Emerging randomized data favored oral anticoagulation for lower-risk patients with atrial fibrillation (Afib), researchers found.
Among patients with Afib and one thromboembolic risk factor in the SINGLE-AF trial, direct oral anticoagulant (DOAC) therapy reduced the risk of composite cardiovascular events at 24 months compared with no anticoagulation (0.5% vs 1.5%, HR 0.31, 95% CI 0.10-0.94).
SINGLE-AF is thus the first randomized trial to support a clinical benefit to DOAC therapy in these patients, according to Boyoung Joung, MD, of Yonsei University College of Medicine in Seoul, Korea, speaking at the European Society of Cardiology meeting held this year in Munich, Germany.
However, the study logged very few primary endpoint events — with an annual stroke incidence of just 0.6% without anticoagulation and 0.15% with DOACs — leading authors to suspect that the results may overestimate the true magnitude of benefit from DOACs in the intermediate-risk setting.
The low event rates also made for inconclusive results regarding the individual components of the primary endpoint:
- Stroke leaned toward a numerical benefit: 0.3% with DOACs vs 1.1% without (HR 0.30, 95% CI 0.08-1.08).
- Systemic embolism (0 vs 0.1%) and major bleeding (0.3% vs 0.5%) appeared at similar rates between DOAC and control groups.
- No deaths from cardiovascular causes occurred in either group.
“Given the lower-than-expected number of end-point events, the precision of the estimated treatment effect is limited, and these findings should be interpreted with caution,” Joung and colleagues wrote in their manuscript, simultaneously published in the New England Journal of Medicine.
DOACs are the established first-line therapy for people with Afib with two or more risk factors for stroke (CHA2DS2-VASc score ≥2 in men and ≥3 in women), the evidence being consistent regarding their prevention of stroke or systemic embolism. Given an accompanying higher risk of gastrointestinal bleeding, however, their use is limited in lower-risk patients for fear of tipping the scale to more harm than benefit.
“Patients who receive DOACs or vitamin K antagonists have an increased risk of bleeding, with 60 to 100% more major bleeds than patients who receive no anticoagulation or antiplatelet therapy, respectively. Therefore, the decision to initiate or continue anticoagulation must weigh the risk of treatment-induced bleeding against the benefit of stroke prevention with oral anticoagulation,” explained Paulus Kirchhof, MD, of University Heart and Vascular Center Hamburg, University Hospital Hamburg–Eppendorf in Germany, in an accompanying editorial.
As such, in the absence of a rigorous trial, U.S. guidelines currently give DOAC therapy a modest class IIa indication for intermediate-risk people with Afib (CHA2DS2-VASc score of 1 in men and 2 in women).
SINGLE-AF recruited this very patient population, namely men and women with Afib and just one CHA2DS2-VASc risk factor (beyond female sex): congestive heart failure (or LVEF 40% or below), hypertension, age 65 or older, diabetes, stroke or transient ischemic attack, or vascular disease.
“Taken within the context of the results of the SINGLE-AF trial, the use of anticoagulation in patients with atrial fibrillation and a single risk factor for stroke may be encouraged. In patients with a low atrial fibrillation burden, no therapy may be preferred,” Kirchhof said.
Looking forward, there is also interest in asundexian and other factor XI inhibitors in the pipeline, as these show promise for being safer anticoagulants for the intermediate-risk Afib population given their uncoupling of thrombosis and hemostasis.
“Additional treatment options for patients with a single risk factor for stroke may emerge in the coming years, including therapeutic reduction of atrial fibrillation burden and new antithrombotic therapies,” according to Kirchhof.
SINGLE-AF was a multicenter open-label trial conducted in South Korea from 2020 to 2023. Eligible participants were Afib patients with a CHA2DS2-VASc score of 1 for men and 2 for women.
Investigators had 1,803 individuals randomized to either DOAC therapy or no anticoagulation.
This cohort had a mean age of 60.4 years and was 23.7% women. CHA2DS2-VASc scores came out to a median of 1 and average of 1.3; HAS-BLED scores were a median 0 and mean 0.5. Afib was largely paroxysmal for this cohort (71.8%). Median time since Afib diagnosis was 21 months.
The most frequently used DOAC was apixaban 5 mg (Eliquis; 67.4%), followed by rivaroxaban 20 mg (Xarelto; 14.1%) and rivaroxaban 15 mg (13.9%).
Patients assigned DOACs were prescribed the full dose in 81.6% of cases and a reduced dose in the remainder.
Antiplatelet therapy was used in 0.4% of the patients in the DOAC group and in 36.5% of controls.
According to Joung’s team, follow-up reached a median 730 days and serious adverse events occurred in 8.9% and 9.3% of DOAC and no-anticoagulant groups, respectively. The most common serious adverse event was hospitalization related to Afib (34 vs 15 events).
Study authors cautioned that although the SINGLE-AF trial employed blinded outcome assessment, its open-label design may have introduced some bias regardless. Results are also of unknown generalizability beyond an East Asian population.
