A total of 1
965 valid QTc measurements were extracted from 1
333 electrocardiograms (98.4%). Of the study patients receiving a prescription of interest, 38
397 had an electrocardiogram within the 14–90 day window. Characteristics of this cohort and the proportion receiving each medication are summarised in table 1. Table 1 also indicates association between each sociodemographic and clinical feature and QTc interval. Age, race, sex, insurance, year of electrocardiogram, history of major depression, history of myocardial infarction, history of ventricular arrhythmia, history of hypertension, history of hyperlipidaemia, and Charlson comorbidity score were all significantly associated with QTc interval (P<0.01).
Table 1 Demographics and clinical features of study cohort of 38 397 adult patients with an electrocardiogram recorded 14–90 days after prescription of antidepressant or methadone between February 1990 and August 2011. Values are numbers (more ...)
Patients prescribed a medication of interest but with no QTc measurements in the exposure period were compared with those with available electrocardiograms to assess selection bias (see table A in supplementary material on bmj.com). As expected, those with an electrocardiogram in the exposure period included in the study cohort were in general older, with greater medical comorbidity and use of healthcare services than patients excluded from the study cohort because no electrocardiogram was available.
Standard thresholds at which QTc prolongation is associated with elevated risk for arrhythmia have been reported.19
To allow comparison with these reports, individuals with available electrocardiogram data were categorised according to those thresholds, which differ by sex. Supplementary fig B on bmj.com illustrates the proportion of each cohort with QTc characterised as normal, borderline, abnormal, and high. Of note, in this population 20.4% of individuals were characterised as having abnormal or high QTc values; these proportions were similar across treatment groups.
For each medication of interest, dose-QTc curves were plotted (figure) and tested for dose-response relation using a linear model adjusted for features associated with QTc (table 1). Dose was found to be a significant predictor of QTc in citalopram (adjusted beta 0.10 (SE 0.04) P<0.01), escitalopram (adjusted beta 0.58 (0.15), P<0.001), and amitriptyline (adjusted beta 0.11 (0.03), P<0.001). As expected, increasing methadone dose was also associated with increased QTc (adjusted beta 0.30 (0.06), P<0.001). Increasing doses of bupropion were found to significantly decrease QTc (adjusted beta 0.02 (0.01), P<0.05).
Mean (SD) corrected QT (QTc) interval recorded on electrocardiogram 14–90 days after prescription of antidepressant or methadone, by drug dose
Where dose was a significant predictor of QTc (table 2), post hoc pairwise tests compared each dose interval (table 3). The figure also indicates doses significantly different from the previous dose. Escalating doses with significant increases in QTc were observed in citalopram 10 mg to 20 mg (adjusted beta 9.8 (SE 1.6), P<0.001), citalopram 40 mg to 60 mg (adjusted beta 6.1 (2.1), P<0.01), escitalopram 5 mg to 10 mg (adjusted beta 11.0 (4.5), P<0.05), escitalopram 10 mg to 20 mg (adjusted beta 4.7 (1.6), P<0.01), and amitriptyline 25 mg to 50 mg (adjusted beta 3.4 (1.4), P<0.05). Sensitivity analyses restricting individuals based on refill status, exposure window and concomitant medications did not meaningfully alter the results (supplementary tables B, C, and D on bmj.com).
Table 2 Overall effect of dose of antidepressant or methadone on corrected QT (QTc) interval 14–90 days after drug prescription in cohort of 38 397 adult patients. Results are beta values (SE) from linear regression analysis
Table 3 Post hoc comparison of doses of antidepressants or methadone with an overall significant effect on corrected QT (QTc) interval in cohort of 38 397 adult patients. Results are beta values (SE) from linear regression analysis
In the within-subject crossover dose analysis, QTc was characterised before and after dose increase in 467 subjects for whom electrocardiogram data were available for multiple doses of citalopram, escitalopram, amitriptyline, bupropion, and methadone. Statistically significant increases in QTc were observed in 59 patients taking citalopram with daily dose increase from 10 mg to 20 mg (mean QTc increase 7.8 (SE 3.6) ms, adjusted P<0.05) and in 107 patients with citalopram increasing from 20 mg to 40 mg (mean QTc increase 10.3 (4.0) ms, adjusted P<0.01) but not in other dose increases (table 4). We also observed a significant decrease in QTc in 13 patients with an increased daily dose for bupropion from 100 mg to 200 mg (mean QTc decrease 19.2 (8.7) ms, adjusted P<0.05). Of note, 13.1% of patients who started taking citalopram with a QTc in the normal range shifted to “abnormal” after dose increase.
Table 4 Results of within-patient change in corrected QT (QTc) interval after escalating doses of antidepressants or methadone for drugs with a significant dose association