Journal Article Annotations
2022, 3rd Quarter

Pyschonephrology

Annotations by Sahil Munjal, MD
October, 2022

The modifying effect of the serum-to-dialysate potassium gradient on the cardiovascular safety of SSRIs in the hemodialysis population: a pharmacoepidemiologic study.

PUBLICATION #1 — Pyschonephrology

The modifying effect of the serum-to-dialysate potassium gradient on the cardiovascular safety of SSRIs in the hemodialysis population: a pharmacoepidemiologic study.

Magdalene M Assimon, Patrick H Pun, Sana M Al-Khatib, M Alan Brookhart, Bradley N Gaynes, Wolfgang C Winkelmayer, Jennifer E Flythe

Abstract: Nephrol Dial Transplant. 2022 Jul 6;gfac214. doi: 10.1093/ndt/gfac214. Online ahead of print.

Background:
Hypokalemia is a risk factor for drug-induced QT-prolongation. Larger serum-to-dialysate potassium gradients during hemodialysis may augment the proarrhythmic risks of selective serotonin reuptake inhibitors (SSRIs).

Methods:
We conducted a cohort study using 2007-2017 data from the United States Renal Data System and a large dialysis provider to examine if the serum-to-dialysate potassium gradient modifies SSRI cardiac safety. Using a new-user design, we compared 1-year sudden cardiac death (SCD) risk among hemodialysis patients newly treated with higher (citalopram, escitalopram) vs. lower (fluoxetine, fluvoxamine, paroxetine, sertraline) QT-prolonging potential SSRIs, overall and stratified by baseline potassium gradient (≥4 vs. <4 mEq/L). We used inverse probability of treatment weighted survival models to estimate weighted hazard ratios (HRs) and 95% confidence intervals (CIs), and conducted a confirmatory nested case-control study.

Results:
The study included 25,099 patients: 11,107 (44.3%) higher QT-prolonging potential SSRI new-users and 13,992 (55.7%) lower QT-prolonging potential SSRI new-users. Overall, higher vs. lower QT-prolonging potential SSRI use was not associated with SCD, weighted HR of 1.03 (95% CI, 0.86-1.24). However, a greater risk of SCD was associated with higher vs. lower QT-prolonging potential SSRI use among patients with baseline potassium gradients ≥4 mEq/L, but not among those with gradients <4 mEq/L, weighted HR of 2.17 (95% CI, 1.16-4.03) vs. 0.95 (0.78-1.16). Nested case-control analyses yielded analogous results.

Conclusions:
The serum-to-dialysate potassium gradient may modify the association between higher vs. lower QT-prolonging SSRI use and SCD among people receiving hemodialysis. Minimizing the potassium gradient in the setting of QT-prolonging medication use may be warranted.

Annotation

The finding:
In this retrospective cohort study, risk for sudden cardiac death (SCD) was associated with higher(escitalopram/citalopram) versus lower QT-prolonging potential SSRI use among hemodialysis patients with a baseline potassium gradient ≥4 mEq/l [HR 2.17 (95% CI 1.16–4.03)].

Strength and weaknesses:
Strengths include the authors’ use of a large linked dataset with detailed administrative claims and clinical information including relevant biochemical indexes and dialysis treatment parameters. Particular limitations relate to the risks of residual confounding and outcome misclassification.

Relevance:
The study highlights drug–dialysis treatment interaction in patients prescribed citalopram/escitalopram. Dialyzing against larger serum-to-dialysate potassium gradients can result in transient intra- or postdialysis hypokalemia, which itself is a risk factor for QT prolongation. In addition to EKG monitoring in these patients, CL- psychiatrists should discuss with the nephrology team the benefits of reducing the potassium gradients <4 mEq/l by lowering predialysis serum potassium levels and/or raising dialysate potassium concentrations.