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QT interval effects of Cisapride in the clinical setting
International Journal of Cardiology 80 (2001) 179–183 www.elsevier.com / locate / ijcard
QT interval effects of Cisapride in the clinical setting a, b a a a a S.H. Wang *, C.Y. Lin , T.Y. Huang , W.S. Wu , C.C. Chen , S.H. Tsai a
Section of Cardiology, Department of Internal Medicine, Chi-Mei Medical Center, 901, Chung-Hwa Road, Yung-Kang City, Tainan, 701, Taiwan b Section of Gastroenterology, Department of Internal Medicine, Chi-Mei Medical Center, 901, Chung-Hwa Road, Yung-Kang City, Tainan, 701, Taiwan Received 12 December 2000; received in revised form 23 April 2001; accepted 16 May 2001
Abstract Purpose: The clinical effect of cisapride on QT intervals was prospectively studied. Subjects: Consecutive adult patients were recruited in whom cisapride was indicated for gastroesophogeal reflux, gastric ulcer, duodenal ulcer, diabetic gastroparesis or chronic constipation refractory to laxatives. Exclusion criteria included disorders and medications affecting cardiac conduction, electrolyte homeostasis, drug clearance and membrane stability. Methods: Seventy-five patients were included and followed at 1 to 2 week intervals. Patients took cisapride 5 mg thrice daily for 1 to 4 weeks (lower dose stage), followed by 10 mg thrice daily for another 1 to 4 weeks (higher dose stage). Twelve-lead ECGs were performed before commencing cisapride (group B), at completion of the lower dose stage (group L) and at completion of the higher dose stage (group H). Results: No patients experienced presyncope or syncope. Seventeen patients failing to comply, and 7 complaining of abdominal discomfort or diarrhea were excluded, leaving 51 participants. Group H’s corrected QT interval (QTc) was longer than group B’s by 13615 ms (P,0.001), and longer than group L’s by 7611 ms (P,0.001). Group L’s QTc was longer than group B’s by 7621 ms (P,0.05). QT dispersion did not differ significantly among groups. Neither torsade de pointe nor ventricular tachycardia were noted in Holter monitoring of 33 patients during the higher dose stage. Conclusion: cisapride dosedependently prolongs the QT interval. Further study is needed to examine the arrhythmogenicity of cisapride in higher doses and for longer durations. 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Cisapride; QT interval; Arrhythmia
1. Introduction Cisapride is a gastrointestinal prokinetic agent for the treatment of gastroesophageal reflux, functional dyspepsia, gastroparesis, chronic constipation and irritable bowel syndrome [1]. Inappropriate lengthening of the QT interval and induction of major cardiac rhythm disturbances, such as torsade de pointes, have recently been reported [2–9]. Although some of these episodes have occurred at high doses of cisapride, *Corresponding author. Tel.: 1886-6-281-2811; fax: 1886-6-2099454. E-mail address: [email protected] (S.H. Wang).
several unanticipated cases of torsade de pointes (TdP) and sudden death have been seen in patients, including children, receiving clinically recommended doses of the drug [2,7]. Recent animal studies have demonstrated that cisapride exerts typical class III anti-arrhythmic agent properties [10], prolonging cardiac repolarization and inducing early depolarization in rabbit Purkinje fibers. Further studies have shown that the QT-lengthening effect of cisapride is essentially due to blocking of the rapid component of delayed rectifying current (Ikr) [10,11]. A recent study in healthy volunteers demonstrated that monotherapy with 10 mg cisapride taken four times a day leads to a concentration-dependent elevation of the
0167-5273 / 01 / $ – see front matter 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S0167-5273( 01 )00485-5
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S.H. Wang et al. / International Journal of Cardiology 80 (2001) 179 – 183
corrected QT interval (QTc), amounting to 6 ms during steady state [12]. The effects of cisapride on the QT interval and on QT dispersion in clinical patients has not been reported in the literature. Consequently, this prospective study aimed to characterize the ECG effects of cisapride when used in the clinical setting.
2. Methods Consecutive adult patients with clinical indications for cisapride use, including gastroesophageal reflux, functional dyspepsia, diabetic gastroparesis, chronic constipation refractory to laxatives, duodenal ulcer and peptic ulcer were recruited. Detailed medical histories were obtained and cardiovascular examinations performed. ECG and biochemical profiles were also obtained. Patients were excluded if they had a history of or evidence of bundle branch block, intraventricular conduction delay, ventricular preexcitation, sinus bradycardia or tachycardia, supraventricular or ventricular tachyarrhythmia, second or third-degree AV block, angina pectoris, or myocardial infarction, or any other ECG abnormalities that complicated either the measurement or the interpretation of the QT interval. Male patients with a baseline QTc longer than 450 ms and female patients with a baseline QTc longer than 470 ms were excluded. Patients were also excluded if they had hypokalemia, alcoholism, abnormal renal function, or hepatobiliary disorders. Additionally, patients were excluded if they were taking any of the following medications: (1) class I or III antiarrhythmic agents, (2) imidazole antifungal agents, (3) macrolide antibiotics, (4) major tranquilizers or tricyclic antidepressants, (5) H2 blockers, and (6) diltiazem. Patients using diuretics were not excluded if follow-up potassium levels were within normal limits. Informed consent was obtained from each patient and the study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki. All patients were given cisapride 5 mg thrice daily for 1 to 4 weeks (lower dose stage), followed by 10 mg thrice daily for another 1 to 4 weeks (higher dose stage). Twelve-lead ECGs were recorded at 50 mm / s on the day before commencing cisapride, after using
cisapride at the lower dose for at least 1 week, and after using cisapride at the higher dose for at least 1 week. To avoid diurnal variations, follow-up ECGs for each patient were performed at the same time as the baseline ECG, or as close to that time as possible. Holter monitoring was performed during the 2nd to 4th week of the higher dose stage. Patients were followed at 1 to 2 week intervals and each case was closed after 8 weeks’ follow-up. After each case was closed, the decision regarding continued use or cessation of cisapride was left to the patient’s treating doctors. At follow-up visits, patients were routinely asked two series of questions. Series I questions were: (1) ‘‘Have you taken the medication as prescribed?’’; (2) ‘‘Have you missed any doses of the medication in the past 3 days?’’; (3) ‘‘How many pills of cisapride are left?’’; (4) ‘‘Have you commenced any new medications since the last visit?’’. A patient was excluded from further participation in the study if drug compliance was judged to be inadequate or if the patient took one or more new medications not in use in the baseline period. ECG tracings were obtained only if the patient had not missed any single dose of cisapride in the 3 days prior to a scheduled ECG recording. Series II questions included: (1) ‘‘Have you experienced fainting or near fainting since the last visit?’’; (2) ‘‘Have you experienced palpitations since the last visit? Were they associated with chest tightness, general weakness or shortness of breath?’’. A single observer, unaware of the patient’s diagnosis and treatment, measured the QT interval from the onset of the QRS complex to the end of the T wave (defined as its return to the T / P baseline), doing so only in those leads where this was clearly identifiable. When U waves were present, the end of the T wave was defined as the intersection of the repolarization slope tangent with the isoelectric line [13]. Measurements of the QT interval were assessed as the mean over three beats. The corrected QT interval (QTc) was calculated using Bazett’s formula. The twelve-lead-averaged QTc was calculated as the average QTc of all leads with a measurable QT interval. QT interval dispersion was computed as [(the difference between maximum and minimum values of QT) / square root of n], where n is the number of leads with a measurable QT interval. QT dispersion was not computed if n,9 [13].
S.H. Wang et al. / International Journal of Cardiology 80 (2001) 179 – 183
2.1. Statistics
181
The mean 12-lead-averaged QTc in the baseline group (group B), the lower dose cisapride group (group L) and the higher dose cisapride group (group H) were 416630, 423631, and 430629 ms, respectively. The differences between the mean 12-leadaveraged QTc intervals was 7621 ms (95% confidence interval 7–12 ms, P,0.05) between group L and group B, 7611 ms (95% confidence interval 4–10 ms, P,0.001) between group H and group L, and 13615 ms (95% confidence interval 9–18 ms, P,0.001) between group H and group B. The QTc data for the 12 different leads are shown in Table 1. Of note, the QTc intervals of group H were significantly higher than those of group B in all leads (all P,0.001), and were higher than those of group L in all leads but lead V2. The QTc intervals of group L were significantly higher than those of group B only in leads II, avR, avF, and V4. QT dispersions were 15.866.2 ms, 16.066.6 ms, and 14.866.9 ms in group B, L and H, respectively, and were not significantly different between groups.
Data were divided into three groups; the baseline group (group B), the lower dose group (group L) and the higher dose group (group H); and were presented as mean6S.D. Differences in the QTc and QT dispersion among groups were compared with repeated-measurement ANOVA. Differences between two groups were compared using the paired t-test. A difference was considered statistically significant if the P-value was ,0.05.
3. Results Between July 1998 and December 1999, 75 patients were recruited. The study was aborted in 17 patients due to inadequate drug compliance, and in another seven patients because of abdominal discomfort or diarrhea after taking cisapride. The remaining 51 patients, comprising 27 males and 24 females with ages ranging between 20 to 86 (55615) years, completed the study. Underlying diseases present in the study poluation included hypertension in 13, diabetes mellitus in seven, and emphysema in 1 patient. Their medications included proton blockers in 14 (lansoprazole in 11 and omeprazole in three), beta-blockers in 6, calcium channel blockers in 10, diuretics in 4, alpha-blockers in 2, an angiotensin converting enzyme inhibitor in 1, oral hypoglycemic agents in 4, benzodiazepines in 5, and aminophylline in 1 patient. The reasons for using cisapride included peptic ulcer in 18, gastroesophageal reflux in 15, gastropathy in 8, and constipation in 10 patients. The duration of treatment with a cisapride dose of 15 mg / day ranged from 7 to 28 (1767) days, and the intervals of treatment with a cisapride dose of 30 mg / day ranged from 7 to 28 (1668) days.
3.1. Intraobserver variability in measurement of QT interval One hundred and twenty-five single-lead tracings were selected randomly for repeated measurement of QT intervals. Correlation coefficient between the first and the second set of measurements was 0.964. The difference between the two observations was 24.768.8 ms. No patients presented with presyncope, syncope or palpitations associated with general weakness, dyspnea or chest tightness during the 8 week study period. Twenty four h Holter monitoring was performed in 33 patients between day 12 and 26 of the high-dose stage. Neither torsade de pointe, nor VT were noted in these 33 recordings.
Table 1 Corrected QT intervals (mean6S.D. ms) in 12 leads a Lead
I [&
II $[&
III [&
avR$[&
avL [&
avF $[&
V1 [&
V2 &
V3 [&
V4 $[&
V5 [&
V6 [&
Average of 12 leads $[&
Group B Group L Group H
408633 414631 422632
416629 423628 431629
398621 408635 415631
414631 422631 427630
395636 404646 414645
404624 415624 423623
405639 409645 420642
422622 425623 430623
432633 431633 438626
425632 433633 439630
424632 431633 435630
421633 425635 433632
416630 423631 430629
a
$: group L vs. group B, P,0.05; [: group H vs. group L, P,0.05; &: group H vs. group B, P#0.001.
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S.H. Wang et al. / International Journal of Cardiology 80 (2001) 179 – 183
4. Discussion Our data show that the use of cisapride in the clinical setting dose-dependently prolongs the QT interval. With the thrice daily 10 mg dosing regime, the QTc increased by 13615 ms (95% confidence interval 9–18 ms). There was no change in QT dispersion. Drug-induced QT prolongation is known to be a risk factor for TdP and sudden cardiac death. Individual changes in the QTc of less than 30 ms are generally thought unlikely to raise significant concern but individual changes greater than 60 ms raise clear concern about the potential risk of a drug-induced arrhythmia including TdP [14]. There have been several case reports of TdP or sudden death in patients treated with cisapride. In most of those cases, use of a relatively large dose of cisapride or concomitant use of agents that may also prolong the QT interval or interfere with the metabolism of cisapride were noted. In a recent report, the incidence of arrhythmic events was 1.6 times greater in periods in which cisapride had been used recently. With adjustment for clinical history, use of CYP3A inhibitors and the use of drugs that prolong the QT interval, the odds ratio for cisapride inducing arrhythmic events was 1.0 [15]. In this study, every effort was made to exclude pathology or agents that could potentially prolong the QT interval, such as hypokalemia and class Ia or III antiarrhythmic agents, and agents that could interfere with cisapride metabolism, such as macrolide antibiotics or azole antifungal drugs [15]. None of the patients, which were a relatively select group, developed symptoms or signs of ventricular tachycardia or torsade de pointe during the study period. Nevertheless, only small doses of cisapride were tested in this study, patients were followed for no longer than 2 months and the number of patients was small. Further studies with a larger number of patients and a longer follow-up are needed to clarify the safety of long-term cisapride use in this particular patient population. The safety of cisapride at a dose higher than 30 mg per day in this population also needs to be determined. QT dispersion has been used as an indirect measurement of inhomogeneity of ventricular repolarization, and increases in QT dispersion have been thought to be arrhythmogenic [13]. Some class III
antiarrhythmic agents, such as amiodarone and biperidil, seldom cause TdP despite their pronounced QT-prolonging effects. In contrast, other drugs which are more likely to cause TdP, such as class Ia antiarrhythmics, have only a modest effect on the QT interval. This disparity between prolongation of the QT interval and the propensity to cause TdP has been attributed to the fact that drugs such as amiodarone and biperidil have less effect upon dispersion of ventricular repolarization than class I antiarrhythmic drugs [16]. Our data show that cisapride 10 mg thrice daily does not cause a change in QT dispersion.
4.1. Limitations of study (1) It has been known that slower heart rates tend to undercorrect and faster heart rates overcorrect the measured QT interval. To reduce theses effects of heart rates, we have excluded patients with sinus tachycardia or bradycardia. (2) Serum concentration of the drug were not measured. Conseqeuently, the timing of QT measurement might not have coincided with the maximum plasma concentration of the drug.
5. Conclusion We conclude that the use of cisapride in the clinical setting may dose-dependently prolong the QT interval. The use of cisapride at 30 mg per day prolongs the QTc by 13615 ms but has no effect on QTc dispersion. In terms of the arrhythmogenicity of cisapride, further studies are needed to clarify the safety of use of cisapride with higher doses (.30 mg / day), longer durations of use (.2 months), and possibly a less select group of patients.
References [1] Bran S, Murray WA, Hirsch IB, Palmer JP. Long QT syndrome during high-dose cisapride. Arch Intern Med 1995;155:765–8. [2] Lewin MB, Bryant RM, Fenrich AL, Grifka RG. Cisapride induced long QT interval. J Pediatr 1996;128:279–81. [3] Ahmad RS, Wolfe SM. Cisapride and torsade de pointes [letter]. Lancet 1995;345:508. [4] Piquette RK. Torsade de pointes induced by cisapride / clarithromycin interaction. Ann Pharmacotherapy 1999;33:22–6. [5] Vitola J, Vukanovic J, Roden DM. Cisapride-induced torsade de pointes. J Cardiovasc Electrophysiol 1998;9:1109–13.
S.H. Wang et al. / International Journal of Cardiology 80 (2001) 179 – 183 [6] Wysowski DK, Bacsanyi J. Cisapride and fatal arrhythmia. N Engl J Med 1996;335:290–1. [7] Pettignano R, Chambliss CR, Darsey E et al. Cisapride-induced dysrhythmia in a pediatric patient receiving extracorporeal life support. Crit Care Med 1996;24:1268–71. [8] Farrington E. Cardiac toxicity with cisapride. Pediatr Nursing 1996;22:256, Letter. [9] Olsson S, Edwards IR. Tachycardia during cisapride treatment. Br Med J 1992;305:748–9. [10] Puisieux FL, Adamntidis MM, Dumotier BM, Dupuis BA. Cisapride-induced prolongation of cardiac action potential and early afterdepolarizations in rabbit Purkinje fibers. Br J Pharmacol 1996;117:1377–9. [11] Drolet B, Khalifa M, Daleau P et al. Block of the Rapid Component of the Delayed Rectifier Potassium Current by the Prokinetic Agent Cisapride underlies drug-related lengthening of the QT interval. Circulation 1998;97:204–10. [12] van Haarst AD, van’t Klooster GAE, van Gerven JMA et al. The influence of cisapride and clarithromycin on QT intervals in healthy volunteers. Clin Pharmacol Ther 1998;64:542–6.
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[13] Statters DJ, Malik M, Ward DE, Camm J. QT dispersion: Problems of methodology and clinical significance. J Cardiovasc Electrophysiol 1994;5:672–85. [14] The European Agency for the Evaluation of Medicinal Products, Committee for proprietary medicinal products. Points to consider: the assessment of the potential for QT interval prolongation by non-cardiovascular medicinal products. London, 1997: CPMP/ 986 / 96. [15] Walker AM, Szneke P, Weatherby LB et al. The risk of serious cardiac arrhythmias among cisapride users in the United Kingdom and Canada. Am J Med 1999;107:356–62. [16] Hii JTY, Wyse DG, Gillis AM et al. Precordial QT interval dispersion as a marker of torsade de pointes. Disparate effects of class Ia antiarrhythmic drugs and amiodarone. Circulation 1992;86:1374–83.
QT interval effects of Cisapride in the clinical setting a, b a a a a S.H. Wang *, C.Y. Lin , T.Y. Huang , W.S. Wu , C.C. Chen , S.H. Tsai a
Section of Cardiology, Department of Internal Medicine, Chi-Mei Medical Center, 901, Chung-Hwa Road, Yung-Kang City, Tainan, 701, Taiwan b Section of Gastroenterology, Department of Internal Medicine, Chi-Mei Medical Center, 901, Chung-Hwa Road, Yung-Kang City, Tainan, 701, Taiwan Received 12 December 2000; received in revised form 23 April 2001; accepted 16 May 2001
Abstract Purpose: The clinical effect of cisapride on QT intervals was prospectively studied. Subjects: Consecutive adult patients were recruited in whom cisapride was indicated for gastroesophogeal reflux, gastric ulcer, duodenal ulcer, diabetic gastroparesis or chronic constipation refractory to laxatives. Exclusion criteria included disorders and medications affecting cardiac conduction, electrolyte homeostasis, drug clearance and membrane stability. Methods: Seventy-five patients were included and followed at 1 to 2 week intervals. Patients took cisapride 5 mg thrice daily for 1 to 4 weeks (lower dose stage), followed by 10 mg thrice daily for another 1 to 4 weeks (higher dose stage). Twelve-lead ECGs were performed before commencing cisapride (group B), at completion of the lower dose stage (group L) and at completion of the higher dose stage (group H). Results: No patients experienced presyncope or syncope. Seventeen patients failing to comply, and 7 complaining of abdominal discomfort or diarrhea were excluded, leaving 51 participants. Group H’s corrected QT interval (QTc) was longer than group B’s by 13615 ms (P,0.001), and longer than group L’s by 7611 ms (P,0.001). Group L’s QTc was longer than group B’s by 7621 ms (P,0.05). QT dispersion did not differ significantly among groups. Neither torsade de pointe nor ventricular tachycardia were noted in Holter monitoring of 33 patients during the higher dose stage. Conclusion: cisapride dosedependently prolongs the QT interval. Further study is needed to examine the arrhythmogenicity of cisapride in higher doses and for longer durations. 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Cisapride; QT interval; Arrhythmia
1. Introduction Cisapride is a gastrointestinal prokinetic agent for the treatment of gastroesophageal reflux, functional dyspepsia, gastroparesis, chronic constipation and irritable bowel syndrome [1]. Inappropriate lengthening of the QT interval and induction of major cardiac rhythm disturbances, such as torsade de pointes, have recently been reported [2–9]. Although some of these episodes have occurred at high doses of cisapride, *Corresponding author. Tel.: 1886-6-281-2811; fax: 1886-6-2099454. E-mail address: [email protected] (S.H. Wang).
several unanticipated cases of torsade de pointes (TdP) and sudden death have been seen in patients, including children, receiving clinically recommended doses of the drug [2,7]. Recent animal studies have demonstrated that cisapride exerts typical class III anti-arrhythmic agent properties [10], prolonging cardiac repolarization and inducing early depolarization in rabbit Purkinje fibers. Further studies have shown that the QT-lengthening effect of cisapride is essentially due to blocking of the rapid component of delayed rectifying current (Ikr) [10,11]. A recent study in healthy volunteers demonstrated that monotherapy with 10 mg cisapride taken four times a day leads to a concentration-dependent elevation of the
0167-5273 / 01 / $ – see front matter 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S0167-5273( 01 )00485-5
180
S.H. Wang et al. / International Journal of Cardiology 80 (2001) 179 – 183
corrected QT interval (QTc), amounting to 6 ms during steady state [12]. The effects of cisapride on the QT interval and on QT dispersion in clinical patients has not been reported in the literature. Consequently, this prospective study aimed to characterize the ECG effects of cisapride when used in the clinical setting.
2. Methods Consecutive adult patients with clinical indications for cisapride use, including gastroesophageal reflux, functional dyspepsia, diabetic gastroparesis, chronic constipation refractory to laxatives, duodenal ulcer and peptic ulcer were recruited. Detailed medical histories were obtained and cardiovascular examinations performed. ECG and biochemical profiles were also obtained. Patients were excluded if they had a history of or evidence of bundle branch block, intraventricular conduction delay, ventricular preexcitation, sinus bradycardia or tachycardia, supraventricular or ventricular tachyarrhythmia, second or third-degree AV block, angina pectoris, or myocardial infarction, or any other ECG abnormalities that complicated either the measurement or the interpretation of the QT interval. Male patients with a baseline QTc longer than 450 ms and female patients with a baseline QTc longer than 470 ms were excluded. Patients were also excluded if they had hypokalemia, alcoholism, abnormal renal function, or hepatobiliary disorders. Additionally, patients were excluded if they were taking any of the following medications: (1) class I or III antiarrhythmic agents, (2) imidazole antifungal agents, (3) macrolide antibiotics, (4) major tranquilizers or tricyclic antidepressants, (5) H2 blockers, and (6) diltiazem. Patients using diuretics were not excluded if follow-up potassium levels were within normal limits. Informed consent was obtained from each patient and the study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki. All patients were given cisapride 5 mg thrice daily for 1 to 4 weeks (lower dose stage), followed by 10 mg thrice daily for another 1 to 4 weeks (higher dose stage). Twelve-lead ECGs were recorded at 50 mm / s on the day before commencing cisapride, after using
cisapride at the lower dose for at least 1 week, and after using cisapride at the higher dose for at least 1 week. To avoid diurnal variations, follow-up ECGs for each patient were performed at the same time as the baseline ECG, or as close to that time as possible. Holter monitoring was performed during the 2nd to 4th week of the higher dose stage. Patients were followed at 1 to 2 week intervals and each case was closed after 8 weeks’ follow-up. After each case was closed, the decision regarding continued use or cessation of cisapride was left to the patient’s treating doctors. At follow-up visits, patients were routinely asked two series of questions. Series I questions were: (1) ‘‘Have you taken the medication as prescribed?’’; (2) ‘‘Have you missed any doses of the medication in the past 3 days?’’; (3) ‘‘How many pills of cisapride are left?’’; (4) ‘‘Have you commenced any new medications since the last visit?’’. A patient was excluded from further participation in the study if drug compliance was judged to be inadequate or if the patient took one or more new medications not in use in the baseline period. ECG tracings were obtained only if the patient had not missed any single dose of cisapride in the 3 days prior to a scheduled ECG recording. Series II questions included: (1) ‘‘Have you experienced fainting or near fainting since the last visit?’’; (2) ‘‘Have you experienced palpitations since the last visit? Were they associated with chest tightness, general weakness or shortness of breath?’’. A single observer, unaware of the patient’s diagnosis and treatment, measured the QT interval from the onset of the QRS complex to the end of the T wave (defined as its return to the T / P baseline), doing so only in those leads where this was clearly identifiable. When U waves were present, the end of the T wave was defined as the intersection of the repolarization slope tangent with the isoelectric line [13]. Measurements of the QT interval were assessed as the mean over three beats. The corrected QT interval (QTc) was calculated using Bazett’s formula. The twelve-lead-averaged QTc was calculated as the average QTc of all leads with a measurable QT interval. QT interval dispersion was computed as [(the difference between maximum and minimum values of QT) / square root of n], where n is the number of leads with a measurable QT interval. QT dispersion was not computed if n,9 [13].
S.H. Wang et al. / International Journal of Cardiology 80 (2001) 179 – 183
2.1. Statistics
181
The mean 12-lead-averaged QTc in the baseline group (group B), the lower dose cisapride group (group L) and the higher dose cisapride group (group H) were 416630, 423631, and 430629 ms, respectively. The differences between the mean 12-leadaveraged QTc intervals was 7621 ms (95% confidence interval 7–12 ms, P,0.05) between group L and group B, 7611 ms (95% confidence interval 4–10 ms, P,0.001) between group H and group L, and 13615 ms (95% confidence interval 9–18 ms, P,0.001) between group H and group B. The QTc data for the 12 different leads are shown in Table 1. Of note, the QTc intervals of group H were significantly higher than those of group B in all leads (all P,0.001), and were higher than those of group L in all leads but lead V2. The QTc intervals of group L were significantly higher than those of group B only in leads II, avR, avF, and V4. QT dispersions were 15.866.2 ms, 16.066.6 ms, and 14.866.9 ms in group B, L and H, respectively, and were not significantly different between groups.
Data were divided into three groups; the baseline group (group B), the lower dose group (group L) and the higher dose group (group H); and were presented as mean6S.D. Differences in the QTc and QT dispersion among groups were compared with repeated-measurement ANOVA. Differences between two groups were compared using the paired t-test. A difference was considered statistically significant if the P-value was ,0.05.
3. Results Between July 1998 and December 1999, 75 patients were recruited. The study was aborted in 17 patients due to inadequate drug compliance, and in another seven patients because of abdominal discomfort or diarrhea after taking cisapride. The remaining 51 patients, comprising 27 males and 24 females with ages ranging between 20 to 86 (55615) years, completed the study. Underlying diseases present in the study poluation included hypertension in 13, diabetes mellitus in seven, and emphysema in 1 patient. Their medications included proton blockers in 14 (lansoprazole in 11 and omeprazole in three), beta-blockers in 6, calcium channel blockers in 10, diuretics in 4, alpha-blockers in 2, an angiotensin converting enzyme inhibitor in 1, oral hypoglycemic agents in 4, benzodiazepines in 5, and aminophylline in 1 patient. The reasons for using cisapride included peptic ulcer in 18, gastroesophageal reflux in 15, gastropathy in 8, and constipation in 10 patients. The duration of treatment with a cisapride dose of 15 mg / day ranged from 7 to 28 (1767) days, and the intervals of treatment with a cisapride dose of 30 mg / day ranged from 7 to 28 (1668) days.
3.1. Intraobserver variability in measurement of QT interval One hundred and twenty-five single-lead tracings were selected randomly for repeated measurement of QT intervals. Correlation coefficient between the first and the second set of measurements was 0.964. The difference between the two observations was 24.768.8 ms. No patients presented with presyncope, syncope or palpitations associated with general weakness, dyspnea or chest tightness during the 8 week study period. Twenty four h Holter monitoring was performed in 33 patients between day 12 and 26 of the high-dose stage. Neither torsade de pointe, nor VT were noted in these 33 recordings.
Table 1 Corrected QT intervals (mean6S.D. ms) in 12 leads a Lead
I [&
II $[&
III [&
avR$[&
avL [&
avF $[&
V1 [&
V2 &
V3 [&
V4 $[&
V5 [&
V6 [&
Average of 12 leads $[&
Group B Group L Group H
408633 414631 422632
416629 423628 431629
398621 408635 415631
414631 422631 427630
395636 404646 414645
404624 415624 423623
405639 409645 420642
422622 425623 430623
432633 431633 438626
425632 433633 439630
424632 431633 435630
421633 425635 433632
416630 423631 430629
a
$: group L vs. group B, P,0.05; [: group H vs. group L, P,0.05; &: group H vs. group B, P#0.001.
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4. Discussion Our data show that the use of cisapride in the clinical setting dose-dependently prolongs the QT interval. With the thrice daily 10 mg dosing regime, the QTc increased by 13615 ms (95% confidence interval 9–18 ms). There was no change in QT dispersion. Drug-induced QT prolongation is known to be a risk factor for TdP and sudden cardiac death. Individual changes in the QTc of less than 30 ms are generally thought unlikely to raise significant concern but individual changes greater than 60 ms raise clear concern about the potential risk of a drug-induced arrhythmia including TdP [14]. There have been several case reports of TdP or sudden death in patients treated with cisapride. In most of those cases, use of a relatively large dose of cisapride or concomitant use of agents that may also prolong the QT interval or interfere with the metabolism of cisapride were noted. In a recent report, the incidence of arrhythmic events was 1.6 times greater in periods in which cisapride had been used recently. With adjustment for clinical history, use of CYP3A inhibitors and the use of drugs that prolong the QT interval, the odds ratio for cisapride inducing arrhythmic events was 1.0 [15]. In this study, every effort was made to exclude pathology or agents that could potentially prolong the QT interval, such as hypokalemia and class Ia or III antiarrhythmic agents, and agents that could interfere with cisapride metabolism, such as macrolide antibiotics or azole antifungal drugs [15]. None of the patients, which were a relatively select group, developed symptoms or signs of ventricular tachycardia or torsade de pointe during the study period. Nevertheless, only small doses of cisapride were tested in this study, patients were followed for no longer than 2 months and the number of patients was small. Further studies with a larger number of patients and a longer follow-up are needed to clarify the safety of long-term cisapride use in this particular patient population. The safety of cisapride at a dose higher than 30 mg per day in this population also needs to be determined. QT dispersion has been used as an indirect measurement of inhomogeneity of ventricular repolarization, and increases in QT dispersion have been thought to be arrhythmogenic [13]. Some class III
antiarrhythmic agents, such as amiodarone and biperidil, seldom cause TdP despite their pronounced QT-prolonging effects. In contrast, other drugs which are more likely to cause TdP, such as class Ia antiarrhythmics, have only a modest effect on the QT interval. This disparity between prolongation of the QT interval and the propensity to cause TdP has been attributed to the fact that drugs such as amiodarone and biperidil have less effect upon dispersion of ventricular repolarization than class I antiarrhythmic drugs [16]. Our data show that cisapride 10 mg thrice daily does not cause a change in QT dispersion.
4.1. Limitations of study (1) It has been known that slower heart rates tend to undercorrect and faster heart rates overcorrect the measured QT interval. To reduce theses effects of heart rates, we have excluded patients with sinus tachycardia or bradycardia. (2) Serum concentration of the drug were not measured. Conseqeuently, the timing of QT measurement might not have coincided with the maximum plasma concentration of the drug.
5. Conclusion We conclude that the use of cisapride in the clinical setting may dose-dependently prolong the QT interval. The use of cisapride at 30 mg per day prolongs the QTc by 13615 ms but has no effect on QTc dispersion. In terms of the arrhythmogenicity of cisapride, further studies are needed to clarify the safety of use of cisapride with higher doses (.30 mg / day), longer durations of use (.2 months), and possibly a less select group of patients.
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