Association between gabapentinoids and oedema treated with loop diuretics: A pooled sequence symmetry analysis from the USA and Denmark

Abstract

Aims To assess the gabapentinoid–oedema–loop diuretic prescribing cascade in adults using large administrative health care databases from the USA and Denmark. Methods This study used a sequence symmetry analysis to assess loop diuretic initiation before and after the initiation of gabapentinoids among patients aged 20 years or older without heart failure or chronic kidney disease. Data from MarketScan Commercial and Medicare Supplemental Claims databases (2005 to 2019) and Danish National Prescription Register (2005 to 2018) were analyzed. Use of loop diuretics associated with initiation of selective norepinephrine reuptake inhibitors (SNRI) was used as a negative control. We assessed the pooled temporality of loop diuretic initiation relative to gabapentinoid or SNRI initiation across the 2 countries. Secular trend‐adjusted sequence ratios (aSRs) with 95% confidence intervals (CIs) were calculated using data from 90 days before and after initiation of gabapentinoids. Pooled ratio of aSRs were calculated by comparing gabapentinoids to SNRIs. Results Among the 1 511 493 gabapentinoid initiators (Denmark [n = 338 941]; USA [n = 1 172 552]), 20 139 patients had a new loop diuretic prescription 90 days before or after gabapentinoid initiation, resulting in a pooled aSR of 1.33 (95% CI 1.06–1.67). The pooled aSR for the negative control (i.e., SNRI) was 0.84 (95% CI 0.75–0.94), which resulted in a pooled ratio of aSRs of 1.58 (95% CI 1.23–2.04). Pooled estimated incidence of the gabapentinoid–loop diuretic prescribing cascade was 8.14 (95% CI, 1.92–34.49) events per 1000 patient‐years. Conclusion We identified evidence of the gabapentinoid–oedema–loop diuretic prescribing cascade in 2 countries.

Which older adults are at highest risk of prescribing cascades? A national study of the gabapentinoid–loop diuretic cascade

“…Our findings confirm the presence of the gabapentinoid–LD prescribing cascade in the US veteran population, as previously identified in other studies from the United States, Canada, and Denmark 8,11 . Prior studies have used both PSSA and retrospective cohort designs to examine this particular cascade.…”

“…Importantly, one should interpret both findings with caution given the risk of multiple hypothesis testing. In general, these findings extend prior PSSA work on the gabapentinoid–LD cascade by Vouri et al, 11 which took a univariable approach to examining heterogeneity of effects between subgroups (e.g., by stratification). Despite the previously discussed salient differences in populations between our studies, in their stratified analysis, results were generally concordant with those presented here, with little variance in stratified aSR estimates around an overall study aSR of 1.24 (for a 180‐day follow‐up window).…”

Pain management considerations in patients living with both pain syndromes and cardiovascular diseases and disorders

“…Similar to CCBs, the addition of loop diuretics to help mitigate gabapentinoid-induced edema is not well studied, may not be beneficial, and may result in increasing the risk of AEs such as electrolyte and/or pH disturbances. 13,14 In patients with a risk for or with pre-existing HF, limited data describe the safety of the use of gabapentinoids in HF, despite the risk for gabapentinoid-induced peripheral edema. 12 Other pain management options should be considered in patients with HF.…”

Diuretics, SGLT2 inhibitors and falls in older heart failure patients: to prescribe or to deprescribe? A clinical review

“…In fact, one of the most common prescribing cascades is initiation of a loop diuretic for ankle edema after starting a calcium channel blocker (e.g., amlodipine) that is erroneously considered to be caused by new-onset HF instead of a drug side effect [ 26 ]. Often overlooked, but also relevant to consider in this regard is the gabapentinoid–oedema–loop diuretic prescribing cascade [ 27 ]. Not only is diuretic therapy not indicated in this setting, but it may also even be harmful by causing neurohumoral activation leading to secondary aldosteronism and sodium retention.…”