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

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.

Figure 1.. Study Flowchart of Patients With Acute Coronary Syndrome Who Underwent Percutaneous Coronary Intervention and Received Ticagrelor or Clopidogrel

Figure 2.. Kaplan-Meier Plots for the Risks of the Primary Outcome (Net Adverse Clinical Events) Associated With Ticagrelor and Clopidogrel

Net adverse clinical events comprise ischemic events (recurrent acute myocardial infarction, revascularization, or ischemic stroke) and hemorrhagic events (hemorrhagic stroke or gastrointestinal bleeding) in propensity score–matched cohorts from each data source. A, For the Optum electronic health record source, median follow-up was 365 days for ticagrelor patients (interquartile range [IQR], 213-365) and for clopidogrel patients, 365 days (IQR, 181-365). B, For the IQVIA hospital source, median follow-up was 285 days for ticagrelor patients (IQR, 63-365) and for clopidogrel patients, 253 days (IQR, 55-365). C, For the Health Insurance Review and Assessment Service source, median follow-up was 365 days for ticagrelor patients (IQR, 154-365) and for clopidogrel patients, 365 days (IQR, 138-365). P values in survival curves were estimated using Cox proportional hazard regression models. Shading in the survival curves indicates 95% CIs.

Figure 3.. Risk of the Primary Outcome (NACE) at 1 Year

Net adverse clinical events comprise ischemic events (recurrent acute myocardial infarction, revascularization, or ischemic stroke) and hemorrhagic events (hemorrhagic stroke or gastrointestinal bleeding) in propensity score-matched cohorts from each data source. The summary hazard ratios were calculated using a random-effects model. A hazard ratio greater than 1 indicates higher risk in the ticagrelor group. The size of the data marker indicates the weight of the study. Error bars indicate 95% CIs.

Figure 4.. Risks of the Net Adverse Clinical Events or Mortality, Ischemic Event, Ischemic Stroke, Acute Myocardial Infarction, Revascularization, and Hemorrhagic Event at 1 Year

The summary hazard ratios were calculated using a random-effects model. A hazard ratio greater than 1 indicates higher risk in the ticagrelor group. The size of the data marker indicates the weight of the study. Error bars indicate 95% CIs.

Figure 5.. Risks of Hemorrhagic Stroke, Gastrointestinal Bleeding, All-Cause Mortality, Cardiovascular-Related Mortality, Major Adverse Cardiovascular Events, and Dyspnea at 1 Year

The summary hazard ratios were calculated using a random-effects model. A hazard ratio greater than 1 indicates higher risk in the ticagrelor group. The size of the data marker indicates the weight of the study. Error bars indicate 95% CIs.