Limited Evidence for Risk Factors for Proarrhythmia and Sudden Cardiac Death in Patients Using Antidepressants: Dutch Consensus on ECG Monitoring

Limited Evidence for Risk Factors for Proarrhythmia and Sudden Cardiac Death in Patients Using... Drug Saf (2018) 41:655–664 https://doi.org/10.1007/s40264-018-0649-z LEADING ARTICLE Limited Evidence for Risk Factors for Proarrhythmia and Sudden Cardiac Death in Patients Using Antidepressants: Dutch Consensus on ECG Monitoring 1,2,3 2,4 1,5 6,7 • • • • Mirjam Simoons Adrie Seldenrijk Hans Mulder Tom Birkenha ¨ ger 8 9 10 • • • Mascha Groothedde-Kuyvenhoven Rob Kok Cornelis Kramers 11,12 2 3,13 14,15 • • • • Wim Verbeeck Mirjam Westra Eric van Roon Roberto Bakker 2,16,17 Henricus Ruhe ´ Published online: 26 February 2018 The Author(s) 2018. This article is an open access publication Abstract Currently, there is a lack of international and recommendations on the management of QT(c) prolonga- national guidelines or consensus documents with specific tion (with antidepressant treatment) emphasize that special recommendations for electrocardiogram (ECG) screening attention should be given to high-risk patients; however, and monitoring during antidepressant treatment. To make a clinicians are in need of more concrete suggestions about proper estimation of the risk of cardiac arrhythmias and how to select patients for ECG screening and monitoring. sudden (cardiac) death during antidepressant use, both the Based on a review of the literature, a Dutch multidisci- drug and patient-specific factors should be taken into plinary expert panel aimed to formulate specific guidelines account; however, solid evidence on how this should be to identify patients at risk for cardiac arrhythmias and done in clinical practice is lacking. Available sudden death by developing a consensus statement regarding ECG screening before, and monitoring during, antidepressant use. We first reviewed the literature to Mirjam Simoons and Adrie Seldenrijk share first authorship. identify the relative risks of various risk factors on cardiac arrhythmia and sudden (cardiac) death during antidepres- Roberto Bakker and Henricus Ruhe´ share senior authorship. sant use. These relative contributions of risk factors could Electronic supplementary material The online version of this not be determined since no systematic reviews or meta- article (https://doi.org/10.1007/s40264-018-0649-z) contains supple- analyses quantitatively addressed this topic. Because mentary material, which is available to authorized users. Department of Clinical Pharmacy, Deventer Hospital, & Henricus Ruhe Deventer, The Netherlands h.g.ruhe@umcg.nl Department of Old Age Psychiatry, Parnassia Psychiatric Department of Clinical Pharmacy, Wilhelmina Hospital Institute, The Hague, The Netherlands Assen, Assen, The Netherlands Department of Internal Medicine, Radboudumc, Nijmegen, Department of Psychiatry, Interdisciplinary Centre for The Netherlands Psychopathology and Emotion Regulation, University Vincent van Gogh Institute for Psychiatry, ADHD and Medical Centre Groningen, University of Groningen, Autism Circuit, Venray, The Netherlands Groningen, The Netherlands Department of Pharmacology and Toxicology, Radboudumc, Unit of Pharmacotherapy, -Epidemiology and -Economics, Nijmegen, The Netherlands Department of Pharmacy, University of Groningen, Groningen, The Netherlands Department of Clinical Pharmacy and Clinical Pharmacology, Medical Centre Leeuwarden, Leeuwarden, Department of Research and Innovation, GGZ InGeest, The Netherlands Amsterdam, The Netherlands Psychiatric Centre GGz Centraal, Amersfoort, The Psychiatric Hospital GGZ Drenthe, Assen, The Netherlands Netherlands Department of Psychiatry, Erasmus Medical Centre, Department of Psychiatry and Psychology, South Limburg Rotterdam, The Netherlands Mental Health and Teaching Network, Maastricht University Collaborative Antwerp Psychiatric Research Institute Medical Centre, Maastricht, The Netherlands (CAPRI), University of Antwerp, Antwerp, Belgium 656 M. Simoons et al. evidence was insufficient, additional expert opinion was death as a consequence of all cardiac arrhythmias in gen- used to formulate recommendations. This resulted in eral occurs even more rarely [1]. However, the tragic readily applicable recommendations for clinical practice anecdotes of physically healthy patients encountering car- for selection of high-risk patients for ECG screening and diac arrest and sudden (cardiac) death after the use of monitoring. ECG screening and monitoring is recom- psychotropic drugs have underscored that some of these mended before and following the start of QTc-prolonging drugs may increase the risk of arrhythmias. This proar- antidepressants in the presence of vulnerability to QTc rhythmic effect is often marked by a prolongation of the prolongation or two or more risk factors (age[65 years, QT interval/QTc interval (QT interval corrected for heart female sex, concomitant use of a QTc-prolonging drug or rate) on an electrocardiogram (ECG) [2]. concomitant use of a drug that influences the metabolism of Of the psychotropic drugs, antipsychotics are well a QTc-prolonging drug, cardiac disease, excessive dosing known for their QT(c)-prolonging effects and association and specific electrolyte disturbances). with TdP and sudden cardiac death, although the available evidence may not support this reputation per se [3]. The incidence rate of sudden cardiac death in users of antipsychotics was 2.9 per 1000 patient-years—a signifi- Key Points cantly doubled risk compared with (non-psychiatric) non- users [3]. Some antidepressants have proven to also pro- Evidence from systematic reviews and meta- long the QT(c) interval. Although a recent meta-analysis analyses with respect to risk factors for showed significant QTc prolongation by tricyclic antide- antidepressant-induced cardiac arrhythmia or sudden pressants (TCAs; doxepin, nortriptyline and amitriptyline) (cardiac) death is insufficient to generate relative and some selective serotonin reuptake inhibitors (SSRIs; risks for individual risk factors. citalopram, escitalopram and sertraline) relative to placebo We present clinically applicable consensus [4], CredibleMeds, the internationally renowned source for guidelines for the selection of high-risk patients for evidence-based classification of drugs according to their electrocardiogram (ECG) screening and monitoring QTc-prolonging abilities, only classifies citalopram and during antidepressant use. escitalopram as antidepressant drugs with a known risk of TdP, and clomipramine, desipramine, imipramine, nor- ECG screening and monitoring is recommended triptyline, mirtazapine, trimipramine and venlafaxine as before and following the start of QTc-prolonging antidepressants with a possible risk of TdP [5]. Moreover, antidepressants in the presence of known the US FDA has issued several drug safety communica- vulnerability to QTc prolongation or two or more tions, including for citalopram in 2011 and 2012. The risk factors (age[65 years, female sex, concomitant warnings stated that citalopram use could lead to abnormal use of a QTc-prolonging drug or concomitant use of heart rhythms, and prescription doses should not exceed a drug that influences the metabolism of a QTc- 40 mg/day in adults and 20 mg in patients[65 years of prolonging drug, cardiac disease, excessive dosing age [6, 7]. and specific electrolyte disturbances). To make a proper estimation of the risk of arrhythmia, the combination of characteristics of the antidepressant therapy and patient-specific factors should be taken into account. A number of risk factors that add to the arrhyth- mia risk, including non-cardiac risk factors, have been 1 Introduction proposed, including female sex, older age, (ischemic) heart disease or a history thereof, electrolyte disturbances (in- The effect of psychotropic drugs on cardiac repolarization cluding hypomagnesemia, hypokalemia and hypocal- has increasingly gained attention in research and clinical cemia), pharmacokinetic and pharmacodynamic genetic practice over the last 2 decades. The absolute risk of car- factors, congenital long QTc syndrome, and a range of diac arrhythmia, such as Torsade de Pointes (TdP), is other medical conditions [8–11]. Several studies aimed to generally low [14 per 10,000 patients over 1 year (95% verify and synthesize the available evidence for QTc pro- confidence interval 11–17/10,000)], and sudden cardiac longation into a risk score for use in non-psychiatric hos- pitalized patients [12, 13]. In addition, it has been shown that the risk for arrhythmia increases with increasing Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, UK numbers of such risk factors [8–10]; however, the relative risks of the individual risk factors for the outcome Department of Psychiatry, Radboudumc, Nijmegen, The arrhythmia are still unclear. Netherlands ECG monitoring in Patients Using Antidepressants 657 Apart from the ECG monitoring recommendations in the nursing specialist, a patient representative, three (hospital) Summary of Product Characteristics (SmPC) for individual pharmacists, and a postdoctoral researcher. QT(c)-prolonging antidepressant drugs, there are no clear and concrete national or international guidelines on if, 2.2 Literature Search when, and how often an ECG should be performed before and during treatment with antidepressant drugs. In the In order to retrieve relevant literature as a base for our Dutch multidisciplinary guideline for depression, only with recommendations, two authors (AS and MS) searched for TCA treatment in elderly patients is an ECG recommended studies addressing the relative risks of risk factors (such as before the start of treatment (although this is to rule out older age and female sex) for cardiac arrhythmia and contraindications such as a right bundle branch block to sudden (cardiac) death, associated with antidepressant use. assist in drug choice, which is not the focus of this con- We did not use a restriction in the time period of publi- sensus document) and ECG monitoring with nortriptyline cation and applied no language restrictions. For practical treatment in elderly with cardiac risk [14]. Although some reasons and because of time restrictions for the project, we of the available international depression guidelines do not limited our search to systematic reviews and meta- mention ECG monitoring with antidepressant treatment analyses. [15, 16], other depression guidelines and some consensus We conducted a search of MEDLINE using the search documents for the management of QT(c) prolongation strategy ‘‘Psychotropic Drugs’’[MeSH] AND ((((Arrhyth- emphasize that special attention should be given to ‘high- mias, Cardiac[MeSH] OR arrhythmi*[tiab] OR proar- risk’ patients in order to prevent unfavorable cardiac out- rhythmi*[tiab] OR long QT[tiab] OR (prolong*[tiab] AND comes [8, 10, 17–19]. For example, in a consensus docu- QT[tiab]) OR torsade de pointes[tiab] OR torsades de ment, Dodd and colleagues suggest ECG monitoring pointes[tiab] OR Death, Sudden, Cardiac[MeSH] OR car- during the use of TCAs [20]. They also recommend con- diac death[tiab] OR cardiac mortality[tiab] OR ‘‘Cardio- sidering ECG monitoring during SSRI and serotonin vascular Diseases/mortality’’[MeSH]) AND (drug- noradrenaline reuptake inhibitor (SNRI) treatment in ‘high- induced[tiab] OR drug effects[sh] OR adverse effects[sh])) risk’ individuals, although they consider it usually unnec- AND (Risk factors[MeSH] OR risk factors[tiab] OR essary [20]. However, how ‘high-risk’ must be quantified prognost*[tiab] OR predict*[tiab])) AND (systematic*[- in clinical practice remains an enigma that hampers tiab] OR review*[tiab] OR meta-analysis[tiab] OR Meta- implementation of such recommendations in clinical Analysis[ptyp] OR systematic[sb])). We used the broader practice. term ‘psychotropic drugs’ instead of antidepressant-speci- Therefore, we aimed to answer the following important, fic search terms because a pilot search showed insufficient unanswered questions in order to prevent cardiac arrhyth- studies on risk factors for cardiac arrhythmia and sudden mia and sudden (cardiac) death during antidepressant use: (cardiac) death when we used antidepressants in the search. (1) should the ECG be monitored with antidepressant Bibliographies of retrieved studies were scanned for addi- treatment, and (2) if so, for which patients (with which risk tional systematic reviews and meta-analyses. We per- factors), when, and how often? formed the last update of the search on 14 March 2017. 2.3 Selection Criteria 2 Methods The study selection was performed independently by two 2.1 The Multidisciplinary Expert Panel authors (AS and MS) and discrepancies were resolved through discussion. We selected systematic reviews and In 2015, the Dutch Network for Quality Development in meta-analyses of studies in (older) adult patients using Mental Health Care funded the development of recom- psychotropic drugs registered in The Netherlands. Papers mendations about the prevention, monitoring, and treat- limited to overdose, intoxication, supratherapeutic dosage ment of side effects of psychotropic drugs. A or antidepressants as add-on intervention were excluded. In multidisciplinary expert panel for antidepressant drugs our selection, we focused on cardiac arrhythmia and sud- addressed the association between the use of antidepres- den (cardiac) death as outcomes and excluded publications sants and proarrhythmic effects and related ECG moni- solely on QTc interval as a surrogate measure for cardiac toring issues. The expert panel for antidepressants arrhythmia and sudden (cardiac) death. The latter was consisted of four psychiatrists (two being specialized in the applied because QTc intervals are of limited value due to treatment of children/adolescents or elderly patients, one the use of different formulas to correct for heart rate (e.g. additionally in training as a clinical pharmacologist), a Bazett or Fridericia) and because the relationship between general practitioner, an internist clinical pharmacologist, a drug-induced QTc prolongation and the likelihood of 658 M. Simoons et al. arrhythmia appears to be, at best, modest and neither linear by psychotropic drugs, mainly, but not exclusively, by nor straightforward [21, 22]. Eligible studies should report antipsychotics (not further specified). Of the psychotropic on the risk for cardiac arrhythmia and sudden (cardiac) drug-induced TdP cases, 71.4% were female, 44.7% used death in association with risk factors [e.g. age, sex, cardiac additional drugs that caused drug interactions (i.e. impairs disease, electrolyte disturbances, prolonged QT(c) interval the metabolism of QT-prolonging drugs or concomitant use (syndrome), use of QT(c)-prolonging drugs]. of two or more QT-prolonging drugs), 43.1% had existing cardiac disease, 27% used an excessive dose (leading to 2.4 Formulation of Recommendations drug toxicity but excluding cases of suicidal overdose), 17.9% had hypokalemia, and 17.1% had a vulnerability to In order to formulate recommendations, the multidisci- QT prolongation (familial history of long QT syndrome, plinary expert panel received a summary of extracted data history of drug-induced TdP, prolonged QT interval before from selected studies. The odds ratios, relative risks and/or drug administration). Cases using psychotropic drugs had, prevalences of cardiac arrhythmia and sudden (cardiac) on average, 2.2 risk factors. No odds ratios for the different death associated with the investigated risk factors were risk factors were given. presented for each review/meta-analysis. This evidence A study by Astro¨m-Lilja et al. investigated the preva- served as input for discussion on the indication and timing lence of a small set of risk factors for arrhythmia in drug- for ECG screening and monitoring at treatment initiation induced TdP [26]. Since Zeltser et al. did not assess age as and during use of antidepressants. When consensus was a risk factor, the study by Astrom-Lilja et al. was consid- reached, each recommendation was graded evidence level ered of substantial added value for the expert panel, despite 1–4 according to the Dutch criteria for evidence-based the fact that it was not a systematic review or meta-anal- guideline development (EBRO), based on the Appraisal of ysis. This series of 88 cases was based on data from the Guidelines Research and Evaluation (AGREE) Collabora- Swedish pharmacovigilance database, which was not tion [23–25]. restricted to psychotropic drugs [8/88 (9%) used antide- pressants]. The age of the TdP cases ranged from 15 to 90 years, with the median age being 74 years. Seventy-two 3 Results of the Literature Research percent of the TdP cases were over 65 years of age. Existing heart disease, female sex, and hypokalemia were We retrieved 100 publications of potential systematic present in 90, 70, and 12% of cases, respectively, while two reviews and/or meta-analyses (see electronic supplemen- or more established risk factors were present in 85% of tary material). Seven titles and abstracts appeared to match cases (75/88). our inclusion criteria; all seven studies were in English. Based on their full-text, four publications met our selection criteria [26–29]. The major reasons for exclusion of pub- 4 Considerations of the Expert Panel lications were failure to meet our population criterion, no investigation of risk factors, or solely outcomes other than In order to translate the available evidence to recommen- cardiac arrhythmia and sudden (cardiac) death. dations for daily clinical practice, we addresses several In a systematic review of TdP cases, Meyer-Massetti issues. et al. investigated the prevalences of a predefined set of risk First, the expert panel concluded that the relative con- factors (age, sex, dose, electrolyte imbalance, cardiac dis- tributions of risk factors to cardiac arrhythmias and sudden ease, concomitant proarrhythmic drugs and other drugs (cardiac) death during antidepressant use could not be influencing cardiac function and baseline QTc) in 54 determined since no systematic reviews or meta-analyses patients with intravenous administration of the antipsy- addressed this topic specifically. chotic haloperidol [27]. Vieweg et al. provided prevalences Second, the absence of a reference group (e.g. drug-free of various risk factors in only a small number of TdP cases TdP cases or patients using psychotropic drugs who did not (n = 4) associated with the antipsychotic risperidone [28]. develop TdP) in the included reports hampered us to put Because of the low number of cases and the focus on the prevalences of risk factors into perspective and/or antipsychotics, the results of these studies were not gen- calculate odds ratios or relative risks. Therefore, it is eralizable to patients using antidepressants and these two impossible to draw firm conclusions on the relative systematic reviews were therefore excluded. importance of certain factors or the definition of a high-risk Zeltser et al. performed a systematic review of TdP population for ECG screening and monitoring. cases and described the prevalence of six risk factors for Third, we took the average time to steady state into arrhythmia in 249 cases of TdP induced by non-cardiac account when drafting the advice about the timing of the drugs [29]. In brief, 70 of these cases (28.1%) were caused follow-up ECG after reaching the target dose of treatment ECG monitoring in Patients Using Antidepressants 659 with a QTc-prolonging antidepressant. Time to steady state 2. has two or more of the risk factors listed below is four to five times the half-life of the drug, which is (based on the two reviews from the literature approximately 1 week for antidepressant drugs. search discussed above [26, 29]): Fourth, the expert panel would like to point out that the – age over 65 years; current literature is inconclusive regarding the intraindi- – female sex; vidual circadian variation in the length of the QTc interval, – concomitant use of a QTc-prolonging drug which may range from\10 ms to up to 75–100 ms (list of drugs with a known risk of TdP [21, 30, 31]. It is therefore preferable to register ECG according to CredibleMeds [5]) or concomi- recordings at fixed time points during the day in order to tant use of a drug that influences the avoid bias in the change between two subsequent ECGs as metabolism of the antidepressant with known a result of circadian variation. or possible risk of TdP (i.e. citalopram, Fifth, because threshold values for a prolonged QTc clomipramine, desipramine, escitalopram, imi- interval, such as those of the AHA/ACCF/HRS, are the pramine, mirtazapine, nortriptyline, trim- result of consensus, the expert panel suggested to consider ipramine and venlafaxine [5]); a similar threshold value for women and men – cardiac disease (myocardial infarction, heart (i.e.[450 ms, instead of[450 ms for men and[460 ms failure, valvulopathy, cardiomyopathy); for women [32]), which will reduce complexity for clinical – excessive dosing (higher than the highest dose practice. This is supported by the consideration that women according to the SmPC, or standard dose with are at increased risk for QTc prolongation and TdP; low- a relevant kidney or liver problem); ering the threshold for a prolonged QTc interval – specific electrolyte disturbances (hypocal- to[450 ms in women also, will result in earlier identifi- cemia, hypokalemia, hypomagnesemia) cation than with[460 ms [33]. [26, 29]. Last, the expert panel noted that because of the actions Additional remark: In case of a strong suspi- of sex hormones on the QTc interval, the difference cion of electrolyte disturbances, e.g. with between women and men in the prolonged QTc-interval alcoholism, anorexia nervosa, diarrhea, the risk disappears during menopause [34, 35]. use of loop diuretics, etc., the calcium, potas- sium and magnesium serum level should be quantified. 5 Recommendations • Paroxetine, duloxetine and fluoxetine do not affect the QTc interval in comparison with placebo, while Based on the limited literature results and the consensus reached by our expert panel, we formulated the following fluvoxamine shortens the QTc interval compared with recommendations, all graded 4—expert opinion (Fig. 1) placebo [4]. For other antidepressants, evidence for [23–25]. determining their QTc-prolonging ability is currently • ECG screening and monitoring is recommended for insufficient. antidepressants with known or possible risk of TdP • In general, it is unnecessary to make an ECG prior to according to CredibleMeds (citalopram, clomipramine, starting any antidepressant if the patient is not at risk of QTc prolongation, and all of the abovementioned risk desipramine, escitalopram, imipramine, mirtazapine, nortriptyline, trimipramine and venlafaxine) [5]) if the factors for cardiac arrhythmia or conduction disorders are absent. patient • ECG screening and monitoring should consist of an 1. is having a known risk of QTc prolongation: ECG before treatment initiation and 1 week after – known prolonged QTc interval; reaching the target dose of a the QTc-prolonging – history of TdP; antidepressant (i.e. when steady state has been – family history of long QTc syndrome or sudden reached). cardiac death; and choosing an antidepressant • In case the ECG shows a QTc interval of 450 ms or above, it is advisable to consult a cardiologist. without QTc-prolonging ability is not possible; Remark: If the risk of QTc prolongation cannot Remark: although we focus on the QTc interval in this consensus document, the PQ and QRS intervals may be determined, it can be considered absent for decision-making purposes. also be relevant during psychotropic drug use. • If needed, for example in acute situations or highly or severe mentally ill cases, the treating physician can 660 M. Simoons et al. Fig. 1 Decision tree for ECG monitoring with antidepressant treatment. QTc QT interval corrected for heart rate, ECG electrocardiogram, TdP Torsades de Pointes. Based on CredibleMeds.org [5], which represents available and evolving evidence that is constantly re-evaluated when new evidence becomes available. If the risk of QTc prolongation cannot be determined, it can be considered absent for decision-making purposes. In case of a strong suspicion of electrolyte disturbances, e.g. with alcoholism, anorexia nervosa, diarrhea, use of loop diuretics, etc., the calcium, potassium and magnesium serum level should be quantified deviate from the recommended ECG at treatment medication should be monitored, but most experts and initiation. authors of previous reviews emphasize that ECG screening and monitoring is only necessary in high-risk patients [20, 22, 36]. Current guidelines do not provide uniform recommendations with respect to ECG screening and 6 Discussion monitoring in patients using antidepressants. Unfortu- nately, there is a lack of evidence that ECG screening and In this Dutch consensus document on ECG screening and monitoring indeed can prevent cases of arrhythmia or monitoring in patients using antidepressants, no need for sudden cardiac death. For this, the ‘number needed to ECG screening and monitoring is recommended in patients ECG’ (NNE) would be an interesting number to indicate without QTc-prolongation vulnerability and other risk the number of patients who should be monitored (with factors for cardiac arrhythmia during antidepressant ther- consecutive ECGs) to prevent one additional death or apy. ECG screening and monitoring is recommended adverse event due to QTc prolongation. Given the rising before and following the start of antidepressants with costs of (mental) health, the apparent pressure to increase known or possible risk of TdP (i.e. citalopram, clomipra- productivity, and high administrative workload, it would mine, desipramine, escitalopram, imipramine, mirtazapine, also be appropriate to perform a proper health economical nortriptyline, trimipramine and venlafaxine [5]) in the cost–benefit assessment before issuing general recom- presence of vulnerability to QTc prolongation or two or mendations on ECG screening and monitoring. An opti- more risk factors (age[65 years, female sex, concomitant mized balance between costs and yield of ECG screening use of a QTc-prolonging drug or concomitant use of a drug and monitoring to detect aberrances would support clini- that influences the metabolism of the QTc-prolonging cians in their treatment decisions, while unnecessary ECGs antidepressant, cardiac disease, excessive dosing and could be eliminated as much as possible. specific electrolyte disturbances). Because of a relative lack of systematic reviews and Some authors, guidelines, and drug labels state that all meta-analyses that compare risk factors (despite a number patients receiving QTc-prolonging psychotropic ECG monitoring in Patients Using Antidepressants 661 of studies on risk scores for QTc prolongation), the relative guide future ECG screening and monitoring guidelines. risks of risk factors for cardiac arrhythmia and sudden However, given the low prevalence of QTc prolongation (cardiac) death cannot be established/quantified, which and outcomes such as cardiac arrhythmia and sudden death, hampers a better determination of a ‘high-risk’ population. performing such an RCT requires large numbers of patients Therefore, we decided to consider the various risk factors and resources. Therefore a non-randomized approach as that were put forward in two earlier reviews of TdP cases used by Vandael et al. might be most feasible [38]. [26, 29]. The contribution of these risk factors to cardiac For implementation, the counting of risk factors to arrhythmia and sudden (cardiac) death have not yet been determine the need for ECG screening and monitoring quantified. However, the results of our literature study are would ideally be incorporated in automated clinical deci- corroborated by a recent systematic review by Vandael sion support systems that alert prescribers to obtain ECG et al. of large randomized controlled trials and observa- screening and monitoring [39]. The combination of infor- tional studies that assessed the level of evidence for several mation from electronic medical records and an electronic factors to increase the risk of QTc prolongation in a general prescribing system would be supportive in preventing population [37]. Although strong evidence was found for a undesirable outcomes of QTc-prolonging drugs and few risk factors (including hypokalemia and use of drugs increased efficacy of ECG screening and monitoring in with known risk of TdP as listed by CredibleMeds [5]), specifically high-risk patients [39]. little or no evidence was found for many other risk factors [37]. 6.1 Strength and Limitations Based on the identified risk factors, Vandael et al. sub- sequently aimed at developing a risk score to identify The strengths of this paper are the clear recommendations patients at low/high risk for QTc prolongation in an to select ‘high-risk patients’ for ECG screening and mon- observational study in hospital patients with a first pre- itoring when prescribing a QTc-prolonging antidepressant, scription for haloperidol or a QTc-prolonging antibiotic or which are easily applicable in clinical practice. However, antimicotic [38]. The RISQ-PATH index, using more and some critical issues must be addressed. some other risk factors than we mention in this paper, was The first limitation of our work is the restriction of our able to exclude low-risk patients from further ECG follow- search to systematic reviews and meta-analyses, which up when starting QTc-prolonging drugs [high sensitivity provided a summary of available case-series but did not (96.2%)], but also resulted in many false positives [low exclude the possibility that reports such as additional case- specificity (32.9%)] [38]. Because the aim of a risk score series or cohort studies might have been missed. Further- would be to safely exclude patients with low risk from the more, we could only identify papers on patients using psychotropic drugs in general, without a focus on antide- total population, this tool seems a promising instrument. The RISQ-PATH index is similar to our recommendations pressants. We loosened our restriction to include reports on for ECG screening and monitoring, except that it addi- antidepressants only after our pilot search showed insuffi- tionally contains a weighing of risk factors based on the cient studies when we used ‘antidepressants’ as a search level of evidence—not relative risk—found in their sys- term. Given our restriction of systematic reviews and meta- tematic review. Instead of a risk score, we chose the analyses, we think this was the best compromise to retrieve dichotomous cut-off of two risk factors as a threshold, reviews on patients using antidepressants and risk factors based on the evidence of a higher risk of cardiac arrhyth- for cardiac arrhythmia. From four studies initially selected, mia outcomes with an increasing number of risk factors, only two studies were informative as they included a larger the average number of risk factors found in the two reviews number of patients also using antidepressants. One of these from our literature study, the general low absolute risk of was not a systematic review, but was still considered rel- our primary outcomes, and approximation of the same high evant in the absence of additional adequate evidence from sensitivity (i.e. yield of ‘high risk’ cases for cardiac systematic reviews and meta-analyses. Our recommenda- arrhythmia and/or sudden [cardiac] death vs. costs and tions are based on the currently limited available literature logistics of obtaining ECGs in mental health). Further and almost entirely on expert opinion (specific for antide- research is warranted to quantify the relative risks of each pressants) to make them readily applicable in clinical risk factor and the sensitivity/specificity of a risk score in practice. people prescribed an antidepressant before implementation Second, risk factors for unfavorable cardiac (arrhyth- of such a weighted risk index in clinical practice. To obtain mia) outcomes may be generalizable across populations efficacy and (cost-)effectiveness data, ideally a randomized using psychotropic and other drugs. If so, a broader review controlled trial is performed to assign patients to be mon- of studies in patients using non-psychotropic drugs might itored according to their risk score versus treatment as have revealed more information, e.g. Vandael et al. [37]. usual. This would also enable to determine an NNE to We suggest to evaluate and amend our recommendations 662 M. Simoons et al. after new relevant studies have been released, with addi- recommendations should thereafter be evaluated and tional practice-based experience following implementation amended if necessary. in clinical practice. Third, we did not include a recommendation on the need Funding This project was funded by the Dutch Network for Quality for periodic follow-up (e.g. yearly) after the baseline and Development in Mental Health Care (Grants P140019 and P140040 to follow-up ECG during antidepressant use. Because evi- Henricus Ruhe and Roberto Bakker). This organization had no dence on the timing of cardiac arrhythmia and sudden influence on the content of this study/manuscript. (cardiac) death relative to the start of antidepressant ther- Compliance with Ethical Standards apy is scarce, and existence of risk factors may vary with time, it cannot be expected that a normal ECG after Conflict of interest Henricus Ruhe´ obtained an investigator-initiated treatment initiation will indefinitely predict a low risk of trial grant and speaking fees from Lundbeck BV, which are not later cardiac arrhythmia outcomes. Therefore, it might be related to the current work. Mirjam Simoons, Adrie Seldenrijk, Hans Mulder, Tom Birkenha¨ger, Mascha Groothedde-Kuyvenhoven, Rob necessary to repeat ECG screening and monitoring over Kok, Cornelis Kramers, Wim Verbeeck, Mirjam Westra, Eric van time, for which additional recommendations must be for- Roon and Roberto Bakker have no conflicts of interest that are mulated when more data are available. directly relevant to the content of this study. Fourth, the evidence for the QTc-prolonging abilities of Ethical approval Ethical approval was not applicable for this study. psychotropic drugs is scarce, with inconsistent results. For sertraline, for example, results on QTc prolongation are Patient consent Patient consent was not applicable for this study. contradictory [40, 41]. The initial classification based on a recent comparative systematic review and meta-analysis Open Access This article is distributed under the terms of the [4] was carefully re-evaluated. Despite this systematic Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which per- review, and in the absence of more specific evidence for mits any noncommercial use, distribution, and reproduction in any fatal cardiac events for the remaining antidepressants on medium, provided you give appropriate credit to the original the list from this review, we decided to follow the Credi- author(s) and the source, provide a link to the Creative Commons bleMeds classification for our recommendations. Together license, and indicate if changes were made. with this choice, we would like to emphasize again that our recommendations are not final and may change when additional evidence appears. References Finally, ECG screening and monitoring recommenda- tions should be actively and adequately implemented. 1. 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Emmelkamp PMG, Hermens MLM et al. Multidisciplinary Circadian rhythm of the corrected QT interval: impact of dif- Guideline Depression (third revision). 2013. https://www. ferent heart rate correction models. Pacing Clin Electrophysiol. ggzrichtlijnen.nl/depressie. Accessed 28 Sept 2017. Article in 2003;26:383–6. Dutch. 32. Rautaharju PM, Surawicz B, Gettes LS, Bailey JJ, Childers R, 15. National Institute for Health and Care Excellence (NICE). Deal BJ, et al. AHA/ACCF/HRS recommendations for the stan- Depression in adults: recognition and management (CG 90). dardization and interpretation of the electrocardiogram: part IV: 2009. https://www.nice.org.uk/guidance/cg90/resources/depression- the ST segment, T and U waves, and the QT interval: a scientific in-adults-recognition-and-management-pdf-975742636741. Acces- statement from the American Heart Association Electrocardiog- sed28Sept2017. raphy and Arrhythmias Committee, Council on Clinical Cardi- 16. 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Are ECG monitoring recommendations before pre- grams after FDA warnings and ADA/APA recommendations for scription of QT-prolonging drugs applied in daily practice? The second-generation antipsychotic drugs. Arch Gen Psychiatry. example of haloperidol. Pharmacoepidemiol Drug Saf. 2010;67:17–24. 2015;24:701–8. 46. Cheung D, Wolfe B, Wald H, Cumbler E. Unsafe use of intra- venous haloperidol: evaluation of recommendation-concordant http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Drug Safety Springer Journals

Limited Evidence for Risk Factors for Proarrhythmia and Sudden Cardiac Death in Patients Using Antidepressants: Dutch Consensus on ECG Monitoring

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Abstract

Drug Saf (2018) 41:655–664 https://doi.org/10.1007/s40264-018-0649-z LEADING ARTICLE Limited Evidence for Risk Factors for Proarrhythmia and Sudden Cardiac Death in Patients Using Antidepressants: Dutch Consensus on ECG Monitoring 1,2,3 2,4 1,5 6,7 • • • • Mirjam Simoons Adrie Seldenrijk Hans Mulder Tom Birkenha ¨ ger 8 9 10 • • • Mascha Groothedde-Kuyvenhoven Rob Kok Cornelis Kramers 11,12 2 3,13 14,15 • • • • Wim Verbeeck Mirjam Westra Eric van Roon Roberto Bakker 2,16,17 Henricus Ruhe ´ Published online: 26 February 2018 The Author(s) 2018. This article is an open access publication Abstract Currently, there is a lack of international and recommendations on the management of QT(c) prolonga- national guidelines or consensus documents with specific tion (with antidepressant treatment) emphasize that special recommendations for electrocardiogram (ECG) screening attention should be given to high-risk patients; however, and monitoring during antidepressant treatment. To make a clinicians are in need of more concrete suggestions about proper estimation of the risk of cardiac arrhythmias and how to select patients for ECG screening and monitoring. sudden (cardiac) death during antidepressant use, both the Based on a review of the literature, a Dutch multidisci- drug and patient-specific factors should be taken into plinary expert panel aimed to formulate specific guidelines account; however, solid evidence on how this should be to identify patients at risk for cardiac arrhythmias and done in clinical practice is lacking. Available sudden death by developing a consensus statement regarding ECG screening before, and monitoring during, antidepressant use. We first reviewed the literature to Mirjam Simoons and Adrie Seldenrijk share first authorship. identify the relative risks of various risk factors on cardiac arrhythmia and sudden (cardiac) death during antidepres- Roberto Bakker and Henricus Ruhe´ share senior authorship. sant use. These relative contributions of risk factors could Electronic supplementary material The online version of this not be determined since no systematic reviews or meta- article (https://doi.org/10.1007/s40264-018-0649-z) contains supple- analyses quantitatively addressed this topic. Because mentary material, which is available to authorized users. Department of Clinical Pharmacy, Deventer Hospital, & Henricus Ruhe Deventer, The Netherlands h.g.ruhe@umcg.nl Department of Old Age Psychiatry, Parnassia Psychiatric Department of Clinical Pharmacy, Wilhelmina Hospital Institute, The Hague, The Netherlands Assen, Assen, The Netherlands Department of Internal Medicine, Radboudumc, Nijmegen, Department of Psychiatry, Interdisciplinary Centre for The Netherlands Psychopathology and Emotion Regulation, University Vincent van Gogh Institute for Psychiatry, ADHD and Medical Centre Groningen, University of Groningen, Autism Circuit, Venray, The Netherlands Groningen, The Netherlands Department of Pharmacology and Toxicology, Radboudumc, Unit of Pharmacotherapy, -Epidemiology and -Economics, Nijmegen, The Netherlands Department of Pharmacy, University of Groningen, Groningen, The Netherlands Department of Clinical Pharmacy and Clinical Pharmacology, Medical Centre Leeuwarden, Leeuwarden, Department of Research and Innovation, GGZ InGeest, The Netherlands Amsterdam, The Netherlands Psychiatric Centre GGz Centraal, Amersfoort, The Psychiatric Hospital GGZ Drenthe, Assen, The Netherlands Netherlands Department of Psychiatry, Erasmus Medical Centre, Department of Psychiatry and Psychology, South Limburg Rotterdam, The Netherlands Mental Health and Teaching Network, Maastricht University Collaborative Antwerp Psychiatric Research Institute Medical Centre, Maastricht, The Netherlands (CAPRI), University of Antwerp, Antwerp, Belgium 656 M. Simoons et al. evidence was insufficient, additional expert opinion was death as a consequence of all cardiac arrhythmias in gen- used to formulate recommendations. This resulted in eral occurs even more rarely [1]. However, the tragic readily applicable recommendations for clinical practice anecdotes of physically healthy patients encountering car- for selection of high-risk patients for ECG screening and diac arrest and sudden (cardiac) death after the use of monitoring. ECG screening and monitoring is recom- psychotropic drugs have underscored that some of these mended before and following the start of QTc-prolonging drugs may increase the risk of arrhythmias. This proar- antidepressants in the presence of vulnerability to QTc rhythmic effect is often marked by a prolongation of the prolongation or two or more risk factors (age[65 years, QT interval/QTc interval (QT interval corrected for heart female sex, concomitant use of a QTc-prolonging drug or rate) on an electrocardiogram (ECG) [2]. concomitant use of a drug that influences the metabolism of Of the psychotropic drugs, antipsychotics are well a QTc-prolonging drug, cardiac disease, excessive dosing known for their QT(c)-prolonging effects and association and specific electrolyte disturbances). with TdP and sudden cardiac death, although the available evidence may not support this reputation per se [3]. The incidence rate of sudden cardiac death in users of antipsychotics was 2.9 per 1000 patient-years—a signifi- Key Points cantly doubled risk compared with (non-psychiatric) non- users [3]. Some antidepressants have proven to also pro- Evidence from systematic reviews and meta- long the QT(c) interval. Although a recent meta-analysis analyses with respect to risk factors for showed significant QTc prolongation by tricyclic antide- antidepressant-induced cardiac arrhythmia or sudden pressants (TCAs; doxepin, nortriptyline and amitriptyline) (cardiac) death is insufficient to generate relative and some selective serotonin reuptake inhibitors (SSRIs; risks for individual risk factors. citalopram, escitalopram and sertraline) relative to placebo We present clinically applicable consensus [4], CredibleMeds, the internationally renowned source for guidelines for the selection of high-risk patients for evidence-based classification of drugs according to their electrocardiogram (ECG) screening and monitoring QTc-prolonging abilities, only classifies citalopram and during antidepressant use. escitalopram as antidepressant drugs with a known risk of TdP, and clomipramine, desipramine, imipramine, nor- ECG screening and monitoring is recommended triptyline, mirtazapine, trimipramine and venlafaxine as before and following the start of QTc-prolonging antidepressants with a possible risk of TdP [5]. Moreover, antidepressants in the presence of known the US FDA has issued several drug safety communica- vulnerability to QTc prolongation or two or more tions, including for citalopram in 2011 and 2012. The risk factors (age[65 years, female sex, concomitant warnings stated that citalopram use could lead to abnormal use of a QTc-prolonging drug or concomitant use of heart rhythms, and prescription doses should not exceed a drug that influences the metabolism of a QTc- 40 mg/day in adults and 20 mg in patients[65 years of prolonging drug, cardiac disease, excessive dosing age [6, 7]. and specific electrolyte disturbances). To make a proper estimation of the risk of arrhythmia, the combination of characteristics of the antidepressant therapy and patient-specific factors should be taken into account. A number of risk factors that add to the arrhyth- mia risk, including non-cardiac risk factors, have been 1 Introduction proposed, including female sex, older age, (ischemic) heart disease or a history thereof, electrolyte disturbances (in- The effect of psychotropic drugs on cardiac repolarization cluding hypomagnesemia, hypokalemia and hypocal- has increasingly gained attention in research and clinical cemia), pharmacokinetic and pharmacodynamic genetic practice over the last 2 decades. The absolute risk of car- factors, congenital long QTc syndrome, and a range of diac arrhythmia, such as Torsade de Pointes (TdP), is other medical conditions [8–11]. Several studies aimed to generally low [14 per 10,000 patients over 1 year (95% verify and synthesize the available evidence for QTc pro- confidence interval 11–17/10,000)], and sudden cardiac longation into a risk score for use in non-psychiatric hos- pitalized patients [12, 13]. In addition, it has been shown that the risk for arrhythmia increases with increasing Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, UK numbers of such risk factors [8–10]; however, the relative risks of the individual risk factors for the outcome Department of Psychiatry, Radboudumc, Nijmegen, The arrhythmia are still unclear. Netherlands ECG monitoring in Patients Using Antidepressants 657 Apart from the ECG monitoring recommendations in the nursing specialist, a patient representative, three (hospital) Summary of Product Characteristics (SmPC) for individual pharmacists, and a postdoctoral researcher. QT(c)-prolonging antidepressant drugs, there are no clear and concrete national or international guidelines on if, 2.2 Literature Search when, and how often an ECG should be performed before and during treatment with antidepressant drugs. In the In order to retrieve relevant literature as a base for our Dutch multidisciplinary guideline for depression, only with recommendations, two authors (AS and MS) searched for TCA treatment in elderly patients is an ECG recommended studies addressing the relative risks of risk factors (such as before the start of treatment (although this is to rule out older age and female sex) for cardiac arrhythmia and contraindications such as a right bundle branch block to sudden (cardiac) death, associated with antidepressant use. assist in drug choice, which is not the focus of this con- We did not use a restriction in the time period of publi- sensus document) and ECG monitoring with nortriptyline cation and applied no language restrictions. For practical treatment in elderly with cardiac risk [14]. Although some reasons and because of time restrictions for the project, we of the available international depression guidelines do not limited our search to systematic reviews and meta- mention ECG monitoring with antidepressant treatment analyses. [15, 16], other depression guidelines and some consensus We conducted a search of MEDLINE using the search documents for the management of QT(c) prolongation strategy ‘‘Psychotropic Drugs’’[MeSH] AND ((((Arrhyth- emphasize that special attention should be given to ‘high- mias, Cardiac[MeSH] OR arrhythmi*[tiab] OR proar- risk’ patients in order to prevent unfavorable cardiac out- rhythmi*[tiab] OR long QT[tiab] OR (prolong*[tiab] AND comes [8, 10, 17–19]. For example, in a consensus docu- QT[tiab]) OR torsade de pointes[tiab] OR torsades de ment, Dodd and colleagues suggest ECG monitoring pointes[tiab] OR Death, Sudden, Cardiac[MeSH] OR car- during the use of TCAs [20]. They also recommend con- diac death[tiab] OR cardiac mortality[tiab] OR ‘‘Cardio- sidering ECG monitoring during SSRI and serotonin vascular Diseases/mortality’’[MeSH]) AND (drug- noradrenaline reuptake inhibitor (SNRI) treatment in ‘high- induced[tiab] OR drug effects[sh] OR adverse effects[sh])) risk’ individuals, although they consider it usually unnec- AND (Risk factors[MeSH] OR risk factors[tiab] OR essary [20]. However, how ‘high-risk’ must be quantified prognost*[tiab] OR predict*[tiab])) AND (systematic*[- in clinical practice remains an enigma that hampers tiab] OR review*[tiab] OR meta-analysis[tiab] OR Meta- implementation of such recommendations in clinical Analysis[ptyp] OR systematic[sb])). We used the broader practice. term ‘psychotropic drugs’ instead of antidepressant-speci- Therefore, we aimed to answer the following important, fic search terms because a pilot search showed insufficient unanswered questions in order to prevent cardiac arrhyth- studies on risk factors for cardiac arrhythmia and sudden mia and sudden (cardiac) death during antidepressant use: (cardiac) death when we used antidepressants in the search. (1) should the ECG be monitored with antidepressant Bibliographies of retrieved studies were scanned for addi- treatment, and (2) if so, for which patients (with which risk tional systematic reviews and meta-analyses. We per- factors), when, and how often? formed the last update of the search on 14 March 2017. 2.3 Selection Criteria 2 Methods The study selection was performed independently by two 2.1 The Multidisciplinary Expert Panel authors (AS and MS) and discrepancies were resolved through discussion. We selected systematic reviews and In 2015, the Dutch Network for Quality Development in meta-analyses of studies in (older) adult patients using Mental Health Care funded the development of recom- psychotropic drugs registered in The Netherlands. Papers mendations about the prevention, monitoring, and treat- limited to overdose, intoxication, supratherapeutic dosage ment of side effects of psychotropic drugs. A or antidepressants as add-on intervention were excluded. In multidisciplinary expert panel for antidepressant drugs our selection, we focused on cardiac arrhythmia and sud- addressed the association between the use of antidepres- den (cardiac) death as outcomes and excluded publications sants and proarrhythmic effects and related ECG moni- solely on QTc interval as a surrogate measure for cardiac toring issues. The expert panel for antidepressants arrhythmia and sudden (cardiac) death. The latter was consisted of four psychiatrists (two being specialized in the applied because QTc intervals are of limited value due to treatment of children/adolescents or elderly patients, one the use of different formulas to correct for heart rate (e.g. additionally in training as a clinical pharmacologist), a Bazett or Fridericia) and because the relationship between general practitioner, an internist clinical pharmacologist, a drug-induced QTc prolongation and the likelihood of 658 M. Simoons et al. arrhythmia appears to be, at best, modest and neither linear by psychotropic drugs, mainly, but not exclusively, by nor straightforward [21, 22]. Eligible studies should report antipsychotics (not further specified). Of the psychotropic on the risk for cardiac arrhythmia and sudden (cardiac) drug-induced TdP cases, 71.4% were female, 44.7% used death in association with risk factors [e.g. age, sex, cardiac additional drugs that caused drug interactions (i.e. impairs disease, electrolyte disturbances, prolonged QT(c) interval the metabolism of QT-prolonging drugs or concomitant use (syndrome), use of QT(c)-prolonging drugs]. of two or more QT-prolonging drugs), 43.1% had existing cardiac disease, 27% used an excessive dose (leading to 2.4 Formulation of Recommendations drug toxicity but excluding cases of suicidal overdose), 17.9% had hypokalemia, and 17.1% had a vulnerability to In order to formulate recommendations, the multidisci- QT prolongation (familial history of long QT syndrome, plinary expert panel received a summary of extracted data history of drug-induced TdP, prolonged QT interval before from selected studies. The odds ratios, relative risks and/or drug administration). Cases using psychotropic drugs had, prevalences of cardiac arrhythmia and sudden (cardiac) on average, 2.2 risk factors. No odds ratios for the different death associated with the investigated risk factors were risk factors were given. presented for each review/meta-analysis. This evidence A study by Astro¨m-Lilja et al. investigated the preva- served as input for discussion on the indication and timing lence of a small set of risk factors for arrhythmia in drug- for ECG screening and monitoring at treatment initiation induced TdP [26]. Since Zeltser et al. did not assess age as and during use of antidepressants. When consensus was a risk factor, the study by Astrom-Lilja et al. was consid- reached, each recommendation was graded evidence level ered of substantial added value for the expert panel, despite 1–4 according to the Dutch criteria for evidence-based the fact that it was not a systematic review or meta-anal- guideline development (EBRO), based on the Appraisal of ysis. This series of 88 cases was based on data from the Guidelines Research and Evaluation (AGREE) Collabora- Swedish pharmacovigilance database, which was not tion [23–25]. restricted to psychotropic drugs [8/88 (9%) used antide- pressants]. The age of the TdP cases ranged from 15 to 90 years, with the median age being 74 years. Seventy-two 3 Results of the Literature Research percent of the TdP cases were over 65 years of age. Existing heart disease, female sex, and hypokalemia were We retrieved 100 publications of potential systematic present in 90, 70, and 12% of cases, respectively, while two reviews and/or meta-analyses (see electronic supplemen- or more established risk factors were present in 85% of tary material). Seven titles and abstracts appeared to match cases (75/88). our inclusion criteria; all seven studies were in English. Based on their full-text, four publications met our selection criteria [26–29]. The major reasons for exclusion of pub- 4 Considerations of the Expert Panel lications were failure to meet our population criterion, no investigation of risk factors, or solely outcomes other than In order to translate the available evidence to recommen- cardiac arrhythmia and sudden (cardiac) death. dations for daily clinical practice, we addresses several In a systematic review of TdP cases, Meyer-Massetti issues. et al. investigated the prevalences of a predefined set of risk First, the expert panel concluded that the relative con- factors (age, sex, dose, electrolyte imbalance, cardiac dis- tributions of risk factors to cardiac arrhythmias and sudden ease, concomitant proarrhythmic drugs and other drugs (cardiac) death during antidepressant use could not be influencing cardiac function and baseline QTc) in 54 determined since no systematic reviews or meta-analyses patients with intravenous administration of the antipsy- addressed this topic specifically. chotic haloperidol [27]. Vieweg et al. provided prevalences Second, the absence of a reference group (e.g. drug-free of various risk factors in only a small number of TdP cases TdP cases or patients using psychotropic drugs who did not (n = 4) associated with the antipsychotic risperidone [28]. develop TdP) in the included reports hampered us to put Because of the low number of cases and the focus on the prevalences of risk factors into perspective and/or antipsychotics, the results of these studies were not gen- calculate odds ratios or relative risks. Therefore, it is eralizable to patients using antidepressants and these two impossible to draw firm conclusions on the relative systematic reviews were therefore excluded. importance of certain factors or the definition of a high-risk Zeltser et al. performed a systematic review of TdP population for ECG screening and monitoring. cases and described the prevalence of six risk factors for Third, we took the average time to steady state into arrhythmia in 249 cases of TdP induced by non-cardiac account when drafting the advice about the timing of the drugs [29]. In brief, 70 of these cases (28.1%) were caused follow-up ECG after reaching the target dose of treatment ECG monitoring in Patients Using Antidepressants 659 with a QTc-prolonging antidepressant. Time to steady state 2. has two or more of the risk factors listed below is four to five times the half-life of the drug, which is (based on the two reviews from the literature approximately 1 week for antidepressant drugs. search discussed above [26, 29]): Fourth, the expert panel would like to point out that the – age over 65 years; current literature is inconclusive regarding the intraindi- – female sex; vidual circadian variation in the length of the QTc interval, – concomitant use of a QTc-prolonging drug which may range from\10 ms to up to 75–100 ms (list of drugs with a known risk of TdP [21, 30, 31]. It is therefore preferable to register ECG according to CredibleMeds [5]) or concomi- recordings at fixed time points during the day in order to tant use of a drug that influences the avoid bias in the change between two subsequent ECGs as metabolism of the antidepressant with known a result of circadian variation. or possible risk of TdP (i.e. citalopram, Fifth, because threshold values for a prolonged QTc clomipramine, desipramine, escitalopram, imi- interval, such as those of the AHA/ACCF/HRS, are the pramine, mirtazapine, nortriptyline, trim- result of consensus, the expert panel suggested to consider ipramine and venlafaxine [5]); a similar threshold value for women and men – cardiac disease (myocardial infarction, heart (i.e.[450 ms, instead of[450 ms for men and[460 ms failure, valvulopathy, cardiomyopathy); for women [32]), which will reduce complexity for clinical – excessive dosing (higher than the highest dose practice. This is supported by the consideration that women according to the SmPC, or standard dose with are at increased risk for QTc prolongation and TdP; low- a relevant kidney or liver problem); ering the threshold for a prolonged QTc interval – specific electrolyte disturbances (hypocal- to[450 ms in women also, will result in earlier identifi- cemia, hypokalemia, hypomagnesemia) cation than with[460 ms [33]. [26, 29]. Last, the expert panel noted that because of the actions Additional remark: In case of a strong suspi- of sex hormones on the QTc interval, the difference cion of electrolyte disturbances, e.g. with between women and men in the prolonged QTc-interval alcoholism, anorexia nervosa, diarrhea, the risk disappears during menopause [34, 35]. use of loop diuretics, etc., the calcium, potas- sium and magnesium serum level should be quantified. 5 Recommendations • Paroxetine, duloxetine and fluoxetine do not affect the QTc interval in comparison with placebo, while Based on the limited literature results and the consensus reached by our expert panel, we formulated the following fluvoxamine shortens the QTc interval compared with recommendations, all graded 4—expert opinion (Fig. 1) placebo [4]. For other antidepressants, evidence for [23–25]. determining their QTc-prolonging ability is currently • ECG screening and monitoring is recommended for insufficient. antidepressants with known or possible risk of TdP • In general, it is unnecessary to make an ECG prior to according to CredibleMeds (citalopram, clomipramine, starting any antidepressant if the patient is not at risk of QTc prolongation, and all of the abovementioned risk desipramine, escitalopram, imipramine, mirtazapine, nortriptyline, trimipramine and venlafaxine) [5]) if the factors for cardiac arrhythmia or conduction disorders are absent. patient • ECG screening and monitoring should consist of an 1. is having a known risk of QTc prolongation: ECG before treatment initiation and 1 week after – known prolonged QTc interval; reaching the target dose of a the QTc-prolonging – history of TdP; antidepressant (i.e. when steady state has been – family history of long QTc syndrome or sudden reached). cardiac death; and choosing an antidepressant • In case the ECG shows a QTc interval of 450 ms or above, it is advisable to consult a cardiologist. without QTc-prolonging ability is not possible; Remark: If the risk of QTc prolongation cannot Remark: although we focus on the QTc interval in this consensus document, the PQ and QRS intervals may be determined, it can be considered absent for decision-making purposes. also be relevant during psychotropic drug use. • If needed, for example in acute situations or highly or severe mentally ill cases, the treating physician can 660 M. Simoons et al. Fig. 1 Decision tree for ECG monitoring with antidepressant treatment. QTc QT interval corrected for heart rate, ECG electrocardiogram, TdP Torsades de Pointes. Based on CredibleMeds.org [5], which represents available and evolving evidence that is constantly re-evaluated when new evidence becomes available. If the risk of QTc prolongation cannot be determined, it can be considered absent for decision-making purposes. In case of a strong suspicion of electrolyte disturbances, e.g. with alcoholism, anorexia nervosa, diarrhea, use of loop diuretics, etc., the calcium, potassium and magnesium serum level should be quantified deviate from the recommended ECG at treatment medication should be monitored, but most experts and initiation. authors of previous reviews emphasize that ECG screening and monitoring is only necessary in high-risk patients [20, 22, 36]. Current guidelines do not provide uniform recommendations with respect to ECG screening and 6 Discussion monitoring in patients using antidepressants. Unfortu- nately, there is a lack of evidence that ECG screening and In this Dutch consensus document on ECG screening and monitoring indeed can prevent cases of arrhythmia or monitoring in patients using antidepressants, no need for sudden cardiac death. For this, the ‘number needed to ECG screening and monitoring is recommended in patients ECG’ (NNE) would be an interesting number to indicate without QTc-prolongation vulnerability and other risk the number of patients who should be monitored (with factors for cardiac arrhythmia during antidepressant ther- consecutive ECGs) to prevent one additional death or apy. ECG screening and monitoring is recommended adverse event due to QTc prolongation. Given the rising before and following the start of antidepressants with costs of (mental) health, the apparent pressure to increase known or possible risk of TdP (i.e. citalopram, clomipra- productivity, and high administrative workload, it would mine, desipramine, escitalopram, imipramine, mirtazapine, also be appropriate to perform a proper health economical nortriptyline, trimipramine and venlafaxine [5]) in the cost–benefit assessment before issuing general recom- presence of vulnerability to QTc prolongation or two or mendations on ECG screening and monitoring. An opti- more risk factors (age[65 years, female sex, concomitant mized balance between costs and yield of ECG screening use of a QTc-prolonging drug or concomitant use of a drug and monitoring to detect aberrances would support clini- that influences the metabolism of the QTc-prolonging cians in their treatment decisions, while unnecessary ECGs antidepressant, cardiac disease, excessive dosing and could be eliminated as much as possible. specific electrolyte disturbances). Because of a relative lack of systematic reviews and Some authors, guidelines, and drug labels state that all meta-analyses that compare risk factors (despite a number patients receiving QTc-prolonging psychotropic ECG monitoring in Patients Using Antidepressants 661 of studies on risk scores for QTc prolongation), the relative guide future ECG screening and monitoring guidelines. risks of risk factors for cardiac arrhythmia and sudden However, given the low prevalence of QTc prolongation (cardiac) death cannot be established/quantified, which and outcomes such as cardiac arrhythmia and sudden death, hampers a better determination of a ‘high-risk’ population. performing such an RCT requires large numbers of patients Therefore, we decided to consider the various risk factors and resources. Therefore a non-randomized approach as that were put forward in two earlier reviews of TdP cases used by Vandael et al. might be most feasible [38]. [26, 29]. The contribution of these risk factors to cardiac For implementation, the counting of risk factors to arrhythmia and sudden (cardiac) death have not yet been determine the need for ECG screening and monitoring quantified. However, the results of our literature study are would ideally be incorporated in automated clinical deci- corroborated by a recent systematic review by Vandael sion support systems that alert prescribers to obtain ECG et al. of large randomized controlled trials and observa- screening and monitoring [39]. The combination of infor- tional studies that assessed the level of evidence for several mation from electronic medical records and an electronic factors to increase the risk of QTc prolongation in a general prescribing system would be supportive in preventing population [37]. Although strong evidence was found for a undesirable outcomes of QTc-prolonging drugs and few risk factors (including hypokalemia and use of drugs increased efficacy of ECG screening and monitoring in with known risk of TdP as listed by CredibleMeds [5]), specifically high-risk patients [39]. little or no evidence was found for many other risk factors [37]. 6.1 Strength and Limitations Based on the identified risk factors, Vandael et al. sub- sequently aimed at developing a risk score to identify The strengths of this paper are the clear recommendations patients at low/high risk for QTc prolongation in an to select ‘high-risk patients’ for ECG screening and mon- observational study in hospital patients with a first pre- itoring when prescribing a QTc-prolonging antidepressant, scription for haloperidol or a QTc-prolonging antibiotic or which are easily applicable in clinical practice. However, antimicotic [38]. The RISQ-PATH index, using more and some critical issues must be addressed. some other risk factors than we mention in this paper, was The first limitation of our work is the restriction of our able to exclude low-risk patients from further ECG follow- search to systematic reviews and meta-analyses, which up when starting QTc-prolonging drugs [high sensitivity provided a summary of available case-series but did not (96.2%)], but also resulted in many false positives [low exclude the possibility that reports such as additional case- specificity (32.9%)] [38]. Because the aim of a risk score series or cohort studies might have been missed. Further- would be to safely exclude patients with low risk from the more, we could only identify papers on patients using psychotropic drugs in general, without a focus on antide- total population, this tool seems a promising instrument. The RISQ-PATH index is similar to our recommendations pressants. We loosened our restriction to include reports on for ECG screening and monitoring, except that it addi- antidepressants only after our pilot search showed insuffi- tionally contains a weighing of risk factors based on the cient studies when we used ‘antidepressants’ as a search level of evidence—not relative risk—found in their sys- term. Given our restriction of systematic reviews and meta- tematic review. Instead of a risk score, we chose the analyses, we think this was the best compromise to retrieve dichotomous cut-off of two risk factors as a threshold, reviews on patients using antidepressants and risk factors based on the evidence of a higher risk of cardiac arrhyth- for cardiac arrhythmia. From four studies initially selected, mia outcomes with an increasing number of risk factors, only two studies were informative as they included a larger the average number of risk factors found in the two reviews number of patients also using antidepressants. One of these from our literature study, the general low absolute risk of was not a systematic review, but was still considered rel- our primary outcomes, and approximation of the same high evant in the absence of additional adequate evidence from sensitivity (i.e. yield of ‘high risk’ cases for cardiac systematic reviews and meta-analyses. Our recommenda- arrhythmia and/or sudden [cardiac] death vs. costs and tions are based on the currently limited available literature logistics of obtaining ECGs in mental health). Further and almost entirely on expert opinion (specific for antide- research is warranted to quantify the relative risks of each pressants) to make them readily applicable in clinical risk factor and the sensitivity/specificity of a risk score in practice. people prescribed an antidepressant before implementation Second, risk factors for unfavorable cardiac (arrhyth- of such a weighted risk index in clinical practice. To obtain mia) outcomes may be generalizable across populations efficacy and (cost-)effectiveness data, ideally a randomized using psychotropic and other drugs. If so, a broader review controlled trial is performed to assign patients to be mon- of studies in patients using non-psychotropic drugs might itored according to their risk score versus treatment as have revealed more information, e.g. Vandael et al. [37]. usual. This would also enable to determine an NNE to We suggest to evaluate and amend our recommendations 662 M. Simoons et al. after new relevant studies have been released, with addi- recommendations should thereafter be evaluated and tional practice-based experience following implementation amended if necessary. in clinical practice. Third, we did not include a recommendation on the need Funding This project was funded by the Dutch Network for Quality for periodic follow-up (e.g. yearly) after the baseline and Development in Mental Health Care (Grants P140019 and P140040 to follow-up ECG during antidepressant use. Because evi- Henricus Ruhe and Roberto Bakker). This organization had no dence on the timing of cardiac arrhythmia and sudden influence on the content of this study/manuscript. (cardiac) death relative to the start of antidepressant ther- Compliance with Ethical Standards apy is scarce, and existence of risk factors may vary with time, it cannot be expected that a normal ECG after Conflict of interest Henricus Ruhe´ obtained an investigator-initiated treatment initiation will indefinitely predict a low risk of trial grant and speaking fees from Lundbeck BV, which are not later cardiac arrhythmia outcomes. Therefore, it might be related to the current work. Mirjam Simoons, Adrie Seldenrijk, Hans Mulder, Tom Birkenha¨ger, Mascha Groothedde-Kuyvenhoven, Rob necessary to repeat ECG screening and monitoring over Kok, Cornelis Kramers, Wim Verbeeck, Mirjam Westra, Eric van time, for which additional recommendations must be for- Roon and Roberto Bakker have no conflicts of interest that are mulated when more data are available. directly relevant to the content of this study. Fourth, the evidence for the QTc-prolonging abilities of Ethical approval Ethical approval was not applicable for this study. psychotropic drugs is scarce, with inconsistent results. For sertraline, for example, results on QTc prolongation are Patient consent Patient consent was not applicable for this study. contradictory [40, 41]. The initial classification based on a recent comparative systematic review and meta-analysis Open Access This article is distributed under the terms of the [4] was carefully re-evaluated. Despite this systematic Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which per- review, and in the absence of more specific evidence for mits any noncommercial use, distribution, and reproduction in any fatal cardiac events for the remaining antidepressants on medium, provided you give appropriate credit to the original the list from this review, we decided to follow the Credi- author(s) and the source, provide a link to the Creative Commons bleMeds classification for our recommendations. Together license, and indicate if changes were made. with this choice, we would like to emphasize again that our recommendations are not final and may change when additional evidence appears. References Finally, ECG screening and monitoring recommenda- tions should be actively and adequately implemented. 1. 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Drug SafetySpringer Journals

Published: Feb 26, 2018

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