Elsevier

The Lancet

Volume 374, Issue 9694, 19–25 September 2009, Pages 989-997
The Lancet

Fast track — Articles
Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: an analysis of two randomised trials

https://doi.org/10.1016/S0140-6736(09)61525-7Get rights and content

Summary

Background

Proton-pump inhibitors (PPIs) are often prescribed in combination with thienopyridines. Conflicting data exist as to whether PPIs diminish the efficacy of clopidogrel. We assessed the association between PPI use, measures of platelet function, and clinical outcomes for patients treated with clopidogrel or prasugrel.

Methods

In the PRINCIPLE-TIMI 44 trial, the primary outcome was inhibition of platelet aggregation at 6 h assessed by light-transmission aggregometry. In the TRITON-TIMI 38 trial, the primary endpoint was the composite of cardiovascular death, myocardial infarction, or stroke. In both studies, PPI use was at physician's discretion. We used a multivariable Cox model with propensity score to assess the association of PPI use with clinical outcomes.

Findings

In the PRINCIPLE-TIMI 44 trial, 201 patients undergoing elective percutaneous coronary intervention were randomly assigned to prasugrel (n=102) or high-dose clopidogrel (n=99). Mean inhibition of platelet aggregation was significantly lower for patients on a PPI than for those not on a PPI at 6 h after a 600 mg clopidogrel loading dose (23·2±19·5% vs 35·2±20·9%, p=0·02), whereas a more modest difference was seen with and without a PPI after a 60 mg loading dose of prasugrel (69·6±13·5% vs 76·7±12·4%, p=0·054). In the TRITON-TIMI 38 trial, 13 608 patients with an acute coronary syndrome were randomly assigned to prasugrel (n=6813) or clopidogrel (n=6795). In this study, 33% (n=4529) of patients were on a PPI at randomisation. No association existed between PPI use and risk of the primary endpoint for patients treated with clopidogrel (adjusted hazard ratio [HR] 0·94, 95% CI 0·80–1·11) or prasugrel (1·00, 0·84–1·20).

Interpretation

The current findings do not support the need to avoid concomitant use of PPIs, when clinically indicated, in patients receiving clopidogrel or prasugrel.

Funding

Daiichi Sankyo Company Limited and Eli Lilly and Company sponsored the trials. This analysis had no funding.

Introduction

Both clopidogrel and prasugrel are prodrugs that are metabolised by the cytochrome P450 enzyme system to form their active metabolites. Prasugrel achieves greater and more consistent platelet inhibition than standard doses or higher doses of clopidogrel.1, 2, 3 This difference might partly be caused by a more efficient conversion of prasugrel into its active metabolite.2

Proton-pump inhibitors (PPIs) are often administered in combination with thienopyridines to help reduce the risk of gastrointestinal bleeding, a strategy that is endorsed by existing consensus guidelines.4 However, several studies have raised concerns that many PPIs, especially omeprazole, might diminish the antiplatelet effects5, 6, 7 and the clinical effectiveness8, 9, 10 of clopidogrel, possibly through inhibition of the hepatic cytochrome P450 2C19 (CYP2C19) isoenzyme and, therefore, the conversion of clopidogrel into its active metabolite. By contrast, a preliminary report of data from another trial did not find an association between use of a PPI in combination with clopidogrel and an increased risk of adverse outcomes.11

With these conflicting results, the clinical implications of co-administration of a PPI and clopidogrel remain unclear. Whether concomitant use of a PPI attenuates the pharmacodynamic effect or clinical efficacy of prasugrel is also unknown. Therefore, we assessed the association between the use of a PPI, measures of platelet function, and clinical outcomes for patients treated with either clopidogrel or prasugrel in the PRINCIPLE (Prasugrel In Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation)-TIMI 44 and TRITON (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel)-TIMI 38 trials.3, 12

Section snippets

Patients

The PRINCIPLE-TIMI 44 trial was a double-blind, two-phase crossover study that randomly assigned 201 individuals undergoing cardiac catheterisation with planned percutaneous coronary intervention to prasugrel (n=102; 60 mg loading dose, 10 mg a day maintenance dose) or to high-dose clopidogrel (n=99; 600 mg loading dose, 150 mg a day maintenance dose).3 Inhibition of platelet aggregation with 20 μM ADP by light-transmission aggregometry was to be recorded in all patients at 30 min (±5), 2 h

Results

Of the 201 patients enrolled in the PRINCIPLE-TIMI 44 trial, 53 (26·4%) were recorded to be taking a PPI at the time of randomisation. Baseline platelet aggregation was similar for patients who were or were not on a PPI before administration of study drug in either randomised treatment arm. Table 1 shows baseline characteristics of patients who were or were not treated with a PPI and stratified by treatment arm.

For patients randomly assigned to a 600 mg loading dose of clopidogrel (n=99), the

Discussion

In a large population of patients with an acute coronary syndrome undergoing percutaneous coronary intervention, the use of a PPI was not independently associated with increased risk of adverse clinical outcomes for patients treated with either clopidogrel or the novel thienopyridine prasugrel. Our findings contrast with data from some observational studies that reported an increased risk of adverse events in patients treated with a PPI in combination with clopidogrel.8, 9, 10 However, we

References (28)

  • DL Bhatt et al.

    ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents

    Circulation

    (2008)
  • D Sibbing et al.

    Impact of proton pump inhibitors on the antiplatelet effects of clopidogrel

    Thromb Haemost

    (2009)
  • DN Juurlink et al.

    A population-based study of the drug interaction between proton pump inhibitors and clopidogrel

    CMAJ

    (2009)
  • PM Ho et al.

    Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome

    JAMA

    (2009)
  • Cited by (714)

    View all citing articles on Scopus
    View full text