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Can Thienopyridines and Proton-Pump Inhibitors Peacefully Coexist?

An observational analysis of trial data confirms the functional interaction but provides no evidence of adverse clinical effects.

In response to conflicting results of recent studies (JW Cardiol Mar 3 2009), regulatory agencies have issued warnings about the possible risks of combining a thienopyridine with a proton-pump inhibitor (PPI), leaving many clinicians perplexed about how best to treat patients who are at risk for both thrombotic events and gastrointestinal bleeding. To assess whether PPI use might influence measures of platelet function and clinical outcomes in patients treated with clopidogrel or prasugrel, these investigators conducted a retrospective analysis of data from two randomized trials.

In PRINCIPLE-TIMI 44, a double-blind, two-phase crossover study, 201 patients scheduled to undergo percutaneous coronary intervention were randomized to receive either prasugrel or clopidogrel. Twenty-six percent were taking a PPI at randomization. PPI use was associated with a lower mean inhibition of platelet aggregation, both in patients assigned to clopidogrel (P=0.06) and in those assigned to prasugrel (P=0.01). Prasugrel resulted in more-potent platelet inhibition than clopidogrel; thus, fewer prasugrel than clopidogrel recipients met the prespecified definition of hyporesponsiveness.

TRITON-TIMI 38 was a double-blind trial in which 13,608 patients undergoing PCI for acute coronary syndromes were randomized to receive prasugrel or clopidogrel. One third were taking a PPI at randomization. Incidence of the primary endpoint — the composite of MI, stroke, or death from cardiovascular causes — did not differ significantly between PPI recipients and nonrecipients. Use of a PPI was not associated with an increased risk for MI or stent thrombosis or with a decreased risk for bleeding. The lack of association did not vary by PPI type. Results restricted to patients with a single reduced-function CYP2C19 allele were consistent with the overall findings.

Comment: This issue is bound to remain contentious: Some physicians will find the clinical results of TRITON-TIMI 38 reassuring, but others will find the clear differences in platelet inhibition demonstrated in PRINCIPLE-TIMI 44 more persuasive. Wide confidence intervals make it difficult to exclude the possibility of clinically important differences in adverse events. As the controversy continues, it seems sensible for clinicians to avoid this combination unless no other reasonable choice is available.

— Harlan M. Krumholz, MD, SM

Published in Journal Watch Cardiology September 1, 2009

Citation(s):

O'Donoghue ML et al. Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: An analysis of two randomised trials. Lancet 2009 Sep 1; [e-pub ahead of print]. (http://dx.doi.org/10.1016/S0140-6736(09)61525-7)