Time-based measures of treatment effect: reassessment of ticagrelor and clopidogrel from the PLATO trial

Abstract

Objective: Treatment effects to binary endpoints using time-to-event data in randomised controlled trials are typically summarised by reporting HRs derived with Cox proportional hazard models. Alternative and complementary methods include summarising the between-treatment differences on the metric time scale, quantifying the effect as delay of the event (DoE). The aim of this study was to reassess data from the PLATO study expressing the effects as the time by which the main outcomes are delayed or hastened due to treatment.

Methods: PLATO was a randomised controlled double-blind multicentre study (n=18,624), conducted between 2006 and 2008, which demonstrated superiority of the antiplatelet treatment ticagrelor over clopidogrel in reducing risk of several cardiovascular events. In the present study, four of the main PLATO outcomes were reassessed by calculating the time by which an event may be delayed due to the treatment.

Results: The effects of ticagrelor, as compared with clopidogrel, consisted of a substantial delay of the evaluated outcomes, ranging from 83 to 98 days over 400-day follow-up. The Delay of Events Curves showed that the effects progressively increased over time, and the significant findings were concordant with those presented in the original PLATO study.

Conclusions: This study confirmed evidence of a beneficial effect of ticagrelor over clopidogrel, and provided the magnitude of such effects in terms of delayed event time. Investigating time-to-event data with a percentile approach allows presenting treatment effects from randomised controlled studies as absolute measures of the time by which an event may be delayed due to the treatment.

Trial registration number: PLATO (www.clinicaltrials.gov; NCT00391872); Results.

Keywords: acute coronary syndrome; anticoagulation; clinical trials.

Conflict of interest statement

Competing interests: ABE: None. L Wallentin: institutional research grants, consultancy fees, lecture fees, and travel support from Bristol-Myers Squibb/Pfizer, AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim; institutional research grants from Merck & Co, Roche; consultancy fees from Abbott; holds two patents involving GDF-15. NO: None. S James: institutional research grant, honoraria and consultant/advisory board fee fromAstraZeneca; institutional research grant and consultant/advisory board fee from Medtronic; institutional research grants and honoraria from The Medicines Company; consultant/advisory board fees from Janssen, Bayer. CPC: research grants from AstraZeneca, Takeda, GlaxoSmithKline, BoerhingerIngelheim, Merck, Arisaph, Janssen, Accumetrics; consultant fees from GlaxoSmithKline, Takeda, Merck, Bristol-Myers Squibb, Alnylam, Pfizer, Essentialis, Kowa, Lipimedix, Regeneron, Sanofi, Boerhinger Ingelheim; travel support from AstraZeneca, BoerhingerIngelheim; personal fees from CSL Behring. A H: employee of AstraZeneca. JS: None. H Renlund: institutional research grant from AstraZeneca. PL: None.

Figures

Figure 1

Cumulative incidence in clopidogrel and ticagrelor groups, and Delay of eEvents associated with ticagrelor use for death from vascular causes/MI or stroke (A), MI (B), death from vascular causes, MI, stroke (C), death from any cause, MI or stroke (D), total major bleeding (E) and non-CABG major bleeding (F). CABG, coronary-artery bypass grafting; MI, myocardial infarction; TIA, transient ischaemic attack; CV, cardiovascular; SRI, serious recurrent ischaemia; RI, recurrent ischaemia.

Figure 2

Cumulative incidence in clopidogrel and ticagrelor groups, and Delay of eEvents associated with ticagrelor use for death from vascular causes/myocardial infarction or stroke.