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. 2022 Sep;15(9):2105-2115.
doi: 10.1111/cts.13319. Epub 2022 Jun 22.

Serious arrhythmia in initiators of citalopram, escitalopram, and other selective serotonin reuptake inhibitors: A population-based cohort study in older adults

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Serious arrhythmia in initiators of citalopram, escitalopram, and other selective serotonin reuptake inhibitors: A population-based cohort study in older adults

Mia Aakjaer et al. Clin Transl Sci. 2022 Sep.

Abstract

The selective serotonin reuptake inhibitors (SSRIs) citalopram and escitalopram are associated with QT prolongation, which increases the risk of serious arrhythmia. Consequently, regulatory agencies issued safety warnings in 2011. This study aimed to investigate the risk of serious arrhythmia following initiation of citalopram or escitalopram compared to other SSRIs and the risk in the periods before and after the warnings were issued. We conducted a series of nationwide cohort studies emulating a target trial using Danish healthcare register data from January 1, 2002, to December 31, 2016. We included patients (aged ≥65 years) who filled an SSRI prescription with a 1-year washout period before the index date. The outcome was an event of serious arrhythmia. Individuals were followed for a maximum of 6 months using an intention-to-treat approach. Log-binomial regression analyses were performed, estimating risk ratios (RRs) and 95% confidence intervals (CIs) adjusting for age and sex, comorbidities, and comedications with propensity scores. Dose-response effects were not investigated because dosage instructions were not available. We included 167,366 (146,014 individuals), 40,113 (37,069 individuals), and 50,281 (44,754 individuals) person-trials of citalopram, escitalopram, and other SSRIs, respectively. In total, there were 228 events of serious arrhythmia. No difference in risk was observed in the entire study period for either citalopram (0.87 [0.62-1.22]) or escitalopram (0.85 [0.53-1.40]). We identified lower point estimates after the safety warning, RR 0.54 (95% CI 0.31-0.93) for citalopram and 0.58 (0.20-1.63) for escitalopram. Initiation of citalopram and escitalopram was not associated with an increased risk of serious arrhythmia. However, lower point estimates were observed after the safety warning.

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Conflict of interest statement

At the time of the study, M.L.D.B. was an employee of the Copenhagen Centre for Regulatory Science (CORS). CORS is a cross‐faculty university‐anchored institution involving various public (Danish Medicines Agency, Copenhagen University) and private (Novo Nordisk A/S, Lundbeck A/S, Ferring pharmaceuticals A/S, LEO pharma A/S) stakeholders as well as patient organizations (Rare Diseases Denmark). The center is purely devoted to the scientific aspects of the regulatory field and has a patient‐oriented focus, and the research is not a company‐specific product or directly company related. Currently, M.L.D.B. is employed by Utrecht University to conduct research under the umbrella of the Utrecht Centre for Pharmaceutical Policy and Regulation. This center receives no direct funding or donations from private parties, including the pharma industry. Research funding from public–private partnerships (e.g., IMI, The Escher Project; http://escher.lygature.org/), is accepted under the condition that no company‐specific study is conducted. The center has received unrestricted research funding from public sources (e.g., World Health Organization, Netherlands Organization for Health Research and Development, the Dutch National Health Care Institute, EC Horizon 2020, the Dutch Medicines Evaluation Board, and the Dutch Ministry of Health). M.An. has participated in research projects funded by AstraZeneca, H. Lundbeck & Mertz, Novartis, and Pfizer, and has received fees for leading courses and teaching from Atrium, the Danish Association of the Pharmaceutical Industry. All other authors declared no competing interests for this work.

Figures

FIGURE 1
FIGURE 1
Flow chart from initiators of selective serotonin reuptake inhibitors (SSRIs) to the final cohort.
FIGURE 2
FIGURE 2
Repeated inclusions. formula image Prescription included as a person‐trial (eligibility, exposure washout, and exclusion criteria fulfilled); formula image Prescription not included (criteria not fulfilled); ● Outcome within 6 months after the index date; ○ Censoring (death, emigration, end of follow‐up, or end of study); formula image 1‐year washout for the exposure.

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