Background: DOACs, NVAF, and the bleeding-stroke balance
Atrial fibrillation (AF) and atrial flutter (AFL) elevate stroke risk, driving the widespread use of oral anticoagulants. Direct oral anticoagulants (DOACs)—apixaban, rivaroxaban, dabigatran, and edoxaban—offer non-inferiority to warfarin with distinct bleeding profiles. In real-world practice, apixaban often shows the lowest overall bleeding, particularly GI bleeding, while rivaroxaban and dabigatran can carry higher bleeding risk in certain patient groups. However, the interaction between cardiac hemodynamics and DOAC-specific outcomes has remained incompletely understood.
Objective and study design
A retrospective cohort study analyzed NVAF patients newly started on a DOAC, with detailed transthoracic echocardiography (TTE) data to assess right heart pressures and left ventricular function. The primary outcome was time to first major bleed according to the International Society on Thrombosis and Haemostasis (ISTH) criteria. Secondary outcomes included intracranial and GI bleeding, plus time to first stroke (restricted to those without prior stroke). Echocardiographic metrics—ejection fraction (LVEF) and right ventricular systolic pressure (RVSP)—were central to stratifying risk and exploring interactions with DOAC choice.
Key hemodynamic factors: LVEF and RVSP
Left ventricular ejection fraction (LVEF) was categorized as ≤40%, 41–49%, and ≥50%. RVSP was grouped into normal (0–34 mmHg), moderately elevated (35–44 mmHg), and high (≥45 mmHg). These thresholds aimed to detect biologic gradients and minimize data sparsity in multivariable analyses. The study enrolled 2,308 NVAF patients treated with a DOAC, with 68 stroke events observed during follow-up.
Bleeding outcomes and DOAC-specific patterns
Across all DOACs, major bleeding occurred at a rate of about 4.75 per 100 person-years. In unadjusted comparisons, rivaroxaban and dabigatran did not differ significantly from apixaban. However, when multivariable analyses controlled for age, comorbidities, and other confounders, rivaroxaban showed a notable association with higher major bleeding risk (HR 1.41) compared with apixaban. Dabigatran showed a non-significant trend toward higher bleeding. The interaction between RVSP and DOAC choice revealed a pronounced pattern: higher bleeding risk with dabigatran and rivaroxaban intensified as RVSP rose, whereas apixaban maintained a relatively flat bleeding risk across RVSP categories. Notably, in the highest RVSP group (≥45 mmHg), rivaroxaban and dabigatran bleeding risks nearly doubled compared with apixaban.
Gastrointestinal bleeding and intracranial hemorrhage
Gastrointestinal (GI) bleeding occurred at a rate of 2.96 per 100 person-years. When adjusting for covariates, overall DOAC choice did not significantly change GI bleeding rates, but interactions showed that dabigatran and rivaroxaban carried higher GI bleeding in patients with elevated RVSP or reduced LVEF, compared with apixaban. Intracranial hemorrhage remained rare and showed no clear pattern across DOACs or RVSP strata, suggesting similar intracranial safety among agents in this cohort.
Stroke outcomes and their relationship to hemodynamics
Stroke incidence was 1.71 per 100 person-years, with several factors influencing stroke risk beyond DOAC selection, including dose indicator, AF type, CKD stage, and RVSP. After adjusting for confounders, rivaroxaban did not show a statistically significant reduction in stroke versus apixaban overall. However, when incorporating RVSP interactions, higher stroke rates emerged for certain subgroups on apixaban and dabigatran as RVSP increased, while rivaroxaban did not follow a linear trend. This pattern implies that elevated right-sided pressures may shift the balance of DOAC effectiveness versus bleeding risk in complex ways.
Biologic interpretation: why hemodynamics matter
Heart failure and pulmonary hypertension causing right heart strain can alter drug absorption and distribution. In congestive heart failure, edema and intestinal changes may affect DOAC bioavailability, potentially amplifying variability in drug exposure. Apixaban, with favorable absorption and less GI bleeding, appears more forgiving in high-RVSP contexts. In contrast, dabigatran and rivaroxaban, which depend more on hepatic or renal clearance and have distinct absorption profiles, may exhibit greater bleeding risk when venous pressures are elevated. These dynamics offer a plausible explanation for the observed interaction between RVSP and DOAC-specific bleeding and stroke rates.
Clinical implications and limitations
For clinicians, echocardiographic hemodynamics—especially RVSP—may inform DOAC selection in NVAF beyond traditional risk scores. In patients with markedly elevated RVSP, apixaban may confer lower bleeding risk, while in certain subgroups, stroke risk could be differentially affected. Yet, this study is observational and retrospective, and causation cannot be established. Noninvasive RVSP estimates via TTE have limitations, and changes in patient status over time may influence results. Prospective studies with invasive hemodynamic measurements could further clarify these relationships.
Conclusion
The interaction between echocardiographic hemodynamics and DOAC choice appears to shape both bleeding and stroke outcomes in NVAF. Specifically, higher RVSP magnifies bleeding risk with dabigatran and rivaroxaban relative to apixaban, while stroke risk trends with hemodynamics are nuanced and DOAC-specific. Integrating echocardiographic data into anticoagulation decision-making could optimize safety and effectiveness for patients with NVAF.
