Basic And Clinical Researchs On The Risk Of Adverse Outcomes Associated With Concomitant Use Of Clopidogrel And Omeprazole

Background and Objective At present, omeprazole is often prescribed prophylactically with initiation of clopidogrel, with the goal of reducing the risk of gastrointestinal tract bleeding while taking dual-antiplatelet therapy. Recent mechanistic studies, however, suggest that omeprazole may reduce the inhibitory effect of clopidogrel on platelet aggregation. In addition, variations in platelet reactivity have been associated with adverse outcomes following stent implantation. To date, there remains significantly ongoing controversy regarding the clinical outcomes of patients taking clopidogrel and omeprazole. To investigate long-term prognosis for patients with acute coronary syndromes (ACS) associated with concomitant use of clopidogrel and omeprazole, we attempted to retrospectively evaluate the long-term efficacy and safety of concomitant use of clopidogrel and omeprazole. Morcover, in order to provide experimental evidence for clinical application of combination therapy regimen, we analyzed the effects of clopidogrel on platelet function in patients with ACS undergoing successful coronary stenting.Methods (1) From January 2005 to December 2007, a total of 930 hospitalized patients with ACS taking dual-antiplatelet therapy were enrolled in the First Affiliated Hospital of Soochow University and the Nanjing First Hospital of Nanjing Medical University. They were assigned to case (concomitant use of clopidogrel and omeprazole) and control (taking clopidogrel without omeprazole) group. The follow-up period for all patients was 24 months. It was retrospectively analyzed and compared between them in clinical data (baseline clinical characteristics, drug treament data, angiographic and procedural characteristics), primary end points (all-cause mortality, myocardial infarction) and second end points (cardiac death, nonfatal myocardial infarction, target vessel revascularization, stent thrombosis,the major adverse cardiac events) within 1 and 2 years. The statistical methods were used to compare the clinical prognosis and assess relative risks of adverse events in all patients. Finally, Cox's proportional-hazards models were used to identify independent predictors of adverse events after percutaneous coronary intervention (PCI) with stent implantation at 1 and 2 years.(2) 50 in-hospital patients with ACS undergoing successful coronary stenting were randomized to receive either concomitant use of clopidogrel and omeprazole (cases, 38 patients) or use of clopidogrel without omeprazole (controls, 12 patients) from November of 2009 to February of 2010. ADP-induced maximum platelet aggregation ratio and ADP-induced platelet aggregation inhibitor were measured before taking clopidogrel plus omeprazole and after PCI for 72 hours by optical aggregometry.Results (1) Retrospective clinical study: The baseline clinical, angiographic and procedural characteristics were comparable for the two groups. There are not significant differ in clinical basic characteristics between cases and controls, except that age, LEVF, LDL, stents implanted per patient, overall length of stents in individual patients (P>0.05). At 1 year, compared with control group, the stent thrombosis were signifieantly inreased ( 1.4% vs 0.2%, P=0.019) in cases. At 2 year, compared with control group, the nonfatal myocardial infarction had signifieantly inreased (2.6% vs 0.9%, P=0.034) in cases. However, there are not signifieantly statistical differ in death, myocardial infarction, revascularization and the composite end point between cases and controls (P>0.05).(2) Prospective platelet function trial: The baseline clinical characteristics did not differ significantly between the two groups. There were no significant differs in the baseline level or 72h value after PCI of the maximum platelet aggregation rate (MPAR) between the two groups. The margin between the twice measurements were [(32.4±20.8)% vs (36.2±16.0)%, P>0.05] for△MPAR and platelet aggregation inhibition (IPA) were [(59.1±32.5%) vs (70.1±22.0%), (P>0.05)] in cases and controls, respectively. There are not significant differ in△MPAR or IPA between cases and controls at the 72 hours after stenting. Conclusion Compared with the patients of control group, concomitant use of clopidogrel and omeprazole for patients with ACS following stent implantation has been shown to significantly increase the incidence of stent thrombosis at 1 year and nonfatal MI at 2 year. Experimental evidence had shown that omeprazole reduced the inhibitory effect of clopidogrel on platelet aggregation, and raise the trend of the increasion of clopidogrel resistance, but there was no significant differ (P>0.05). So, large scale, randomized, controled clinical trials are needed to confirm the efficacy and safety of the combination therapy regimen, and further basic study are also needed to illuminate the effects of combination therapy regimen on platelet function.