Results Inconclusive on Oral Anticoagulation in Patients With Previous Intracranial Hemorrhage

Rustam Al-Shahi Salman, PhD, MBBChir, FRCP

Results from the Start or Stop Anticoagulants Randomized Trial (SoSTART) (NCT03153150) were inconclusive as to whether starting oral anticoagulation was noninferior to avoiding it in patients with atrial fibrillation after intracranial hemorrhage. Although, rates of recurrent intracranial hemorrhage in the study were lower than anticipated. 

Investigators for SoSTART obtained consent from 218 patients who had survived at least 24 hours after symptomatic spontaneous intracranial hemorrhage, had atrial fibrillation, and had a CHA2DS2-VASc score of at least 2. Patients were enrolled between March 29, 2018, and February 27, 2020, from 61 hospitals in the UK. 

A total of 203 patients were randomized at a median of 115 days (interquartile range [IQR], 49-265) after intracranial hemorrhage onset. Of these patients, 101 were assigned to start long-term full treatment oral anticoagulation and 102 were assigned to avoid it. Over a median follow-up period of 1 to 2 years (IQR, 0.97-1.96; completeness, 97.2%), investigators found that starting anticoagulation was not noninferior to avoiding it, as 8 participants in the start group (8%) had intracranial hemorrhage recurrences, compared with 4 participants in the avoid group (4%) for an adjusted HR of 2.42 (95% CI, 0.72-8.09; P = .152). 

“We did not find evidence that starting oral anticoagulation was noninferior to avoiding oral anticoagulation with respect to intracranial hemorrhage. In analyses of 3 composite secondary outcomes, we found weak evidence that starting oral anticoagulation might be superior to avoiding oral anticoagulation for preventing any symptomatic major ischemic or hemorrhagic vascular event,” first author Rustam Al-Shahi Salman, PhD, MBBChir, FRCP, professor of clinical neurology, Centre for Clinical Brain Sciences, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, et al wrote. “This trial exceeded its recruitment target and is, to our knowledge, the largest published randomized trial of oral anticoagulation for atrial fibrillation after intracranial hemorrhage to date.”

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Patients were restricted to the use of either a direct oral anticoagulant (factor Xa inhibitor [apixaban, rivaroxaban, or edoxaban] or direct thrombin inhibitor [dabigatran etexilate]) or vitamin K antagonist [warfarin sodium, acenocoumarol, or phenindione]) at full treatment dose. Treatment was initiated within 24 hours of randomization and adjusted if required for renal function, age, body weight, or concomitant medication. 

In the start anticoagulation group, serious adverse events (SAEs) occurred in 17 participants (17%) and 22 participants (22%) died. In the avoid group, SAEs occurred in 15 participants (15%) and 11 participants died (11%). 

At 1-year follow-up, investigators had received 202 (>99%) of 203 primary care practitioner questionnaires and 71 (90%) at 2-year follow up. Investigators also received 177 (88%) of the questionnaires sent to 180 surviving participants at 1-year follow-up, and 59 (97%) of 61 at 2-year follow-up. Using both patient and provider follow-up methods, study participants were followed up for a median of 1.2 years (IQR, 0.97-1.95), and investigators collected 251.25 of the intended 258.52 person-years in the cohort, for an overall completeness rate of 97.2%. 

Several limitations were noted, including the less precise estimate of effect on the primary outcome due to rates being lower than assumed in the sample size calculation. Investigators observed more non-cardiovascular deaths in the group that started oral anticoagulation, which was identified as a competing risk. Additionally, the recruitment rates were lower in the feasibility phase than in a smaller feasibility study, women were underrepresented (63% of study participants were male), and most participants were white (93% of study participants).

“Further randomized trials are justified to investigate the noninferiority of the effects of oral anticoagulation on major bleeding for patients with atrial fibrillation after intracranial hemorrhage or whether oral anticoagulation might be superior for preventing symptomatic major vascular events (especially those that are fatal or disabling),” Salman et al wrote. 

REFERENCE

Al-Shahi Salman R, Keerie C, Stephen J, et al. Effects of oral anticoagulation for atrial fibrillation after spontaneous intracranial haemorrhage in the UK: a randomised, open-label, assessor-masked, pilot-phase, non-inferiority trial. Lancet Neurol. 2021; 20(1):842-853. doi:10.1016/S1474-4422(21)00264-7