Bleeding risk in patients prescribed dual antiplatelet therapy and triple therapy after coronary interventions: the ADAPTT retrospective population-based cohort studies

Jessica Harris, Koen B Pouwels, Thomas Johnson, Jonathan Sterne, Christalla Pithara, Kalaivani Mahadevan, Barney Reeves, Umberto Benedetto, Yoon Loke, Daniel Lasserson, Brett Doble, Noreen Hopewell-Kelly, Sabi Redwood, Sarah Wordsworth, Andrew Mumford, Chris Rogers, Maria Pufulete*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

Abstract

BACKGROUND: Bleeding among populations undergoing percutaneous coronary intervention or coronary artery bypass grafting and among conservatively managed patients with acute coronary syndrome exposed to different dual antiplatelet therapy and triple therapy (i.e. dual antiplatelet therapy plus an anticoagulant) has not been previously quantified.

OBJECTIVES: The objectives were to estimate hazard ratios for bleeding for different antiplatelet and triple therapy regimens, estimate resources and the associated costs of treating bleeding events, and to extend existing economic models of the cost-effectiveness of dual antiplatelet therapy.

DESIGN: The study was designed as three retrospective population-based cohort studies emulating target randomised controlled trials.

SETTING: The study was set in primary and secondary care in England from 2010 to 2017.

PARTICIPANTS: Participants were patients aged ≥ 18 years undergoing coronary artery bypass grafting or emergency percutaneous coronary intervention (for acute coronary syndrome), or conservatively managed patients with acute coronary syndrome.

DATA SOURCES: Data were sourced from linked Clinical Practice Research Datalink and Hospital Episode Statistics.

INTERVENTIONS: Coronary artery bypass grafting and conservatively managed acute coronary syndrome: aspirin (reference) compared with aspirin and clopidogrel. Percutaneous coronary intervention: aspirin and clopidogrel (reference) compared with aspirin and prasugrel (ST elevation myocardial infarction only) or aspirin and ticagrelor.

MAIN OUTCOME MEASURES: Primary outcome: any bleeding events up to 12 months after the index event. Secondary outcomes: major or minor bleeding, all-cause and cardiovascular mortality, mortality from bleeding, myocardial infarction, stroke, additional coronary intervention and major adverse cardiovascular events.

RESULTS: The incidence of any bleeding was 5% among coronary artery bypass graft patients, 10% among conservatively managed acute coronary syndrome patients and 9% among emergency percutaneous coronary intervention patients, compared with 18% among patients prescribed triple therapy. Among coronary artery bypass grafting and conservatively managed acute coronary syndrome patients, dual antiplatelet therapy, compared with aspirin, increased the hazards of any bleeding (coronary artery bypass grafting: hazard ratio 1.43, 95% confidence interval 1.21 to 1.69; conservatively-managed acute coronary syndrome: hazard ratio 1.72, 95% confidence interval 1.15 to 2.57) and major adverse cardiovascular events (coronary artery bypass grafting: hazard ratio 2.06, 95% confidence interval 1.23 to 3.46; conservatively-managed acute coronary syndrome: hazard ratio 1.57, 95% confidence interval 1.38 to 1.78). Among emergency percutaneous coronary intervention patients, dual antiplatelet therapy with ticagrelor, compared with dual antiplatelet therapy with clopidogrel, increased the hazard of any bleeding (hazard ratio 1.47, 95% confidence interval 1.19 to 1.82), but did not reduce the incidence of major adverse cardiovascular events (hazard ratio 1.06, 95% confidence interval 0.89 to 1.27). Among ST elevation myocardial infarction percutaneous coronary intervention patients, dual antiplatelet therapy with prasugrel, compared with dual antiplatelet therapy with clopidogrel, increased the hazard of any bleeding (hazard ratio 1.48, 95% confidence interval 1.02 to 2.12), but did not reduce the incidence of major adverse cardiovascular events (hazard ratio 1.10, 95% confidence interval 0.80 to 1.51). Health-care costs in the first year did not differ between dual antiplatelet therapy with clopidogrel and aspirin monotherapy among either coronary artery bypass grafting patients (mean difference £94, 95% confidence interval -£155 to £763) or conservatively managed acute coronary syndrome patients (mean difference £610, 95% confidence interval -£626 to £1516), but among emergency percutaneous coronary intervention patients were higher for those receiving dual antiplatelet therapy with ticagrelor than for those receiving dual antiplatelet therapy with clopidogrel, although for only patients on concurrent proton pump inhibitors (mean difference £1145, 95% confidence interval £269 to £2195).

CONCLUSIONS: This study suggests that more potent dual antiplatelet therapy may increase the risk of bleeding without reducing the incidence of major adverse cardiovascular events. These results should be carefully considered by clinicians and decision-makers alongside randomised controlled trial evidence when making recommendations about dual antiplatelet therapy.

LIMITATIONS: The estimates for bleeding and major adverse cardiovascular events may be biased from unmeasured confounding and the exclusion of an eligible subgroup of patients who could not be assigned an intervention. Because of these limitations, a formal cost-effectiveness analysis could not be conducted.

FUTURE WORK: Future work should explore the feasibility of using other UK data sets of routinely collected data, less susceptible to bias, to estimate the benefit and harm of antiplatelet interventions.

TRIAL REGISTRATION: This trial is registered as ISRCTN76607611.

FUNDING: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 8. See the NIHR Journals Library website for further project information.

Original languageEnglish
Pages (from-to)1-257
Number of pages257
JournalHealth Technology Assessment
Volume27
Issue number8
DOIs
Publication statusPublished - 1 May 2023

Bibliographical note

Funding Information:
The research reported in this issue of the journal was funded by the HTA programme as project number 14/192/89. The contractual start date was in April 2016. The draft report began editorial review in July 2020 and was accepted for publicaD鸀on in July 2021. The authors have been wholly responsible for all data collecD鸀on, analysis and interpretaD鸀on, and for wriD鸀ng up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the reviewers for their construcD鸀ve comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.

Funding Information:
This report presents independent research funded by the NaD鸀onal InsD鸀tute for Health and Care Research (NIHR). The views and opinions expressed by authors in this publicaD鸀on are those of the authors and do not necessarily reflect those of the NHS, the NIHR, the HTA programme or the Department of Health and Social Care. If there are verbaD鸀m quotaD鸀ons included in this publicaD鸀on the views and opinions expressed by the interviewees are those of the interviewees and do not necessarily reflect those of the authors, those of the NHS, the NIHR, the HTA programme or the Department of Health and Social Care.

Funding Information:
This project was funded by the NaD鸀onal InsD鸀tute for Health Research (NIHR) Health Technology Assessment programme. The BriD鸀sh Heart FoundaD鸀on and the NIHR Biomedical Research Centre at University Hospitals Bristol and Weston NHS FoundaD鸀on Trust and the University of Bristol funded some staff D鸀me (MP, JH, BR and TJ). This study is based on data from the CPRD obtained under licence from the UK Medicines and Healthcare products Regulatory Agency and data from NHS Digital. The funders had no role in the design and conduct of the study; collecD鸀on, management, analysis and interpretaD鸀on of the data; or preparaD鸀on, review or approval of the manuscript for submission.

Publisher Copyright:
© 2023 Harris et al.

Keywords

  • Humans
  • Acute Coronary Syndrome/drug therapy
  • Aspirin/adverse effects
  • Clopidogrel/therapeutic use
  • Platelet Aggregation Inhibitors/adverse effects
  • Prasugrel Hydrochloride
  • Retrospective Studies
  • ST Elevation Myocardial Infarction
  • Ticagrelor
  • Cohort Studies

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