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

Nephrol Dial Transplant. 2022 Oct 19;37(11):2241-2252. doi: 10.1093/ndt/gfac214.


Background: Hypokalemia is a risk factor for drug-induced QT prolongation. Larger serum-to-dialysate potassium gradients during hemodialysis (HD) 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 HD patients newly treated with higher (citalopram, escitalopram) versus lower (fluoxetine, fluvoxamine, paroxetine, sertraline) QT-prolonging potential SSRIs, overall and stratified by baseline potassium gradient (≥4 versus <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 versus lower QT-prolonging potential SSRI use was not associated with SCD [weighted HR 1.03 (95% CI 0.86-1.24)]. However, a greater risk of SCD was associated with higher versus 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 2.17 (95% CI 1.16-4.03) versus 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 versus lower QT-prolonging SSRI use and SCD among people receiving HD. Minimizing the potassium gradient in the setting of QT-prolonging medication use may be warranted.

Keywords: SSRI; USRDS; hemodialysis; potassium gradient; sudden cardiac death.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Case-Control Studies
  • Citalopram / adverse effects
  • Cohort Studies
  • Death, Sudden, Cardiac / epidemiology
  • Death, Sudden, Cardiac / etiology
  • Dialysis Solutions*
  • Fluoxetine
  • Fluvoxamine
  • Humans
  • Paroxetine
  • Potassium
  • Renal Dialysis / adverse effects
  • Selective Serotonin Reuptake Inhibitors* / adverse effects
  • Sertraline
  • United States


  • Dialysis Solutions
  • Serotonin Uptake Inhibitors
  • Citalopram
  • Fluoxetine
  • Sertraline
  • Fluvoxamine
  • Paroxetine
  • Potassium