Conflicting Results Between Randomized Trials and Observational Studies on the Impact of Proton Pump Inhibitors on Cardiovascular Events When Coadministered With Dual Antiplatelet Therapy

Abstract

Background: Discordant results have been reported on the effects of concomitant use of proton pump inhibitors (PPIs) and dual antiplatelet therapy (DAPT) for cardiovascular outcomes. We conducted a systematic review comparing the effectiveness and safety of concomitant use of PPIs and DAPT in the postdischarge treatment of unstable angina/non-ST segment elevation myocardial infarction (UA/NSTEMI) patients. Methods and Results: We searched for clinical studies in MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews, from 1995–2012. Reviewers screened and extracted data, assessed applicability and quality, and graded the strength of evidence. We performed meta-analyses of direct comparisons when outcomes and follow-up periods were comparable. Thirty-five studies were eligible. Five (4 RCTs, 1 observational) assessed the effect of omeprazole when added to DAPT; the other 30 (observational) assessed the effect of PPIs as a class compared with no PPIs. Random-effects meta-analyses of the studies assessing PPIs as a class consistently reported higher event rates in patients receiving PPIs for various clinical outcomes at 1 year (composite ischemic endpoints, all-cause mortality, nonfatal MI, stroke, revascularization, and stent thrombosis). However, the results from RCTs evaluating omeprazole compared with placebo showed no difference in ischemic outcomes, despite a reduction in upper gastrointestinal bleeding with omeprazole. Conclusions: Large, well-conducted observational studies of PPIs and RCTs of omeprazole seem to provide conflicting results for the effect of PPIs on cardiovascular outcomes when coadministered with DAPT. Prospective trials that directly compare pharmacodynamic parameters and clinical events among specific PPI agents in UA/NSTEMI patients treated with DAPT are warranted.

Proton Pump Inhibitors in cancer patients: How useful they are? A review of the most common indications for their use

“…Some pharmacologic studies led the FDA in 2009 to warn against combining Clopidogrel and PPIs. Conflicting clinical data have been published (Ho et al, 2009;Juurlink et al, 2009): one meta-analysis of 31 observational studies found that patients using PPIs with Clopidogrel have about a 30% increased risk of cardiovascular events compared with nonusers of PPIs, although the four randomized trials assessing Omeprazole or Esomeprazole did not confirm the increased risk (Melloni et al, 2015).…”

Prescription of Proton Pump Inhibitors in Elderly Subjects in Real Life: A Retrospective Study in a Gastroenterology Department

“…As far as the inhibition of the CYP 2C19 by the PPI is reversible and considering the short half-life of the PPI, some authors suggested minimizing the clinical consequences of this interaction by prescribing the PPI in the morning and the clopidogrel in the evening with an interval of 12 hours by separating both the takings [55]. However, the published randomized forward-looking studies did not find this interaction and confirmed the beneficial effects of the PPI on the digestive bleedings [31,56,57,58]. In 2012, these data allowed Afssaps (become ANSM: National agency of Safety of the Medicine) to remove, the PPI-clopidogrel interaction from the thesaurus of the medicinal interactions [59].…”

Should Proton Pump Inhibitors Be Withheld From Patients Taking Clopidogrel?

“…Finally, closely examine the event curves in the randomized trials included in the analysis by Melloni et al 1 These trials do not simply fail to confirm that a negative interaction might exist. The virtually superimposable strongly curves would seem to strongly refute that a clinically significant interaction exists at all.…”

“…How can it be, then, that certain PPIs (and statins and calcium channel blockers) inhibit the ex vivo inhibition of aggregation (they do), and reduce the level of clopidogrel's active metabolite (they do), but do not reduce the efficacy of clopidogrel? 1,2,7 The answer is not entirely clear. Possible explanations include that the reduction in inhibition of aggregation (and levels of active metabolite) are too small to be clinically significant and that perhaps the relationship between ex vivo aggregability (and metabolite levels) and risk of thrombosis is curvilinear rather than linear.…”

“…It is timely, therefore, that a talented group of investigators from Duke would study the quality of the evidence supporting the existence of a clinically relevant interaction between PPIs and clopidogrel, reported in this issue of Circulation: Cardiovascular Quality and Outcomes. 1 Briefly, the investigators found that all randomized trials (they included 4 in their analysis) examining the issue suggest that no clinically detectable interaction exists, but that most of the 36 observational studies they analyzed suggest that an interaction does exist that patients on clopidogrel and a PPI have more thrombotic events that those taking clopidogrel without a PPI. The authors conclude that unmeasured confounders in the observational studies are the likely explanation of the discordant findings between randomized control trials and observational studies, and call for more studies examining the issue.…”