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Cardiac risk factors and prevention
Original research article
Time-based measures of treatment effect: reassessment of ticagrelor and clopidogrel from the PLATO trial
  1. Andrea Bellavia1,
  2. Lars Wallentin2,3,
  3. Nicola Orsini4,
  4. Stefan K James2,3,
  5. Christopher P Cannon5,6,
  6. Anders Himmelmann7,
  7. Johan Sundström2,3,
  8. Henrik Renlund3 and
  9. Per Lytsy8
  1. 1 Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
  2. 2 Department of Medical Sciences, Cardiology, Uppsala University, Uppsala, Sweden
  3. 3 Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden
  4. 4 Department of Public Health Science, Karolinska Institutet, Stockholm, Sweden
  5. 5 Division of Cardiovascular, Brigham and Women’s Hospital, Boston, Massachusetts, USA
  6. 6 HarvardClinical Research Institute, Boston, Massachusetts, USA
  7. 7 AstraZeneca Research and Development, Gothenburg, Sweden
  8. 8 Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden
  1. Correspondence to Dr Andrea Bellavia; abellavi{at}hsph.harvard.edu

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.

  • anticoagulation
  • clinical trials
  • acute coronary syndrome

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

https://doi.org/10.1136/openhrt-2016-000557

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    Footnotes

    • Contributors LW, SKJ, CPC and AH designed the PLATO trial. AB, NO, JS and PL developed the aims and the analysis of this study. HR performed statistical analysis and produced tables and figures. AB and PL drafted the manuscript. All authors critically interpreted the results and reviewed the manuscript, giving their final consent to the final version.

    • Funding The PLATO study was funded by AstraZeneca. Support for the analysis and interpretation of results and preparation of the manuscript was provided through funds to the Uppsala Clinical Research Center and Duke Clinical Research Institute as part of the Clinical Study Agreement.

    • 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.

    • Provenance and peer review Not commissioned; internally peer reviewed

    • Data sharing statement Data from this study are unavailable. Further information can be obtained by contacting the PLATO committe at Uppsala University." This information can be included where most appropriate.