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Association of Ticagrelor vs Clopidogrel With Net Adverse Clinical Events in Patients With Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention

Educational Objective
To understand differences in outcomes associated with the use of platelet inhibition drugs.
1 Credit CME
Key Points

Question  For patients with acute coronary syndrome (ACS) treated with percutaneous coronary intervention (PCI), is ticagrelor, compared with clopidogrel, associated with better outcomes in routine clinical practice?

Findings  In a retrospective cohort study that included 62 580 propensity score–matched patients, ticagrelor use, compared with clopidogrel, was not associated with statistically significant difference in the risk of net clinical adverse events (defined as recurrent myocardial infarction, revascularization, ischemic stroke, hemorrhagic stroke, and gastrointestinal bleeding) at 12 months (hazard ratio, 1.05).

Meaning  Ticagrelor, compared with clopidogrel, was not associated with better outcomes for patients with ACS treated with PCI in clinical practice.

Abstract

Importance  Current guidelines recommend ticagrelor as the preferred P2Y12 platelet inhibitor for patients with acute coronary syndrome (ACS), primarily based on a single large randomized clinical trial. The benefits and risks associated with ticagrelor vs clopidogrel in routine practice merits attention.

Objective  To determine the association of ticagrelor vs clopidogrel with ischemic and hemorrhagic events in patients undergoing percutaneous coronary intervention (PCI) for ACS in clinical practice.

Design, Setting, and Participants  A retrospective cohort study of patients with ACS who underwent PCI and received ticagrelor or clopidogrel was conducted using 2 United States electronic health record–based databases and 1 nationwide South Korean database from November 2011 to March 2019. Patients were matched using a large-scale propensity score algorithm, and the date of final follow-up was March 2019.

Exposures  Ticagrelor vs clopidogrel.

Main Outcomes and Measures  The primary end point was net adverse clinical events (NACE) at 12 months, composed of ischemic events (recurrent myocardial infarction, revascularization, or ischemic stroke) and hemorrhagic events (hemorrhagic stroke or gastrointestinal bleeding). Secondary outcomes included NACE or mortality, all-cause mortality, ischemic events, hemorrhagic events, individual components of the primary outcome, and dyspnea at 12 months. The database-level hazard ratios (HRs) were pooled to calculate summary HRs by random-effects meta-analysis.

Results  After propensity score matching among 31 290 propensity-matched pairs (median age group, 60-64 years; 29.3% women), 95.5% of patients took aspirin together with ticagrelor or clopidogrel. The 1-year risk of NACE was not significantly different between ticagrelor and clopidogrel (15.1% [3484/23 116 person-years] vs 14.6% [3290/22 587 person-years]; summary HR, 1.05 [95% CI, 1.00-1.10]; P = .06). There was also no significant difference in the risk of all-cause mortality (2.0% for ticagrelor vs 2.1% for clopidogrel; summary HR, 0.97 [95% CI, 0.81-1.16]; P = .74) or ischemic events (13.5% for ticagrelor vs 13.4% for clopidogrel; summary HR, 1.03 [95% CI, 0.98-1.08]; P = .32). The risks of hemorrhagic events (2.1% for ticagrelor vs 1.6% for clopidogrel; summary HR, 1.35 [95% CI, 1.13-1.61]; P = .001) and dyspnea (27.3% for ticagrelor vs 22.6% for clopidogrel; summary HR, 1.21 [95% CI, 1.17-1.26]; P < .001) were significantly higher in the ticagrelor group.

Conclusions and Relevance  Among patients with ACS who underwent PCI in routine clinical practice, ticagrelor, compared with clopidogrel, was not associated with significant difference in the risk of NACE at 12 months. Because the possibility of unmeasured confounders cannot be excluded, further research is needed to determine whether ticagrelor is more effective than clopidogrel in this setting.

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Article Information

Corresponding Author: Harlan M. Krumholz, MD, SM, Center for Outcomes Research and Evaluation (CORE), Yale New Haven Hospital, One Church St, Ste 200, New Haven, CT 06510 (harlan.krumholz@yale.edu).

Accepted for Publication: August 10, 2020.

Author Contributions: Dr You had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs You and Rho contributed equally. Drs Rae Woong Park and Krumholz are cosenior authors.

Concept and design: You, Rho, Bikdeli, Weaver, Londhe, Schuemie, Suchard, Madigan, Hripcsak, Ryan, R. W. Park, Krumholz.

Acquisition, analysis, or interpretation of data: You, Rho, Bikdeli, Kim, Siapos, Weaver, Londhe, Cho, J. Park, Schuemie, Suchard, Hripcsak, Gupta, Reich, Ryan, R. W. Park, Krumholz.

Drafting of the manuscript: You, Cho, J. Park, Suchard, Hripcsak, Gupta.

Critical revision of the manuscript for important intellectual content: You, Rho, Bikdeli, Kim, Siapos, Weaver, Londhe, Schuemie, Suchard, Madigan, Hripcsak, Gupta, Reich, Ryan, R. W. Park, Krumholz.

Statistical analysis: You, Rho, Kim, Siapos, Weaver, Londhe, Cho, J. Park, Schuemie, Suchard, Madigan, Hripcsak, Ryan.

Obtained funding: Hripcsak, R. W. Park.

Administrative, technical, or material support: You, Rho, Weaver, Londhe, Cho, Park, Hripcsak, Reich, R. W. Park.

Supervision: Bikdeli, Suchard, Ryan, R. W. Park.

Other - Providing suggestions for revisions, and additional analyses: Bikdeli.

Conflict of Interest Disclosures: Mr Weaver reports holding shares in Janssen Research and Development, and that it is a subsidiary of Johnson & Johnson. Dr Schuemie reports holding shares in Janssen Research and Development, and that it is a subsidiary of Johnson & Johnson. Dr Ryan reports holding shares in Johnson & Johnson and that his employer, Janssen Research and Development, is a subsidiary of Johnson & Johnson. Mr Londhe reports being employed by Amgen but was an employee of Janssen Research and Development (a subsidiary of Johnson & Johnson) at the time of analysis, and he reports holding shares with Johnson & Johnson and Amgen. Dr Krumholz reports working under contract with the Centers for Medicare & Medicaid Services; receipt of research grants through Yale from Medtronic and the US Food and Drug Administration and from Medtronic and Johnson & Johnson; receipt of a research agreement through Yale from the Shenzhen Center for Health Information; personal fees from the National Center for Cardiovascular Diseases in Beijing, the law firms of Arnold & Porter (work related to Sanofi clopidogrel litigation), Martin/Baughman (work related to Cook IVC filter litigation), and Siegfried & Jensen (work related to Vioxx litigation), UnitedHealth (chairing a cardiac scientific advisory board), IBM Watson Health Life Sciences Board (participant/participant representative), Element Science (advisory board), Facebook, and Aetna (physician advisory board); consultancy with F-Prime; and being a cofounder of HugoHealth and Refactor Health. Dr Bikdeli reports being an expert (on behalf of the plaintiff) in litigation related to a specific type of IVC filter. Dr Gupta reports receipt of personal fees from the law firms of Arnold & Porter (work related to Sanofi clopidogrel litigation) and Martin/Baughman (work related to Cook IVC filter litigation); and consulting fees from Edwards Lifesciences. Dr Madigan reports having testified as an expert in litigation related to a number of drugs and devices but not related to any of the products considered in this study. Dr Hripcsak reports receipt of grant funding from Janssen through his university outside the submitted work and grants from the National Institutes of Health National Library of Medicine during the conduct of the study. Dr Suchard reported grants from Janssen Research & Development, grants from IQVIA, and grants from National Institutes of Health outside the submitted work. No other disclosures were reported.

Funding/Support: This work was supported by the Bio Industrial Strategic Technology Development Program (20001234) funded by the Ministry of Trade, Industry, & Energy (MOTIE, Korea); a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI16C0992); and a grant from the National Institutes of Health (R01 LM006910).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: Amgen, Janssen, and IQVIA did not have input in the design, execution, interpretation of results, or decision to publish.

Additional Contributions: We thank the Korean Health Insurance Review and Assessment Service for providing the data, Woohyun Cho, MFA, (Medical Information and Media Center, Ajou University) for graphical assistance, and Maria Johnson, MBA (Research Associate, Internal Medicine, Cardiology, Yale University) for her contribution to proofreading the manuscript. None of them received compensation for their contributions.

Additional Information: The analysis is based in part on work from the Observational Health Sciences and Informatics collaborative (OHDSI, http://ohdsi.org).

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