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TRITON-TIMI 38 Trial results: The risk of cardiovascular event for patients treated with clopidogrel or prasugrel in combination with a Proton Pump Inhibitor

Clinical Trial Update II

Acute Coronary Syndromes (ACS)



Presenter | see Discussant report

Michelle O'Donoghue  (United States of America)

Presentation webcast

Presentation slides

List of Authors:

Michelle L. O’Donoghue, Stephen D. Wiviott , Elliott M. Antman, Sabina A. Murphy, Charles F. Contant, Eric R. Bates, Yoseph Rozenman, Carolyn H. McCabe, Jessica L. Mega, Marc S. Sabatine, Eugene Braunwald

Background:
Prasugrel significantly reduces cardiovascular events as compared with clopidogrel in patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI), but with an increased risk of bleeding. Proton pump inhibitors (PPI) are often prescribed to patients in combination with thienopyridines to help reduce the risk of gastrointestinal bleeding. Some data suggest that many PPIs may reduce the antiplatelet effects of clopidogrel by inhibiting CYP2C19 and thus the conversion of clopidogrel to its active metabolite. The clinical implications of co-administration of a PPI with either clopidogrel or prasugrel remain undefined.

Methods:
The TRITON-TIMI 38 trial randomized 13,608 subjects with ACS and planned PCI to prasugrel or clopidogrel, in addition to standard therapy. The primary endpoint of the trial was cardiovascular death, MI or stroke. The decision to treat with a proton pump inhibitor was left to the discretion of the treating physician and was captured on the case-report forms. A multivariable Cox proportional hazards model was used to evaluate the association between use of a PPI at randomization and the risk of long-term clinical outcomes. The multivariable model included potential confounders and a propensity score constructed with 15 variables associated with use of a PPI. Further sensitivity analyses were performed to evaluate the association between use of a PPI at different timepoints during follow-up, different types of PPIs, and the risk of short- or long-term cardiovascular events.

Results:
Of the 13,608 subjects enrolled in TRITON-TIMI 38, 33% of subjects were being treated with a PPI at randomization. For patients randomized to clopidogrel, the rate of the primary endpoint through long-term follow-up was 11.8% in subjects on a PPI and 12.2% in subjects not on a PPI (HR 0.98, 95% CI 0.84-1.14, P=0.80). For patients randomized to prasugrel, the rate of the primary endpoint was 10.2% in subjects on a PPI and 9.7% in subjects not on a PPI (HR 1.05, 95% CI 0.89-1.23, P=0.58). After adjusting for known confounders and the propensity to treat with a PPI, there remained no significant association between the use of a PPI and the risk of the primary endpoint, both for patients treated with clopidogrel (adjusted HR 0.94, 95% CI 0.80-1.11) or for those treated with prasugrel (adjusted HR 1.00, 95% CI 0.84-1.20). Similarly, the use of a PPI was not associated with an increased risk of MI, stent thrombosis, or urgent revascularization, or a decreased risk of bleeding, for patients treated with either clopidogrel or prasugrel (Table). Sensitivity analyses demonstrated consistency of the results based on use of PPI at different timepoints during follow-up, different types of PPIs, and varying durations of follow-up.

Conclusion:
In a large population of subjects treated with clopidogrel or prasugrel, the use of a PPI was not associated with an increased risk of cardiovascular events.

Clopidogrel (n=6795)Prasugrel (n=6813)Treated with a PPI(n=2257)Not treated with a PPI(n=4538)Adjusted HR (95% CI)Treated with a PPI(n=2272)Not treated with a PPI(n=4541)Adjusted HR(95% CI)CV death, MI or stroke 11.8%12.2%0.94(0.80-1.11)10.2%9.7%01.00(0.84-1.20)

Myocardial infarction9.5%9.8%0.98(0.82-1.17)7.7%7.3%1.02(0.84-1.25)Stent thrombosis (ARC definite or probable)2.4%2.3%1.08(0.75-1.55)1.1%1.1%1.03(0.60-1.76)TIMI major bleeding2.4%1.6%1.20(0.80-1.79)2.5%2.4%0.97(0.67-1.39)Net clinical outcome(death, MI, stroke or TIMI major non-CABG bleeding)13.9%13.8%0.96(0.83-1.12)12.6%12.1%0.99(0.85-1.17)


Discussant | see Presenter abstract

Kurt Huber, FESC (Austria)

Report:

Background:
In this interesting study the authors investigated by retrospective analysis of patients of the TRITON TIMI-38 trial whether the use of proton pump inhibitors (PPI) negatively influences clinical outcome compared with non-use. Controversial data of clinical outcome from other authors as well as studies, which demonstrated a reduced action of clopidogrel on in vitro testing of platelet function when PPIs, especially omeprazole, were used, were the background of the investigation. Of special interest was the opportunity to test the potential influence of PPIs on prasugrel, a new thienopyridine, which showed favorable effects over clopidgrel in the TRITON TIMI-38 trial.

Methods and Statistics:
The TRITON-TIMI 38 trial randomized 13,608 subjects with ACS and planned PCI to prasugrel or clopidogrel, in addition to standard therapy, of which 4,538 (20%) were being treated with a PPI at randomization. Use of a PPI was at the discretion of the treating physician and not randomized. A multivariable Cox proportional hazards model, which included potential confounders and a propensity score constructed with 15 variables associated with use of a PPI, was used to evaluate the association between use of a PPI at randomization and the risk of long-term clinical outcomes.

Results:
After adjusting for known confounders and the propensity to treat with a PPI, there remained no significant association between the use of a PPI and the risk of the primary endpoint, either for patients treated with clopidogrel (adjusted HR 0.94, 95% CI 0.78-1.13) or for those treated with prasugrel (adjusted HR 0.94, 95% CI 0.77-1.16).

Comments: 
Contrary to several other investigations with higher patient numbers, in this population of subjects treated with clopidogrel or prasugrel, the use of a PPI was not associated with an increased risk of cardiovascular events. What are the differences between TRITON TIMI-38 and other investigations, which make the results more reliable for clinical practice? Based on the fact that patients were not randomized to receive or not to receive a PPI in all studies published so far, different inclusion bias might have triggered the different clinical outcomes. In addition, the current data come from a prospective randomized trial with a well-defined study population. This might be different to the study populations of other trials and registries including patients with higher age and more co-morbidities - which is frequently the reason for using PPIs - and therefore at higher risk for clinical events. Differences in outcome might also be explained by different statistical approaches. Also the consistent use of PPIs during dual antiplatelet therapy might have impacted on clinical outcome. It would be interesting to know whether the authors have performed in vitro platelet function testing and whether the test results are related with the clinical outcome. Unfortunately, also the TRITON TIMI-38 substudy on the impact of use or non-use of PPIs on clinical outcome in clopidogrel or prasugrel-treated patients does not fully answer the still open questions. Only a prospective randomized trial of PPI use will be capable of establishing the safety of PPIs in combination with thienopyridines.

References


2694-2695

SessionTitle:

The risk of cardiovascular event for patients treated with clopidogrel or prasugrel in combination with a Proton Pump Inhibitor: Results from the TRITON-TIMI 38 Trial

Notes to editor


This congress report accompanies a presentation given at the ESC Congress 2009. Written by the author himself/herself, this report does not necessarily reflect the opinion of the European Society of Cardiology.

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.