We appreciated the meta-analysis from Gómez-Outes et al (1) describing the high risk of death in patients receiving direct oral anticoagulant (DOAC) reversal agents. The accompanying editorial advocates use of DOACs and states “the best way to deal with bleeding is to prevent it” by avoiding/stopping antiplatelet therapy and using proton pump inhibitors in patients with prior gastrointestinal bleeding (2).
We agree prevention is the best strategy and want to call attention to noncardiovascular agents that increase bleeding risk: nonsteroidal anti-inflammatory agents and selective-serotonin and serotonin-norepinephrine reuptake inhibitor antidepressants. Alcohol, fish oils, and supplements (St John’s wort, ginger, gingko biloba, horse chestnut, turmeric, and plants used in traditional Chinese medicine) are also variably reported to increase bleeding risks.
It may also be time to consider another factor associated with increased risks for bleeding: DOAC concentrations. A well-established relationship exists between increasing DOAC concentrations and increased bleeding, experimentally and in randomized trials. Relationships between strokes and DOAC concentrations are less steep or flat (3), suggesting that above a therapeutic level, further increases in concentrations increase bleeding risk without additional benefit. A small patient series reported higher DOAC concentrations in patients with intracranial hemorrhage (4). Although simplified dosing is an advantage of DOACs over warfarin, that is not to say that DOAC prescribing cannot be optimized to reduce bleeding complications. It is time to evaluate the plausible hypothesis that excessive DOAC concentrations are an important and modifiable risk factor for bleeding during DOAC therapy.
Clinicians should address use of concomitant medications, alcohol, and supplements to reduce bleeding with DOACs. Clinicians may also want to consider assessing DOAC measurements in patients at higher risks of bleeding (older age, prior hemorrhage, stroke or transient ischemic attack, diabetes, lower creatinine clearance, or decreased hematocrit) (5).
Acknowledgments
Supported by the National Institute on Aging (grant R21AG067463). The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Footnotes
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.
REFERENCES
- 1.Gómez-Outes A, ALcubiLLa P, CaLvo-Rojas G, et al. Meta-analysis of reversal agents for severe bleeding associated with direct oral anticoagulants. J Am Coll Cardiol. 2021;77(24):2987–3001. [DOI] [PubMed] [Google Scholar]
- 2.Granger CB, Pokorney SD. Preventing and managing bleeding with anticoagulation for atrial fibrillation. J Am Coll Cardiol. 2021;77:3002–3004. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Ruff CT, Giugliano RP, Braunwald E, et al. Association between edoxaban dose, concentration, anti-Factor Xa activity, and outcomes: an analysis of data from the randomised, double-blind ENGAGE AF-TIMI 48 trial. Lancet. 2015;385(9984):2288–2295. [DOI] [PubMed] [Google Scholar]
- 4.Shin H, Cho MC, Kim RB, et al. Laboratory measurement of apixaban using anti-factor Xa assays in acute ischemic stroke patients with non-valvular atrial fibrillation. J Thromb Thrombolysis. 2018;45(2): 250–256. [DOI] [PubMed] [Google Scholar]
- 5.Hylek EM, Held C, Alexander JH, et al. Major bleeding in patients with atrial fibrillation receiving apixaban or warfarin: the ARISTOTLE Trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation): predictors, characteristics, and clinical outcomes. J Am Coll Cardiol. 2014;63(20):2141–2147 [DOI] [PubMed] [Google Scholar]