Sex-Based Outcomes in Patients With a High Bleeding Risk After Percutaneous Coronary Intervention and 1-Month Dual Antiplatelet Therapy: A Secondary Analysis of the LEADERS FREE Randomized Clinical Trial

Abstract

Importance: Female sex has been identified as a risk factor for bleeding after percutaneous coronary intervention (PCI) and may have contributed to the underuse of drug-eluting stents in women. This risk may be further enhanced among patients with a high bleeding risk.

Objective: To assess the 2-year outcomes by sex in patients with a high bleeding risk who were enrolled in the LEADERS FREE trial.

Design, setting, and participants: This cohort study is a prespecified, sex-based secondary analysis of the LEADERS FREE double-blind, randomized clinical trial that was conducted at 68 sites in 20 countries from December 2012 to May 2014. Patients with a high bleeding risk who underwent PCI and met the trial eligibility criteria were enrolled at the participating sites and followed up for up to 2 years.

Interventions: Patients were randomized 1:1 to either a bare-metal stent or a polymer-free, biolimus A9-eluting drug-coated stent with 1-month of dual antiplatelet therapy.

Main outcomes and measures: The primary safety end point was a composite of cardiac death, myocardial infarction, or stent thrombosis. The primary efficacy end point was clinically driven target lesion revascularization. Bleeding was assessed using the Bleeding Academic Research Consortium (BARC) scale, and the source of bleeding was recorded.

Results: A total of 2432 patients with a high bleeding risk were included in the study. Of these patients, the mean (SD) age was 75 (9) years, and 1694 (69.7%) were men and 738 (30.3%) were women. Women and men had similar incidence of the 2-year primary safety (14.7% vs 13.6%; P = .37) and efficacy (9.2% vs 9.5%; P = .70) end points. The drug-coated stent was found to be superior to the bare-metal stent in both sexes, with lower target lesion revascularization (women: 6.3% vs 12.1%; men: 7.0% vs 12.0%; P for interaction = .70) and similar rates of the primary safety end point (women: 12.4% vs 17.0%; men: 12.6% vs 14.5%; P for interaction = .40). Overall, 2-year BARC types 3 to 5 major bleeding (10.2% vs 8.6%; P = .14) was not statistically different between the sexes, but women experienced greater BARC types 3 to 5 major bleeding within the first 30 days (5.1% vs 2.4%; P = .007) and greater vascular access site major bleeding than men (2.2% vs 0.5%; P < .001). In both sexes, vascular (women: hazard ratio [HR], 3.45 [95% CI, 1.51-7.87]; men: HR, 4.14 [95% CI, 1.33-12.95]) and nonvascular major bleeding (women: HR, 3.76 [95% CI, 2.17- 6.53]; men: HR, 4.62 [95% CI, 3.23-6.61]) were associated with greater 2-year mortality.

Conclusions and relevance: This study found no sex differences in the ischemic outcomes of patients with a high bleeding risk after PCI, but women appeared to demonstrate greater early bleeding and major bleeding from the vascular access site. Both women and men with major bleeding seemed to experience worse 2-year mortality, suggesting that bleeding avoidance strategies should be uniformly adopted for all patients, with close attention dedicated to women to avoid denying them the benefits of PCI.

Trial registration: ClinicalTrials.gov Identifier: NCT02843633.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Mehran reported receiving grants from Eli Lilly/DSI, AstraZeneca, The Medicines Company, BMS, and OrbusNeich as well as consulting fees from Janssen Pharmaceuticals Inc, Medscape, Osprey Medical Inc, and Watermark Research Partners outside the submitted work. Dr Urban reported receiving personal fees from Biosensors and other support from Centre Européen de Recherche Cardiovasculaire (CERC) during the conduct of the study as well as other support from MedAlliance and personal fees from Edwards Lifescience outside the submitted work. Dr Lang reported receiving other support from Biosensors Europe SA during the conduct of the study and grants from Actelion and AOP Orphan Pharma outside the submitted work. Dr Windhoevel reported receiving other support from CERC during the conduct of the study. Dr Spaulding reported receiving other support from Medtronic, Zoll, Medpass, Xeltis, Stentys, and Techwald outside the submitted work as well as personal fees from Abiomed, Abbott, and AstraZeneca. Dr Copt reported receiving other support from and being an employee of Biosensors SA during the conduct of the study. Dr Stoll reported receiving other from Biosensors International during the conduct of the study and outside the submitted work. Dr Morice reported being the chief executive officer of CERC. No other disclosures were reported.

Figures

Figure 1.. Sex Differences in Enrollment Characteristics

DAPT indicates dual antiplatelet therapy; NSAID, nonsteroidal anti-inflammatory drug; and PCI, percutaneous coronary intervention.

Figure 2.. Kaplan-Meier Curves of 2-Year Cumulative Incidence of Clinical Events Among Women and Men With a High Bleeding Risk

A, The primary safety end point was a composite of cardiac death, myocardial infarction, and stent thrombosis. B, The primary efficacy end point was clinically driven target lesion revascularization. C, Bleeding was assessed using the Bleeding Academic Research Consortium scale. HR indicates hazard ratio; PCI, percutaneous coronary intervention.

Figure 3.. Sex Differences in Vascular and Nonvascular Bleeding

A and B, Bleeding was assessed using the Bleeding Academic Research Consortium (BARC) scale. C, The percutaneous coronary intervention access site was either radial or femoral.