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Giovanna Liuzzo, Carlo Patrono, Aspirin-free antiplatelet strategies: is the evidence supporting a paradigm shift?, European Heart Journal, Volume 42, Issue 39, 14 October 2021, Pages 4011–4012, https://doi.org/10.1093/eurheartj/ehab573
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This individual patient-level meta-analysis of randomized controlled trials (RCTs)1 evaluated the ischaemic and bleeding risks of antiplatelet treatment strategies after coronary revascularization, consisting of the withdrawal of aspirin after 1–3 months of dual antiplatelet therapy (DAPT) and continuation with P2Y12 inhibitor (P2Y12i) monotherapy vs. continuation of DAPT.
Six RCTs were included, ranging in size from 334 to 7509 patients undergoing coronary revascularization [mean age, 65 years; 23% females; 60% with acute coronary syndrome (ACS) at presentation; 99% undergoing percutaneous coronary intervention (PCI), mostly one lesion, one stent]: 11 634 were randomly allocated to P2Y12i monotherapy (22% clopidogrel, 1% prasugrel, 77% ticagrelor) and 11 674 to 12-month DAPT (37% aspirin and clopidogrel, 1% aspirin and prasugrel, 62% aspirin and ticagrelor). The primary efficacy endpoint was the composite of all-cause death, myocardial infarction (MI), and stroke. The key safety outcome was Bleeding Academic Research Consortium type-3 or -5 bleeding. For these analyses, events that occurred during the initial DAPT phase were censored.
During a median follow-up of 334 days, there were no statistically significant differences between the two arms in the primary efficacy endpoint, both in the per-protocol [3.0% in the P2Y12i monotherapy group and 3.3% in the DAPT group; hazard ratio ( HR), 0.93; 95% confidence interval (CI), 0.79–1.09; P = 0.005 for noninferiority; P = 0.38 for superiority] and in the intention-to-treat analyses (2.9% vs. 3.4%; HR, 0.90; 95% CI, 0.77–1.05; P = 0.18 for superiority). Results were consistent across all prespecified subgroups, except for sex, suggesting that P2Y12i monotherapy may reduce the risk of the primary outcome in women (HR, 0.64; 95% CI 0.46–0.89) but not in men (HR, 1.00; 95% CI, 0.83–1.19; P for interaction = 0.02).
The risk of bleeding was lower with P2Y12i monotherapy than with DAPT (0.9% vs. 1.8%; HR, 0.49; 95% CI, 0.39–0.63; P < 0.001). This finding was consistent across all subgroups, except for P2Y12i type in the control group, suggesting potentially greater benefit with a more recent P2Y12i (HR, 0.41; 95% CI, 0.30–0.55) than with clopidogrel (HR, 0.77; 95% CI, 0.50–1.18; P for interaction = 0.02).
The results of P2Y12 Inhibitor Monotherapy or Dual Antiplatelet Therapy after Coronary Revascularisation: Individual Patient Level Meta-Analysis of Randomised Controlled Trials have been published in Br Med J. doi:10.1136/bmj.n1332.
Comment
DAPT is the treatment of choice after coronary revascularization, regardless of the strategy used (PCI or bypass surgery) and the clinical presentation of coronary artery disease (CAD).2 Although it prevents atherothrombotic complications, DAPT is associated with increased risk of bleeding, in turn associated with increased mortality and morbidity.3 Early withdrawal (after 1–3 months of DAPT) of aspirin has gained popularity as a strategy to reduce major bleeding complications while preserving or possibly enhancing the ischaemic benefit, largely based on disputed evidence that P2Y12i may inhibit platelet thromboxane A2 (TXA2) as much as aspirin, thus making aspirin use redundant when combined with a P2Y12i.4 The GLOBAL LEADERS trial5 was designed to test this hypothesis with a superiority design. Its failure to demonstrate a statistically significant reduction in the primary outcome of all-cause death or non-fatal, new Q-wave MI in post-PCI patients receiving a ticagrelor-based aspirin-free regimen as compared to standard therapy did not support this hypothesis.
The subsequent trials evaluating the aspirin-free approach were generally powered for non-inferiority with respect to ischaemic endpoints, based on questionable non-inferiority margins, and/or superiority with respect to bleeding or net adverse clinical events, including a combination of ischaemic and bleeding outcomes.1,4 These considerations inspired the present meta-analysis.1
Several limitations of the trials contributing to this carefully conducted study should be outlined: (i) although the six trials were sponsored by academic organizations, they were all funded by industry, three by the ticagrelor manufacturer, including the two largest trials,6,7 possibly explaining the fact that ticagrelor was over-represented and prasugrel was under-represented among the newer P2Y12i, both as monotherapy and as DAPT; (ii) the risk of bias assessment identified some concerns for five of six trials related to their open-label design; (iii) four of six trials involved 9594 patients (40% of total) entirely recruited in South Korea, Japan, and China, among populations with heterogeneous genetic backgrounds potentially affecting clopidogrel pharmacokinetics; (iv) five of the six trials did not include an important control group, i.e. an aspirin monotherapy arm; and (v) the prevalence of ACS as the clinical presentation varied from 38% to 100%, with a sizeable proportion of patients presenting with stable CAD, often receiving inappropriately intensified and/or prolonged DAPT.8
Although the authors correctly indicate that a statistically significant treatment-by-sex interaction remains hypothesis generating, this finding is overemphasized throughout the paper. In fact, given 13 comparisons and lack of correction for multiple comparisons, an apparently significant interaction is likely to be due to chance, in the absence of a biologically and pharmacologically plausible explanation.
Interestingly, similar ischaemic and bleeding risk profiles as with aspirin-free regimens were previously obtained with an early ‘P2Y12i dropping’ strategy while maintaining aspirin.9 Within the limitations of indirect comparisons, the results of these meta-analyses1,9 suggest that following PCI, early discontinuation of low-dose aspirin has a similar effect on bleeding risk as a shorter duration of P2Y12i therapy, as would be expected following recovery of either of two equally important mechanisms of platelet activation, i.e. TXA2 and ADP, respectively.10
The authors conclude that their results support a paradigm shift in antithrombotic management and question the central role of DAPT beyond one to three months after PCI.1 We believe that a paradigm shift requires a pragmatic, randomized comparison of aspirin monotherapy vs. P2Y12i monotherapy, after 1–3-month DAPT following PCI, with stratification according to the gender and type of P2Y12i, to assess long-term tolerability and safety of the two monotherapy options, because the relevant medical question is not what happens over the next few months but over the next years.
Conflict of interest: G.L. received grant support (to the institution) for investigator-initiated research from American Heart Association, Italian National Health Service and Italian Minister of Education, University and Research. She is currently involved in the Research Programs of the Italian Cardiovascular Network. She received personal fees from Astra Zeneca, Boehringer Ingelheim, Novo Nordisk, and Daiichi Sankyo. C.P. received consultant and speaker fees from Acticor Biotech, Amgen, Bayer, Eli Lilly, GlaxoSmithKline, Tremeau, and Zambon, and grant support (to the institution) for investigator-initiated research from AIFA (Italian Drug Agency), Bayer, Cancer Research UK, and European Commission; he chairs the Scientific Advisory Board of the International Aspirin Foundation.
