FYI.
Stroke Literature Synopsis (Clinical)
Atrial fibrillation (AF) is the commonest arrhythmia and represents a major challenge in stroke. AF predisposes to cardioembolic stroke, and while anticoagulation therapy can reduce ischemic stroke risk, it can also bring bleeding issues that are equally dangerous. This synopsis will review 3 studies with a clinical AF focus.
For people living with AF, risk of cardioembolic stroke is not consistent and anticoagulation therapy is reserved for those at higher risk. The term subclinical AF is used to describe short-duration, asymptomatic episodes. Whether the stroke risk associated with this arrhythmia merits anticoagulation has been unclear. This provides the rationale for the ARTESiA trial ([Apixaban for the Reduction of Thrombo-Embolism in Patients With Device-Detected Subclinical Atrial Fibrillation]; Healey JS, et al. Apixaban for stroke prevention in subclinical atrial fibrillation. N Engl J Med. 2024;390:107–117. doi: 10.1056/NEJMoa2310234). This trial enrolled people with subclinical AF lasting between 6 minutes to 24 hours picked up on an implanted pacemaker, defibrillator, or cardiac monitor. Participants were randomized to either receive the direct oral anticoagulant (DOAC) apixaban or aspirin. The primary outcome was stroke or systemic embolism, assessed in the intention to treat population, while the safety outcome was major bleeding assessed in the on-treatment population.
The study participants were 4012 patients across 16 countries, all aged 75 years or over, and at risk of stroke. The mean study follow-up was 3.5 years. The mean duration of detected AF was 1.4 hours. The risk of stroke or embolism was 37% lower in the apixaban arm (95% CI, 12–55), and risk of disabling or fatal stroke was 49% lower. However, the group taking apixaban was also at increased risk of major bleeding (hazard ratio, 1.80 [95% CI, 1.26–2.57), although, the risk of fatal or intracranial hemorrhage (ICH) was similar between arms. The authors argue that as bleeding is more amenable to reversal or treatment than ischemic stroke, then these data favor anticoagulant treatment in subclinical AF. ARTESIA also reminds us that cardioembolic strokes can be associated with substantial disability and that aspirin is not free from bleeding risk.
Even with anticoagulation therapy people with AF remain at risk of stroke. A common clinical dilemma is how to treat acute ischemic stroke when the person is anticoagulated. Traditional guidance stated that exposure to therapeutic levels of anticoagulant was an absolute contraindication to systemic thrombolysis due to risk of bleeding. However, this view was primarily based on studies of vitamin K antagonists such as warfarin. As DOACs have a different mode of action, pharmacokinetics, and pharmacodynamics, observations from warfarin may not be valid with these drugs. An international, multicenter analysis aimed to provide more evidence on thrombolysis and DOACs (Meinel TR, et al. Intravenous thrombolysis in patients with ischemic stroke and recent ingestion of direct oral anticoagulants. JAMA Neurol. 2023;80:233–243. doi: 10.1001/jamaneurol.2022.4782). The authors collated individual patient-level data from multiple international registers and cohorts, pooling the data to create a case-control study comparing those with ingestion of DOAC 48 hours before intravenous thrombolysis against those with no anticoagulant exposure. The primary outcome was symptomatic ICH.
Data from over 33 000 patients were included in the analysis, 832 with recent DOAC ingestion and 32 375 without. Those in the DOAC group were typically older, with greater prestroke disability and comorbidity. Interventions to reverse anticoagulation were used in 252 (30%) of the DOAC group. The authors found that, after adjusting for baseline predictors of bleeding, recent DOAC ingestion was not associated with an increased risk of symptomatic ICH; in fact, there was a suggestion of lesser risk (adjusted odds ratio, 0.57 [95% CI, 0.36–0.92]). Functional outcomes were similar between groups, again with data favoring the DOAC exposure group (adjusted odds ratio, 1.13 [95% CI, 0.94–1.36]). These results challenge the assumption that DOAC therapy is a barrier to thrombolysis. However, observational data come with many caveats including the risk of selection bias. Robust prospective trials may be necessary to definitively settle the issue and support changes to current guidelines.
For those with AF who experience ICH, there are yet more difficult therapeutic decisions. The benefits of anticoagulation for reducing the risk of ischemic stroke must be balanced against the risk of precipitating or worsening another bleed. Useful data come from the COCROACH (Collaboration of Controlled Randomised Trials of Long-Term Oral Antithrombotic Agents After Spontaneous Intracranial Haemorrhage) group. The group performed an individual patient-level data meta-analysis of 4 trials, which included patients with spontaneous ICH and AF who were randomized to (re)start anticoagulation or avoid anticoagulation (Al-Shahi Salman R, et al. Effects of oral anticoagulation in people with atrial fibrillation after spontaneous intracranial haemorrhage (COCROACH): prospective, individual participant data meta-analysis of randomised trials. Lancet Neurol. 2023;22:1140–1149. doi: 10.1016/S1474-4422(23)00315-0). The primary outcome of interest was a composite of cardiovascular events, stroke (ischemic and hemorrhagic), and death.
In total, 412 people with AF were included in the meta-analysis. Of these, 212 participants (51.5%) were assigned to start anticoagulation, almost exclusively DOACs. A third of patients who did not receive anticoagulation were prescribed antiplatelet monotherapy. The primary outcome occurred in 14% of the anticoagulation arm, compared with 22% of those not anticoagulated (hazard ratio, 0.68 [95% CI, 0.42 to 1.10]). No significant differences were seen in rates of ICH, but there was a suggestion of increased bleeding with anticoagulation (7% if anticoagulated, 5% if not, hazard ratio, 1.80 [95% CI, 0.77 to 4.21]). No difference was found between groups for death or dependence at 1 year. These are useful data for informing discussions around anticoagulation and highlight the power of individual patient-level data approaches. However, even these pooled data may give a sample size too small to definitively answer questions around ICH and anticoagulation, especially in subgroups. There are 5 active trials looking at anticoagulation following ICH, and we await these results and subsequent updated meta-analyses.
For stroke clinicians, the trade-off between reducing ischemic events and not increasing bleeding events can feel like we are stuck between a rock and a hard place. In this context, research is vital to provide an evidence base to assist with decision-making. The studies presented here resolve some of the controversies and open up new questions requiring more research.
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