Trade-off Between Bleeding and Thrombotic Risk in Patients With Academic Research Consortium for High Bleeding Risk

Urban et al¹ recently developed the Academic Research Consortium for high bleeding risk (ARC-HBR) trade-off model. The new scores provide the predicted 1-year risk of nonperiprocedural major bleeding (Bleeding Academic Research Consortium [BARC] types 3-5 bleeding) and thrombotic events (myocardial infarction [MI] and/or definite or probable stent thrombosis [ST]) after coronary stenting in patients with HBR. In the development and validation cohorts, the C statistics were 0.68 and 0.74 for major bleeding and 0.68 and 0.74 for thrombotic events, respectively; C statistics in validation cohorts typically are lower than those observed in the development cohort. To support individual optimal antiplatelet therapy, bleeding and thrombotic risk scores should achieve helpful discrimination (C statistics, ≥0.60) in contemporary treatment strategies.² We applied the scores to the GLOBAL LEADERS trial population.³

The GLOBAL LEADERS trial investigated aspirin-free antiplatelet treatment (experimental arm, 1 month of dual antiplatelet therapy [DAPT] followed by 11 months of ticagrelor monotherapy vs reference arm, 12 months of DAPT) in an all-comers population. All patients provided informed consent. The trial was approved by the institutional review board at each center and followed the ethical principles of the Declaration of Helsinki (Supplement 1). Patients were enrolled between July 2013 to November 2015 and had an outpatient clinic visit at 30 days and 3, 6, 12, 18, and 24 months after the index procedure. Data were analyzed during January 2021. The ARC-HBR trade-off model was externally validated in patients with ARC-HBR in the GLOBAL LEADERS trial. Multiple imputation (20 times) of missing values was conducted based on the correlation between all potential predictors and clinical outcomes to make efficient use of the available data without introducing bias under the missing-at-random assumption.⁴ The discriminative abilities for BARC types 3 to 5 bleeding and MI and/or ST between 3 to 365 days were assessed using the Harrell C statistic (C index). Agreement between observed and predicted rates was assessed by calibration plot.⁴ The discriminative abilities of the PARIS and PRECISE-DAPT scores were also assessed. Analyses were performed using R, version 3.6.0 (R Foundation for Statistical Computing).

Among 15 968 patients, 1926 patients (12.1%) satisfied the ARC-HBR criteria based on age (3002 of 15 968 [18.8%]), estimated glomerular filtration rate (2171 of 15 883 [13.7%]), hemoglobin levels (2044 of 15 215 [13.4%]), and previous stroke (421 of 15 945 [2.6%]). Twenty-nine patients (1.5%) did not receive a stent, and 42 patients (2.2%) experienced BARC types 3 to 5 bleeding, MI and/or ST, or death during the first 2 days (36 [85.7%]) or were lost to follow-up (6 [14.3%]). Of 1855 patients, within 3 and 365 days, BARC type 3 to 5 bleeding occurred in 48 patients (2.6%), and MI and/or ST occurred in 55 patients (3.0%).

C statistics of the ARC-HBR trade-off model were 0.56 (95% CI, 0.48-0.65) for BARC types 3 to 5 bleeding and 0.67 (95% CI, 0.59-0.75) for MI and/or ST (Figure 1). The ARC-HBR trade-off model showed a good calibration (intercept = −0.22; slope = 1.06) for predicting 1-year MI and/or ST, but overestimated 1-year BARC types 3 to 5 bleeding (Figure 2). According to the treatment strategies, C statistics in the experimental arm were 0.56 (95% CI, 0.44-0.68) for bleeding and 0.71 (95% CI, 0.62-0.81) for thrombotic events; in the reference arm, they were 0.56 (95% CI, 0.44-0.68) for bleeding and 0.62 (95% CI, 0.50-0.75) for thrombotic events.

In patients with HBR in the GLOBAL LEADERS trial, the PARIS and PRECISE-DAPT scores^5,6 had C statistics of 0.57 (95% CI, 0.49-0.65) and 0.59 (95% CI, 0.50-0.69) for predicting 1-year BARC type 3 to 5 bleeding and C statistics of 0.67 (95% CI, 0.60-0.74) and 0.61 (95% CI, 0.54-0.69) for 1-year thrombotic event prediction, respectively (Figure 1).

The ARC-HBR trade-off model demonstrated helpful discrimination and a good calibration for 1-year thrombotic events; however, the ARC-HBR trade-off model overestimated 1-year BARC types 3 to 5 bleeding, and its discrimination was poor in the GLOBAL LEADERS patients. The ARC-HBR trade-off model was developed in a population of patients with ARC-HBR, whereas PARIS and PRECISE-DAPT scores are not limited to patients with ARC-HBR. In this analysis of GLOBAL LEADERS patients who satisfied the ARC-HBR criteria, the ARC-HBR trade-off model had similar discrimination for nonperiprocedural major bleeding and thrombotic events compared with PARIS and PRECISE-DAPT scores. This research is based on a post hoc analysis and all the presented findings must be interpreted strictly as hypothesis generating. Importantly, the BARC type 3 to 5 bleeding rate of 2.6% in the GLOBAL LEADERS trial was site reported and not adjudicated, and was lower than the event rate in the 6 studies used for model development (5.7%). The lower event rate in the GLOBAL LEADERS trial might have contributed to the poorer discrimination of the ARC-HBR model for major bleeding events, but this finding suggests that further efforts to refine the prediction of bleeding in patients with HBR are warranted.

Accepted for Publication: April 6, 2021.

Published Online: June 2, 2021. doi:10.1001/jamacardio.2021.1558

Corresponding Author: Patrick W. Serruys, MD, PhD, National University of Ireland, Galway (NUIG), University Road, Galway, H91 TK33, Ireland (patrick.w.j.c.serruys@gmail.com).

Author Contributions: Drs Hara and Serruys had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Hara, Onuma, Serruys.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Hara, Ono, Serruys.

Critical revision of the manuscript for important intellectual content: Hara, Kawashima, Onuma, Serruys.

Statistical analysis: Hara, Ono, Onuma.

Obtained funding: Serruys.

Administrative, technical, or material support: Kawashima.

Supervision: Onuma, Serruys.

Conflict of Interest Disclosures: Dr Hara reported grants from the Japanese Circulation Society and Fukuda Foundation for Medical Technology outside the submitted work. Dr Serruys reported personal fees from Biosensors, Micel Technologies, Sinomedical Sciences Technology, Philips/Volcano, Xeltis, and HeartFlow outside the submitted work. No other disclosures were reported.

Funding/Support: GLOBAL LEADERS study was sponsored by the European Clinical Research Institute, which received funding from Biosensors International, AstraZeneca, and the Medicines Company.

Role of the Funder/Sponsor: The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 2.