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

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

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

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

Using active comparators in self‐controlled studies

Background: When self‐controlled designs are used to study the triggering of medication‐related adverse effects, time‐varying confounding by indication can occur if the indication or its severity varies over time.Objectives: We aimed to describe how self‐controlled designs might mitigate or eliminate such confounding by indication by incorporating active comparators with similar indications, illustrated by an empirical exampleMethods: Practical approaches to incorporating active comparators will be described for case‐crossover, case‐time‐control, self‐controlled case‐series and symmetry analyses.In the empirical example, we used nation‐wide data from Denmark to study the association between narrow‐spectrum penicillin and venous thromboembolism (VTE), using a case‐crossover design. Macrolide antibiotics were selected as active comparator. This example was chosen because upper respiratory infection ‐ the main indication for narrow‐spectrum penicillin and macrolides ‐ is a transient risk factor for venous thromboembolism, i.e., representing time‐dependent confounding by indication.We identified Danish VTE patients, born 1950 or earlier, during the period 1995–2012. If patients had more than one VTE, we included only the first. The focal window was the 14‐d period before VTE diagnosis. We compared the odds of exposure in that window with one reference window 29–42 days before the VTE. We counted a window as exposed if one of the two antibiotics (penicillin or macrolide) was dispensed within it. We used a Wald‐based method and an interaction term in a conditional logistic regression model to estimate the exposure odds ratio (OR) with 95% confidence limits (CI) for the narrow‐spectrum penicillin users, having the macrolide users as active comparators, i.e. adjusted for transient confounding by indication.Results: We identified 57486 patients, of whom 4898 (8.5%) were dispensed penicillin during the focal window, and 2226 (3.9%) during the reference window. Corresponding figures were 1192 (2.1% and 572 (1.0%) for macrolide antibiotics. The case‐crossover estimate for penicillin was 2.45 (CI: 2.32–2.59) and 2.22 (CI: 2.00–2.47) for macrolide antibiotics. The Wald‐based estimate for penicillin with macrolide antibiotics as active comparator was 1.10 (CI: 0.98–1.24), and the interaction‐term based estimate was 1.22 (CI: 1.07–1.39).Conclusions: The strong association of penicillin and macrolides with VTE suggests both are due mostly to time‐varying confounding by indication. Such confounding can be mitigated by applying an active comparator drug that has an similar indication

Comparing risk of major bleeding between users of different oral anticoagulants in patients with nonvalvular atrial fibrillation

AIMS: The introduction of direct oral anticoagulants (DOACs) has broadened the treatment arsenal for nonvalvular atrial fibrillation, but observational studies on the benefit–risk balance of DOACs compared to vitamin K antagonists (VKAs) are needed. The aim of this study was to characterize the risk of major bleeding in DOAC users using longitudinal data collected from electronic health care databases from 4 different EU‐countries analysed with a common study protocol. METHODS: A cohort study was conducted among new users (≥18 years) of DOACs or VKAs with nonvalvular atrial fibrillation using data from the UK, Spain, Germany and Denmark. The incidence of major bleeding events (overall and by bleeding site) was compared between current use of DOACs and VKAs. Cox regression analysis was used to calculate hazard ratios and 95% confidence intervals (CI) and adjust for confounders. RESULTS/CONCLUSION: Overall, 251 719 patients were included across the 4 study cohorts (mean age ~75 years, % females between 41.3 and 54.3%), with overall hazard ratios of major bleeding risk for DOACs vs VKAs ranging between 0.84 (95% CI: 0.79–0.90) in Denmark and 1.13 (95% CI 1.02–1.25) in the UK. When stratifying according to the bleeding site, risk of gastrointestinal bleeding was increased by 48–67% in dabigatran users and 30–50% for rivaroxaban users compared to VKA users in all data sources except Denmark. Compared to VKAs, apixaban was not associated with an increased risk of gastrointestinal bleeding in all data sources and seemed to be associated with the lowest risk of major bleeding events compared to dabigatran and rivaroxaban

Comparative effectiveness of heterologous third dose vaccine schedules against severe covid-19 during omicron predominance in Nordic countries : population based cohort analyses

OBJECTIVETo investigate the comparative vaccine effectiveness of heterologous booster schedules (ie, three vaccine doses) compared with primary schedules (two vaccine doses) and with homologous mRNA vaccine booster schedules (three vaccine doses) during a period of omicron predominance.DESIGNPopulation based cohort analyses.SETTINGDenmark, Finland, Norway, and Sweden, 27 December 2020 to 31 December 2022.PARTICIPANTSAll adults aged 218 years who had received at least a primary vaccination schedule of AZD1222 (OxfordAstraZeneca) or monovalent SARS-CoV-2 wild type (ancestral) strain based mRNA vaccines BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna), in any combination.MAIN OUTCOME MEASURESThe main outcome measure was country combined risks of covid-19 related hospital admission and death with covid-19 and additional outcomes of covid-19 related admission to an intensive care unit and SARS-CoV-2 infection. During a period of omicron predominance, these outcomes were compared in those who received a heterologous booster versus primary schedule (matched analyses) and versus those who received a homologous mRNA vaccine booster (weighted analyses). Follow-up was for 75 days from day 14 after the booster dose; comparative vaccine effectiveness was calculated as 1-risk ratio.RESULTSAcross the four Nordic countries, 1 086 418 participants had received a heterologous booster schedule of AZD1222+BNT162b2 or mRNA-1273 and 2 505 093 had received a heterologous booster schedule of BNT162b2+mRNA-1273. Compared with the primary schedule only (two doses), the vaccine effectiveness of heterologous booster schedules comprising AZD1222+BNT162b2 or mRNA-1273 and BNT162b2+mRNA-1273 was 82.7% (95% confidence interval 77.1% to 88.2%) and 81.5% (78.9% to 84.2%) for covid-19 related hospital admission and 95.9% (91.6% to 100.0%) and 87.5% (82.5% to 92.6%) for death with covid-19, respectively. Homologous mRNA booster schedules were similarly associated with increased protection against covid-19 related hospital admission (276.5%) and death with covid-19 (284.1%) compared with previous primary course vaccination only. When a heterologous booster schedule was compared with the homologous booster schedule, vaccine effectiveness was 27.2% (3.7% to 50.6%) for AZD1222+BNT162b2 or mRNA-1273 and 23.3% (15.8% to 30.8%) for BNT162b2+mRNA-1273 schedules against covid-19 related hospital admission and 21.7% (-8.3% to 51.7%) and 18.4% (-15.7% to 52.5%) against death with covid-19, respectively.CONCLUSIONHeterologous booster schedules are associated with increased protection against severe, omicron related covid-19 outcomes compared with primary course schedules and homologous booster schedules.Peer reviewe