Clopidogrel and interaction with proton pump inhibitors: comparison between cohort and within person study designs

Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK.
BMJ (online) (Impact Factor: 16.38). 07/2012; 345:e4388. DOI: 10.1136/bmj.e4388
Source: PubMed

ABSTRACT To measure the association between use of proton pump inhibitors and a range of harmful outcomes in patients using clopidogrel and aspirin.
Observational cohort study and self controlled case series.
United Kingdom General Practice Research Database with linked data from the Myocardial Ischaemia National Audit Project (MINAP) and the Office for National Statistics (the cardiovascular disease research using linked bespoke studies and electronic records (CALIBER) collaboration)
24,471 patients receiving clopidogrel and aspirin.
The primary outcome was death or incident myocardial infarction. Secondary outcomes were death, incident myocardial infarction, vascular death, and non-vascular death. Comparisons were made between proton pump inhibitor use and non-use.
Of the 24,471 patients prescribed clopidogrel and aspirin, 12,439 (50%) were also prescribed a proton pump inhibitor at some time during the study. Death or incident myocardial infarction occurred in 1419 (11%) patients while they were receiving a proton pump inhibitor compared with 1341 (8%) who were not receiving a proton pump inhibitor. In multivariate analysis, the hazard ratio for the association between proton pump inhibitor use and death or incident myocardial infarction was 1.37 (95% confidence interval 1.27 to 1.48). Comparable results were seen for secondary outcomes and with other 2C19 inhibitors and with non-2C19 inhibitors. With the self controlled case series design to remove the effect of differences between people, there was no association between proton pump inhibitor use and myocardial infarction, with a rate ratio of 0.75 (0.55 to 1.01). Similarly, with the self controlled case series there was no association with myocardial infarction for other 2C19 inhibitors/non-inhibitors.
The lack of a specific association and the discrepancy between findings of the analyses between and within people suggests that the interaction between proton pump inhibitors and clopidogrel is clinically unimportant.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Patients often fail to stop clopidogrel appropriately before non-cardiac surgery. Thromboelastography platelet mapping (TEG-PM) can be used to measure the percentage adenosine 5′-diphosphate platelet receptor inhibition (ADP-PRI) by clopidogrel in these patients.Methods This prospective case–control study investigated the risk of bleeding in patients who had taken clopidogrel within 7 days of scheduled operation. Patients underwent TEG-PM to stratify their bleeding risk. Low-risk (ADP-PRI below 30 per cent) and urgent priority high-risk (ADP-PRI 30 per cent or more) patients proceeded to surgery. The outcomes of these patients were compared with those of matched controls. Regression analysis, with bootstrapping validation, was used to identify independent risk factors for bleeding and an optimal cut-off value of ADP-PRI for cancellation of surgery.ResultsFrom May 2008 to October 2013, 182 patients failed to discontinue clopidogrel. No correlation was observed between duration of clopidogrel omission and percentage ADP-PRI; 112 low-risk and 19 high-risk patients proceeded to surgery. High-risk patients had significantly greater intraoperative packed red blood cell (PRBC) transfusion in comparison with their matched controls, and a strong positive correlation between percentage ADP-PRI and units of intraoperative PRBCs transfused (r = 0·749, 95 per cent confidence interval (c.i.) 0·410 to 0·940; P < 0·001). Percentage ADP-PRI was the only independent risk factor for intraoperative PRBC transfusion (odds ratio 1·07, 95 per cent c.i. 1·02 to 1·13; P = 0·005).Conclusion An objective measure of platelet inhibition with TEG-PM, using an ADP-PRI cut-off of 34 per cent, can be used to prevent unnecessary cancellations, while minimizing patient risk.
    British Journal of Surgery 07/2014; 101(11). DOI:10.1002/bjs.9592 · 5.21 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Several studies have suggested that proton-pump inhibitors (PPIs), mostly omeprazole, interact with clopidogrel efficacy by inhibiting the formation of its active metabolite via CYP2C19 inhibition. Whether this occurs with all PPIs is a matter of debate. As rabeprazole is a less potent CYP2C19 inhibitor than other PPIs, we studied the interaction between rabeprazole and the antiplatelet actions and pharmacokinetics of clopidogrel. To demonstrate the non-inferiority of rabeprazole over placebo using change in platelet reactivity index (PRI; vasodilator-stimulated phosphoprotein [VASP] assay) in a predefined population of good clopidogrel responders. Omeprazole was used as the positive control. In this randomized three-period crossover study in healthy volunteers, 36 healthy men received clopidogrel (75mg/day for 7 days) with placebo, omeprazole (20mg/day) or rabeprazole (20mg/day). Clopidogrel antiplatelet effects and disposition kinetics were assessed on day 7 of combination therapy. Non-inferiority threshold was predefined as an upper limit of the 90% confidence interval for the difference in change in PRI between placebo and rabeprazole of<10% in good clopidogrel responders. In good clopidogrel responders (inhibition of VASP index>30%), the clopidogrel antiplatelet effect remained non-inferior to placebo during rabeprazole (difference 3.4% [-1.7; 8.5]) but not omeprazole (difference 7.5% [2.5; 12.6]) co-administration. The AUC0-24 and Cmax of active clopidogrel metabolite decreased with both omeprazole and rabeprazole, and conditions of bioequivalence were not met, except for AUC0-24 with rabeprazole. Rabeprazole does not interact with clopidogrel to the same extent as omeprazole. However, under our experimental conditions and proton-pump inhibitor doses, there was no significant pharmacodynamic interaction between rabeprazole or omeprazole and clopidogrel, despite a significant decrease in the formation of clopidogrel active metabolite.
    Archives of cardiovascular diseases 11/2013; 106(12). DOI:10.1016/j.acvd.2013.09.002 · 1.66 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The effect of proton pump inhibitors (PPIs) on the pharmacokinetics and pharmacodynamics of clopidogrel was assessed in two healthy volunteer crossover studies. Study 1: subjects received clopidogrel alone (300-mg loading dose, then 75 mg/day for 28 days) and two of three PPIs (omeprazole 80 mg, esomeprazole 40 mg or lansoprazole 60 mg) plus clopidogrel for 29 days in three treatment periods (randomized treatment sequence assignment). Study 2: subjects received clopidogrel alone (75 mg/day for 9 days) and clopidogrel alone for 4 days followed by clopidogrel plus fixed-combination esomeprazole 20 mg/low-dose acetylsalicylic acid (ASA) 81 mg for 5 days in two treatment periods (randomized treatment sequence assignment). Pharmacokinetic effects were estimated by measuring active metabolite of clopidogrel, and pharmacodynamic effects by inhibition of adenosine diphosphate (ADP)-induced platelet aggregation. There was a relative decrease of up to 50 % in exposure to the active metabolite of clopidogrel with the different PPIs (study 1), and close to 40 % with esomeprazole/low-dose ASA (study 2), compared with clopidogrel alone. There was an absolute decrease of up to 17 % in inhibition of ADP-induced platelet aggregation with co-administration of different PPIs, compared with clopidogrel alone; however, no differences in platelet inhibition were observed during co-administration with the esomeprazole/low-dose ASA fixed-dose combination. Omeprazole, esomeprazole and lansoprazole decreased systemic exposure to the active metabolite of clopidogrel in healthy volunteers, leading to modest decreases in its antiplatelet effect. However, no apparent differences in platelet inhibition were observed when esomeprazole was co-administered with low-dose ASA as a fixed-dose combination.
    American Journal of Cardiovascular Drugs 03/2014; 14(3). DOI:10.1007/s40256-014-0073-4 · 2.20 Impact Factor


Available from