Anticoagulants and Bleeding Risk in Atrial Fibrillation

Dr Fahad Almehmadi, assistant professor of medicine at King Saud Bin Abdulaziz University for Health Sciences, answers questions about anticoagulants and bleeding risk in atrial fibrillation.

It's been more than a decade since the novel oral anticoagulants for the prevention of stroke in patients with atrial fibrillation (AF) hit the market. Initially, though the efficacy of the medications was not in question there was concern about potential bleeding risks in patients receiving them. Now that 10 years have passed, are reversal agents available and have these initial concerns been resolved?

I think many physicians may have forgotten how difficult it was to manage patients with AF on vitamin K antagonists (VKAs). Major studies of direct-acting oral anticoagulants (DOACs) have shown that, in addition to dosing convenience, use of DOACs vs VKAs shows a 50% risk reduction in the most feared bleeding complication: intracranial hemorrhage. The equivalence or superiority of DOACs in these trials was evident even before the availability of a reversal agent in the market, where a four-factor prothrombin complex concentrate was enough to manage bleeding events. In a meta-analysis of ≈ 4700 patients from 60 studies, effective hemostasis was achieved in 78% of patients who developed bleeding regardless of the use of a DOAC-specific agent.

Idarucizumab (a direct thrombin Inhibitor–specific reversal agent) and andexanet alfa (an anti-factor X–specific reversal agent) were approved in 2015 and 2018, respectively. These agents provide robust and rapid reversal of DOACs in patients with life-threatening bleeding. However, their utilization is limited owing to their availability and cost. Kanjee and colleagues showed that in 2021, these medications were missing in up to 50% of the US Medicaid trauma centers. Andexanet alfa availability was even more limited despite its "need," as anti–factor X DOACs are prescribed 20 times more than their direct thrombin inhibitor counterparts.

Overall, conservative management along with fresh frozen plasma or complex concentrate will probably be adequate in controlling bleeding events in patient receiving DOACs. Reversal agents may make physicians more comfortable about prescribing the DOACs, but I don't think they have changed the patterns of stroke prophylaxis prescribing.

How is major bleeding in nonsurgical patients defined in current scoring systems, and how has that evolved?

The majority of the DOAC trials defined bleeding as either major bleeding or clinically relevant nonmajor bleeding. Major bleeding was defined as any intracranial hemorrhage, any bleeding that required hospitalization, retroperitoneal bleeding, or bleeding that led to a drop in hemoglobin > 2 units or led to > 2 units of blood transfusion. Clinically relevant nonmajor bleeding was defined as any bleeding that led to an intervention, unscheduled physician contact, or stopping the prescribed medication. These definitions are consistent with the International Society on Thrombosis and Haemostasis bleeding definitions.

What are the risk factors for bleeding in patients with AF, and which of them are considered to be modifiable? How successful are current scoring systems in assessing patient risk?

Many scoring systems have been developed: HAS-BLED, HEMORR₂HAGES, GARFIELD-AF, ORBIT, and ATRIA. These models share some of these predictors, which include age, hypertension, any stroke history, diabetes, history of heart failure, prior bleeding history, chronic kidney disease, concomitant use of antiplatelet agents, cancer, abnormal liver function, labile international normalized ratio (INR), and recurrent falling risk. You may notice that many of these factors are incorporated in our stroke prediction score, affecting the utility of these scores in day-to-day practice. Most of the bleeding scores were developed before the wide adoption of DOACs. Still, in those cohorts, their performance were at best modest, with a C-statistic of about 0.5-0.6. This means that if HAS-BLED scoring flagged about 100 patients at risk for major bleeding, only three will actually experience it.

I think the real value of any bleeding score system is to identify the factors that we as physicians can modify to reduce the patient's future risk for bleeding. A high bleeding risk score should not be a reason to withhold stroke prophylaxis options, as stated in the most recent AF guidelines.

Let's talk about specific patient populations that are at increased risk and things to look out for in these patient populations.

Overall, as stated above, many of the patients who are at greatest risk for stroke are the ones at greatest risk for bleeding. For example, stroke risk increases as a patient ages. Being older than 75 years adds 2 points to a patient's risk in CHA₂DS₂-VASc; at the same time, it increases bleeding estimation when assessed using the GARFIELD-AF or ATRIA scoring systems. Not all two-way predictors are included in the commonly known prediction models. For example, chronic kidney disease is a well-known risk factor for both thrombotic and bleeding events. It is included in most of the bleeding prediction models, but attempts to incorporate renal function indicators into stroke prediction models lead to a minor improvement in the model's C-statistic.

Because AF and coronary artery disease share common risk factors, these diseases tend to coexist, and many patients need concomitant administration of an OAC and antiplatelet therapy. Such combination doubles a patient's bleeding risk, but an optimal duration of management per published guidelines is crucial to modulate a patient's high-risk period if needed. In addition, physicians should be vigilant about combining OACs with over-the-counter medications, such as nonsteroidal anti-inflammatory drugs.

Because some patients with AF still remain on VKAs, maintenance of a therapeutic INR is key. It may seem obvious, but a patient's bleeding risk is increased twofold with every 1-unit increase in INR.

Are there specific biomarkers that could be identified to evaluate bleeding risk? If so, how specific are they, and how might they be used in daily current clinical practice?

Many biomarkers that we use in our daily practice can predict bleeding. Troponin is a highly sensitive biomarker for bleeding; cystatin C as an estimate of the patient's renal function and hemoglobin and hematocrit as markers of anemia can also predict bleeding. Other novel biomarkers, such as growth differentiation factor 15 (GDF-15) as a marker of cellular aging and occult cancer, have been found to be predictive of future bleeding in patients receiving OAC therapy.

Anemia and renal function biomarkers are incorporated in some of the current bleeding prediction models, with modest overall performance as stated above. Incorporating novel biomarkers (ie, the ABC model) was found to be superior. The ABC model (A = Age; B = Biomarkers, namely GDF-15, hemoglobin, and high-sensitivity troponin; and C = Clinical History), derived from RE-LY and ARISTOTLE data, outperformed the HAS-BLED and ORBIT scoring systems in predicting bleeding, with a C-statistic approaching 0.68 compared with 0.5-0.6 in other models. Data are still evolving, and our prediction accuracy and non-OAC stroke prevention methods will only get better. We may get to the point where a model can be good enough to recommend left atrial appendage closure over an OAC. Time will tell.

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Cite this: Anticoagulants and Bleeding Risk in Atrial Fibrillation - Medscape - Feb 22, 2022.