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Risk Assessment of QT Prolongation with Citalopram and Escitalopram: An Evidence Based Review André S. Pollmann1, Joel C. Bergman1, Katie L. Lines1 1BSc Pharm canditate, College of Pharmacy, Faculty of Health Professions, Dalhousie University Recent health advisories have identified a risk of QT prolongation with the commonly used antidepressants citalopram (Celexa®) and escitalopram (Cipralex®). Pertinent literature was searched for, uncovered, and critically assessed to determine the comparative risk of arrhythmias or death between citalopram and escitalopram. No data were found directly addressing our clinical question by evaluating the two antidepressants for their comparative risk. However, several randomized and crossover trials, as well as a cohort study, were found to address questions regarding the cardiovascular risk of each agent. Available studies indicate a dose-related lengthening of the QT interval with both antidepressants, suggesting that these agents should be used at lower doses in patients with risk factors for arrhythmias. Overall, the evidence suggests that there is no clear advantage to using escitalopram in place of citalopram to minimize the risk of QT prolongation resulting in fatal arrhythmias.
Citalopram and escitalopram have been the subject Escitalopram, the (S)-enantiomer of citalopram, is of several Health Canada and U.S. Food and Drug given at a lower dose than the racemic mixture while Administration (FDA) advisories issued since August maintaining efficacy in the treatment of unipolar 2011.1-5 They raise concern over the potential for these depression.18-20 The question as to whether this agents to cause QT prolongation. Excessive lengthening translates into a decreased risk of QTc prolongation of the heart rate-corrected QT (QTc) interval may remains unanswered. This report endeavors to in rare cases induce Torsade de Pointes (TdP), a determine if escitalopram has evidence to suggest its tachyarrhythmia associated with ventricular fibrillation, use in place of citalopram to lower the risk of QTc cardiac arrest, and in about 10 to 17% of cases, death.6,7 prolongation-related morbidity and mortality in adult As patient heart rhythm is not continuously monitored patients with cardiovascular risk factors.
and death occurs rapidly, measuring the rate of TdP and the resulting mortality is exceptionally difficult, Clinical Question especially in the outpatient setting.8 In a middle-aged patient with the QTc prolonging risk factor of heart disease and recurrent major depressive In adults, the normal QTc interval is <430 msec in males disorder previously responsive to citalopram, is and <450 msec in females.9 Prolongation above 450 escitalopram an effective and safe option compared msec and 470 msec in males and females, respectively, to citalopram to induce remission of depression while has been estimated to be associated with a two- to minimizing the risk of a serious and potentially fatal threefold increased risk of sudden cardiac death.8-10 arrhythmia? Risk factors for QTc prolongation or arrhythmias include taking multiple QTc prolonging medications, Search Strategy age greater than 65 years, heart disease, electrolyte The Cochrane Library, PubMed, EMBASE, and imbalances, and decreased systemic clearance of ClinicalTrials.gov were searched for studies pertinent to the clinical question. The keywords "citalopram", "serotonin uptake inhibitor", "long QT syndrome", Case reports and cross sectional studies suggest that and "cardiac arrhythmia" were used as medical search QTc prolongation with citalopram and escitalopram headings (MeSH). Searches of titles and abstracts were is dose-related.16,17 To address this concern, federal conducted using keywords and additionally the terms bulletins have recommend that daily doses of "escitalopram", "selective serotonin reuptake inhibitor", citalopram and escitalopram should not exceed 40 mg "QTc", and "QT prolongation". Three assessors and 20 mg, respectively, and that both agents be used at independently analyzed titles and abstracts of retrieved the lowest effective dose or avoided entirely in patients articles, and deemed 43 articles from EMBASE with risk factors.1,5 and three articles from PubMed, as potentially contributory to the question. These studies discussed DMJ • Spring 2014 • 40(2) 14 QT Prolongation with Citalopram and Escitalopram QTc prolongation or arrhythmias in the context of limit of change in QTc duration. While this may not citalopram or escitalopram. accurately represent the risk in clinical practice, theoretically 1 of every 40 patients taking citalopram We excluded non-English articles, trials reporting 20 mg/day may have a QTc duration increase of 39.1 non-quantitative or unusable data21, and studies msec from baseline. Comparatively, 1 of 40 patients examining only acute overdoses (Figure 1).22 Searching taking escitalopram 10 mg/day may experience a QTc references of the included articles yielded two additional duration increase of 29.7 msec. Moxifloxacin 400 mg/ studies that were relevant to the case.23,24 Using Web of day showed a mean increase of 13.4 msec (90% CI, 10.9 Science, we searched for relevant reviews and articles to 15.9) in the citalopram study and 9.0 msec (90% CI, citing the selected studies.16,25,26 7.3 to 10.8) in the escitalopram study. The variability in moxifloxacin's effect indicates that the degree of QTc prolongation between citalopram and escitalopram may be more similar than suggested by these studies' results (Figure 2). The FDA did not report cases of TdP or QTc changes with placebo. The inability to assess study details and patient characteristics, limits the inferences that can be drawn. The findings suggest a dose-dependent increase in QTc duration with both citalopram and escitalopram and neither agent appears safer at comparable doses. A >30 msec lengthening of the QTc interval or a duration >500 msec suggests an increased risk of arrhythmias including TdP.9 The subsequent risk of mortality in about 1 of 40 patients taking citalopram or escitalopram may be clinically significant for those with QTc prolonging risk factors.
Figure 1. Search strategy and findings.
In a 12-month RCT by Hanash et al., escitalopram 10 mg/day was compared to placebo in 240 adults with acute coronary syndromes (ACS) for prophylaxis of depression.27 ECG measurements showed no difference Two randomized controlled trials (RCTs), two crossover in QTc duration between the groups at six months and studies, and one cohort study were considered as the 12 months (P>0.10). The overall incidence of major best evidence addressing the clinical question (Table 1). cardiac events was not significantly different between The FDA summarized the results of two unpublished escitalopram and placebo (13.3% vs. 10.9%; P=0.59). crossover studies assessing QTc prolongation with Major cardiac events included recurrent acute coronary citalopram and escitalopram.5 RCTs by Hanash et al.27 syndrome (7.5% in the escitalopram group vs. 4.2% in and Lespérance et al.23 investigated escitalopram and placebo group; P=NS), need for acute revascularization citalopram therapy in patients with cardiovascular (5.0% vs. 2.5%; P=NS), and death (5.0% vs. 3.3%; P=NS).
disease. The study by Leonard et al. assessed clinical outcomes of ventricular arrhythmia and sudden death Lespérance et al. conducted a parallel group RCT (VA/SD) in a large cohort of antidepressant users.24 comparing citalopram 20 to 40 mg with matching placebo in 284 adults diagnosed with coronary artery In each blinded crossover trial analyzed by the FDA, disease (CAD) and depression.23 No statistically subjects received sequential therapy of increasing significant difference was found in mean QTc duration doses of citalopram or escitalopram, followed by between citalopram and placebo after 12 weeks (P=0.18) moxifloxacin and placebo.5 Citalopram 20 mg/day and no cases of serious QTc prolongation (>525 msec) increased QTc duration by a mean of 8.5 msec (90% were reported. This confirms that the 1 in 40 risk of CI, 6.2 to 10.8) from baseline. Escitalopram 10 mg/ potentially clinically significant QTc prolongation is day showed a mean change in QTc duration of 4.5 likely exaggerated from the theoretical assumptions msec (90% CI, 2.5 to 6.4). Based on the results, we extrapolated from the FDA studies.
calculated the standard deviation estimating the upper DMJ • Spring 2014 • 40(2) 15 QT Prolongation with Citalopram and Escitalopram herapy, PC: placebo controlled, QTc: heart rate-corrected QT interval, R: : Torsade de Pointes Mean change (90% CI) in QTc interval (msec): Citalopram 20 mg: 8.5(6.2-10.8) Citalopram 60 mg: 18.5(16.0-15.9) Moxifloxacin 400 mg: 13.4(10.9-15.9) Mean change (90% CI) in QTc interval (msec): Escitalopram 10 mg: 4.5(2.5-6.4) Escitalopram 30 mg: 10.7(8.7-12.7) Moxifloxacin 400 mg: 9.0(7.3-10.8) Mean QTc interval (msec) at baseline vs. 12 month follow-up (SD): Escitalopram: 399(26) vs. 396(29) Placebo: 398(35) vs. 388(19) Patients at baseline vs. 12 months with QTc interval >450 msec: Escitalopram: 5.0% vs. 2.5% Placebo: 5.0% vs. 0.0% One year incidence of major cardiac events, escitalopram vs. placebo: 13.3% vs. 10.9% (p=0.59) Crude incidence rate of SD or VA per 1000 person-years (95% CI): Citalopram: 3.61(3.29-3.94) Paroxetine: 3.15(2.93-3.38) Data unavailable for adjusted hazard ratio.
Mean QTc interval (msec) at baseline vs. 12 week Citalopram: 416.3(27.36) vs. 418.1(23.77) Placebo: 416.4(19.59) vs. 415.1(17.03) No evidence of difference in QTc interval between citalopram and placebo groups (p=0.18) No QTc prolongation >525 msec in either Cardiac assessments at baseline, 6 months, and 12 months. Ambulatory 24-hour ECGs.
Incident first-listed ER or inpatient diagnosis of SD/VA ECG at baseline and 12 weeks ER: emergency room, FDA: U.S. Food and Drug Administration, HAM-D: Hamilton Rating Scale for Depression, IPT: inter-personal t ective serotonin reuptake inhibitors, SNRIs: serotonin norepinephrine reuptake inhibitors, TCAs: tricyclic antidepressants, TdP Each patient received citalopram (20 mg/day and 60 mg/day), moxifloxacin 400 mg/day, and placebo Each patient received citalopram (20 mg/day and 60 mg/day), moxifloxacin 400 mg/day, and placebo 1 year treatment with either escitalopram 10 mg/day or Exposures: SSRIs, SNRIs, TCAs, lithium, and others Control: paroxetine 2 separate randomizations: 1) Clinical management with 2) 12 weeks of citalopram 20-40 mg/day (mean dose: 33.1 mg/day) or matching Table 1: Summary of best available evidence: QTc prolongation, arrhythmias, and sudden cardiac death with citalopram and escitalopram.
ACS: acute coronary syndromes, CAD: coronary artery disease, CI: confidence interval, DB: double blind, ECG: electrocardiogram, randomized, RCT: randomized controlled trial, SD: standard deviation, SD/VA: sudden death or ventricular arrhythmia, SSRIs: sel DMJ • Spring 2014 • 40(2) 16 QT Prolongation with Citalopram and Escitalopram Figure 2. FDA study: 90% confidence intervals of mean QTc interval change with citalopram, escitalopram, and moxifloxacin.5 Hanash et al. and Lespérance et al. performed RCTs Conclusion with adequate sample sizes to address efficacy of The available studies provide inconclusive data to their intervention.23,28 However, when assessing the suggest that either citalopram or escitalopram is secondary outcome of clinical QTc prolongation more likely to cause fatal arrhythmias due to QTc both studies lacked adequate power, suggesting an prolongation. There is a lack of head-to-head trials overall inability to detect QTc changes at therapeutic comparing these agent's potential to cause QTc doses. These studies contradict the FDA's findings associated mortality at therapeutic doses. that citalopram and escitalopram are associated with significant QTc changes.5 The FDA's evidence favors low doses of both citalopram and escitalopram as both agents showed dose related Leonard et al. completed a cohort study of over 3 QTc prolongation.5 Citalopram (20 mg/day) and million patients to examine the association between escitalopram (10 mg/day) may theoretically increase antidepressant exposure and hospital admission for the QTc interval by between 30 to 40 msec in 1 of VA/SD.24 Paroxetine was selected as the reference 40 patients, and therefore put those with underlying exposure to limit potential confounding by indication factors at risk of arrhythmias or sudden death.
(depression) and due to its limited effect on the QTc interval. The unadjusted incidence rate ratio of 1.14 Contrasting the FDA's findings, studies by Hanash et (95% CI, 1.02 to 1.28) versus paroxetine suggested that al.27 and Lesperance et al.23 found neither escitalopram exposure to citalopram may carry a slightly higher 10 mg/day nor citalopram 20-40 mg/day lengthened the risk of VA/SD (Relative Risk=14%). However, after QTc interval in patients at increased risk of arrhythmias adjusting for potential confounders, including age, sex, due to heart disease. Similarly, Leonard et al.24 suggest and nursing home residence, no difference in hazard that exposure to citalopram carries no greater risk of was found (data unavailable). This analysis suggests VA/SD compared to paroxetine, an antidepressant with that citalopram may not increase the risk of VA/SD a low propensity for QTc prolongation.
compared to paroxetine's baseline incidence rate of 3.15 (95% CI, 2.93 to 3.38) cases per 1000 patient years. Considering the lack of evidence to suggest escitalopram has a safer cardiovascular profile than citalopram, a reasonable approach could be to consider citalopram DMJ • Spring 2014 • 40(2) 17 QT Prolongation with Citalopram and Escitalopram 20 mg/day as a safe and effective option. Based on the management of drug-related QT interval prolongation. FDA's assessment, 20 mg/day instead of 40 mg/day is 13. Heist EK, Ruskin JN. Drug-induced arrhythmia. Circulation a prudent recommendation due to the dose related effect on the QTc interval. While not contraindicated, 14. Malik M, Camm AJ. Evaluation of drug-induced QT interval the tolerability and efficacy of escitalopram is unknown prolongation: implications for drug approval and labelling. Drug and the increased cost of therapy may compromise 15. Kanjanauthai S, Kanluen T, Chareonthaitawee P. Citalopram adherence and persistence with antidepressant therapy. induced torsade de pointes, a rare life threatening side effect. Int J Physicians should regularly screen for QTc prolonging risk factors and strongly consider an ECG at baseline and 16. Vieweg WV, Hasnain M, Howland RH, Hettema JM, Kogut C, Wood MA. Citalopram, QTc interval prolongation, and torsade after six months of therapy. In addition to counselling de pointes. how should we apply the recent FDA ruling? Am J and antidepressant therapy, patients should be advised to promptly report dizziness, palpitations, or syncope, 17. Castro VM, Clements CC, Murphy SN, Gainer VS, Fava M, as these symptoms may be indicative of cardiovascular Weilburg JB. QT interval and antidepressant use: a cross sectional study of electronic health records. BMJ 2013;346:f288.
18. Ali MK, Lam RW. Comparative efficacy of escitalopram in the treatment of major depressive disorder. Neuropsychiatr Dis Treat We would like to thank Dr. David Gardner for his 19. Cipriani A, Santilli C, Furukawa TA, Signoretti A, Nakagawa A, McGuire H. Escitalopram versus other antidepressive agents for thoughtful feedback on several drafts of this report.
depression. Cochrane Database Syst Rev 2009;2:CD006532.
20. Culpepper L. Escitalopram: A new SSRI for the treatment of depression in primary care. Prim Care Companion J Clin 1. "Antidepressant Cipralex (escitalopram): Updated information regarding dose-related heart risk." 7 May 2012. < http:// Rasmussen SL, Overo KF, Tanghoj P. Cardiac safety of citalopram: prospective trials and retrospective analyses. J Clin sc/2012/13674a-eng.php> (14 Nov 2012).
2. "Celexa (citalopram) - Association with Abnormal Heart Rhythms 22. Hayes BD, Klein-Schwartz W, Clark RF, Muller AA, Miloradovich - For the Public." 30 Jan 2012. <http://www.healthycanadians.
JE. Comparison of toxicity of acute overdoses with citalopram and escitalopram. J Emerg Med 2010;39(1):44-8.
23. Lesperance F, Frasure-Smith N, Koszycki D, Laliberte MA, van Zyl 3. "Citalopram: Health Canada reviewing dose-related heart risk." LT, Baker B. Effects of citalopram and interpersonal psychotherapy 13 Oct 2011. <http://www.healthycanadians.gc.ca/recall-alert- on depression in patients with coronary artery disease: the rappel-avis/hc-sc/2011/13549a-eng.php> (14 Nov 2012).
canadian cardiac randomized evaluation of antidepressant and 4. "FDA Drug Safety Communication: Abnormal heart rhythms psychotherapy efficacy (CREATE) trial. JAMA 2007;297(4):367- associated with high doses of Celexa (citalopram hydrobromide)." 24 Aug 2011. <http://www.fda.gov/Drugs/DrugSafety/ 24. Leonard CE, Bilker WB, Newcomb C, Kimmel SE, Hennessy ucm269086.htm> (14 Nov 2012).
S. Antidepressants and the risk of sudden cardiac death 5. "FDA Drug Safety Communication: Revised recommendations and ventricular arrhythmia. Pharmacoepidemiol Drug Saf for Celexa (citalopram hydrobromide) related to a potential risk of abnormal heart rhythms with high doses." 28 Mar 2012. <http:// 25. Howland RH. A critical evaluation of the cardiac toxicity www.fda.gov/drugs/drugsafety/ucm297391.htm> (14 Nov 2012).
of citalopram: part 1. J Psychosoc Nurs Ment Health Serv 6. Shah RR. The significance of QT interval in drug development. Br J Clin Pharmacol 2002;54(2):188-202.
26. Howland RH. A critical evaluation of the cardiac toxicity 7. Salle P, Rey JL, Bernasconi P, Quiret JC, Lombaert M. Torsades de of citalopram: part 2. J Psychosoc Nurs Ment Health Serv pointe. apropos of 60 cases. Ann Cardiol Angeiol 1985;34(6):381- 27. Hanash JA, Hansen BH, Hansen JF, Nielsen OW, Rasmussen A, 8. Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon Birket-Smith M. Cardiovascular safety of one-year escitalopram V, et al. Prevention of torsade de pointes in hospital settings: a therapy in clinically nondepressed patients with acute coronary scientific statement from the american heart association and the syndrome: results from the DEpression in patients with coronary american college of cardiology foundation. J Am Coll Cardiol ARtery disease (DECARD) trial. J Cardiovasc Pharmacol 9. Committee for Proprietary Medicinal Products. Points to 28. Hansen BH, Hanash JA, Rasmussen A, Hansen JF, Birket- consider: the assessment of the potential for QT interval Smith M. Rationale, design and methodology of a double- prolongation by non-cardiovascular medicinal products. London, blind, randomized, placebo-controlled study of escitalopram in UK: The European Agency for the Evaluation of Medicinal prevention of depression in acute coronary syndrome (DECARD) Products: Human Medicines Evaluation Unit; 1997. Trials. 2009;10:20.
10. Straus SM, Kors JA, De Bruin ML, van der Hooft CS, Hofman A, Heeringa J. Prolonged QTc interval and risk of sudden cardiac death in a population of older adults. J Am Coll Cardiol 11. Wenzel-Seifert K, Wittmann M, Haen E. QTc prolongation by psychotropic drugs and the risk of torsade de pointes. Dtsch Arztebl Int 2011;108(41):687-93.
12. Crouch MA, Limon L, Cassano AT. Clinical relevance and DMJ • Spring 2014 • 40(2) 18

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