Study findings raise new questions about DAPT recommendations following ACS

Treatment with the P2Y12 antiplatelet drug ticagrelor was not associated with significantly better outcomes compared to treatment with clopidogrel in patients with acute coronary syndrome undergoing percutaneous coronary interventions (PCIs) in a retrospective study, but its use was associated with higher risk for hemorrhagic events and dyspnea.

In the retrospective cohort study that involved more than 62,500 propensity score-matched patients, dual antiplatelet therapy (DAPT) with ticagrelor and aspirin was not associated with a statistically significant difference at 1-year compared to clopidogrel DAPT in the composite outcomes of recent heart attack, revascularization, or ischemic stroke and hemorrhagic stroke or gastrointestinal bleeding (15.1% in the ticagrelor group versus 14.6% in the clopidogrel group).

The ticagrelor-DAPT group had a higher incidence of bleeding events and treatment-related shortness of breath, leading researchers to conclude that ticagrelor-treatment was not associated with better outcomes.

The findings, published online Oct. 27 in the Journal of the American Medical Association, raise new questions about antiplatelet therapy guidelines in the U.S. and Europe recommending ticagrelor and aspirin over clopidogrel and aspirin as DAPT in patients with acute coronary syndrome (ACS).

Researcher Harlan Krumholz, MD, of Yale New Haven Hospital, and colleagues, noted that their findings are consistent with several other recent trials, including a 2018 study involving older patients in Europe, but they differ from the overall findings of the PLATO trial which led to the guideline recommendations favoring ticagrelor.

The international PLATO study showed ticagrelor to be more effective than clopidogrel in the management of patients with ACS, but the efficacy benefit was not seen in an analysis of PLATO patients in North America.

“Other concerns about the safety of ticagrelor include the drug-induced dyspnea and higher hemorrhagic events associated with its use, which can lead to early discontinuation,” Krumholz and colleagues wrote.

Their retrospective cohort study included patients with ACS who underwent PCI and were treated with ticagrelor or clopidogrel. The patients, treated with PCI from late November 2011 through early 2019, were identified through two U.S. electronic health record databases and one nationwide South Korean health records database. The patients were matched using a large-scale propensity scoring algorithm.

The primary study endpoint was net adverse clinical events (NACE) at 12 months, defined as composite outcome of ischemic events (recurrent myocardial infarction (MI), revascularization or ischemic stroke) and hemorrhagic events (hemorrhagic stroke or gastrointestinal bleeding).

Secondary outcomes included 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.

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% [3,484/23 116 person-years] versus 14.6% [3,290/22 587 person-years]; summary HR, 1.05; 95% CI, 1.00-1.10: P=0.06).

Among the other main findings:

  • No significant difference in all-cause mortality risk was seen (2.0% for ticagrelor versus 2.1% for clopidogrel; summary HR, 0.97; 95% CI, 0.81-1.16: P=0.74) or ischemic events (13.5% for ticagrelor versus 13.4% for clopidogrel; summary HR, 1.03; 95% CI, 0.98-1.08: P=0.32).
  • Hemorrhagic event risk was significantly higher in the ticagrelor-treated patients (2.1% for ticagrelor versus 1.6% for clopidogrel; summary HR, 1.35; 95% CI, 1.13-1.61: P=0.001), as was dyspnea risk (27.3% for ticagrelor versus 22.6% for clopidogrel; summary HR, 1.21; 95% CI, 1.17-1.26]: P<0.001).

Drug adherence in the ticagrelor group was lower than in the clopidogrel group, which has been consistently reported in recent randomized trials comparing the drug to other antiplatelet therapies.

The researchers noted that the poor adherence was “mostly due to non-serious adverse events, including dyspnea and non-major bleeding,” but they also hypothesized that in routine clinical practice, “twice-daily dosing and costs also may be important factors for nonadherence.”

They noted that in the 2018 PRAGUE-18 study, which compared ticagrelor to prasugrel in patients undergoing angioplasty for MI, almost half (45%) of patients in the ticagrelor group switched to clopidogrel “for economic reasons, mostly within 8 days.”

They further cited a 2018 analysis of trends in P2Y12 receptor inhibitor use and adherence by Elias Dayoub, MD, of the University of Pennsylvania, and colleagues.

“Dayoub et al. argued that increased prescription of newer, more expensive P2Y12 inhibitors in clinical practice has reduced the overall adherence of P2Y12 inhibitors after PCI,” Krumholz and colleagues wrote. “Furthermore, it has exacerbated socioeconomic health disparities because adherence disproportionately affects the most economically disadvantaged patients, even among the insured population in the United States.”

In an accompanying editorial, Eric R. Bates, MD, of the University of Michigan, Ann Arbor, wrote that the retrospective cohort analysis findings and other studies “challenge the conventional wisdom promoted in clinical guidelines and communicated by thought leaders and in the media that ticagrelor is more effective than clopidogrel in DAPT.”

“Ticagrelor has a more favorable pharmacodynamic profile than clopidogrel. However, compared with clopidogrel and prasugrel, ticagrelor may not demonstrate greater clinical benefit because of adverse effects (dyspnea), inconvenience (twice-daily dosing), or higher cost (clopidogrel and prasugrel are generics), which may decrease medication adherence,” Bates wrote.

He added that, “the pragmatic clinical recommendation, yet to be proven in randomized trials, may be to prescribe ticagrelor (or prasugrel because it was more effective than ticagrelor in one randomized trial) for patients with ACS, if the patient tolerates and can afford this medication, and to consider deescalating to clopidogrel at 1 month after the greatest ischemic risk period has passed to decrease subsequent bleeding risk and cost. At 12 months, DAPT can be transitioned to low-risk aspirin monotherapy for secondary prevention.”

  1. Treatment with the P2Y12 antiplatelet drug ticagrelor was not associated with significantly better outcomes compared to treatment with clopidogrel in acute coronary syndrome patients undergoing percutaneous coronary interventions.

  2. Dual antiplatlet therapy (DAPT) with ticagrelor and aspirin was not associated with a statistically significant difference at 1 year compared to clopidogrel DAPT in the composite outcomes of recent heart attack, revascularization, ischemic stroke, hemorrhagic stroke, and gastrointestinal bleeding (15.1% in the ticagrelor group vs. 14.6% in the clopidogrel group).

Salynn Boyles, Contributing Writer, BreakingMED™

This study was funded by the Korean Ministry of Trade, Industry & Energy, the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, and the Ministry of Health & Welfare, Republic of Korea.

Principal researcher Harlan M. Krumholz reported working under contract with the Centers for Medicare & Medicaid Services; receipt of research grants through Yale from Medtronic and the FDA 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, IBMWatson Health Life Sciences Board, Element Science (advisory board), Facebook, and Aetna (physician advisory board); consultancy with F-Prime; and being a cofounder of HugoHealth and Refactor Health.

Editorial writer Eric R. Bates disclosed no relevant relationships.

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