Effect of Proton Pump Inhibitor Use on Risk of CV Events in Patients Treated with Rivaroxaban and a Thienopyridine

Previous studies have shown that the use of proton pump inhibitors (PPIs) such as omeprazole and esomeprazole can reduce the pharmacodynamic effects of the oral, thienopyridine-class antiplatelet agent clopidogrel.

In the ATLAS ACS 2-TIMI 52 study, investigators looked at the effect of low-dose rivaroxaban on the risk of cardiovascular (CV) events in patients with acute coronary syndrome (ACS) “regardless of background use of clopidogrel,” reporting that treatment with rivaroxaban reduced the risk of CV events. They also examined whether rivaroxaban efficacy was impacted by the use of PPIs in patients also on clopidogrel.

Michelle L. O’Donoghue, MD, and colleagues from Brigham and Women’s Hospital presented results from a related study, ATLAS ACS 2-TIMI 51, during a poster session at the 2013 American Heart Association Scientific Sessions. For this study, 15,258 patients with ACS were randomized to receive aspirin plus twice-daily oral rivaroxaban 2.5 mg, twice-daily oral rivaroxaban 5 mg, or placebo. Average treatment duration was 13 months.

For the current study, researchers looked at data from the cohort of patients who also intended to take a thienopyridine (omeprazole or esomeprazole). They wrote that patients were “considered to be on a PPI if they reported use of omeprazole or esomeprazole at the baseline visit.”

A total of 2,203 patients (15.2%) were being treated with omeprazole or esomeprazole at baseline.

The study authors reported that treatment with rivaroxaban (combined data for both doses) reduced the risk of CV death, myocardial infarction, or stroke in patients regardless of whether they were also taking a PPI at baseline [HR 0.68 (95% CI 0.50-0.93); HR 0.86 (95% CI 0.75-0.99), respectively; P for interaction=0.18].

Risk reduction for CV death, myocardial infarction, or stroke persisted at 30-day follow-up for patients regardless of PPI status at baseline [HR 0.94 (95% CI 0.51-1.76) for patients on PPI; HR 0.69 (95% CI 0.51-0.91) for patients not taking PPI; P for interaction=0.37].

Twice-daily oral rivaroxaban 2.5 mg reduced long-term risk of CV death (HR 0.68, 95% CI 0.52-0.90) and all-cause death (HR 0.67, 95% CI 0.52-0.87) in patients who were not taking a PPI at baseline but were taking a thienopyridine. The researchers reported “no heterogeneity for patients who were or were not on a PPI in regards to the risk of long-term bleeding events on rivaroxaban.”

For all three treatment arms (twice-daily oral rivaroxaban 2.5 mg, twice-daily oral rivaroxaban 5 mg, or placebo), PPI use was not associated with increased risk of CV events in patients on a thienopyridine.

These results led the authors to conclude that treatment with rivaroxaban reduced the risk of long-term CV events in patients with ACS on a thienopyridine regardless of PPI use. They also reported that PPI use “did not appear to attenuate the clinical efficacy of clopidogrel.”