Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Sep 19;148(12):936-946.
doi: 10.1161/CIRCULATIONAHA.123.064556. Epub 2023 Aug 25.

Development and Validation of the DOAC Score: A Novel Bleeding Risk Prediction Tool for Patients With Atrial Fibrillation on Direct-Acting Oral Anticoagulants

Rahul Aggarwal  1   2 , Christian T Ruff  3 , Saverio Virdone  4 , Sylvie Perreault  5 , Ajay K Kakkar  4   6 , Michael G Palazzolo  3 , Marc Dorais  7 , Gloria Kayani  4 , Daniel E Singer  8 , Eric Secemsky  1 , Jonathan Piccini  9 , Usman A Tahir  1 , Changyu Shen  10 , Robert W Yeh  1
Affiliations

Development and Validation of the DOAC Score: A Novel Bleeding Risk Prediction Tool for Patients With Atrial Fibrillation on Direct-Acting Oral Anticoagulants

Rahul Aggarwal et al. Circulation. .

Abstract

Background: Current clinical decision tools for assessing bleeding risk in individuals with atrial fibrillation (AF) have limited performance and were developed for individuals treated with warfarin. This study develops and validates a clinical risk score to personalize estimates of bleeding risk for individuals with atrial fibrillation taking direct-acting oral anticoagulants (DOACs).

Methods: Among individuals taking dabigatran 150 mg twice per day from 44 countries and 951 centers in this secondary analysis of the RE-LY trial (Randomized Evaluation of Long-Term Anticoagulation Therapy), a risk score was developed to determine the comparative risk for bleeding on the basis of covariates derived in a Cox proportional hazards model. The risk prediction model was internally validated with bootstrapping. The model was then further developed in the GARFIELD-AF registry (Global Anticoagulant Registry in the Field-Atrial Fibrillation), with individuals taking dabigatran, edoxaban, rivaroxaban, and apixaban. To determine generalizability in external cohorts and among individuals on different DOACs, the risk prediction model was validated in the COMBINE-AF (A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation) pooled clinical trial cohort and the Quebec Régie de l'Assurance Maladie du Québec and Med-Echo Administrative Databases (RAMQ) administrative database. The primary outcome was major bleeding. The risk score, termed the DOAC Score, was compared with the HAS-BLED score.

Results: Of the 5684 patients in RE-LY, 386 (6.8%) experienced a major bleeding event, within a median follow-up of 1.74 years. The prediction model had an optimism-corrected C statistic of 0.73 after internal validation with bootstrapping and was well-calibrated based on visual inspection of calibration plots (goodness-of-fit P=0.57). The DOAC Score assigned points for age, creatinine clearance/glomerular filtration rate, underweight status, stroke/transient ischemic attack/embolism history, diabetes, hypertension, antiplatelet use, nonsteroidal anti-inflammatory use, liver disease, and bleeding history, with each additional point scored associated with a 48.7% (95% CI, 38.9%-59.3%; P<0.001) increase in major bleeding in RE-LY. The score had superior performance to the HAS-BLED score in RE-LY (C statistic, 0.73 versus 0.60; P for difference <0.001) and among 12 296 individuals in GARFIELD-AF (C statistic, 0.71 versus 0.66; P for difference = 0.025). The DOAC Score had stronger predictive performance than the HAS-BLED score in both validation cohorts, including 25 586 individuals in COMBINE-AF (C statistic, 0.67 versus 0.63; P for difference <0.001) and 11 945 individuals in RAMQ (C statistic, 0.65 versus 0.58; P for difference <0.001).

Conclusions: In individuals with atrial fibrillation potentially eligible for DOAC therapy, the DOAC Score can help stratify patients on the basis of expected bleeding risk.

Keywords: DOAC Score; apixaban; atrial fibrillation; dabigatran; edoxaban; hemorrhage; risk; rivaroxaban.

PubMed Disclaimer

Conflict of interest statement

Disclosures R.A. is involved in research funded by the Bristol Myers Squibb-Pfizer alliance and a consultant for Lexicon Pharmaceuticals. C.R. is a member of the TIMI Study Group, which has received institutional research grant support through Brigham and Women’s Hospital from Abbott, Amgen, Anthos Therapeutics, ARCA Biopharma, Inc, AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc, Daiichi-Sankyo, Eisai, Intarcia, Ionis Pharmaceuticals, Inc, Janssen Research and Development, LLC, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, Regeneron Pharmaceuticals, Inc, Roche, Siemens Healthcare Diagnostics, Inc, Softcell Medical Limited, The Medicines Company, and Zora Biosciences. Through his institution, he receives research grant support from Anthos, AstraZeneca, Daiichi Sankyo, Janssen, and Novartis. He receives honoraria for scientific advisory boards and consulting from Anthos, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Janssen, and Pfizer. A.K.K. reports research grants from Bayer Pharma AG and Sanofi. He reports personal fees from Anthos Therapeutics, Bayer Pharma AG, and Sanofi SA. M.P. is a member of the TIMI Study Group, which has received institutional research grant support through Brigham and Woman’s Hospital from Abbott, Amgen, Anthos Therapeutics, ARCA Biopharma, Inc, AstraZeneca, Daiichi-Sankyo, Ionis Pharmaceuticals, Inc, Janssen Research and Development, LLC, MedImmune, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc, Roche, Softcell Medical Limited, The Medicines Company, and Zora Biosciences. D.E.S. has received research grants from Bristol Myers Squibb and has consulting agreements with Bristol Myers Squibb, Fitbit, Medtronic, and Pfizer. E.A.S. reports the following research grants to Beth Israel Deaconess Medical Center: National Institutes of Health/National Heart, Lung, and Blood Institute, Food and Drug Administration, BD, Boston Scientific, Cook, CSI, Laminate Medical, Medtronic, and Philips. He also endorses consulting/speaking with Abbott, Bayer, BD, Boston Scientific, Cook, Cordis, CSI, Inari, Medtronic, Philips, Shockwave, and VentureMed. J.P.P. receives grants for clinical research from Abbott, American Heart Association, Association for the Advancement of Medical Instrumentation, Bayer, Boston Scientific, and Philips; and serves as a consultant to Abbott, Abbvie, Ablacon, Altathera, Biotronik, Boston Scientific, Bristol Myers Squibb, LivaNova, Medtronic, Milestone, ElectroPhysiology Frontiers, Pfizer, Sanofi, Philips, and Up-to-Date. C.S. reports that he is an employee of Biogen and owns Biogen stocks. R.W.Y. reports grants and consulting fees from Abbott Vascular, Boston Scientific, and Medtronic. The other authors report no conflicts.

Figures

Figure 1.
Figure 1.. Cumulative Incidence for Bleeding Outcomes by Predicted Risk Category in The Development Cohorts: RE-LY and GARFIELD-AF.
Presented are the cumulative incidence curves for individuals in the development cohort (RE-LY trial) (1A) and the refinement cohort (GARFIELD-AF registry) (1B). Cumulative incidence curves were based on the risk category assigned to individuals by the DOAC Score. Risk-scores were 0-10, with risk categories assigned as: very low (score 0-3), low (score 4-5), moderate (score 6-7), high (score 8-9) and very high (score 10). Individuals in RE-LY were included if they were in the dabigatran 150 mg twice daily arm of the trial. Individuals in GARFIELD-AF were included if they were on any direct-acting oral anticoagulant (DOAC), irrespective of dose. A) Cumulative Incidence for Major Bleeding by Risk Category in RE-LY B) Cumulative Incidence for Major Bleeding by Risk Category in GARFIELD-AF
Figure 1.
Figure 1.. Cumulative Incidence for Bleeding Outcomes by Predicted Risk Category in The Development Cohorts: RE-LY and GARFIELD-AF.
Presented are the cumulative incidence curves for individuals in the development cohort (RE-LY trial) (1A) and the refinement cohort (GARFIELD-AF registry) (1B). Cumulative incidence curves were based on the risk category assigned to individuals by the DOAC Score. Risk-scores were 0-10, with risk categories assigned as: very low (score 0-3), low (score 4-5), moderate (score 6-7), high (score 8-9) and very high (score 10). Individuals in RE-LY were included if they were in the dabigatran 150 mg twice daily arm of the trial. Individuals in GARFIELD-AF were included if they were on any direct-acting oral anticoagulant (DOAC), irrespective of dose. A) Cumulative Incidence for Major Bleeding by Risk Category in RE-LY B) Cumulative Incidence for Major Bleeding by Risk Category in GARFIELD-AF
Figure 2.
Figure 2.. Cumulative Incidence for Bleeding Outcomes by Predicted Risk Category in the Validation Cohorts: COMBINE-AF and RAMQ.
Presented are the Cumulative Incidence curves for individuals in the COMBINE-AF clinical trial cohort (2A), and RAMQ administrative database (2B). Cumulative incidence curves were based on the risk category assigned to individuals by the DOAC Score. Risk-scores were 0-10, with risk categories assigned as: very low (score 0-3), low (score 4-5), moderate (score 6-7), high (score 8-9) and very high (score 10). Individuals in COMBINE-AF were included if they were on any direct-acting oral anticoagulant (DOAC). Individuals in RAMQ AF were included if they were on apixaban 5mg twice per day or rivaroxaban 20mg daily. A) Cumulative Incidence for Major Bleeding by Risk Category in COMBINE-AF B) Cumulative Incidence for Major Bleeding by Risk Category in RAMQ
Figure 2.
Figure 2.. Cumulative Incidence for Bleeding Outcomes by Predicted Risk Category in the Validation Cohorts: COMBINE-AF and RAMQ.
Presented are the Cumulative Incidence curves for individuals in the COMBINE-AF clinical trial cohort (2A), and RAMQ administrative database (2B). Cumulative incidence curves were based on the risk category assigned to individuals by the DOAC Score. Risk-scores were 0-10, with risk categories assigned as: very low (score 0-3), low (score 4-5), moderate (score 6-7), high (score 8-9) and very high (score 10). Individuals in COMBINE-AF were included if they were on any direct-acting oral anticoagulant (DOAC). Individuals in RAMQ AF were included if they were on apixaban 5mg twice per day or rivaroxaban 20mg daily. A) Cumulative Incidence for Major Bleeding by Risk Category in COMBINE-AF B) Cumulative Incidence for Major Bleeding by Risk Category in RAMQ
See this image and copyright information in PMC

Comment in

References

    1. January Craig T, Samuel Wann L., Hugh Calkins, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons. Circulation 2019;140:e125–51. doi:10.1161/CIR.0000000000000665 - DOI - PubMed
    1. Singer DE, Chang Y, Fang MC, et al. The net clinical benefit of warfarin anticoagulation in atrial fibrillation. Ann Intern Med 2009;151:297–305. doi:10.7326/0003-4819-151-5-200909010-00003 - DOI - PMC - PubMed
    1. Lip GYH, Nieuwlaat R, Pisters R, et al. Refining Clinical Risk Stratification for Predicting Stroke and Thromboembolism in Atrial Fibrillation Using a Novel Risk Factor-Based Approach: The Euro Heart Survey on Atrial Fibrillation. CHEST 2010;137:263–72. doi:10.1378/chest.09-1584 - DOI - PubMed
    1. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association of Cardio-Thoracic Surgery (EACTS) | European Heart Journal | Oxford Academic. 10.1093/eurheartj/ehaa612/5899003 (accessed 3 Nov 2020). - DOI
    1. 1 Recommendations | Atrial fibrillation: management | Guidance | NICE. https://www.nice.org.uk/guidance/cg180/chapter/1-Recommendations (accessed 18 Aug 2020).

Publication types