Fast track — ArticlesPharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: an analysis of two randomised trials
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
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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)
- et al.
A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related to active metabolite formation
Am Heart J
(2007) - et al.
Influence of omeprazol on the antiplatelet action of clopidogrel associated to aspirin
J Thromb Haemost
(2006) - et al.
Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomized, double-blind OCLA (Omeprazole CLopidogrel Aspirin) study
J Am Coll Cardiol
(2008) - et al.
Evaluation of prasugrel compared with clopidogrel in patients with acute coronary syndromes: design and rationale for the TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet InhibitioN with prasugrel Thrombolysis In Myocardial Infarction 38 (TRITON-TIMI 38)
Am Heart J
(2006) - et al.
Comparison of inhibitory effects of the proton pump-inhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450 activities
Drug Metab Dispos
(2004) - et al.
Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study
Lancet
(2009) - et al.
Relation of cytochrome P450 2C19 loss-of-function polymorphism to occurrence of drug-eluting coronary stent thrombosis
Am J Cardiol
(2009) - et al.
Comparison of clinical benefits of clopidogrel therapy in patients with acute coronary syndromes taking atorvastatin versus other statin therapies
Am J Cardiol
(2003) - et al.
Prasugrel achieves greater inhibition of platelet aggregation and a lower rate of non-responders compared with clopidogrel in aspirin-treated patients with stable coronary artery disease
Eur Heart J
(2006) - et al.
Prasugrel compared with high loading- and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention: the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 trial
Circulation
(2007)
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
Impact of proton pump inhibitors on the antiplatelet effects of clopidogrel
Thromb Haemost
A population-based study of the drug interaction between proton pump inhibitors and clopidogrel
CMAJ
Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome
JAMA
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