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Original Investigation
January 13, 2020

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

Author Affiliations
  • 1Department of Pharmacy, Vancouver General Hospital, Vancouver, British Columbia, Canada
  • 2Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada
  • 3Division of Cardiology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada
  • 4Alberta SPOR Support Unit, University of Alberta, Edmonton, Alberta, Canada
  • 5Libin Cardiovascular Institute, University of Calgary, Calgary, Alberta, Canada
  • 6Division of Nephrology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada
JAMA Intern Med. Published online January 13, 2020. doi:10.1001/jamainternmed.2019.6447
Key Points

Question  What is the association between ticagrelor vs clopidogrel and major adverse coronary events, major bleeding, and dyspnea in patients with acute coronary syndrome treated with percutaneous coronary intervention?

Findings  In this cohort study of 11 185 patients, ticagrelor was not associated with a statistically significantly lower risk of major adverse coronary events compared with clopidogrel. However, it was associated with statistically significantly more major bleeding and dyspnea.

Meaning  Ticagrelor was not associated with a lower risk of major adverse coronary events in patients with acute coronary syndrome who underwent percutaneous coronary intervention.


Importance  Guidelines currently recommend ticagrelor over clopidogrel for patients with acute coronary syndrome (ACS) based on randomized clinical trial data in which ticagrelor reduced major adverse coronary events (MACE) vs clopidogrel but increased bleeding and dyspnea.

Objective  To compare the risk of MACE with ticagrelor vs clopidogrel in patients with ACS treated with percutaneous coronary intervention (PCI), to compare major bleeding and dyspnea, and to evaluate the association between P2Y12 inhibitor adherence and MACE.

Design, Setting, and Participants  Population-based cohort study using data of patients discharged alive after PCI for ACS from the Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease registry from April 1, 2012, to March 31, 2016, with follow-up to 1 year. Analysis began April 2018.

Exposures  Outpatient prescription for ticagrelor or clopidogrel within 31 days after PCI. Adherence was defined as a medication refill adherence value of 80% or higher.

Main Outcomes and Measures  Major adverse coronary events, a composite of all-cause death, hospitalization for ACS, unplanned coronary revascularization, or stent thrombosis within 365 days after index PCI. Secondary outcomes included hospitalization for major bleeding and emergency department visit for dyspnea.

Results  Of 11 185 individuals who underwent PCI, the median (interquartile range) age was 61 (54-71) years, and 2760 (24.7%) were women. Ticagrelor users (4076 [36.4%]) were generally younger and had fewer cardiac and noncardiac comorbidities than clopidogrel users. Ticagrelor was not associated with lower risk of MACE (adjusted hazard ratio [aHR], 0.97; 95% CI, 0.85-1.10); however, it was associated with an increased risk of major bleeding (aHR, 1.51; 95% CI, 1.29-1.78) and dyspnea (aHR, 1.98; 95% CI, 1.47-2.65). A total of 3328 ticagrelor users (81.6%) were adherent during the study vs 5256 of clopidogrel users (73.9%) (P < .001; χ2 = 86.4). In the full cohort, adherence was associated with a lower MACE risk (aHR, 0.79; 95% CI, 0.69-0.90 for adherence of ≥80% vs <80%). Differences in other secondary outcomes were not statistically significant. Sensitivity and subgroup analyses were consistent with primary analyses.

Conclusions and Relevance  In this population-based cohort study of patients with ACS who underwent PCI, outpatient use of ticagrelor was not associated with a statistically significant reduction in MACE vs clopidogrel; however, it was associated with more major bleeding and dyspnea.

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    1 Comment for this article
    Tailored P2Y12 inhibition in outpatients after percutaneous coronary intervention
    Giuseppe Ando, MD, PhD | University of Messina, Italy
    Turgeon et al explored effectiveness and safety of ticagrelor compared to clopidogrel in outpatients discharged after acute coronary syndrome (ACS) and treated with percutaneous coronary intervention (PCI) in a registry-based cohort study of 11,185 patients. The main finding was that ticagrelor, after adjusted Cox modeling or propensity-score matching, was not associated with a lower risk of major adverse coronary events (MACE) compared to clopidogrel, whereas it was associated with significantly higher rates of bleeding and dyspnea.
    This study challenges the results of the landmark PLATO-invasive trial and current guidelines supporting the preference of ticagrelor (or prasugrel) over clopidogrel in
    patients with ACS. By externally validating the conclusions of randomized trials and generating hypotheses for subsequent investigations, such cohort studies have a definite role in the hierarchy of evidence.
    The absolute rate of 1-year composite incidence of death/ACS/stroke in ticagrelor arm of this study (8.0%) is ≈10% lower than that of PLATO-invasive (9.0%), and all-cause mortality is ≈60% lower (1.5% vs 3.9%), thus suggesting that this study cohort might be at a somehow lower risk than PLATO-invasive. This likely happened both because events occurring within hospitalization were not captured and because all patients had received PCI, resulting a lower-risk population. Being also smaller than PLATO-invasive, this study might be actually underpowered to detect differences favoring ticagrelor: indeed, the direction of ischemic benefit in adjusted models is consistent with the unadjusted ones.
    Higher rates of dyspnea and bleeding are related to the mechanism of action of ticagrelor, and they likely account for the known 25% higher risk of discontinuation than comparators5. Since factors associated with low adherence to P2Y12 inhibitors were more prevalent in (sicker) patients receiving clopidogrel, the Authors hypothesize that this may have caused lower adherence and persistence in clopidogrel than in ticagrelor arm. Conversely, ticagrelor users experienced more dyspnea and bleeding, events known to induce discontinuation of P2Y12 inhibitors, and more stent thrombosis, a likely consequence of discontinuation. Altogether, these counterintuitive observations suggest that unmeasured residual confounders might have not been accounted for.
    However, adherence to P2Y12 inhibition was associated with 21% lower relative risk of MACE compared with non-adherence. This is likely the most compelling evidence of this study for which the authors deserve congratulations, as it underscores the role of tailored antiplatelet therapy, considering drug tolerability and expected adherence: adherence appears more strongly associated with risk of MACE than choice of the P2Y12 inhibitor itself.