Ivabradine-associated atrial fibrillation: proarrhythmic effect or enhanced detection? A combined meta-analysis and FAERS disproportionality analysis
A Spadotto, M Fusaroli, M Carelli, E Nardi, M Amadori, G Massaro, V De Angelis, M Gatti, E Raschi, E Poluzzi, I DiembergerAbstract
Background
Prior randomized trials and meta-analyses have reported a higher incidence of atrial fibrillation among patients receiving ivabradine. However, these studies were not focused on AF diagnosis, therefore, no specific monitoring approach was performed and the diagnosis was symptoms-driven, carried out secondary to thromboembolic events, or during pre-specified follow-up visits. Furthermore, ivabradine's higher specificity for the sinoatrial node, with minimal effect on the atrioventricular node, may increase the heart rate gap between sinus rhythm and AF, enhancing AF symptoms, and thus supporting its diagnosis.
Purpose
Taken together, these observations leave open the question of whether the ivabradine-AF association reflects a true proarrhythmic effect or, instead, heightened recognition of AF episodes. If this hypothesis is true, an earlier diagnosis of AF, and subsequent earlier prophylaxis with anticoagulants, may result in a reduced incidence of ischemic cerebrovascular events.
Methods
In the absence of direct evidence to validate this hypothesis, we evaluated the available data triangulating different approaches: first, a meta-analysis of published clinical trials, and second, a disproportionality analysis of individual case safety reports in the FDA Adverse Event Reporting System (FAERS). To contextualize ivabradine’s signal in the pharmacovigilance analysis, β-blockers were included as a comparator group, given their known dromotropic effects on the atrioventricular node.
Results
From 555 studies screened in the meta-analysis, only three were considered eligible. Ivabradine was associated with a higher incidence of atrial fibrillation compared with the control group (RR 1.25; 95% CI 1.05–1.48; p = 0.01); however, this increase did not translate into a higher rate of ichemic cerebrovascular events (RR 0.90; 95% CI 0.71–1.13; p = 0.37) (Figure 1). In the FAERS analysis, across all subgroups defined by the approved indications for ivabradine, AF was disproportionately reported with both ivabradine and beta-blockers, whereas ischemic cerebrovascular events were disproportionately reported only with beta-blockers (Figure 2).
Conclusion
Our findings consistently show an association between ivabradine and AF, without a corresponding signal for ischemic cerebrovascular events. This pattern aligns with the hypothesis that ivabradine could facilitate AF recognition, potentially enabling earlier anticoagulation, rather than directly promoting AF onset. This proposed mechanism is biologically plausible, yet remains inferential and cannot be established with the current evidence. Prospective studies with continuous ECG monitoring and standardized outcome assessment will be essential to clarify the temporal dynamics and mechanistic link between ivabradine exposure, AF detection and cerebrovascular risk.