Patients with rheumatoid arthritis who develop atrial fibrillation may face a higher risk of ischemic stroke compared with patients without rheumatoid arthritis, according to a new nationwide registry study from Norway. The study also found that patients with rheumatoid arthritis and atrial fibrillation may be less likely to receive oral anticoagulant treatment for stroke prevention.

In the study, published in Rheumatology, investigators used data from the 2008 to 2017 Norwegian Cardio-Rheuma Register to identify 2,750 patients with rheumatoid arthritis (RA) and 158,879 patients without RA who had incident atrial fibrillation (AF) diagnosed between 2010 and 2017. A washout period from 2008 to 2009 was used to identify incident cases. The study employed a 3-month delayed entry model to exclude patients diagnosed with AF and ischemic stroke simultaneously and to allow adjustment for oral anticoagulant (OAC) use.

After a median follow-up of 2.5 years for patients with RA and 3.0 years for patients without RA:

• The unadjusted 5-year cumulative incidence of ischemic stroke was 7.3% (95% confidence interval [CI] = 5.9%–8.7%) for the patients with RA and AF vs 5.0% (95% CI = 4.9%–5.2%) for those without RA.
• In an unadjusted analysis, patients with AF and RA had a hazard ratio (HR) of 1.36 (95% CI = 1.13–1.62) for ischemic stroke compared with those without RA.
• After adjusting for age, sex, diabetes, hypertension, atherosclerotic cardiovascular disease, and OAC treatment, the HR remained elevated at 1.22 (95% CI = 1.02–1.46).
• Patients with RA and AF had a lower risk of receiving OAC treatment within 3 months of AF diagnosis (adjusted odds ratio [OR] = 0.88, 95% CI = 0.80–0.97).

The investigators also conducted subgroup analyses:

• Among men, the presence of RA was associated with an HR of 1.43 (95% CI = 1.08–1.88, P = .01) for ischemic stroke, whereas no statistically significant differences were found in women (HR = 1.09, 95% CI = 0.86–1.37, P = .48).
• In patients with hypertension, the HR was 1.23 (95% CI = 1.01–1.51, P = .04), with no statistically significant differences in those without hypertension.
• Patients with RA not receiving OAC had an HR of 1.44 (95% CI = 0.98–2.10, P = .06) compared with those who didn't have RA, but this did not reach statistical significance.

The investigators further evaluated the impact of antirheumatic treatment on stroke risk in patients with RA. In an adjusted analysis, those with RA using DMARDs had an HR of 0.86 (95% CI = 0.59–1.25) compared with those not using DMARDs, a nonsignificant difference.

Mortality during follow-up was high in both groups but higher in the patients with RA (29.2%) compared with controls (21.5%). Mean CHA2DS2-VASc scores were higher in the RA group (3.40) compared with the non-RA group (2.76), indicating a higher baseline stroke risk. The most common type of ischemic stroke was cerebral infarction due to unspecified occlusion or stenosis (ICD-10 I63.5). In secondary analyses, the risk for ischemic stroke due to embolism of cerebral arteries was not significantly elevated, but the HR for other and unspecified ischemic strokes was 1.32 (95% CI = 1.06–1.64).

The investigators noted several potential mechanisms for the increased stroke risk in patients with RA and AF. These include inflammation-related prothrombotic effects like endothelial injury and hypercoagulability, RA-related atrial myopathy predisposing to thromboembolism, and traditional cardiovascular risk factors that are more prevalent in those with RA. They also mentioned that glucocorticoid use, common in RA treatment, may increase cardiovascular event risk.

Strengths of the study included its nationwide design and generalizability to countries with similar populations and health care systems. Limitations include lack of data on RA disease activity, inability to reliably distinguish cardioembolic stroke, and potential confounding from unmeasured factors such as smoking and obesity.

The investigators emphasized the need for improved stroke prevention in patients with AF and RA, including both increased OAC coverage and better cardiovascular risk factor control.

"Future studies are warranted to explore the effect of implementation of RA as a factor in CHA2DS2-VASc score, and whether increasing OAC coverage among [patients with] AF [and] RA would aid in preventing ischemic strokes," the study authors underscored. 

Additionally, they called for studies with more detailed clinical and imaging data to better characterize stroke subtypes in this population.

The nationwide cohort study was supported by the Research Council of Norway, FOREUM Foundation for Research in Rheumatology, and other nonprofit funders. The authors reported disclosures related to pharmaceutical companies.