Risk of Major Bleeding With Potent Antiplatelet Agents After an Acute Coronary Event: A Comparison of Ticagrelor and Clopidogrel in 5116 Consecutive Patients in Clinical Practice

Abstract

Background Major bleeding after acute coronary syndrome predicts a poor outcome but is challenging to define. The choice of antiplatelet influences bleeding risk. Methods and Results Major bleeding, subsequent myocardial infarction (MI), and all‐cause mortality to 1 year were compared in consecutive patients with acute coronary syndrome treated with clopidogrel (n=2491 between 2011 and 2013) and ticagrelor (n=2625 between 2012 and 2015) in 5 English hospitals. Clinical outcomes were identified from national hospital episode statistics. Bleeding and MI events were independently adjudicated by 2 experienced clinicians, blinded to drug, sequence, and year. Bleeding events were categorized using Bleeding Academic Research Consortium 3 to 5 and PLATO (Platelet Inhibition and Patient Outcomes) criteria and MI by the Third Universal Definition. Multivariable regression analysis was used to adjust outcomes for case mix. The median age was 68 years and 34% were women. 39% underwent percutaneous coronary intervention and 13% coronary artery bypass graft surgery. Clinical outcome data were 100% complete for bleeding and 99.7% for MI. No statistically significant difference was seen in crude or adjusted major bleeding for ticagrelor compared with clopidogrel (Bleeding Academic Research Consortium 3–5, hazard ratio [HR], 1.23; 95% CI, 0.90–1.68; P =0.2, PLATO major adjusted HR, 1.30; 95% CI, 0.98–1.74; P =0.07) except in the non‐coronary artery bypass graft cohort (n=4464), where bleeding was more frequent with ticagrelor (Bleeding Academic Research Consortium 3–5, adjusted HR, 1.58; 95% CI, 1.09–2.31; P =0.017; and PLATO major HR, 1.67; 95% CI, 1.18–2.37; P =0.004). There was no difference in crude or adjusted subsequent MI (adjusted HR, 1.20; 95% CI, 0.87–1.64; P =0.27). Crude mortality was higher in the clopidogrel group but not after adjustment, using either Cox proportional hazards or propensity matched population (HR, 0.90; 95% CI, 0.76–1.10; P =0.21) as was the case for stroke (HR, 0.82; 95% CI, 0.52–1.32; P =0.42). Conclusions This observational study indicates that the apparent benefit of ticagrelor demonstrated in a clinical trial population may not be observed in the broader population encountered in clinical practice. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02484924.

Comparative Safety and Effectiveness of Ticagrelor versus Clopidogrel in Patients With Acute Coronary Syndrome: An On-Treatment Analysis From a Multicenter Registry

“…Despite a sub-analysis from the Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART) registry, more bleeding occurred with ticagrelor than with clopidogrel, as in our study, when patients with a history of major bleeding, prior to hemorrhagic stroke, and those receiving dialyses were excluded from the analysis, no significant difference in the risk of bleeding was found between treatment groups ( 5 ). These findings should be put into perspective with those from recent studies, some of them indicating a reduction in MACE in favor of ticagrelor ( 5 , 16 , 30 , 31 ), others finding neither difference in mortality nor in MACE ( 7 – 11 , 28 ), with the overwhelming majority observing an increased risk of bleeding with ticagrelor vs. clopidogrel ( 5 – 11 ). Nonetheless, the underlying reasons for these contradictory results are still unclear.…”

“…Interestingly, among 66,870 patients included in 4 recent RCTs, the risk of premature discontinuation was 25% higher for ticagrelor-treated patients compared with those receiving the comparator (clopidogrel/placebo) ( 34 ). In view of the existing evidence, differential nonadherence with P2Y 12 inhibitors is a common threat in clinical practice, but as our study suggests, it should also be deemed as a potential source of selection bias to deal with in the observational studies based on the ITT principle ( 7 – 9 ). Nevertheless, despite the inherent limitations of ITT analysis in observational research, not enough attention has been paid to assessing the comparative safety and effectiveness of P2Y 12 inhibitors according to the on-treatment principle.…”

“…Despite these recommendations, an increasing body of evidence has recently shown that ticagrelor is not significantly associated with a reduction in ischemic events, but with an increased risk of major bleeding compared with clopidogrel ( 7 – 13 ). These seemingly conflicting results have raised concerns over the actual net clinical benefit of ticagrelor in nontrial settings.…”

Prevalence of adverse events during ticagrelor versus clopidogrel treatment and its association with premature discontinuation of dual antiplatelet therapy in East Asian patients with acute coronary syndrome

“…A large-scale retrospective cohort analysis has raised the concerns regarding increased risks of bleeding and dyspnea during ticagrelor versus clopidogrel treatment, which could lead to its early discontinuation ( 4 ). It was pointed out that the benefit of ticagrelor identified in a clinical trial may not be observed in a clinical practice ( 5 ).…”

Musk Tongxin Dripping Pills for treating Ticagrelor in Patients After Percutaneous Coronary Intervention: Echocardiography Combined with Untargeted Metabolomics

“…Acute myocardial infarction (AMI) is myocardial necrosis caused by acute and persistent ischemia and hypoxia of the coronary artery ( Liam et al, 2021 ). As the primary cardiovascular disease, AMI seriously affects health and life safety of human beings, which causes over 30% mortality of coronary heart disease patients ( Blais et al, 2020 ; Thomas et al, 2020 ).…”