Gabapentinoid-induced peripheral edema and acute heart failure: A translational approach combining a nationwide pharmacovigilance study with preclinical experimental data

Abstract

Gabapentinoids are ligands of the α2-δ subunit of voltage-gated calcium channels (Cav) that have been associated with a risk of peripheral edema and acute heart failure of unknown clinical and pathophysiological characteristics. Characterize the onset patterns of gabapentinoid-induced peripheral edema and investigate the pharmacological mechanisms. All cases of peripheral edema or heart failure [MedDRA Hight-Level Term ‘total volume fluid increased’ or High-Level Group Term ‘heart failures’] involving gabapentin or pregabalin reported to the French Pharmacovigilance Centers between January 1, 1994 and April 30, 2020 were considered to describe their onset patterns (e.g., time to onset, patient comorbidities). Based on these data, we investigated the impact of gabapentinoids on the myogenic tone of rat third-order mesenteric arteries (Halpern's arteriography) and on the electrophysiological properties of rat ventricular cardiomyocytes (whole-cell voltage-clamp). A total of 58 reports were included (gabapentin n = 5, pregabalin n = 53). The female-to-male ratio was 4:1 and the median age was 77 years (IQR 57–85, range 32–95). The median time to onset were 23 days (IQR 10–54) and 17 days (IQR 3–30) for non-cardiogenic edema and acute heart failure, respectively. Whatever the type of peripheral edema, the main patient comorbidity was hypertension (17/50, 34%), they frequently occurred after a dose escalation (27/45, 60%) and the evolution was rapidly favorable after gabapentinoid discontinuation (median 7 days, IQR 5–13). On rat mesenteric arteries, gabapentinoids significantly decreased the myogenic tone to the same extent as verapamil and nifedipine. Gabapentinoids had no significant effect on Cav1.2 currents of ventricular cardiomyocytes. Gabapentinoids can cause concentration-dependent peripheral edema of early onset. While the pharmacological substrate of gabapentinoid-induced cardiac decompensation deserves further investigations, the primary mechanism of non-cardiogenic peripheral edema is vasodilatory edema secondary to altered myogenic tone, independent of Cav1.2 blockade. Clinicians should be alert to this risk and to the management of gabapentinoid-induced peripheral edema in order to limit any risk of prescribing cascade with diuretics.