleeding was also reduced with omeprazole as compared with placebo ( hazard ratio , 0.13 ; 95 % CI , 0.03 to 0.56 ; P = 0.001 ) . A total of 109 patients had a cardiovascular event , with event rates of 4.9 % with omeprazole and 5.7 % with placebo ( hazard ratio with omeprazole , 0.99 ; 95 % CI , 0.68 to 1.44 ; P = 0.96 ) ; high-risk subgroups did not show significant heterogeneity . The two groups did not differ significantly in the rate of serious adverse events , though the risk of diarrhea was increased with omeprazole . CONCLUSIONS Among patients receiving aspirin and clopidogrel , prophylactic use of a PPI reduced the rate of upper gastrointestinal bleeding . There was no apparent cardiovascular interaction between clopidogrel and omeprazole , but our results do not rule out a clinical ly meaningful difference in cardiovascular events due to use of a PPI . ( Funded by Cogentus Pharmaceuticals ; Clinical Trials.gov number , NCT00557921 . ) BACKGROUND Recent pharmacodynamic and retrospective clinical analyses have suggested that proton pump inhibitors ( PPIs ) may modify the antiplatelet effects of clopidogrel bisulfate . METHODS We conducted a retrospective cohort study of persons enrolled in a multistate health insurance plan with commercial and Medicare clients to evaluate adverse clinical outcomes in patients using clopidogrel plus a PPI compared with clopidogrel alone . Patients who were discharged from the hospital after myocardial infa rct ion ( MI ) or coronary stent placement and treated with clopidogrel plus a PPI ( n = 1033 ) were matched 1:1 ( using propensity scoring ) with patients with similar cardiovascular risk factors treated with clopidogrel alone .  Rehospitalizations for MI or coronary stent placement were evaluated for up to 360 days . A sub analysis was conducted to study the impact of pantoprazole sodium , the most used PPI . RESULTS Patients who received clopidogrel plus a PPI had a 93 % higher risk of rehospitalization for MI ( adjusted hazard ratio , 1.93 ; 95 % confidence interval , 1.05 - 3.54 ; P = .03 ) and a 64 % higher risk of rehospitalization for MI or coronary stent placement ( 1.64 ; 1.16 - 2.32 ; P = .005 ) than did patients receiving  clopidogrel  alone . Increased risk of rehospitalization for MI or coronary stent placement was also observed for the subgroup of patients receiving clopidogrel plus pantoprazole ( adjusted hazard ratio , 1.91 ; 95 % confidence interval , 1.19 - 3.06 ; P = .008 ) . CONCLUSIONS Patients who received clopidogrel plus a PPI had a significantly higher risk of rehospitalization for MI or coronary stent placement than did patients receiving  clopidogrel alone . Prospect i ve clinical trials and laboratory analyses of biochemical interactions are warranted to further evaluate the potential impact of PPIs on the efficacy of clopidogrel CONTEXT Following percutaneous coronary intervention ( PCI ) , short-term clopidogrel therapy in addition to aspirin leads to greater protection from thrombotic complications than aspirin alone . However , the optimal duration of combination oral antiplatelet therapy is unknown . Also , although current clinical data suggest a benefit for beginning therapy with a clopidogrel loading dose prior to PCI , the practical application of this therapy has not been prospect ively studied . OBJECTIVES To evaluate the benefit of long-term ( 12-month ) treatment with clopidogrel after PCI and to determine the benefit of initiating clopidogrel with a preprocedure loading dose , both in addition to aspirin therapy . DESIGN , SETTING , AND PARTICIPANTS The Clopidogrel for the Reduction of Events During Observation ( CREDO ) trial , a r and omized , double-blind , placebo-controlled trial conducted among 2116 patients who were to undergo elective PCI or were deemed at high likelihood of undergoing PCI , enrolled at 99 centers in North America from June 1999 through April 2001 . INTERVENTIONS Patients were r and omly assigned to receive a 300-mg clopidogrel loading dose ( n = 1053 ) or placebo ( n = 1063 ) 3 to 24 hours before PCI . Thereafter , all patients received clopidogrel , 75 mg/d , through day 28 . From day 29 through 12 months , patients in the loading-dose group received clopidogrel , 75 mg/d , and those in the control group received placebo . Both groups received aspirin throughout the study . MAIN OUTCOME MEASURES One-year incidence of the composite of death , myocardial infa rct ion ( MI ) , or stroke in the intent-to-treat population ; 28-day incidence of the composite of death , MI , or urgent target vessel revascularization in the per- protocol population . RESULTS At 1 year , long-term clopidogrel therapy was associated with a 26.9 % relative reduction in the combined risk of death , MI , or stroke ( 95 % confidence interval [ CI ] , 3.9%-44.4 % ; P = .02 ; absolute reduction , 3 % ) . Clopidogrel pretreatment did not significantly reduce the combined risk of death , MI , or urgent target vessel revascularization at 28 days ( reduction , 18.5 % ; 95 % CI , -14.2 % to 41.8 % ; P = .23 ) . However , in a prespecified subgroup analysis , patients who received clopidogrel at least 6 hours before PCI experienced a relative risk reduction of 38.6 % ( 95 % CI , -1.6 % to 62.9 % ; P = .051 ) for this end point compared with no reduction with treatment less than 6 hours before PCI . Risk of major bleeding at 1 year increased , but not significantly ( 8.8 % with clopidogrel vs 6.7 % with placebo ; P = .07 ) . CONCLUSIONS Following PCI , long-term ( 1-year ) clopidogrel therapy significantly reduced the risk of adverse ischemic events . A loading dose of clopidogrel given at least 3 hours before the procedure did not reduce events at 28 days , but subgroup analyses suggest that longer intervals between the loading dose and PCI may reduce events OBJECTIVES The goal of comparative effectiveness analysis is to examine the relationship between two variables , treatment , or exposure and effectiveness or outcome . Unlike data obtained through r and omized controlled trials , research ers face greater challenges with causal inference with observational studies . Recognizing these challenges , a task force was formed to develop a guidance document on method ological approaches to addresses these biases . METHODS The task force was commissioned and a Chair was selected by the International Society for Pharmacoeconomics and Outcomes Research Board of Directors in October 2007 . This report , the second of three reported in this issue of the Journal , discusses the inherent biases when using secondary data sources for comparative effectiveness analysis and provides method ological recommendations to help mitigate these biases . RESULTS The task force report provides recommendations and tools for research ers to mitigate threats to validity from bias and confounding in measurement of exposure and outcome . Recommendations on design of study included : the need for data analysis plan with causal diagrams ; detailed attention to classification bias in definition of exposure and clinical outcome ; careful and appropriate use of restriction ; extreme care to identify and control for confounding factors , including time-dependent confounding . CONCLUSIONS Design of nonr and omized studies of comparative effectiveness face several daunting issues , including measurement of exposure and outcome challenged by misclassification and confounding . Use of causal diagrams and restriction are two techniques that can improve the theoretical basis for analyzing treatment effects in study population s of more homogeneity , with reduced loss of generalizability OBJECTIVES This study sought to compare the effect of 2 proton pump inhibitors ( PPIs ) on platelet response to clopidogrel after coronary stenting for non-ST-segment elevation acute coronary syndrome ( NSTE ACS ) . BACKGROUND Use of omeprazole has been reported to significantly decrease the clopidogrel antiplatelet effect because of cytochrome P450 interaction . Because all PPIs are metabolized by CYP2C19 , but to a varying degree , we hypothesized that the reported negative omeprazole-clopidogrel drug interaction may not be caused by a class effect . METHODS A total of 104 patients undergoing coronary stenting for NSTE ACS were prospect ively included and r and omized to omeprazole or pantoprazole 20 mg . They received at discharge 75-mg aspirin and 150-mg clopidogrel .  Platelet reactivity index ( PRI ) vasoactive stimulated phosphoprotein ( VASP ) was used to assess clopidogrel response and adenosine diphosphate (ADP)-induced aggregation for platelet reactivity ( ADP-Ag ) . RESULTS After 1 month , patients receiving pantoprazole had a significantly better platelet response to clopidogrel as assessed with the PRI VASP : 36 + /- 20 % versus 48 + /- 17 % ( p = 0.007 ) . We identified more clopidogrel nonresponders in the omeprazole group than in the pantoprazole group : 44 % versus 23 % ( p = 0.04 ) , odds ratio : 2.6 ( 95 % confidence interval : 1.2 to 6.2 ) . Conversely , we did not observe any significant difference in platelet reactivity with ADP-Ag between the omeprazole and pantoprazole groups : 52 + /- 15 % and 50 + /- 18 % , respectively ( p = 0.29 ) . CONCLUSIONS The present findings suggest the preferential use of pantoprazole compared with omeprazole in patients receiving clopidogrel to avoid any potential 
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There was also no clinical evidence for a positive interaction according to specific PPIs .
Conclusion The observed association between clopidogrel and PPIs is found uniquely in studies judged to be of low quality and with an increased risk of bias .