Jensen M, Suling A, Metzner A, et al. Early rhythm-control therapy for atrial fibrillation in patients with a history of stroke: a subgroup analysis of the EAST-AFNET 4 trial. Lancet Neurol. 2023 Jan;22(1):45-54. doi: 10.1016/S1474-4422(22)00436-7. (Original study)

BACKGROUND: Patients with atrial fibrillation and a history of stroke are at high risk of recurrent stroke and cardiovascular complications. In the EAST-AFNET 4 trial we showed that a systematic strategy of early rhythm control was associated with a lower risk of cardiovascular outcomes than usual care in patients with atrial fibrillation diagnosed in the past 12 months. In this pre-specified subgroup analysis we aimed to assess whether a strategy of early rhythm control is safe and can prevent adverse cardiovascular outcomes compared with usual care in such patients.

METHODS: EAST-AFNET 4 was a randomised, open-label trial with blinded-outcome assessment done at 135 hospitals and secondary care practices in 11 European countries. Adults with early atrial fibrillation (ie, diagnosed =12 months before enrolment) were randomly assigned (1:1) to either early rhythm control or usual care, with stratification according to site and variable block lengths used for concealment. The first primary outcome was time to first occurrence of the composite of cardiovascular death, ischaemic or haemorrhagic stroke, or hospital admission with worsening of heart failure or acute coronary syndrome. The second primary outcome was the number of nights spent in hospital in 1 year. The primary safety outcome was the composite of any death, stroke, or serious adverse events related to rhythm-control therapy. Here we present the results of these outcomes in patients with a history of stroke. Analyses were done in the intention-to-treat population. EAST-AFNET 4 is registered with ClinicalTrials.gov (NCT01288352), EudraCT (2010-021258-20), and ISRCTN (ISRCTN04708680).

FINDINGS: Between July 28, 2011, and Dec 30, 2016, 2789 patients were randomly assigned in the EAST-AFNET 4 trial to either early rhythm control (n=1395) or usual care (n=1394). Of these patients, five had no information on history of stroke and were excluded from this subgroup analysis. 217 (8%) patients had a history of stroke, of whom 110 were assigned to early rhythm control and 107 to usual care. The median age of participants with a history of stroke was 72·0 years (IQR 66·0-76·0). 95 (44%) participants were female and 122 (56%) were male. During a median follow-up of 4·7 years (3·5-6·4) for patients with a history of stroke, a first primary outcome event occurred in 18 (16%) of 110 patients in the early rhythm-control group (3·7 per 100 person-years) and 33 (31%) of 107 in the usual care group (7·4 per 100 person-years; hazard ratio [HR] 0·52, 95% CI 0·29-0·93). The mean number of nights spent in hospital per year was 5·1 (SD 13·2) for patients with a history of stroke assigned to early rhythm control and 6·6 (10·1) for those assigned to usual care (incidence rate ratio 0·87, 95% CI 0·55-1·38). Among patients with a history of stroke, primary safety events occurred in 17 (15%) patients in the early rhythm-control group versus 30 (28%) in the usual care group.

INTERPRETATION: In this prespecified subgroup analysis in patients with recently diagnosed atrial fibrillation and a history of stroke, the effects of early rhythm control were consistent with the findings of the primary analysis. As the evidence from this subgroup analysis is considered supportive and exploratory, further research is needed to confirm the safety and efficacy of this approach in patients with a history of stroke.

FUNDING: German Ministry of Education and Research, German Center for Cardiovascular Research (DZHK), Atrial Fibrillation Network (AFNET), European Heart Rhythm Association, St Jude Medical-Abbott, Sanofi, and the German Heart Foundation.

Discipline Area Score
Family Medicine (FM)/General Practice (GP) 6 / 7
General Internal Medicine-Primary Care(US) 6 / 7
Hospital Doctor/Hospitalists 6 / 7
Internal Medicine 6 / 7
Cardiology 6 / 7
Neurology 5 / 7
Comments from MORE raters

Cardiology rater

Among patients with atrial fibrillation, those with a history of stroke are at high risk for recurrent stroke or other adverse cardiovascular outcomes. Early rhythm control appears to be effective and safe.

Cardiology rater

AF and stroke are serious conditions that are commonly seen by a wide range of doctors, so this information will be of interest. It suggests that the benefit of rhythm control over rate control in patients recently found to have AF demonstrated in the index trial (EAST-AFNET) is also seen in the subgroup of patients who had a previous stroke. As a subgroup analysis, there are the usual pitfalls around interpretation. I suspect the stroke patients included in the trial are likely to be a fairly select group of stroke patients (e.g., good functional status, not a lot of comorbidity). It cannot be said that the approach to treating AF in these patients should now change to rhythm control, but it would be reasonable to say that it appears safe and may be worthwhile in select stroke patients.

Family Medicine (FM)/General Practice (GP) rater

Baseline characteristics of intention-to-treat population are presented in detail; however, no proportion comparisons are presented. It should be noted that: 1. "Valve disease" is 19% more frequent in the “Usual care” group, which is a statistically significant difference (Chi-squared 7.936, DF=1, p=0.0048); and 2. treatment with "Antiplatelet drugs" is also 12% more frequent in the “usual care” group, which is again a statistically significant difference (Chi-squared 4.7, DF=1, p=0.0302). In other words, we must be cautious in generalizing these results and conclusions because the group of "Usual care" has more patients with valve disease and more prescriptions with antiplatelet drugs.

General Internal Medicine-Primary Care(US) rater

If we can decrease the risk for embolic events opposed to using antiplatelet drugs in this population that is at risk for falls and subsequent injury that can lead to death, that is significant. Obviously, there is a need for more studies, but this is encouraging.

General Internal Medicine-Primary Care(US) rater

Very important information that should guide management for primary care patients with stroke and recent onset of Afib.

Neurology rater

Early rhythm control approach for atrial fibrillation was more advantageous than routine care. This study of a subgroup of patients with prior stroke should be understood in the context of the main study. There is limited relevance for neurologists because the rhythm control decision is largely made by cardiologists.
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