The association between HbA1c variability and strokes in patients receiving anticoagulants

Abstract Background Diabetes, higher glycaemic level, is associated with an increased risk of stroke in patients with atrial fibrillation (AF) and is integrated into the CHA2DS2-VASc score for stroke risk prediction. However, the association between glycaemic variability and stroke risk in AF patients remains unclear. Objective To evaluate the association between glycaemic variability and stroke among diabetic and non-diabetic patients with nonvalvular AF receiving anticoagulants. Methods Newly diagnosed AF from 2013-2018 (n=8,790) were divided by their diabetes status. Variability in glycaemic, represented by coefficient of variation (CV) on HbA1c (haemoglobin A1c), was assessed by at least three HbA1c measurements following enrollment to the end of the follow-up period. Participants with ischaemic stroke (IS)/systemic embolism (SE), haemorrhagic stroke (HS) or all-cause mortality at baseline or within 1 year of enrollment were excluded. Multivariate Cox regression was performed to evaluate the association between variability in HbA1c and subsequent incident IS/SE, HS and all-cause mortality. Sensitivity analyses included defining HbA1c variability using average successive variability (ASV) and variability independent of the mean (VIM). Results Diabetes status significantly modified the relationship between HbA1c variability and risk of IS/SE (Pinteraction = 0.36)and all-mortality (Pinteraction <0.01). Greater incidence rates were observed among individuals with diabetes, compared to those without diabetes (3.74 vs. 2.41 for IS/SE, 0.54 vs. 0.33 for HS and 4.89 vs. 2.42 for all-cause mortality per 100 person years). Among those with diabetes, greater HbA1c variability was significantly associated with increased risk of IS/SE (hazard ratio [HR] = 1.21, 95% confidence interval [CI]: 1.11-1.31), all-cause mortality (HR = 1.13, 95%CI: 1.05-1.20) and HS (HR = 1.10, 95%CI: 1.02-1.23). Similar patterns were found in individuals without diabetes (IS/SE: HR = 1.28, 95%CI: 1.08-1.52; all-cause mortality: HR = 1.50, 95%CI: 1.29-1.75). However, no significant association was observed between glycemia variability and HS among those without diabetes. Results were consistent with alternative measures of HbA1c variability. Conclusion Variability in HbA1c was independently associated with the risk of IS/SE and all-cause mortality among patients with AF, regardless of diabetes status.