***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 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Background —Statins primarily metabolized by cytochrome P450 3A4 ( CYP3A4 ) reportedly reduce clopidogrel ’s metabolism to active metabolite , thus attenuating its inhibition of platelet aggregation ex vivo . However , the clinical impact of this interaction has not been evaluated . Methods and Results —Clopidogrel for the Reduction of Events During Observation ( CREDO ) was a double-blind , placebo-controlled , r and omized trial comparing pretreatment ( 300 mg ) and 1-year ( 75 mg/d ) clopidogrel therapy ( clopidogrel ) with no pretreatment and 1-month clopidogrel therapy ( 75 mg/d ) ( control )  after a planned percutaneous coronary intervention . All patients received aspirin .  The 1-year primary end point was a composite of death , myocardial infa rct ion , and stroke . We performed a post hoc analysis to evaluate the clinical efficacy of concomitant clopidogrel and statin administration , categorizing baseline statin use to those predominantly CYP3A4-metabolized ( atorvastatin , lovastatin , simvastatin , and cerivastatin ) ( CYP3A4-MET ) or others ( pravastatin and fluvastatin ) ( non-CYP3A4-MET ) . Of the 2116 patients enrolled , 1001 received a CYP3A4-MET and 158 a non-CYP3A4-MET statin  . For the overall study population , the primary end point was significantly reduced in the clopidogrel group ( 8.5 % versus 11.5 % , RRR 26.9 % ; P = 0.025 ) . This clopidogrel benefit was similar with statin use , irrespective of treatment with a CYP3A4-MET ( 7.6 % clopidogrel , 11.8 % control , RRR 36.4 % , 95 % CI 3.9 to 57.9 ; P = 0.03 ) or non-CYP3A4-MET statin ( 5.4 % clopidogrel , 13.6 % control , RRR 60.6 % , 95 % CI −23.9 to 87.4 ; P = 0.11 ) . Patients given atorvastatin or pravastatin had similar 1-year event rates . Additionally , concomitant therapy with statins had no impact on major or minor bleeding rates . Conclusions —Although ex vivo testing has suggested a potential negative interaction when coadministering a CYP3A4-metabolized statin with clopidogrel , this was not clinical ly observed statistically in a post hoc analysis of a placebo-controlled study BACKGROUND Despite current treatments , patients who have acute coronary syndromes without ST-segment elevation have high rates of major vascular events . We evaluated the efficacy and safety of the antiplatelet agent clopidogrel when given with aspirin in such patients . METHODS We r and omly assigned 12,562 patients who had presented within 24 hours after the onset of symptoms to receive clopidogrel ( 300 mg immediately , followed by 75 mg once daily ) ( 6259 patients ) or placebo ( 6303 patients ) in addition  to aspirin for 3 to 12 months . RESULTS The first primary outcome --a composite of death from cardiovascular causes , nonfatal myocardial infa rct ion , or stroke -- occurred in 9.3 percent of the patients in the clopidogrel group and 11.4 percent of the patients in the placebo group ( relative risk with clopidogrel as compared with placebo , 0.80 ; 95 percent confidence interval , 0.72 to 0.90 ; P<0.001 ) . The second primary outcome --the first primary outcome or refractory ischemia -- occurred in 16.5 percent of the patients in the clopidogrel group and 18.8 percent of the patients in the placebo group ( relative risk , 0.86 ; 95 percent confidence interval , 0.79 to 0.94 ; P<0.001 ) . The percentages of patients with in-hospital refractory or severe ischemia , heart failure , and revascularization procedures were also significantly lower with clopidogrel . There were significantly more patients with major bleeding in the clopidogrel group than in the placebo group ( 3.7 percent vs. 2.7 percent ; relative risk , 1.38 ; P=0.001 ) , but there were not significantly more patients with episodes of life-threatening bleeding ( 2.2 percent [ corrected ] vs. 1.8 percent ; P=0.13 ) or hemorrhagic strokes ( 0.1 percent vs. 0.1 percent ) . CONCLUSIONS The antiplatelet agent clopidogrel has beneficial effects in patients with acute coronary syndromes without ST-segment elevation . However , the risk of major bleeding is increased among patients treated with clopidogrel Background —We observed that the prodrug clopidogrel was less effective in inhibiting platelet aggregation with coadministration of atorvastatin during point-of-care platelet function testing . Because atorvastatin is metabolized by cytochrome P450 ( CYP ) 3A4 , we hypothesized that clopidogrel might be activated by CYP3A4 . Methods and Results —Platelet aggregation was measured in 44 patients undergoing coronary artery stent implantation treated with clopidogrel or clopidogrel plus pravastatin or atorvastatin , and in 27 volunteers treated with clopidogrel and either erythromycin or trole and omycin , CYP3A4 inhibitors , or rifampin , a CYP3A4 inducer . Atorvastatin , but not pravastatin , attenuated the antiplatelet activity of clopidogrel in a dose-dependent manner . Percent platelet aggregation was 34±23 , 58±15 ( P = 0.027 ) , 74±10 ( P = 0.002 ) , and 89±7 ( P = 0.001 ) in the presence of clopidogrel and 0 , 10 , 20 , and 40 mg of atorvastatin , respectively . Erythromycin  attenuated platelet aggregation inhibition ( 55±12 versus 42±12 % platelet aggregation;P = 0.002 ) , as did trole and omycin ( 78±18 versus 45±18 % platelet aggregation;P < 0.0003 ) , whereas rifampin enhanced platelet aggregation inhibition ( 33±18 versus 56±20 % platelet aggregation , P = 0.001 ) . Conclusions —CYP3A4 activates clopidogrel . Atorvastatin , another CYP3A4 substrate , competitively inhibits this activation . Use of a statin not metabolized by CYP3A4 and point-of-care platelet function testing may be warranted in patients treated with clopidogrel 
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They report no evidence for a specific drug interaction and find that PPIs were associated with an increased risk for adverse cardiovascular outcomes independent of clopidogrel use .
In other words , the adverse effects attributed to this suspected drug interaction are not only 4- to 9-fold larger than clopidogrel 's benefits , as established by RCT data , but also occur in an etiologically implausible time window during which clopidogrel has not been shown to be therapeutically active .
The previous efficacy evidence suggests that the adverse events attributed to concomitant administration of clopidogrel and PPIs are more likely related to residual confounding from unmeasured adverse prognostic variables among patients who receive PPIs .
An abstract publication from a post hoc analysis of the CREDO ( Clopidogrel for the Reduction of Events During Observation ) study ( 2 ) has also reported an increased risk for adverse events with PPIs , independent of clopidogrel exposure .
Although PPIs have been inappropriately prescribed , with a lack of objective benefit , in young patients with dyspepsia , previous works from the same Danish data base ( 13 ) and other data bases ( 14 ) have clearly demonstrated that elderly patients with ACS who receive combination antiplatelet regimens  have a 4- to 5-fold increase in their risk for serious gastrointestinal bleeding , which can be reduced with PPIs ( 15 , 16 ) .
Many studies ( 17 , 18 ) have also suggested that periprocedural bleeding during percutaneous coronary intervention , including gastrointestinal bleeding , is associated with increased long-term mortality .