You might be interested in…Stoke (Part 1) – Stroke and Medical Conditions

Dr Ray O’Connor takes a look at recent clinical papers on stroke, particularly stroke and atrial fibrillation, and stroke and medical conditions

Stroke and Atrial Fibrillation
Clinical practice guidelines recommend initiation of anticoagulation within two weeks after stroke with atrial fibrillation (AF). It is unknown whether there is an optimal starting day within the 14-day period that balances the risks of recurrent embolic events against serious haemorrhagic events. The objective of this phase 2, pragmatic, response-adaptive randomized clinical trial1 was to determine if there is an optimal delay time to initiate treatment with a direct oral anticoagulant after atrial fibrillation-related stroke that minimizes the risk of a composite outcome of ischemic or haemorrhagic events.

Dr Ray O’Connor

The trial was conducted between June 2017 and June 2023 at acute care hospitals in Texas and included patients who had a mild to moderate ischemic stroke with atrial fibrillation and were prescribed a direct oral anticoagulant within two weeks from stroke onset.

Within three to four days after atrial fibrillation-associated ischemic stroke, patients were randomized to a group for treatment start date (Group 1 was day 3 or 4 after stoke onset; Group 2 was day 6; Group 3 was day 10; and Group 4 was day 14) with a direct oral anticoagulant for secondary stroke prevention. The composite primary outcome was an ischemic (stroke or systemic embolism) or haemorrhagic (symptomatic intracranial haemorrhage or major systemic haemorrhage) event observed within 30 days from the index stroke time of onset.

The trial enrolled and randomized 200 patients (50 per cent were female; the median age was 75 years; 17.5 per cent were Asian, Black, or >1 race; 16.5 per cent were Hispanic; the median National Institutes of Health Stroke Scale score was 6.5; and the median lesion diameter was 3.1 cm).

The authors concluded that a clearly superior day to initiate use of a direct oral anticoagulant for secondary stroke prevention in patients with atrial fibrillation was not identified, but the evidence suggests that initiating use of a direct oral anticoagulant earlier is better than at later times within the first two weeks after stroke onset.

There are limited data on the residual risk of recurrent stroke in patients with AF. The objective of this systematic review and meta-analysis2 was to determine the recurrent stroke risk in patients with AF. Eligible studies enrolled patients with prior ischemic stroke and AF, reported information on incidence of recurrent stroke, and had follow-up data for one or more years. The primary outcome was recurrent ischemic stroke. The secondary outcomes were any recurrent stroke (ischemic stroke or intra-cerebral haemorrhage [ICH]) and ICH during follow-up.

A total of 23 studies were identified, which included 78,733 patients and 140,307 years of follow-up. The median proportion of OAC use across studies was 92 per cent. The pooled incidence of recurrent ischemic stroke was 3.75 per cent per year. The risk was higher in noninterventional observational cohorts (4.20 per cent per year) compared with randomized clinical trials (2.26 per cent per year). The risk of any recurrent stroke was 4.88 per cent per year, and the risk of ICH was 0.58 per cent per year.

The authors concluded that even with modern prevention therapy, the residual recurrence risk after AF-related stroke is high, with an estimated 1 in 6 patients experiencing a recurrent ischemic stroke at five years. These data demonstrate an urgent need to improve our understanding of the biological processes responsible for recurrence, improve risk stratification, and need to develop new secondary prevention strategies after AF-related stroke.

Catheter-based closure of the left atrial appendage is an alternative to oral anticoagulation for stroke prevention in patients with AF. The effectiveness of this strategy, as compared with physician-directed best medical care, in patients at high risk for stroke and bleeding is unknown. This was a multicentre randomized trial conducted in Germany.3

The authors assigned patients with AF and a high risk of stroke and bleeding to undergo left atrial appendage closure or to receive physician-directed best medical care (including direct oral anticoagulants, if eligible). The primary end point, tested for noninferiority, was a composite of stroke (ischemic or haemorrhagic), systemic embolism, major bleeding, or cardiovascular or unexplained death, assessed in a time-to-event analysis.

A total of 912 adult patients underwent randomization. The primary end-point analysis included 446 patients who were assigned to undergo left atrial appendage closure (device group) and 442 who were assigned to physician-directed best medical care (medical-therapy group). The mean age was 77.9 years; 38.6 per cent of the patients were women, the mean CHA2DS2-VASc score was 5.2 (range, 0 to 9, with higher scores indicating a greater risk of stroke), and the mean HAS-BLED score was 3.0 (range, 0 to 9, with higher scores indicating higher risk of bleeding).

After a median follow-up of three years, a first primary end-point event had occurred in 155 patients (incidence per 100 patient-years, 16.8) in the device group and in 127 patients (incidence per 100 patient-years, 13.3) in the medical-therapy group (difference in restricted mean survival time, −0.36 years). Serious adverse events occurred in 368 patients (82.5 per cent) in the device group and 342 (77.4 per cent) in the medical-therapy group.

The authors concluded that among patients with atrial fibrillation at high risk for stroke and bleeding, left atrial appendage closure was not noninferior to physician-directed best medical care with regard to a composite end point of stroke, systemic embolism, major bleeding, or cardiovascular or unexplained death.

Stroke with Medical Conditions (Obstructive Sleep Apnoea and Heart Failure)
There exists a significant pathogenic and epidemiological overlap among stroke, obstructive sleep apnoea (OSA), and cardiovascular disease. This systematic review4 aimed to clarify the association between OSA and cardiovascular disease in stroke patients. Fifteen studies, involving a total of 559,296 patients, met the eligibility criteria. The findings revealed that stroke patients with obstructive sleep apnoea (OSA) exhibited a substantially higher risk of hypertension [2.26], arrhythmia [1.29], Coronary Artery Disease [1.28], heart failure [2.31], and vascular lesions [1.50]. However, the risk for other cardiovascular diseases did not exhibit a statistically significant increase.

The authors concluded that their results emphasize the increased susceptibility to cardiovascular diseases in stroke patients with coexisting OSA. Timely identification and treatment of OSA in stroke patients could offer potential for reducing the risk of cardiovascular diseases and their related complications.

Patients with heart failure with reduced ejection fraction (HFrEF) have a heightened stroke risk. However, stroke as an endpoint in heart failure trials remains under-reported. The objective of this systematic review and meta-analysis⁵ was to define the incidence, characteristics, predictors, modifier treatments, and prognostic impact of stroke in patients with HFrEF who were enrolled in randomized controlled trials (RCTs). The authors systematically reviewed MEDLINE for RCTs of pharmacologic and nonpharmacologic treatments in HFrEF.

The annualized stroke incidence was the primary outcome. The findings were as follows. Of 7,104 records, 188 RCTs fulfilled inclusion criteria for the systematic review. Of these, 158 studies (84.0 per cent) did not report stroke outcomes and were excluded from the meta-analysis, leading to a final cohort of 30 studies, with 61 arms and 75,327 patients. Stroke incidence was 1.1% with high heterogeneity across trials. Higher NYHA functional class (P < 0.001), lower systolic blood pressure (P < 0.001), diuretic use (P = 0.001), and diabetes (P < 0.001) were associated with stroke.

No association of renin-angiotensin-aldosterone inhibitors, beta-blockers, mineralocorticoid receptor antagonists, and transcatheter mitral valve replacement with stroke was observed. Stroke was associated with higher risk of all-cause and cardiovascular mortality, heart failure hospitalization and acute coronary syndromes (P < 0.001 for all). The authors concluded that stroke was reported in a vast minority of HFrEF RCTs with heterogeneous definitions and no reference to underlying mechanisms. Despite under-reporting, stroke incidence is non-negligible. Stroke is associated with HFrEF-specific characteristics and outcomes, whereas it is not impacted by current HFrEF treatments.

References:

Warach S et al. Optimal Delay Time to Initiate Anticoagulation After Ischemic Stroke in Atrial Fibrillation: A Pragmatic, Response-Adaptive Randomized Clinical Trial. JAMA Neurol 2025 May 1;82(5):470-476. doi: 10.1001/jamaneurol.2025.0285.
McCabe J et al. Residual Risk of Recurrent Stroke Despite Anticoagulation in Patients With Atrial Fibrillation: A Systematic Review and Meta-Analysis. JAMA Neurol 2025 Jul 1;82(7):696-705. doi: 10.1001/jamaneurol.2025.1337.
Skurk C et al. Left Atrial Appendage Closure or Medical Therapy in Atrial Fibrillation. N Engl J Med 2026;394:1270-1280. doi: 10.1056/NEJMoa2513310. VOL. 394 NO. 13 (Pub Mar 18 2026)
Yang Y et al. Stroke patients with obstructive sleep Apnea: Risk of cardiovascular diseases – A systematic review and meta-analysis. Sleep Med 2025 Oct:134:106667. doi:10.1016/j.sleep.2025.106667. Epub 2025 Jul 7
Gallone G et al. Stroke in Heart Failure With Reduced Ejection Fraction: Systematic Review and Meta-Analysis of Randomized Trials. JACC Heart Fail 2025 Jul;13(7):102389. doi:10.1016/j.jchf.2024.12.008. Epub 2025 Mar 12.