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Comparative Study
. 2019 Apr;30(4):611-623.
doi: 10.1681/ASN.2018101032. Epub 2019 Mar 18.

Comparative Cardiac Safety of Selective Serotonin Reuptake Inhibitors among Individuals Receiving Maintenance Hemodialysis

Magdalene M Assimon  1 , M Alan Brookhart  2 , Jennifer E Flythe  3   4
Affiliations
Comparative Study

Comparative Cardiac Safety of Selective Serotonin Reuptake Inhibitors among Individuals Receiving Maintenance Hemodialysis

Magdalene M Assimon et al. J Am Soc Nephrol. 2019 Apr.

Abstract

Background: Individuals receiving maintenance hemodialysis may be particularly susceptible to the lethal cardiac consequences of drug-induced QT prolongation because they have a substantial cardiovascular disease burden and high level of polypharmacy, as well as recurrent exposure to electrolyte shifts during dialysis. Electrophysiologic data indicate that among the selective serotonin reuptake inhibitors (SSRIs), citalopram and escitalopram prolong the QT interval to the greatest extent. However, the relative cardiac safety of SSRIs in the hemodialysis population is unknown.

Methods: In this retrospective cohort study, we used data from a cohort of Medicare beneficiaries receiving hemodialysis included in the US Renal Data System registry (2007-2014). We used a new-user design to compare the 1-year risk of sudden cardiac death among hemodialysis patients initiating SSRIs with a higher potential for prolonging the QT interval (citalopram, escitalopram) versus the risk among those initiating SSRIs with lower QT-prolonging potential (fluoxetine, fluvoxamine, paroxetine, sertraline). We estimated adjusted hazard ratios using inverse probability of treatment weighted survival models. Nonsudden cardiac death was treated as a competing event.

Results: The study included 30,932 (47.1%) hemodialysis patients who initiated SSRIs with higher QT-prolonging potential and 34,722 (52.9%) who initiated SSRIs with lower QT-prolonging potential. Initiation of an SSRI with higher versus lower QT-prolonging potential was associated with higher risk of sudden cardiac death (adjusted hazard ratio, 1.18; 95% confidence interval, 1.05 to 1.31). This association was more pronounced among elderly individuals, females, patients with conduction disorders, and those treated with other non-SSRI QT-prolonging medications.

Conclusions: The heterogeneous QT-prolonging potential of SSRIs may differentially affect cardiac outcomes in the hemodialysis population.

Keywords: SSRIs; Safety; Sudden cardiac death; hemodialysis.

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Figures

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Graphical abstract
Figure 1.
Figure 1.
Study design. Initiators of higher and lower QT-prolonging–potential SSRIs were defined as hemodialysis patients who had no record of an SSRI prescription in the previous 180 days (i.e., the SSRI washout period). Higher QT-prolonging–potential SSRIs included citalopram and escitalopram. Lower QT-prolonging–potential SSRIs included fluoxetine, fluvoxamine, paroxetine, and sertraline. The index date was defined as the date of SSRI initiation. Baseline covariates were identified in the 180-day period before the index date. Study follow-up began immediately after the index date. Rx, prescription.
Figure 2.
Figure 2.
Flow diagram depicting study cohort assembly. (a) To be included in the study, SSRI new-users had to receive in-center hemodialysis during the 180 days before SSRI initiation (i.e., baseline period) and also have continuous Medicare Part A, B, and D coverage during this period. (b) Higher QT-prolonging–potential SSRIs included citalopram and escitalopram. Lower QT-prolonging–potential SSRIs included fluoxetine, fluvoxamine, paroxetine, and sertraline. Rx, prescription.
Figure 3.
Figure 3.
Initiation of a higher versus lower QT-prolonging–potential SSRI associates with a higher 1-year risk of fatal cardiac outcomes. An on-treatment analytic approach was used in all analyses. Fine and Gray proportional subdistribution hazards models were used to estimate the association between the initiation of higher versus lower QT-prolonging–potential SSRI and the 1-year risk of fatal cardiac outcomes. Higher QT-prolonging–potential SSRIs included citalopram and escitalopram. Lower QT-prolonging–potential SSRIs included fluoxetine, fluvoxamine, paroxetine, and sertraline. Adjusted analyses controlled for baseline covariates listed in Supplemental Table 6 using IPT weighting. 95% CI, 95% confidence interval; ref., referent.
Figure 4.
Figure 4.
Initiation of a higher versus lower QT-prolonging–potential SSRI associates with a higher 1-year risk of sudden cardiac death within clinically relevant subgroups. An on-treatment analytic approach was used in all analyses. Fine and Gray proportional subdistribution hazards models were used to estimate the association between the initiation of higher versus lower QT-prolonging–potential SSRIs and the 1-year risk of sudden cardiac death within clinically relevant subgroups. Higher QT-prolonging–potential SSRIs included citalopram and escitalopram. Lower QT-prolonging–potential SSRIs included fluoxetine, fluvoxamine, paroxetine, and sertraline. Adjusted analyses controlled for baseline covariates listed in Supplemental Table 6 using IPT weighting. The square sizes of HR point estimates are proportional to the size of the subgroup. The larger the square size the larger the subgroup. Within each respective subgroup, the interaction P value was ≥0.05. 95% CI, 95% confidence interval; med, medication.
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