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11th September 2009
This analysis of two studies found that, although PPIs attenuated the in-vitro antiplatelet effects of clopidogrel and prasugrel▼, the combination was not associated with an increased risk of adverse clinical outcomes (CV death, MI or stroke). These findings were consistent regardless of which PPI was used, or whether an H2RA was used.
Level of evidence:
Level 2 evidence according to the SORT criteria.
Action
These data provide reassurance for patients for whom the combination of clopidogrel and a proton pump inhibitor (PPI) is considered necessary. However, until further, higher quality evidence is available, it would still seem sensible to follow MHRA advice and review patients taking the combination. Healthcare professionals should consider stopping either the clopidogrel, if it is being used outside NICE guidance (see below) or beyond the recommended period, or stopping the PPI, or stopping both, unless considered essential. If the original reason for using clopidogrel was due to gastrointestinal (GI) intolerance on aspirin alone, switching to aspirin plus a PPI would seem a reasonable approach. For patients who need to continue taking clopidogrel and also require gastroprotection, there is currently insufficient evidence to recommend H2-receptor antagonists (H2RAs) or other GI therapies as alternatives to PPIs.
What is the background to this?
Clopidogrel can cause GI symptoms and is associated with an increased risk of GI bleeding. It is, therefore, frequently prescribed with a PPI. Both the EMEA and the FDA recently released statements warning of a potential interaction between PPIs and clopidogrel and discouraging their combined use in the absence of a strong indication. The EMEA’s Committee for Medicinal products for Human Use (CHMP) concluded, mainly on the basis of observational studies, that a significant interaction might occur when clopidogrel and a PPI are taken together. The consequence of this is that, while some protection against cardiovascular (CV) thrombotic events (e.g. myocardial infarction [MI]) is provided by the combination of clopidogrel plus a PPI, it appears that this may be slightly less than that provided when clopidogrel is taken without a PPI.
Existing studies have conflicting results and the clinical implications of co-administering a PPI and clopidogrel are still unclear. Neither the EMEA statement nor recently updated information from the US FDA makes reference to any individual PPI being any more or less likely to interact with clopidogrel than any other. The outcome studies do not consistently show the expected effects based on the known pharmacokinetics of PPIs so there may be more than one explanation for this apparent effect on clopidogrel. More evidence is required before any specific recommendations can be made on the risk associated with individual PPIs. Although, on the basis of pharmacokinetic data, H2RAs (except cimetidine) and antacids would not be expected to interact with clopidogrel, there are currently no substantial data from outcome studies to support this.
This study 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-TIMI 44 and TRITON-TIMI 38 trials.
The PRINCIPLE-TIMI 44 trial randomly assigned 201 individuals undergoing cardiac catheterisation with planned percutaneous coronary intervention to prasugrel or high-dose clopidogrel. Inhibition of platelet aggregation at six hours was the primary outcome. The TRITON-TIMI 38 study included 13,608 patients with acute coronary syndrome undergoing planned percutaneous coronary intervention who were randomly assigned to prasugrel or clopidogrel. The primary endpoint was a composite of CV death, non-fatal MI, or non-fatal stroke.
What does this study claim?
In the TRITON-TIMI 38 trial, 33.3% of patients (n=4,529) were recorded to be taking a PPI at randomisation. There was no significant association between PPI use and risk of CV death, MI, or stroke for patients treated with clopidogrel (adjusted hazard ratio [HR] 0.94, 95% confidence interval [CI] 0.80 to 1.11) or prasugrel (HR 1.00, 95%CI 0.84 to 1.20 ). Consistent PPI use was not associated with an increased risk of the primary endpoint in patients treated with either clopidogrel (HR 1.05, 95%CI 0.85 to 1.30) or prasugrel (HR 1.10, 95%CI 0.88 to 1.39) compared with those who were never exposed to a PPI.
There was no independent association between the individual PPIs and the risk of MI or the composite of CV death, MI, or stroke for patients randomly assigned to clopidogrel or prasugrel. Use of an H2RA or PPI at baseline was not associated with an increased risk of the primary outcome in patients randomly assigned to clopidogrel (HR 0.80, 95%CI 0.51 to 1.26) or prasugrel (HR 0.91, 95%CI 0.55 to 1.51).
In the PRINCIPLE-TIMI 44 trial, 26.4% of patients (n=53) were recorded to be taking a PPI. Mean inhibition of platelet aggregation was statistically significantly lower for patients on a PPI than for those not on a PPI at two, six and 18–24 hours after administration of clopidogrel. A more modest difference was seen after administration of prasugrel, which was statistically significantly different after 30 minutes but not at other timepoints.
So what?
The in-vitro antiplatelet effects of high dose clopidogrel and prasugrel were reduced in patients taking PPIs, compared with those who were not taking a PPI. However, this is a surrogate marker and should not be used to guide treatment decisions in preference to clinical events data. After adjusting for potential confounders, PPIs were not associated with an increased risk of clinical patient-oriented outcomes; CV death, MI or stroke. Importantly, the study findings were consistent regardless of the individual PPI, or use of an H2RA. The authors suggest that a modest attenuation of the antiplatelet effects of clopidogrel or prasugrel might have been insufficient to translate into an increased risk of adverse outcomes.
This study has many limitations, which the authors themselves outline. Use of a PPI was not randomised in the two included studies; it was at the physician’s discretion. In addition PPIs could be initiated or discontinued throughout follow-up and TRITON-TIMI 38 was not designed to assess PPI use. Although the study did adjust for many confounding variables, it is possible that some have been missed, which would remain a potential source of bias. However, the analysis is based on randomised controlled trials, rather than observational studies. Therefore, endpoints were strictly defined and adjudicated.
This study is more helpful than existing observational studies, which are confounded by the fact that patients taking concomitant PPIs are generally older and have more comorbidities than those who are not on a PPI (see associated Comment). It concludes that, although a randomised controlled trial would provide higher quality evidence to establish the clinical implications of combining a PPI with clopidogrel or prasugrel, the results do not support the need to avoid the combination. Assuming both clopidogrel or prasugrel and a PPI are clinically indicated, patients with the characteristics of those included in the TRITON-TIMI 38 study can be reassured that they are unlikely to suffer adverse clinical outcomes. However, as the authors of the associated Comment point out, because of the trial exclusion criteria, participants in TRITON-TIMI 38 were younger and less likely to have diabetes mellitus or renal failure than those included in observational studies. Using the combination may require caution in higher-risk patients.
Until more higher quality evidence is available, it would seem sensible to follow- MHRA advice when possible:
- The need for PPI therapy in patients who are also taking clopidogrel should be reviewed at their next appointment: avoid concomitant use of these medicines unless considered essential
- Prescribe PPIs in line with their licensed indications, where possible
- Check whether patients who are taking clopidogrel are buying over-the-counter omeprazole and consider whether another gastrointestinal (GI) therapy would be more suitable. (This advice has been clarified in September Drug Safety Update).
Healthcare professionals should ensure that clopidogrel is being prescribed according to NICE guidance for only the recommended period. NICE guidance on the use of clopidogrel in non-ST elevation acute coronary syndrome (ACS) recommends clopidogrel, in combination with low-dose aspirin, in patients who have non-ST elevation ACS who are at moderate to high risk of MI or death. The guidance defines this group on the basis of clinical signs and symptoms with ECG changes and/or raised cardiac markers. NICE guidance on clopidogrel in the prevention of occlusive vascular events, which applies to patients who have had an occlusive vascular event or have symptomatic peripheral arterial disease, recommends clopidogrel alone only for those who are intolerant of low-dose aspirin. Aspirin intolerance is defined as proven hypersensitivity to aspirin-containing medicines or a history of severe dyspepsia induced by low-dose aspirin.
If the original reason for using clopidogrel was due to GI intolerance on aspirin alone, switching to aspirin plus a PPI would seem a reasonable approach. If the clopidogrel is still indicated, consideration should be given to stopping the PPI. For patients who need to continue taking clopidogrel and also require gastroprotection, there is currently insufficient evidence to recommend H2RAs or other GI therapies as alternatives to PPIs.
For more details see MeReC Stop Press Blog Nos. 271, 354 and 372. Further information on the use of clopidogrel is available on the cardiovascular section of NPC.
PRINCIPLE-TIMI 44 trial
Design: Double-blind two-phase crossover study.
Patients: 201 individuals undergoing cardiac catheterisation with planned percutaneous coronary intervention.
Intervention and comparison: Randomly assigned to prasugrel (n=102; 60mg loading dose, 10mg daily maintenance dose) or high-dose clopidogrel (n=99; 600mg loading dose, 150mg daily maintenance dose). 26.4% of patients (n=53) were recorded to be taking a PPI at randomisation.
Outcomes: The primary outcome was inhibition of platelet aggregation at six hours.
Results: Mean inhibition of platelet aggregation was statistically significantly lower for patients on a PPI than for those not on a PPI at six hours after a loading dose of clopidogrel (23.2 ± 19.5% vs 35.2 ± 20.9%, P=0·02). A non-significant difference was seen with and without a PPI after a loading dose of prasugrel (69.6 ± 13.5% vs 76.7 ± 12.4%, P=0.054).
TRITON-TIMI 38 trial
Design: Double-blind phase 3 trial.
Patients: 13,608 patients with acute coronary syndrome undergoing planned percutaneous coronary intervention. 33.3% (n=4,529) of patients were on a PPI at randomisation. Of these, 1,844 were taking pantoprazole, 1,675 omeprazole, 613 esomeprazole 441 lansoprazole and 66 rabeprazole. Relevant exclusions to participation in the trial included individuals with an increased risk of bleeding, a history of anaemia, thrombocytopenia, pathological intracranial findings, or the use of a thienopyridine within 5 days before randomisation.
Intervention and comparison: Randomly assigned to prasugrel (n=6,813; 60mg loading dose, 10mg daily maintenance dose) or clopidogrel (n=6,795; 300mg loading dose, 75mg daily maintenance dose).
Outcomes: The primary endpoint was a composite of CV death, non-fatal MI, or non-fatal stroke.
Results: There was no significant association between PPI use and risk of the primary endpoint for patients treated with clopidogrel (HR 0.94, 95%CI 0.80 to 1.11) or prasugrel (HR 1.00, 95%CI 0.84 to 1.20).
Because PPIs could be started or discontinued at any time during follow-up, the authors performed sensitivity analyses to look for consistency of the data based on PPI use at different time points and after varying durations of follow-up. They found that PPI use at the time of randomisation was not associated with an increased risk of CV death, MI or stroke during 3 days or 30 days of follow-up in patients treated with clopidogrel or prasugrel. In addition, consistent PPI use was not associated with an increased risk of the primary outcome in patients treated with either clopidogrel (HR 1.05, 95%CI 0.85 to 1.30) or prasugrel (HR 1.10, 95%CI 0.88 to 1.39) compared with those who were never exposed to a PPI.
Additional analyses assessed the effect of individual types of PPIs and other gastric antacid drugs, including H2RAs. Regardless of the type of PPI (including omeprazole alone or the exclusion of pantoprazole), no independent association existed between use of these drugs and the risk of MI or the composite of CV death, MI, or stroke for patients randomly assigned to clopidogrel or prasugrel. Use of an H2RA or PPI at baseline was not associated with risk of CV death, MI or stroke in patients randomly assigned to clopidogrel (HR 0.80, 95%CI 0.51 to 1.26) or prasugrel (HR 0.91, 95%CI 0.55 to 1.51).
Sponsorship: Eli Lilly & Co. and Daiichi Sankyo Co. Ltd. This analysis had no funding.
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