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Monitoring of QT interval in patients treated with psychotropic drugs
International Journal of Cardiology 117 (2007) 329 – 332 www.elsevier.com/locate/ijcard
Monitoring of QT interval in patients treated with psychotropic drugs Tomas Novotny a,⁎, Alena Florianova a , Eva Ceskova b , Marcela Weislamplova a , Vitezslav Palensky b , Jana Tomanova b , Martina Sisakova a , Ondrej Toman a , Jindrich Spinar a a
Department of Internal Medicine and Cardiology, University Hospital Brno, Jihlavska 20 Brno 625 00, Czech Republic b Department of Psychiatry, University Hospital Brno, Brno, Czech Republic Received 9 January 2006; received in revised form 16 March 2006; accepted 28 April 2006 Available online 24 July 2006
Abstract Background: Psychotropic drugs have the potential for QT interval prolongation, the frequency is not known. The aim of this study was to monitor the occurrence of QT interval prolongation in a non-selected population of patients treated with psychotropic drugs with proarrhythmic potential. Methods: In consecutive patients hospitalized at psychotic wards at the Department of Psychiatry treated with antipsychotic and antidepressant drugs with known or unexplored proarrhythmic potential a 12-lead ECG was recorded (50 mm/s, 20 mm/mV) on therapy; the QT interval was measured manually, corrected according to Bazett and Fridericia. QTc intervals of 470 ms (females) and 450 ms (males) were considered borderline, longer QTc intervals were considered pathologic. Results: ECGs were recorded in 452 patients (187 females, 265 males, aged 43 ± 16 years). Using Bazett's correction, abnormal QTc values were observed only in 2% of the whole group and in 1.8% of the patients treated with drugs associated with QT prolongation (the greatest QTc value is 490 ms in female and 480 ms in male). With Fridericia's correction, there was only 1 case of borderline QTc in the whole group (the greatest QTc value is 450 ms in both sex groups). Conclusions: Our 2-year real-life experience shows that occurrence of QTc prolongation in present psychiatric patients is low. Values associated with high risk of arrhythmias (QTc > 500 ms) were not observed. This might be related to the recent changes of spectrum of antipsychotic therapy used, the general trend to use lower doses, and increasing awareness about the drug-induced long QT syndrome. © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Drug induced long QT syndrome; Proarrhythmia; Psychotropic drugs; QT interval
1. Introduction Many drugs possess an undesirable ability to prolong cardiac repolarization that can be objectively measured as prolongation of the QT interval on the surface electrocardiogram (ECG). A prolonged cardiac repolarization creates electrophysiologic conditions that facilitate the development of arrhythmias, most commonly a polymorphic ventricular tachycardia known as torsade des pointes. By degenerating in ventricular fibrillation, torsade des pointes may cause sudden death [1]. The frequency with which a particular drug induces QT prolongation in a clinically relevant way remains largely unknown. ⁎ Corresponding author. E-mail address: [email protected] (T. Novotny). 0167-5273/$ - see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2006.04.087
Psychiatric patients are at an increased risk for sudden death that might be partially attributed to drug-induced torsade des pointes [2,3]. Psychotropic drugs have a known potential for QT interval prolongation. The aim of our study was to monitor the occurrence of QT interval prolongation in a non-selected population of patients treated with psychotropic compounds. The secondary aim was to assess the feasibility of routine QT interval monitoring in this patient population. 2. Methods 2.1. Study population The study population consisted of all adult patients hospitalized consecutively in psychotic wards at the
330
T. Novotny et al. / International Journal of Cardiology 117 (2007) 329–332
Department of Psychiatry of our hospital. They were treated with different antipsychotic and antidepressant drugs both in monotherapy and in combination. No particular drugs were a priori selected for monitoring. Patients with atrial fibrillation, bundle branch block and pacemaker-dependent rhythm were excluded. The study was approved by the local Ethics Committee of the University Hospital Brno and conforms to the ethical guidelines of the 1975 Declaration of Helsinki. An informed consent was obtained from each patient. 2.2. ECG recordings and QT interval assessments ECGs were recorded on paper with a 50 mm/s paper speed and 20 mm/mV voltage gain. ECG recordings were evaluated by 2 independent experienced cardiologists blinded to the treatment. QT intervals were measured manually with the precision of 10 ms and corrected according to Bazett and Fridericia formulae and rounded to the nearest 10 ms (in consistence with present clinical practice). QTc intervals of 470 ms in females and 450 ms in males were considered borderline, QTc intervals above these values were considered pathologic. 3. Results 3.1. Group of patients and drugs Between June 2003 and June 2005, ECG recordings were obtained in 452 patients. Clinical characteristics of study subjects are summarized in Table 1. Patients were treated with 24 different psychotropic drugs, in the case of 14 of these, cases of QT prolongation have previously been reported. Drugs with known potential for QT prolongation were given to 384 patients. In the case of 6 drugs, torsade des pointes has been reported, and these drugs were taken by 70 patients [4–6]. Fifty patients were treated with combined therapy of 2–3 drugs, in 45 of them, at least 1 drug has been associated with QT prolongation. Numbers of patients treated with individual drug are detailed in Table 2.
Table 1 Clinical characteristics of study subjects (n = 452) Male Female Age Other diagnoses Hypertension Diabetes CAD Hypokalemia Psychiatric diagnoses Schizophrenia Schizoaffective syndrome Bipolar disorder Other CAD—coronary artery disease.
265 187 43 ± 16 10% 5.5% 3.5% 2.5% 49% 12.5% 21.5% 17%
Table 2 Psychiatric drugs used in the study Monotherapy Combined therapy
402 patients 50 patients
Generic name
n
Amisulprid Citalopram Clomipramin Clozapin Escitalopram Fluphenazin Fluoxetine Haloperidol Chlorpromazine Chlorprothixen Levomepromazine Milnacipram Mirtazapine Olanzapine Oxyprothepine Paroxetine Quetiapine Risperidone Sertraline Sulpiride Tianeptine Venlafaxine Ziprasidone Zotepine
55 39 2 17 18 1 2 10 2 3 21 7 10 91 2 1 55 98 15 10 9 8 11 14
Reported in literature QT prolongation + + + +
TdP + +
+ + +
+ + +
+ + + + +
+
+ +
TdP—torsade des pointes.
3.2. Occurrence of abnormal QTc values Occurrence of abnormal QTc values is summarized in Table 3. The largest QTc value (Bazett) was 490 ms in a female and 480 ms in a male patient. The largest QTc value (Fridericia) was 450 ms in both sex groups. The average RR interval of the outliers was 708 ± 113 ms. The largest uncorrected QT value was 480 ms (at heart rate of Table 3 Occurrence of abnormal QTc values in subgroups
Whole group (n = 452) Patients treated with drugs associated with QT prolongation (n = 384) Patients treated with drugs associated TdP (n = 69) Patients treated with drugs not associated with QT prolongation (n = 64) Patients treated with drug combination, at least 1 of which associated with QT prolongation (n = 45)
Borderline QTc
Pathologic QTc
Bazett
Fridericia
Bazett
Fridericia
5 (1.1%) 4 (1%)
1 (0.2%) 0
4 (0.9%) 3 (0.8%)
0 0
1 (1.5%)
0
0
0
1 (1.55%) 1 (1.55%) 1 (1.55%) 0
1 (2.2%)
0
1 (2.2%)
QTc—corrected QT interval, TdP—torsade des pointes.
0
T. Novotny et al. / International Journal of Cardiology 117 (2007) 329–332
53 beats/min) in a male and 460 ms (at heart rate of 46 beats/ min) in a female patient. 4. Discussion Our observation represents a 2-year real-life singledepartment experience with a routine QT interval monitoring in patients treated with psychotropic drugs. In all individuals hospitalized at our Department of Psychiatry, ECG is being routinely recorded and QT interval was assessed in order to minimize the risk of proarrhythmia. QT interval monitoring seems appropriate for this purpose since to date, there has not been an example of human TdP induced by a drug that cannot cause QT interval prolongation [7]. Nevertheless, the practicality of the monitoring is complicated by interindividual differences in drug response that are due to polymorphisms in genes encoding drug metabolizing enzymes, drug transporters, drug targets, as well as repolarization physiology [8,9]. Usually, QT prolongation is considered when QTc (Bazett) interval exceeds 440 ms in males and 460 ms in females [10]. The Committee for Proprietary Medicinal Products also proposed that drug-induced QTc intervals exceeding 500 ms are of concern [11]. These cut-off values were used also in our study. However, there is no well-established threshold duration below which QT prolongation might be considered as benign [12]. Moreover, the best correction approach is still subject of controversy. Only recently it has been showed that QT/RR relationship exhibits a substantial inter-subject variability while also showing high intra-subject stability. Therefore no single mathematical formula can be obtained which will describe the QT/RR relationship satisfactorily in all individuals [13]. Nevertheless, while these findings are useful in the clinical pre-approval drug evaluation, there are of little use in clinical practice when only single ECG is available from each individual. Bazett's correction is therefore frequently used, including described cut-off values, despite numerous reports of its inadequacy and despite the understanding that the QTc interval corrected by Bazett is artificially prolonged at heart rates >60 beats/ min and shortened at heart rates < 60 beats/min [14]. Fridericia's formula might perhaps be accepted as a practically reasonable correction in clinical setting, although it is still not entirely accurate [15]. In our survey the average heart rate of the outliers was approximately 85 bpm, suggesting that corrected QTc values might have been artificially prolonged because of the correction procedures used. Psychiatric patients studies in our survey were treated with a wide spectrum of different psychotropic drugs. Majority of these has been reported to influence QT interval [4–6]. Approximately 10% of the patients received combination therapy which is considered as a further risk factor for proarrhythmia. Still, the occurrence of abnormal QTc interval values was low (Table 3). In particular, there was
331
no case of substantial QTc interval prolongation above 500 ms. In principle, our observation is in agreement with reports on the drugs used. Data on isolated QT prolongation associated with psychopharmacologic compounds are available only for some of them and usually, only cases with QTc prolongation > 500 ms are described. Thioridazine is most potent in causing QT prolongation (QTc > 450 ms in 60% of patients) [16], while with ziprasidone, QTc intervals > 500 ms occur in less than 1% of patients [4]. For clomipramine, there are data in children and adolescents showing QTc prolongation of > 450 ms in 11% of individuals [17]. In majority of the other psychotropic drugs, only anecdotal reports are available mostly from cases of poisoning [4–6]. There is only one study dealing with a general psychiatric population, in which in 495 patients QTc prolongation > 450 ms were observed in 8% [18]. High proportion of these patients was treated with thioridazine which is presently used very seldom. Low occurrence of QT prolongation in our population is therefore likely explained by a different spectrum of psychotropic drugs used in present psychiatric clinical practice. Our survey suffers from some important limitations. Firstly, since majority of the patients suffered from chronic psychotic conditions, it was clearly unethical to wash them off therapy for the purposes of baseline ECG recording. Therefore, QT interval change could not have been assessed. In this respect, our survey is a good model of other programs of clinical ECG screening. Therefore an association of a particular drug with QTc value cannot be considered. Secondly, the size of the group of patients who entered our survey is not particularly large. Nevertheless, this is again a reasonable model of a single-centre clinical experience which is appropriate since clinical ECG monitoring is mostly conducted within individual clinical departments. Thirdly, because of the above described reasons, it was not possible to confirm the relationship between particular observation of prolonged QTc and a particular drug. Finally, with ECGs taken in chronically treated patients, the subjects prone to QT prolongation might already be dead due to torsade des pointes. There are no meaningful data to quantify this possible effect and it would equally apply to other monitoring experiences. Hence, our 2-year real-life experience shows that the occurrence of QT prolongation in psychiatric patients subject to contemporary treatment is rather low. This could be related to recent changes of spectrum of antipsychotic drugs used, the general trend to use lower doses of antipsychotic medication and increasing awareness about the drug-induced long QT syndrome. Nevertheless because of possible fatalities the clinical importance of acquired long QT syndrome cannot be underestimated. The low incidence of QT interval prolongation suggests low incidence of torsade des pointes induction in present psychiatric populations but may also lead to an inappropriate underestimation of the
332
T. Novotny et al. / International Journal of Cardiology 117 (2007) 329–332
danger of proarrhythmia. In spite of the fact that the incidence of torsadegenic toxicity is likely decreasing, any complacency by the clinical community might have drastic consequences. The need for preventive measures has not diminished. One of the most effective preventive measures in ECG screening in risk groups of patients remains the QT interval monitoring which has been proved fully feasible by our experience. Acknowledgement This research is supported by the Internal Grant Agency of the Ministry of Health of the Czech Republic Grant IGA MH NA 7424-3. References [1] Haverkamp W, Breithardt G, Camm AJ, et al. The potential for QT prolongation and pro-arrhythmia by non-anti-arrhythmic drugs: clinical and regulatory implications. Report on a Policy conference of the European Society of Cardiology. Cardiovasc Res 2000; 47:219–33. [2] Hennessy S, Bilker WB, Knauss JS, et al. Cardiac arrest and ventricular arrhythmia in patients taking antipsychotic drugs: cohort study using administrative data. BMJ 2002;325:1070–4. [3] Ray WA, Meredith S, Thapa PB, Meador KG, Hall K, Murray KT. Antipsychotics and the risk of sudden cardiac death. Arch Gen Psychiatry 2001;58:1161–7. [4] Camm AJ, Malik M, Yap YG. Risk of QT prolongation and torsades de pointes with psychotropic drugs. In: Camm AJ, Malik M, Yap YG, editors. Acquired long QT syndrome. Oxford: Blackwell Futura; 2004. p. 102–20. [5] Taylor DM. Antipsychotics and QT prolongation. Acta Psychiatr Scand 2003;107:85–9. [6] www.torsades.org. [7] Fenichel RR, Malik M, Antzelevitch C, et al. Independent Academic Task Force. Drug-induced torsades de pointes and implications for drug development. J Cardiovasc Electrophysiol 2004;15:475–95.
[8] Evans WE, McLeod HL. Pharmacogenomics—drug disposition, drug targets and side effects. N Engl J Med 2003;348:538–49. [9] Weinshilboum R. Inheritance and drug response. N Engl J Med 2003;348:529–37. [10] Childers R. Risk assessment: the 12-lead electrocardiogram. In: Malik M, editor. Risk of arrhythmia and sudden death. London: BMJ Books; 2001. p. 65–97. [11] European Agency for the evaluation of Medicinal Products. Human Medicines Evaluation Unit. The Committee for Proprietary Medicinal Products (CPMP). Points to consider: The assessment of the potential for QT interval prolongation by noncardiovascular medicinal products. March 1997 (CPMP/986/96). [12] Moss AJ, Zareba W, Benhorin J, et al. ISHNE guidelines for electrocardiographic evaluation of drug related QT prolongation and other alterations in ventricular repolarization: Task force summary. A report of the task force of the International society for Holter and noninvasive electrocardiology (ISHNE), committee on ventricular repolarization. Ann Noninvasive Electrocardiol 2001;6:333–41. [13] Batchvarov VN, Ghuran A, Smetana P, et al. QT-RR relationship in healthy subjects exhibits substantial intersubject variability and intrasubject stability. Am J Physiol Heart Circ Physiol 2000;282: H2356–63. [14] Hodges M. Rate correction of the QT interval. Card Electrophysiol Rev 1997;1:360–3. [15] Camm AJ, Malik M, Yap YG. Measurement of QT interval and repolarization assessment. In: Camm AJ, Malik M, Yap YG, editors. Acquired Long QT syndrome. Oxford: Blackwell Futura; 2004. p. 24–59. [16] Buckley NA, Whyte IM, Dawson AH. Cardiotoxicity most common in thioridazine overdose than with other neuroleptics. J Toxicol Clin Toxicol 1995;33:199–204. [17] Wilens TE, Biederman J, Baldessarini RJ, et al. Cardiovascular effects of therapeutic doses of tricyclic antidepressants in children and adolescents. J Am Acad Child Adolesc Psychiatry 1996;35:1491–501. [18] Reilly JG, Ayis SA, Ferrier IN, Jones SJ, Thomas SH. QTc interval abnormalities and psychotrophic drug therapy in psychiatric patients. Lancet 2000;355:1048–52.
Monitoring of QT interval in patients treated with psychotropic drugs Tomas Novotny a,⁎, Alena Florianova a , Eva Ceskova b , Marcela Weislamplova a , Vitezslav Palensky b , Jana Tomanova b , Martina Sisakova a , Ondrej Toman a , Jindrich Spinar a a
Department of Internal Medicine and Cardiology, University Hospital Brno, Jihlavska 20 Brno 625 00, Czech Republic b Department of Psychiatry, University Hospital Brno, Brno, Czech Republic Received 9 January 2006; received in revised form 16 March 2006; accepted 28 April 2006 Available online 24 July 2006
Abstract Background: Psychotropic drugs have the potential for QT interval prolongation, the frequency is not known. The aim of this study was to monitor the occurrence of QT interval prolongation in a non-selected population of patients treated with psychotropic drugs with proarrhythmic potential. Methods: In consecutive patients hospitalized at psychotic wards at the Department of Psychiatry treated with antipsychotic and antidepressant drugs with known or unexplored proarrhythmic potential a 12-lead ECG was recorded (50 mm/s, 20 mm/mV) on therapy; the QT interval was measured manually, corrected according to Bazett and Fridericia. QTc intervals of 470 ms (females) and 450 ms (males) were considered borderline, longer QTc intervals were considered pathologic. Results: ECGs were recorded in 452 patients (187 females, 265 males, aged 43 ± 16 years). Using Bazett's correction, abnormal QTc values were observed only in 2% of the whole group and in 1.8% of the patients treated with drugs associated with QT prolongation (the greatest QTc value is 490 ms in female and 480 ms in male). With Fridericia's correction, there was only 1 case of borderline QTc in the whole group (the greatest QTc value is 450 ms in both sex groups). Conclusions: Our 2-year real-life experience shows that occurrence of QTc prolongation in present psychiatric patients is low. Values associated with high risk of arrhythmias (QTc > 500 ms) were not observed. This might be related to the recent changes of spectrum of antipsychotic therapy used, the general trend to use lower doses, and increasing awareness about the drug-induced long QT syndrome. © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Drug induced long QT syndrome; Proarrhythmia; Psychotropic drugs; QT interval
1. Introduction Many drugs possess an undesirable ability to prolong cardiac repolarization that can be objectively measured as prolongation of the QT interval on the surface electrocardiogram (ECG). A prolonged cardiac repolarization creates electrophysiologic conditions that facilitate the development of arrhythmias, most commonly a polymorphic ventricular tachycardia known as torsade des pointes. By degenerating in ventricular fibrillation, torsade des pointes may cause sudden death [1]. The frequency with which a particular drug induces QT prolongation in a clinically relevant way remains largely unknown. ⁎ Corresponding author. E-mail address: [email protected] (T. Novotny). 0167-5273/$ - see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2006.04.087
Psychiatric patients are at an increased risk for sudden death that might be partially attributed to drug-induced torsade des pointes [2,3]. Psychotropic drugs have a known potential for QT interval prolongation. The aim of our study was to monitor the occurrence of QT interval prolongation in a non-selected population of patients treated with psychotropic compounds. The secondary aim was to assess the feasibility of routine QT interval monitoring in this patient population. 2. Methods 2.1. Study population The study population consisted of all adult patients hospitalized consecutively in psychotic wards at the
330
T. Novotny et al. / International Journal of Cardiology 117 (2007) 329–332
Department of Psychiatry of our hospital. They were treated with different antipsychotic and antidepressant drugs both in monotherapy and in combination. No particular drugs were a priori selected for monitoring. Patients with atrial fibrillation, bundle branch block and pacemaker-dependent rhythm were excluded. The study was approved by the local Ethics Committee of the University Hospital Brno and conforms to the ethical guidelines of the 1975 Declaration of Helsinki. An informed consent was obtained from each patient. 2.2. ECG recordings and QT interval assessments ECGs were recorded on paper with a 50 mm/s paper speed and 20 mm/mV voltage gain. ECG recordings were evaluated by 2 independent experienced cardiologists blinded to the treatment. QT intervals were measured manually with the precision of 10 ms and corrected according to Bazett and Fridericia formulae and rounded to the nearest 10 ms (in consistence with present clinical practice). QTc intervals of 470 ms in females and 450 ms in males were considered borderline, QTc intervals above these values were considered pathologic. 3. Results 3.1. Group of patients and drugs Between June 2003 and June 2005, ECG recordings were obtained in 452 patients. Clinical characteristics of study subjects are summarized in Table 1. Patients were treated with 24 different psychotropic drugs, in the case of 14 of these, cases of QT prolongation have previously been reported. Drugs with known potential for QT prolongation were given to 384 patients. In the case of 6 drugs, torsade des pointes has been reported, and these drugs were taken by 70 patients [4–6]. Fifty patients were treated with combined therapy of 2–3 drugs, in 45 of them, at least 1 drug has been associated with QT prolongation. Numbers of patients treated with individual drug are detailed in Table 2.
Table 1 Clinical characteristics of study subjects (n = 452) Male Female Age Other diagnoses Hypertension Diabetes CAD Hypokalemia Psychiatric diagnoses Schizophrenia Schizoaffective syndrome Bipolar disorder Other CAD—coronary artery disease.
265 187 43 ± 16 10% 5.5% 3.5% 2.5% 49% 12.5% 21.5% 17%
Table 2 Psychiatric drugs used in the study Monotherapy Combined therapy
402 patients 50 patients
Generic name
n
Amisulprid Citalopram Clomipramin Clozapin Escitalopram Fluphenazin Fluoxetine Haloperidol Chlorpromazine Chlorprothixen Levomepromazine Milnacipram Mirtazapine Olanzapine Oxyprothepine Paroxetine Quetiapine Risperidone Sertraline Sulpiride Tianeptine Venlafaxine Ziprasidone Zotepine
55 39 2 17 18 1 2 10 2 3 21 7 10 91 2 1 55 98 15 10 9 8 11 14
Reported in literature QT prolongation + + + +
TdP + +
+ + +
+ + +
+ + + + +
+
+ +
TdP—torsade des pointes.
3.2. Occurrence of abnormal QTc values Occurrence of abnormal QTc values is summarized in Table 3. The largest QTc value (Bazett) was 490 ms in a female and 480 ms in a male patient. The largest QTc value (Fridericia) was 450 ms in both sex groups. The average RR interval of the outliers was 708 ± 113 ms. The largest uncorrected QT value was 480 ms (at heart rate of Table 3 Occurrence of abnormal QTc values in subgroups
Whole group (n = 452) Patients treated with drugs associated with QT prolongation (n = 384) Patients treated with drugs associated TdP (n = 69) Patients treated with drugs not associated with QT prolongation (n = 64) Patients treated with drug combination, at least 1 of which associated with QT prolongation (n = 45)
Borderline QTc
Pathologic QTc
Bazett
Fridericia
Bazett
Fridericia
5 (1.1%) 4 (1%)
1 (0.2%) 0
4 (0.9%) 3 (0.8%)
0 0
1 (1.5%)
0
0
0
1 (1.55%) 1 (1.55%) 1 (1.55%) 0
1 (2.2%)
0
1 (2.2%)
QTc—corrected QT interval, TdP—torsade des pointes.
0
T. Novotny et al. / International Journal of Cardiology 117 (2007) 329–332
53 beats/min) in a male and 460 ms (at heart rate of 46 beats/ min) in a female patient. 4. Discussion Our observation represents a 2-year real-life singledepartment experience with a routine QT interval monitoring in patients treated with psychotropic drugs. In all individuals hospitalized at our Department of Psychiatry, ECG is being routinely recorded and QT interval was assessed in order to minimize the risk of proarrhythmia. QT interval monitoring seems appropriate for this purpose since to date, there has not been an example of human TdP induced by a drug that cannot cause QT interval prolongation [7]. Nevertheless, the practicality of the monitoring is complicated by interindividual differences in drug response that are due to polymorphisms in genes encoding drug metabolizing enzymes, drug transporters, drug targets, as well as repolarization physiology [8,9]. Usually, QT prolongation is considered when QTc (Bazett) interval exceeds 440 ms in males and 460 ms in females [10]. The Committee for Proprietary Medicinal Products also proposed that drug-induced QTc intervals exceeding 500 ms are of concern [11]. These cut-off values were used also in our study. However, there is no well-established threshold duration below which QT prolongation might be considered as benign [12]. Moreover, the best correction approach is still subject of controversy. Only recently it has been showed that QT/RR relationship exhibits a substantial inter-subject variability while also showing high intra-subject stability. Therefore no single mathematical formula can be obtained which will describe the QT/RR relationship satisfactorily in all individuals [13]. Nevertheless, while these findings are useful in the clinical pre-approval drug evaluation, there are of little use in clinical practice when only single ECG is available from each individual. Bazett's correction is therefore frequently used, including described cut-off values, despite numerous reports of its inadequacy and despite the understanding that the QTc interval corrected by Bazett is artificially prolonged at heart rates >60 beats/ min and shortened at heart rates < 60 beats/min [14]. Fridericia's formula might perhaps be accepted as a practically reasonable correction in clinical setting, although it is still not entirely accurate [15]. In our survey the average heart rate of the outliers was approximately 85 bpm, suggesting that corrected QTc values might have been artificially prolonged because of the correction procedures used. Psychiatric patients studies in our survey were treated with a wide spectrum of different psychotropic drugs. Majority of these has been reported to influence QT interval [4–6]. Approximately 10% of the patients received combination therapy which is considered as a further risk factor for proarrhythmia. Still, the occurrence of abnormal QTc interval values was low (Table 3). In particular, there was
331
no case of substantial QTc interval prolongation above 500 ms. In principle, our observation is in agreement with reports on the drugs used. Data on isolated QT prolongation associated with psychopharmacologic compounds are available only for some of them and usually, only cases with QTc prolongation > 500 ms are described. Thioridazine is most potent in causing QT prolongation (QTc > 450 ms in 60% of patients) [16], while with ziprasidone, QTc intervals > 500 ms occur in less than 1% of patients [4]. For clomipramine, there are data in children and adolescents showing QTc prolongation of > 450 ms in 11% of individuals [17]. In majority of the other psychotropic drugs, only anecdotal reports are available mostly from cases of poisoning [4–6]. There is only one study dealing with a general psychiatric population, in which in 495 patients QTc prolongation > 450 ms were observed in 8% [18]. High proportion of these patients was treated with thioridazine which is presently used very seldom. Low occurrence of QT prolongation in our population is therefore likely explained by a different spectrum of psychotropic drugs used in present psychiatric clinical practice. Our survey suffers from some important limitations. Firstly, since majority of the patients suffered from chronic psychotic conditions, it was clearly unethical to wash them off therapy for the purposes of baseline ECG recording. Therefore, QT interval change could not have been assessed. In this respect, our survey is a good model of other programs of clinical ECG screening. Therefore an association of a particular drug with QTc value cannot be considered. Secondly, the size of the group of patients who entered our survey is not particularly large. Nevertheless, this is again a reasonable model of a single-centre clinical experience which is appropriate since clinical ECG monitoring is mostly conducted within individual clinical departments. Thirdly, because of the above described reasons, it was not possible to confirm the relationship between particular observation of prolonged QTc and a particular drug. Finally, with ECGs taken in chronically treated patients, the subjects prone to QT prolongation might already be dead due to torsade des pointes. There are no meaningful data to quantify this possible effect and it would equally apply to other monitoring experiences. Hence, our 2-year real-life experience shows that the occurrence of QT prolongation in psychiatric patients subject to contemporary treatment is rather low. This could be related to recent changes of spectrum of antipsychotic drugs used, the general trend to use lower doses of antipsychotic medication and increasing awareness about the drug-induced long QT syndrome. Nevertheless because of possible fatalities the clinical importance of acquired long QT syndrome cannot be underestimated. The low incidence of QT interval prolongation suggests low incidence of torsade des pointes induction in present psychiatric populations but may also lead to an inappropriate underestimation of the
332
T. Novotny et al. / International Journal of Cardiology 117 (2007) 329–332
danger of proarrhythmia. In spite of the fact that the incidence of torsadegenic toxicity is likely decreasing, any complacency by the clinical community might have drastic consequences. The need for preventive measures has not diminished. One of the most effective preventive measures in ECG screening in risk groups of patients remains the QT interval monitoring which has been proved fully feasible by our experience. Acknowledgement This research is supported by the Internal Grant Agency of the Ministry of Health of the Czech Republic Grant IGA MH NA 7424-3. References [1] Haverkamp W, Breithardt G, Camm AJ, et al. The potential for QT prolongation and pro-arrhythmia by non-anti-arrhythmic drugs: clinical and regulatory implications. Report on a Policy conference of the European Society of Cardiology. Cardiovasc Res 2000; 47:219–33. [2] Hennessy S, Bilker WB, Knauss JS, et al. Cardiac arrest and ventricular arrhythmia in patients taking antipsychotic drugs: cohort study using administrative data. BMJ 2002;325:1070–4. [3] Ray WA, Meredith S, Thapa PB, Meador KG, Hall K, Murray KT. Antipsychotics and the risk of sudden cardiac death. Arch Gen Psychiatry 2001;58:1161–7. [4] Camm AJ, Malik M, Yap YG. Risk of QT prolongation and torsades de pointes with psychotropic drugs. In: Camm AJ, Malik M, Yap YG, editors. Acquired long QT syndrome. Oxford: Blackwell Futura; 2004. p. 102–20. [5] Taylor DM. Antipsychotics and QT prolongation. Acta Psychiatr Scand 2003;107:85–9. [6] www.torsades.org. [7] Fenichel RR, Malik M, Antzelevitch C, et al. Independent Academic Task Force. Drug-induced torsades de pointes and implications for drug development. J Cardiovasc Electrophysiol 2004;15:475–95.
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