ESJ Featured Article of the Month- December 2024

December ESJ Featured article Timing of oral anticoagulation initiation for atrial fibrillation after acute ischaemic stroke: A systematic review and meta-analysis, Palaiodimou et al, (Published online May 2024, in print December issue)

https://journals.sagepub.com/doi/full/10.1177/23969873241251931 

When should oral anticoagulation (OAC) be started in a patient with ischaemic stroke and comorbid atrial fibrillation? When is the risk of bleeding balanced by the benefit of preventing recurrent stroke? This is a common clinical conundrum.

The current ESO guidelines highlight this evidence gap saying that further research is needed to identify the optimum time to start OAC after stroke. At present, expert opinion and clinical experience inform these decisions. Experts suggest it is reasonable to start OAC on day 3-4 for mild strokes but wait until day-7 for moderate infarcts, and day-14 for large infarcts. The European Society of Cardiology’s recommendations are similar, advocating the 1-3-6-12 rule.  A 2018 survey of UK physicians found that approximately a third of responders used the 1-3-6-12 rule in practice. Respondents were more comfortable starting OAC in patients with mild strokes,  but reported more uncertainty in patients with moderate strokes.

Featured in ESJ this month, Palaiodimou and colleagues from across Europe have collaborated to summarise the existing data addressing OAC timing after stroke. They performed a systematic review which identified 2 RCTs and 7 observational studies.

First, let’s refresh the included RCTs:

The TIMING trial (2022) compared ‘early’ (≤4 days)  with ‘delayed’ (5-10 days) OAC initiation. TIMING was a non-inferiority trial with a noninferiority margin of 3%. In TIMING, early initiation was non-inferior to delayed initiation for the outcome of recurrent ischaemic stroke and symptomatic intracranial haemorrhage. This means that early OAC is not more than 3% worse than delayed OAC.

The ELAN trial (2023) randomised participants to ‘early’ or ‘late’ anticoagulation, stratified by stroke severity. The timing of ‘early’ and ‘late’ was proportionate to the size and severity of the stroke. Investigators reported rates of recurrent stroke, systemic embolism and major bleeding without hypothesis testing. The results suggested that there was no major difference (2.8 percentage points better to 0.5 percentage points worse) between early and late OAC.

With neither approach showing superiority, Palaiodimou and colleagues meta-analysed the results of ELAN and TIMING, along with 7 further observational studies identified through systematic search. This provided a sample size of almost 10,000 participants. They compared the approaches of ‘early’ versus ‘later’ OAC. The primary outcome was the composite of ischaemic stroke, haemorrhagic events and all-cause mortality at 3-month follow-up.

There are some limitations to this methodology. First, there was between-study heterogeneity in how the time-categories were defined. ‘Early’ was defined as ≤48 hours (2 studies) ≤3 days (1 study), ≤4 days (2 studies) ≤5 days (1 study), ≤6 days (1 study) and ≤7 days (2 studies). ‘Late’ was defined as >2 days (1 study), >3 days (2 studies) , >4 days (2 studies), >5 days (1 study), >6 days (1study) and >7 days (2 studies). In this way, patients assigned to different time-categories could in practice have received OAC at the same time. Individual participant data meta-analysis (IPD-MA) is needed to overcome this limitation.  Additionally, indication bias was observed in the observational studies. Patients who received ‘early’ OAC were more likely to have less severe strokes (their NIHSS score was on average 3-points lower).

The results of the meta-analysis showed that early OAC treatment was associated with a reduced risk of the composite outcome, risk ratio (RR) 0.74 (95% CI 0.56-0.98). When the RCTs and observational studies were evaluated separately, the results were consistent: for RCTs  RR 0.72 (95% CI 0.53-0.98) and for observational studies RR 0.70 (95% CI 0.41-1.20). Both approaches were safe with similar rates of bleeding and no difference in mortality between early and late OAC treatment.

Since this meta-analysis was completed, the OPTIMAS trial has been published. OPTIMAS randomised participants to early (≤4 days) or delayed (7-14 days) OAC, stratified by stroke severity and was designed as a non-inferiority trial, with a non-inferiority margin of 2%. OPTIMAS demonstrated that early OAC was non-inferior to delayed OAC. There is one remaining trial (START NCT03021928) evaluating early versus late OAC, results of which are awaited.

Looking at the totality of evidence, it is reassuring that earlier initiation of OAC is not associated with elevated bleeding risk. However, patient selection is important. Stroke severity and infarct size need to be taken into account.  The summary estimate of the combined ELAN and TIMING results suggest that early OAC may be superior to the delayed approach, however we must be mindful of methodological differences between these trials, especially in the definition of time-categories. Very few of these studies actually gave OAC very early (for example <48 hours) and in ELAN, this was only done in those with TIA or mild stroke. While this meta-analysis suggests for the first time a marginal advantage with early OAC, bias introduced by the observational studies undermines this conclusion. However, maybe these authors will collaborate with investigators of other trials to perform an IPD-MA in future? Such a collaboration may give power for more precise estimates of stroke and bleeding risks at specific time-points across stroke severity strata. In the meantime, an individualised approach to the timing of OAC therapy after stroke is required.

This article was selected as ESO Paper of the Month for December 2024. Learn more about the Paper of the Month

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