Ticagrelor of prasugrel versus clopidogrel bij oudere
patiënten met een acuut coronair syndroom (pijn op de
borst en hartinfarct) en een hoog bloedingsrisico:
Optimaliseren van bloedplaatjes remming bij ouderen
met verhoogd bloedingsrisico

Rationale: Dual antiplatelet therapy is crucial in patients with an acute coronary syndrome (ACS) to prevent atherothrombotic events. The recent guideline of the European Society of Cardiology (ESC) recommends the use of more potent antiplatelet drugs i.e. ticagrelor or prasugrel, which give more bleeding complications, compared to clopidogrel (1). The “Commissie Farmaceutische Hulp” (CFH) concluded that ticagrelor is superior to clopidogrel, mainly because of a mortality reduction observed in the PLATO study (2). However, the representation of the elderly in clinical trials is low. In a subgroup analysis of patients 75 years of age and older, the difference between cardiovascular event rates in ticagrelor versus clopidogrel treated patients, did not reach statistical significance (3). There is a major gap in the knowledge regarding the optimal strategy for the elderly, who have an increased risk of both atherothrombotic and bleeding complications. The ESC guideline advises on the use of the CRUSADE bleeding risk score for risk stratification. However, based on the currently available data it is not clear which antiplatelet treatment should be initiated in those patients with a high bleeding risk, who often also appear to have the highest atherothrombotic risk.

Objective: To assess the safety, efficacy and net clinical benefit of clopidogrel versus the new antiplatelet drugs i.e. ticagrelor and prasugrel, in elderly with a high bleeding risk.

Study design: Randomized, controlled, open label, multicenter study.

Study population: 1,000 patients hospitalized for either myocardial infarction without ST-segment elevation (NSTEMI) or unstable angina (UA), aged at least 75 years and with a score of at least 31 based on the CRUSADE bleeding risk score.
Intervention: Patients randomized to clopidogrel will receive 75 mg daily for one year. Those randomized to the new antiplatelet drugs will be treated with either ticagrelor 90 mg twice daily or prasugrel 5 mg daily, according to hospital’s local standards. The follow-up duration will be one year.

Main study parameters/endpoints: Any bleeding episode classified according to different bleeding scores, see section 7.1.3. and net clinical benefit defined as composite endpoint of death, non-fatal myocardial infarction, non-fatal stroke, PLATO major life threatening (without fatal bleeding), major and minor bleedings. Efficacy in terms of the combined endpoint of death, myocardial infarction, stroke, stent thrombosis. Quality of life assed by the EuroQol 5D and SF36 questionnaires.

Sample size calculation/data analysis: Assuming an alpha of 0.05, beta 0.2 and the combined end point of non-CABG related PLATO major and minor bleedings of 10% in the clopidogrel group versus 17% in the new antiplatelet drugs group, a lost-to-follow-up rate of 10%, the inclusion of 1,000 patients (500 per group) would be sufficient. Intention-to-treat principle will be used in data analysis. Kaplan-Meier analysis will be used and groups will be compared by hazard ratios and 95% confidence intervals.
Nature and extent of the burden and risks associated with participation, benefit and group relatedness: The burden for patients participating in the study is that patients will be contacted twice during the study; 3 months and 12 months after initial diagnosis to fill out a questionnaire, to get information regarding the use of antiplatelet drugs, changes in prescribed drugs and medical condition. At 3 months and 12 months patients will also be requested to fill out EuroQol 5D and SF36 questionnaires to asses quality of life. The patient may be contacted by telephone if this is necessary to complete follow-up data

Since bleeding risk is high in the elderly we hypothesize that clopidogrel is superior to ticagrelor and prasugrel in terms of causing lesser bleeding events and being non inferior in net clinical benefit in patients above 75 years and CRUSADE score ≥ 31 with acuut coronary syndrome.

3 and 12 months after enrollment

clopidogrel versus ticagrelor/prasugrel in patients aged at least 75 year with CRUSADE score of at least 31. At 3 months and 12 months patients will also be requested to fill out questionnaires to asses endpoints of the study. Follow up will be 12 months.