For many patients, ‘a major bleed is any bleed that happens to me’
Key takeaways:
- Any bleeding event regardless of severity can adversely impact a patient.
- Factor XI and XIa inhibitors in development may reduce the odds of bleeding compared with current antithrombotic therapies.
Despite advances in anticoagulant therapies, bleeding remains a critical concern.
Traditionally, the definition of major bleeding has focused on standardizing clinical outcomes, with life-threatening events such as intracranial hemorrhage, significant hemoglobin drops or the need for transfusion flagged as major, according to guidelines from the Bleeding Academic Research Consortium.
However, these clinical definitions often overlook the real-world impact on patients. For many, any bleeding, regardless of clinical classification, feels “major” rather than a nuisance. This growing awareness of patient-relevant bleeding underscores that all bleeding events can have a profound impact on patients, no matter how they're classified in clinical trials and treatment guidelines.
Historically, cardiovascular trials have focused on major bleeding due to its association with mortality and morbidity. From a clinical perspective, this focus is justified, as standardized metrics are necessary to assess and compare outcomes across diverse patient populations and evaluate the efficacy and safety of anticoagulant therapies. Serious events such as intracranial hemorrhage or gastrointestinal bleeding requiring transfusion are understandably classified as major bleeding. However, minor bleeding events can still have a significant effect on a patient’s quality of life. For example, recurrent gingival bleeding during routine toothbrushing or persistent bleeding from a seemingly trivial scratch may not be highlighted in efficacy tables, but for the patient, these events can be relevant and life-altering.
The rise of patient-relevant bleeding
As patient-reported outcomes take on greater importance in clinical research, the focus is shifting toward what truly matters to patients. A gastrointestinal bleed that doesn’t require hospitalization might not fit the clinical definition of a major event, but if it results in missed work, anxiety about hospitalization or medication noncompliance due to fear of side effects, its impact is far from minor. This sentiment is captured well by patients who say: “A major bleed is any bleed that happens to me.” For those on antithrombotic therapy, any bleeding event, regardless of its clinical classification, carries emotional and practical consequences that can influence treatment adherence and overall health outcomes.
The challenge for cardiologists has always been managing the fine line between the prevention of thrombotic events and minimizing bleeding risk. Significant strides have been made over the years, progressing from unfractionated heparin derived from porcine mucosa roughly 60 years ago, to the more effective vitamin K antagonists such as warfarin, and, more recently, direct oral anticoagulants (DOACs). Yet, no matter how far we’ve come, the inherent risk for bleeding persists across all anticoagulant therapies, with some more severe than others. One promising development in this area is the emergence of factor XI inhibitors. These drugs selectively inhibit factor XIa in the coagulation cascade, which appears to allow the same reduction in venous thrombotic events without as much bleeding risk compared with enoxaparin in patients undergoing knee arthroplasty.
Factor XI inhibitors
Factor XI inhibitors offer a distinct advantage over current anticoagulants, such as DOACs and vitamin K antagonists, by targeting factor XI, which plays a role in amplifying clot formation rather than initiating it. This unique mechanism may reduce the likelihood of bleeding while maintaining efficacy in preventing thromboembolic events. Early-phase studies in patients with atrial fibrillation or acute myocardial infarction have shown promising pharmacodynamic profiles and good tolerability. However, it’s important to remember that these are still early-phase studies. Larger, well-powered and longer-term studies are needed to confirm the safety and efficacy of factor XI inhibitors in these patient populations. Indeed, the recent discontinuation of the phase 3 OCEANIC-AF trial, which compared the factor XIa inhibitor asundexian (Bayer) to the DOAC apixaban (Eliquis, Bristol Myers Squibb/Pfizer) in patients with AF demonstrated inferior efficacy, which damped the enthusiasm and emphasized the need to appreciate the role of factor XI inhibitors in the light of dedicated, well-designed clinical outcome-powered studies.
Clinical implications for U.S. cardiologists
For U.S. cardiologists, these developments offer exciting possibilities. The emergence of factor XI inhibitors could mean safer options for patients who are at high risk for both thrombotic and bleeding events. This is particularly relevant for older patients, those with comorbidities and those with a history of bleeding on other anticoagulants. As we move toward a more patient-centered approach to bleeding risks, cardiologists will need to consider not just traditional markers of major bleeding, but also the broader impact that any bleeding event, no matter how minor, can have on a patient’s life. If factor XI inhibitors can match or surpass current therapies in efficacy while reducing bleeding risk, these drugs could play a major role in anticoagulation guidelines in the next decades.
The definition of major bleeding is evolving. For patients, the distinction between major and minor bleeds is often less important than the real-world impact of any bleeding event.
As cardiologists, we must recognize this perspective and ensure that we address the full spectrum of bleeding risks. With the development of factor XI inhibitors, we may be on the cusp of a new class of drugs that not only reduce thrombotic events, but also better align with what patients need: fewer bleeds, whether major or minor. If these new anticoagulants will fit into the current landscape, and whether they will improve clinical safety while having the same efficacy as factor Xa inhibitors, remains to be determined, but the potential is certainly there.
References:
- Galli M, et al. Drugs. 2024;doi:10.1007/s40265-024-02049-w.
- Hara H, et al. Circ Cardiovasc Interv. 2020;doi:10.1161/CIRCINTERVENTIONS.120.009177.
- Mehran R, et al. Circulation. 2011;doi:10.1161/CIRCULATIONAHA.110.009449.
- OCEANIC-AF study stopped early due to lack of efficacy. https://www.bayer.com/media/en-us/oceanic-af-study-stopped-early-due-to-lack-of-efficacy. Published Nov. 19, 2023. Accessed Jan. 29, 2025.
- Weitz JI, et al. N Engl J Med. 2021;doi:10.1056/NEJMoa2113194.
For more information:
C. Michael Gibson, MD, MS, is professor of medicine at Harvard Medical School and CEO of Baim Institute for Clinical Research.
Sem A.O.F. Rikken, MD, is a research fellow at Baim Institute for Clinical Research and a PhD candidate at Cardiovascular Research Institute Maastricht, Netherlands. They can be reached at Harvard Medical School, Baim Institute for Clinical Research, 930 Commonwealth Ave., Third Floor, Boston, MA 02215; email: mgibson@perfuse.org; X (Twitter): @SemRikken and @CMichaelGibson.
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