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Pantoprazole Does Not Reduce the Antiplatelet Effect of Clopidogrel: A Randomized Controlled Trial in Korea.

ABSTRACT: Concerns that proton pump inhibitors (PPIs) diminish the efficacy of clopidogrel could hamper the appropriate prescription of PPIs. We evaluated the influence of pantoprazole on the antiplatelet effect of clopidogrel compared with ranitidine, which is regarded as safe, after stratification of the population according to the presence of a cytochrome (CYP) 2C19 polymorphism in Korea.Forty patients who underwent dual antiplatelet therapy were randomized to receive pantoprazole (n=20) or ranitidine (n=20). Platelet aggregation was evaluated by impedance aggregometry at baseline (D0) and 8 days after acid-lowering treatments (D9). CYP2C19 was genotyped by polymerase chain reaction-restriction fragment length polymorphism.After co-treatment, the percentage of clopidogrel low-response was 11.1% (2/18) in the pantoprazole group and 10.5% (2/19) in the ranitidine group (p=0.954). The impedance values with adenosine diphosphate stimulus after acid-lowering treatments did not significantly differ between the two groups. In a multiple regression analysis, only ST-elevation myocardial infarction was marginally associated with a reduced antiplatelet effect (odds ratio, 12.07; 95% confidence interval, 0.84 to 173.78). However, pantoprazole use did not affect the antiplatelet effect after correction for the CYP2C19 polymorphism.This study showed that pantoprazole does not increase platelet aggregation in patients receiving dual antiplatelet therapy (ClinicalTrials.gov number: NCT02733640).

SUBMITTER: Choi YJ

PROVIDER: S-EPMC5491085 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Pantoprazole Does Not Reduce the Antiplatelet Effect of Clopidogrel: A Randomized Controlled Trial in Korea.

Choi Yoon Jin YJ Kim Nayoung N Jang In-Jin IJ Cho Joo-Youn JY Nam Ryoung Hee RH Park Ji Hyun JH Jo Hyun Jin HJ Yoon Hyuk H Shin Cheol Min CM Park Young Soo YS Lee Dong Ho DH Jung Hyun Chae HC

Gut and liver 20170701 4

<h4>Background/aims</h4>Concerns that proton pump inhibitors (PPIs) diminish the efficacy of clopidogrel could hamper the appropriate prescription of PPIs. We evaluated the influence of pantoprazole on the antiplatelet effect of clopidogrel compared with ranitidine, which is regarded as safe, after stratification of the population according to the presence of a cytochrome (CYP) 2C19 polymorphism in Korea.<h4>Methods</h4>Forty patients who underwent dual antiplatelet therapy were randomized to re ...[more]

PMID: 28395507

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Project description:The arteriovenous fistula is the preferred type of vascular access for hemodialysis because of lower thrombosis and infection rates and lower health care expenditures compared with synthetic grafts or central venous catheters. Early failure of fistulas due to thrombosis or inadequate maturation is a barrier to increasing the prevalence of fistulas among patients treated with hemodialysis. Small, inconclusive trials have suggested that antiplatelet agents may reduce thrombosis of new fistulas.To determine whether clopidogrel reduces early failure of hemodialysis fistulas.Randomized, double-blind, placebo-controlled trial conducted at 9 US centers composed of academic and community nephrology practices in 2003-2007. Eight hundred seventy-seven participants with end-stage renal disease or advanced chronic kidney disease were followed up until 150 to 180 days after fistula creation or 30 days after initiation of dialysis, whichever occurred later.Participants were randomly assigned to receive clopidogrel (300-mg loading dose followed by daily dose of 75 mg; n = 441) or placebo (n = 436) for 6 weeks starting within 1 day after fistula creation.The primary outcome was fistula thrombosis, determined by physical examination at 6 weeks. The secondary outcome was failure of the fistula to become suitable for dialysis. Suitability was defined as use of the fistula at a dialysis machine blood pump rate of 300 mL/min or more during 8 of 12 dialysis sessions.Enrollment was stopped after 877 participants were randomized based on a stopping rule for intervention efficacy. Fistula thrombosis occurred in 53 (12.2%) participants assigned to clopidogrel compared with 84 (19.5%) participants assigned to placebo (relative risk, 0.63; 95% confidence interval, 0.46-0.97; P = .018). Failure to attain suitability for dialysis did not differ between the clopidogrel and placebo groups (61.8% vs 59.5%, respectively; relative risk, 1.05; 95% confidence interval, 0.94-1.17; P = .40).Clopidogrel reduces the frequency of early thrombosis of new arteriovenous fistulas but does not increase the proportion of fistulas that become suitable for dialysis. Trial Registration clinicaltrials.gov Identifier: NCT00067119.

Project description:ImportanceVery short mandatory dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) with a drug-eluting stent may be an attractive option.ObjectiveTo test the hypothesis of noninferiority of 1 month of DAPT compared with standard 12 months of DAPT for a composite end point of cardiovascular and bleeding events.Design, setting, and participantsMulticenter, open-label, randomized clinical trial enrolling 3045 patients who underwent PCI at 90 hospitals in Japan from December 2015 through December 2017. Final 1-year clinical follow-up was completed in January 2019.InterventionsPatients were randomized either to 1 month of DAPT followed by clopidogrel monotherapy (n=1523) or to 12 months of DAPT with aspirin and clopidogrel (n=1522).Main outcomes and measuresThe primary end point was a composite of cardiovascular death, myocardial infarction (MI), ischemic or hemorrhagic stroke, definite stent thrombosis, or major or minor bleeding at 12 months, with a relative noninferiority margin of 50%. The major secondary cardiovascular end point was a composite of cardiovascular death, MI, ischemic or hemorrhagic stroke, or definite stent thrombosis and the major secondary bleeding end point was major or minor bleeding.ResultsAmong 3045 patients randomized, 36 withdrew consent; of 3009 remaining, 2974 (99%) completed the trial. One-month DAPT was both noninferior and superior to 12-month DAPT for the primary end point, occurring in 2.36% with 1-month DAPT and 3.70% with 12-month DAPT (absolute difference, -1.34% [95% CI, -2.57% to -0.11%]; hazard ratio [HR], 0.64 [95% CI, 0.42-0.98]), meeting criteria for noninferiority (P < .001) and for superiority (P = .04). The major secondary cardiovascular end point occurred in 1.96% with 1-month DAPT and 2.51% with 12-month DAPT (absolute difference, -0.55% [95% CI, -1.62% to 0.52%]; HR, 0.79 [95% CI, 0.49-1.29]), meeting criteria for noninferiority (P = .005) but not for superiority (P = .34). The major secondary bleeding end point occurred in 0.41% with 1-month DAPT and 1.54% with 12-month DAPT (absolute difference, -1.13% [95% CI, -1.84% to -0.42%]; HR, 0.26 [95% CI, 0.11-0.64]; P = .004 for superiority).Conclusions and relevanceAmong patients undergoing PCI, 1 month of DAPT followed by clopidogrel monotherapy, compared with 12 months of DAPT with aspirin and clopidogrel, resulted in a significantly lower rate of a composite of cardiovascular and bleeding events, meeting criteria for both noninferiority and superiority. These findings suggest that a shorter duration of DAPT may provide benefit, although given study limitations, additional research is needed in other populations.Trial registrationClinicalTrials.gov Identifier: NCT02619760.

Project description:BACKGROUND:Frequent sickness absence-that is, 3 or more episodes of sickness absence in 1 year-is a problem for employers and employees. Many employees who have had frequent sickness absence in a prior year also have frequent sickness absence in subsequent years: 39% in the first follow-up year and 61% within 4 years. Moreover, 19% have long-term sickness absence (≥6 weeks) in the first follow-up year and 50% within 4 years. We developed an electronic health (eHealth) intervention, consisting of fully automated feedback and advice, to use either as a stand-alone tool (eHealth intervention-only) or combined with consultation with an occupational physician (eHealth intervention-occupational physician). OBJECTIVE:This study aimed to evaluate the effect of the eHealth intervention, with or without additional occupational physician consultation, to reduce sickness absence frequency for employees with frequent sickness absence, versus care as usual (CAU). METHODS:This study was a three-armed randomized controlled trial. Employees with frequent sickness absence received invitational letters, which were distributed by their employers. The primary outcome measure was the number of register-based sickness absence episodes 12 months after completing the baseline questionnaire. Secondary outcome measures were register-based total sickness absence days and self-assessed burnout, engagement, and work ability. In a process evaluation 3 months after baseline, we examined adherence to the intervention and additional actions such as general practitioner and occupational physician visit, communication with the manager, and lifestyle change. RESULTS:A total of 82 participants were included in the analyses, 21 in the eHealth intervention-only group, 31 in the eHealth intervention-occupational physician group, and 30 in the CAU group. We found no significant difference in sickness absence frequency between the groups at 1-year follow-up. Sickness absence frequency decreased in the eHealth intervention-only group from 3 (interquartile range, IQR 3-4) to 1 episode (IQR 0.3-2.8), in the eHealth intervention-occupational physician group from 4 (IQR 3-5) to 3 episodes (IQR 1-4), and in the CAU group from 3 (IQR 3-4) to 2 episodes (IQR 1-3). For secondary outcomes, we found no significant differences between the intervention groups and the control group. The process evaluation showed that only 3 participants from the eHealth intervention-occupational physician group visited the occupational physician on invitation. CONCLUSIONS:Among employees with frequent sickness absence, we found no effect from the eHealth intervention as a stand-alone tool in reducing sickness absence frequency, nor on total sickness absence days, burnout, engagement, or work ability. This might be due to low adherence to the intervention because of insufficient urgency to act. We cannot draw any conclusion on the effect of the eHealth intervention tool combined with an occupational physician consultation (eHealth intervention-occupational physician), due to very low adherence to the occupational physician consultation. An occupational physician consultation could increase a sense of urgency and lead to more focus and appropriate support. As this was the first effectiveness study among employees with frequent sickness absence, strategies to improve recruitment and adherence in occupational eHealth are included. TRIAL REGISTRATION:Netherlands Trial Register NTR4316; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=4316 (Archived by WebCite at http://www.webcitation.org/713DHhOFU).

Project description:Background and purposeThe conversion of clopidogrel to its active metabolite, R-130964, is a two-step cytochrome P450 (CYP)-dependent process. The current investigations were performed to characterize in vitro the effects of different CYP inhibitors on the biotransformation and on the antiplatelet effect of clopidogrel.Experimental approachClopidogrel biotransformation was studied using human liver microsomes (HLM) or specific CYPs and platelet aggregation using human platelets activated with ADP.Key resultsExperiments using HLM or specific CYPs (3A4, 2C19) revealed that at clopidogrel concentrations >10 microM, CYP3A4 was primarily responsible for clopidogrel biotransformation. At a clopidogrel concentration of 40 microM, ketoconazole showed the strongest inhibitory effect on clopidogrel biotransformation and clopidogrel-associated inhibition of platelet aggregation with IC(50) values of 0.03 +/- 0.07 microM and 0.55 +/- 0.06 microM respectively. Clarithromycin, another CYP3A4 inhibitor, impaired clopidogrel biotransformation and antiplatelet activity almost as effectively as ketoconazole. The CYP3A4 substrates atorvastatin and simvastatin both inhibited clopidogrel biotransformation and antiplatelet activity, less potently than ketoconazole. In contrast, pravastatin showed no inhibitory effect. As clopidogrel itself inhibited CYP2C19 at concentrations >10 microM, the CYP2C19 inhibitor lansozprazole affected clopidogrel biotransformation only at clopidogrel concentrations < or =10 microM. The carboxylate metabolite of clopidogrel was not a CYP substrate and did not affect platelet aggregation.Conclusions and implicationsAt clopidogrel concentrations >10 microM, CYP3A4 is mainly responsible for clopidogrel biotransformation, whereas CYP2C19 contributes only at clopidogrel concentrations < or =10 microM. CYP2C19 inhibition by clopidogrel at concentrations >10 microM may explain the conflicting results between in vitro and in vivo investigations regarding drug interactions with clopidogrel.

Dataset Information

Pantoprazole Does Not Reduce the Antiplatelet Effect of Clopidogrel: A Randomized Controlled Trial in Korea.

Publications

Pantoprazole Does Not Reduce the Antiplatelet Effect of Clopidogrel: A Randomized Controlled Trial in Korea.

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