Cerebrovascular Outcomes With Proton Pump Inhibitors and Thienopyridines: A Systematic Review and Meta-Analysis

Stroke. 2018 Feb;49(2):312-318. doi: 10.1161/STROKEAHA.117.019166. Epub 2018 Jan 16.

Abstract

Background and purpose: Pharmacokinetic and prior studies on thienopyridine and proton pump inhibitors (PPI) coadministration provide conflicting data for cardiovascular outcomes, whereas there is no established evidence on the association of concomitant use of PPI and thienopyridines with adverse cerebrovascular outcomes.

Methods: We conducted a systematic review and meta-analysis of randomized controlled trials and cohort studies from inception to July 2017, reporting following outcomes among patients treated with thienopyridine and PPI versus thienopyridine alone (1) ischemic stroke, (2) combined ischemic or hemorrhagic stroke, (3) composite outcome of stroke, myocardial infarction (MI), and cardiovascular death, (4) MI, (5) all-cause mortality, and (6) major or minor bleeding events. After the unadjusted analyses of risk ratios, we performed additional analyses of studies reporting hazard ratios adjusted for potential confounders.

Results: We identified 22 studies (12 randomized controlled trials and 10 cohort studies) comprising 131 714 patients. Concomitant use of PPI with thienopyridines was associated with increased risk of ischemic stroke (risk ratio, 1.74; 95% confidence interval [CI], 1.41-2.16; P<0.001), composite stroke/MI/cardiovascular death (risk ratio, 1.14; 95% CI, 1.01-1.29; P=0.04), and MI (risk ratio, 1.19; 95% CI, 1.00-1.40; P=0.05). Likewise, in adjusted analyses concomitant use of PPI with thienopyridines was again associated with increased risk of stroke (hazard ratios adjusted, 1.30; 95% CI, 1.04-1.61; P=0.02), composite stroke/MI/cardiovascular death (hazard ratios adjusted, 1.23; 95% CI, 1.03-1.47; P=0.02), but not with MI (hazard ratios adjusted, 1.19; 95% CI, 0.93-1.52; P=0.16).

Conclusions: Co-prescription of PPI and thienopyridines increases the risk of incident ischemic strokes and composite stroke/MI/cardiovascular death. Our findings corroborate the current guidelines for PPI deprescription and pharmacovigilance, especially in patients treated with thienopyridines.

Keywords: ischemic stroke; myocardial infarction; pharmacovigilance; proton pump inhibitors; thienopyridines.

Publication types

  • Meta-Analysis
  • Review
  • Systematic Review

MeSH terms

  • Brain Ischemia / drug therapy*
  • Drug Therapy, Combination / methods
  • Humans
  • Platelet Aggregation Inhibitors / therapeutic use*
  • Proton Pump Inhibitors / therapeutic use*
  • Stroke / drug therapy*
  • Thienopyridines / therapeutic use*

Substances

  • Platelet Aggregation Inhibitors
  • Proton Pump Inhibitors
  • Thienopyridines