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Background The gabapentinoids pregabalin and gabapentin are widely used for neuropathic pain. Observational studies have linked gabapentinoid use to fluid retention and an increased risk of heart failure (HF). Pregabalin and gabapentin share a common mechanism of action via binding to α2δ subunits of neuronal voltage-gated calcium channels. However, pregabalin has higher binding affinity and greater potency than gabapentin, raising uncertainty as to whether their cardiovascular risk profiles are directly comparable. National Institute for Health and Care Excellence guidelines recommend either pregabalin or gabapentin as a first-line treatment option for neuropathic pain, without specific HF warnings. However, the British National Formulary and international bodies (the American Heart Association and European Medicines Agency) caution that pregabalin, but not gabapentin, may cause or worsen HF, particularly in older adults and those with cardiovascular disease. This difference in guidance raises uncertainty regarding whether pregabalin and gabapentin can be used interchangeably, particularly in patients with HF or cardiovascular comorbidity. We therefore undertook a novel systematic review and meta-analysis to compare HF outcomes with pregabalin versus gabapentin.Methods We identified observational cohort studies directly comparing pregabalin with gabapentin and reporting HF outcomes. The primary objective was to compare HF outcomes associated with pregabalin versus gabapentin users, examined separately as de novo HF and worsening of pre-existing HF, using population-stratified random-effects meta-analyses. All-cause mortality was assessed as a secondary outcome. Random-effects models using restricted maximum likelihood estimation and Hartung-Knapp adjustment were applied.Results Three eligible cohort studies (total n = 268,737) were included. The characteristics of the included studies are summarised in Table 1. In pooled analyses, comparative HF risk differed by underlying HF population. Among patients without prior HF, the risk of developing de novo HF was numerically higher with pregabalin users compared to gabapentin users (hazard ratio [HR] 1.45, 95% CI 0.56-3.77) ( figure 1). In contrast, among patients with established HF, pregabalin users were associated with a numerically lower risk of worsening HF compared to gabapentin users (HR 0.71, 95% CI 0.09-5.43) (figure 1). Overall, the direction of effect differed by HF population, however, neither of the pooled analyses reached statistical significance. In the secondary analysis of all-cause mortality, no statistically significant difference was observed between pregabalin and gabapentin (HR 1.36, 95% CI 0.65-2.84) (figure 2).Conclusions In this head-to-head analysis of pregabalin versus gabapentin, HF risk could not be meaningfully determined by a single comparative estimate. Instead, results varied across the studied populations defined by different baseline HF status (de novo versus worsening HF), with no statistically significant differences in either analysis. Although limited by small study numbers and imprecision, the opposing direction of comparative risk observed suggests that the cardiovascular risk profile of gabapentinoids may vary depending on the underlying HF status. These findings highlight important gaps in the existing literature and underscore the limitations of unstratified studies, emphasising the need for further population-stratified studies to allow robust comparative risk assessment and inform clinical practice.Abstract 98 Figure 1Random-effects meta-analyses of heart failure outcomes comparing pregabalin versus gabapentin, stratified by underlying heart failure status. (A) Worsening heart failure among patients with established heart failure. (B) De novo heart failure among patients without prior heart failure. Hazard ratios (HRs) greater than 1 indicate a higher risk of heart failure associated with pregabalinAbstract 98 Figure 2Random-effects meta-analyses of all-cause mortality comparing pregabalin versus gabapentin. Hazard ratios (HRs) greater than 1 indicate a higher mortality risk associated with pregabalin