Retrospective analysis of cisapride-induced QT changes in end-stage renal disease patients

Melissa J. Hentges1, Brent W. Gunderson2 and Matthew J. Lewis3,

1 Division of Nephrology, Hennepin County Medical Center, 2 University of Minnesota College of Pharmacy, 3 Division of Nephrology, Hennepin County Medical Center, Minneapolis, Minnesota, USA



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. This study involves a retrospective in-patient chart review of end-stage renal disease (ESRD) patients receiving haemodialysis to observe if cisapride significantly increases heart rate (HR), QT, and corrected QT (QTc) intervals on 12-lead electrocardiograms (ECGs).

Methods. Medical records for 23 patients who were being treated with chronic maintenance haemodialysis and had >=2 ECGs while on cisapride and >=2 ECGs while off cisapride were obtained and reviewed. HR, QT, and QTc on all 12-lead ECGs, reason for admission, and past medical history were analysed.

Results. A total of 529 ECGs (279 on/250 off cisapride) for 23 patients were included. The results, as calculated by each patient's individual averages (n=23), on vs off cisapride respectively, were HR, 88±14 vs 84±17 beats/min (P=0.18); QT, 373±39 vs 382±45 ms (P=0.24); and QTc, 443±27 vs 441±21 ms (P=0.39). No significant difference was found in the number of admissions per month while on or off cisapride. No patient had an average QTc on or off cisapride that was >500 ms. One patient died from ventricular arrhythmia 12 days after discontinuing cisapride. The patient's QTc was significantly longer on vs off cisapride (487 vs 462 ms, P=0.007); however, this patient had an extensive cardiac history and multiple syncopal episodes prior to the use of cisapride.

Conclusions. This study found no significant overall difference in HR, QT, and QTc interval or admissions/month on vs off cisapride in ESRD patients receiving haemodialysis.

Keywords: cisapride; end-stage renal disease; haemodialysis; QT interval; QTc interval



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Gastric motility disorders, primarily diabetic gastroparesis, are common in end-stage renal disease (ESRD) patients. Many of these patients suffer from nausea, vomiting, and decreased appetite, ultimately leading to malnutrition. One of the more effective medications used to increase gastric motility is cisapride (Propulsid®). Cisapride is a third-generation prokinetic agent that improves motility by indirectly facilitating acetylcholine release from the myenteric plexus–longitudinal muscles of the gut, mediated by post-ganglionic nerve endings [1]. The medication has been found to act as a serotonin (5-HT) agonist, stimulating type 4 receptors, and antagonist of 5-HT3 receptors, though the exact mechanism of action is unclear [1].

In June 1998, the manufacturer, Janssen Pharmaceutica, issued a ‘Dear Doctor’ letter contraindicating cisapride use in patients with renal failure due to the possibility of QT interval prolongation and cardiac arrythmias. A review of the Food and Drug Administration's MedWatch reporting programme from September 1993 to April 1996 reported that 34 patients developed torsades de pointes and 23 patients had QT interval prolongation while on cisapride [2]. Fourteen of 57 patients had renal insufficiency or renal failure, while 32 of 57 patients were also receiving medications known to inhibit cytochrome P450 3A4, the enzyme system responsible for the metabolism of cisapride [2].

Since the release of the ‘Dear Doctor’ letter, the manufacturer has decided to stop marketing the drug, making it available only through an investigational limited access programme. The eligibility criteria patients must meet to receive the drug through the programme have yet to be defined.

Individual case reports of cisapride use and either torsades de pointes, QT interval prolongation, or tachycardia have also appeared in the literature [39]. In the majority of these case reports, patients also received medications known to interact with cisapride via the cytochrome P450 3A4 system, thus increasing cisapride serum concentrations.

The problem facing practitioners treating ESRD patients who suffer from gastric motility disorders is what to do with these patients in light of the new action by the manufacturer. Unfortunately, the majority of patients taking cisapride have already failed other therapies and are left with no other good medication alternatives. This study evaluated Hennepin County Medical Center's ESRD population to try to determine whether cisapride therapy prolonged the QT interval and caused patients to have more hospital admissions.



   Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
This study was a retrospective chart review of ESRD patients admitted to Hennepin County Medical Center (HCMC). After institutional review board approval, the medical records for 61 patients were obtained for each in-patient admission. Data was extracted from the first available admission until October 1998. The average time evaluated per patient was 39 months with a range of 2.5–71 months. Data obtained from each patient admission included gender, race, date of birth, admission and discharge dates, reason for admission and cisapride dose. Each admission was also evaluated for the patient's past medical history. The disease states primarily assessed were history of QT prolongation, history of ventricular arrhythmias, ischaemic heart disease, congestive heart failure, hypokalaemia/hypomagnesaemia, and respiratory failure, along with atrial arrhythmias and coronary artery disease, since these have been noted to be risk factors for QT prolongation and torsades de pointes [2]. The cause of ESRD and history of diabetes mellitus (types 1 or 2) were also documented. Heart rate, QT interval, and QTc interval along with the date and time of occurrence were recorded for all 12-lead electrocardiograms (ECGs). The inclusion criteria included active haemodialysis with >=2 ECGs while receiving cisapride and >=2 ECGs while not receiving cisapride. Patients who received a renal transplant were included if they met the inclusion criteria prior to transplantation; however, their data was not included once the graft was functioning.

Statistical analysis
Average heart rate, average QT interval, and average QTc interval were calculated for each patient from the ECG recordings during the time periods while the patient was on or off cisapride therapy. Each individual patient's average heart rate, QT interval, and QTc interval while on and off cisapride was used to generate an overall average value for each parameter. This data was compared using Student's t-test to determine if there was a statistical difference in any of the parameters while the patient was on vs off cisapride.

Multivariate and univariate analysis were used to determine the effects of cisapride on QTc given the cardiac risk factors present (history of coronary artery disease, arrhythmias, congestive heart failure, ischaemia, and myocardial infarction) at the time of individual ECG recordings.

The number of hospital admissions while on and off cisapride was recorded. The data was then used to calculate the admissions per month while receiving and not receiving cisapride with the results being compared using the paired sign test. The data was further analysed by comparing the number of cardiac admissions per month on and off cisapride with the paired sign test.

Multiple Fischer's exact tests were used to compare the number of QT interval and QTc interval measurements (n=529) that were <400 ms, 400–500 ms, or >500 ms while on vs off cisapride.

HR, QT, and QTc from the ECGs of patients receiving high doses (daily dose >=60 mg) were compared to the values from patients receiving low doses (daily dose <60 mg) to see if there was any difference in each parameter based on dose. The mean HR, QT interval, and QTc interval were compared using Student's t-test.

A P value of less than 0.05 was considered statistically significant for all tests.

Power analysis:
A retrospective power analysis was performed to determine the number of patients needed in each group to show statistical difference at a power of 0.80 and an alpha of 0.05. Although controversial, a QTc interval prolongation of 50 ms was chosen to be a clinically significant change. The average QTc interval off cisapride in our patient population was approximately 450 ms. Using an estimated QTc interval standard deviation of 40 ms, it was determined that 21 patients were required in each group to show a statistical difference, if one existed.



   Results
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Of the 61 patients evaluated, 23 met the inclusion criteria. A total of 529 ECGs (279 on/250 off cisapride) were included. Patient demographics are shown in Table 1Go. The average heart rate, QT interval, and QTc interval was calculated for each patient. The number of patients with either a faster, slower, or the same average heart rate on vs off cisapride, along with the number of patients with either a longer, shorter, or the same average QT and QTc intervals, are illustrated in Figure 1Go.


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Table 1. Demographics of the 23 patients meeting the inclusion criteria

 


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Fig. 1. Percentage of patients with statistically significant differences in heart rate or QT/QTc interval on and off cisapride.

 
An overall average heart rate, QT interval, and QTc interval was calculated using the individual patient averages (Figure 2Go). No significant differences were found when comparing the means using Student's t-test.



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Fig. 2. Heart rate, QT interval, and QTc interval comparisons for subjects on and off cisapride.

 
Data collected for the number of hospital admissions is shown in Figure 3Go. No significant differences were found in the overall number or rate of admissions per month for any reason (as documented on the admission form for history of present illness) or in the number or rate of admissions for cardiac conditions while the patients were on or off cisapride.



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Fig. 3. Hospital admissions: percentage of subjects with more, fewer, and the same number of admissions on and off cisapride.

 
Multivariate analysis did not reveal a significant relationship between QTc and cisapride therapy after ECG readings were classified according to presence or absence of cardiac risk factors (QTc off cisapride 445 ms vs 446 ms on cisapride, P>0.50). Univariate analysis did not show that cisapride use in the presence of any of the underlying cardiac risk factors placed the subject at an increased risk of QTc lengthening.

The number of QT and QTc interval measurements that were <400 ms, 400–500 ms, and >500 ms revealed no significant findings between the periods on and off cisapride.

The number of ECGs included in the high-dose cisapride group was 69 vs 210 ECGs in the low-dose cisapride group. The average HR, QT and QTc intervals for the high-dose vs low-dose were 90 vs 88 beats per minute (P=0.31), 349 vs 382 ms (P<0.0001), and 419 vs 455 ms (P<0.0001), respectively. The statistically significant differences found between the high-dose and low-dose QT and QTc intervals were in the opposite direction from that anticipated based on the manufacturer warnings.

Four patients expired during the time frame evaluated (each patient's first available admission until October 1998). Death within 1 month of cisapride use was considered as being on cisapride. Based on this definition, three of the four patients who died were receiving cisapride at the time of death. One patient died after the decision to discontinue haemodialysis was made by the patient and family members. The second patient died secondary to brain haemorrhage and herniation. This patient's past medical history was significant for hypertension and cocaine abuse. Cocaine metabolites were found in the patient's blood at the time of death.

The third patient (patient 7) died 12 days after experiencing a ventricular fibrillation (Vfib) arrest that led to an anoxic brain injury. Four days prior to the Vfib episode, the patient was admitted for shortness of breath. During that admission, the patient was found to have prolonged QTc intervals and multiple premature ventricular complexes (PVCs) on multiple 12-lead ECGs and to be in atrial fibrillation with a rapid ventricular response that spontaneously converted. A cardiology consultation obtained a day after admission (day 2) recommended discontinuing the cisapride 10 mg orally three times a day, which was done that afternoon. The cardiology consult also noted the patient to be at high risk of sudden cardiac death due to cardiac abnormalities and syncopal episodes even before receiving cisapride. The patient was found to have intrinsic ventricular arrhythmias. QTc interval prolongation and multiple PVCs continued during the hospital stay and the patient was discharged from the hospital on day 4, receiving amiodarone and wearing a Holter monitor. The patient collapsed after haemodialysis the day after discharge (day 5) and was found to be in Vfib. On multiple occasions, the Vfib was converted with electric cardioversion, only to reoccur. During the next 12 days, the patient received various anti-arrhythmic agents to try to control the ventricular arrhythmias. On day 16, the family decided to withdraw care and the patient expired on day 17. Unfortunately, a cisapride level was never obtained. This patient had prior admissions while not receiving cisapride for multiple cardiac problems including myocardial infarction x3, multiple syncopal episodes, and angina. Multiple echocardiograms showed regional three-wall motion abnormalities, decreased left ventricular systolic performance (dilatation), left ventricular hypertrophy, aortic, mitral, and tricuspid valve insufficiency (trace to mild), and pulmonary hypertension. Coronary artery bypass surgery had been recommended, which the patient refused. The patient's heart rate, QT interval, and QTc interval for each 12-lead ECG during the last two admissions are listed in Table 2Go.


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Table 2. HR, QT interval, and QTc interval of patient no. 7 prior to death

 



   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
The decision to make cisapride available only from the manufacturer though an investigational limited access programme has created a dilemma for many health-Gocare practitioners taking care of ESRD patients who require the medication. A quality-of-life issue has been raised along with the concern of malnutrition.

Many patients with gastroparesis of any cause suffer from post-prandial fullness (early satiety), nausea, vomiting, regurgitation, diarrhoea, and constipation, thus potentially leading to anorexia. Use of agents that increase gastric motility in some of these patients alleviates the symptoms listed previously, thus enhancing their quality of life.

Prokinetic agents may also enhance these patients' nutritional status by allowing them to consume adequate caloric intake. Diabetic gastropathy and enteropathy have been implicated as potential causes of anorexia in haemodialysis patients. Malnutrition, as indicated by low serum albumin and low body mass index, in ESRD patients is a well-known predictor of increased mortality [1012]. A decreased serum albumin has also been linked with an increased relative risk of septicaemia, pneumonia, and other infections in ESRD patients as well as non-dialysis patients [13].

Cisapride is extensively metabolized with <1% being eliminated renally [14]. The half-life of cisapride does not significantly change with renal impairment (t1/2=7–10 h in healthy volunteers [1] vs t1/2=9.6±3.3 h in ESRD patients [15]). Cisapride is not removed by haemodialysis [15]. Norcisapride, a major metabolite, which has about 15–20% of the prokinetic activity of cisapride, is primarily eliminated via the kidney with its half-life being prolonged in ESRD patients (t1/2=10–16 h in healthy volunteers vs t1/2=51.6±24.6 h in ESRD patient) [15]. A small percentage of norcisapride (<2%) is removed in a 5-h haemodialysis session [15]. Norcisapride is not thought to be arrhythmogenic, though the clinical significance of its accumulation is unknown.

Cisapride has been implicated in causing QT prolongation or torsades de pointes in various case reports cited in the literature including the FDA MedWatch report of 57 patients [29]. Our results in ESRD patients showed no statistically significant changes in average HR, QT interval, and QTc interval while the patients were receiving cisapride vs not receiving cisapride. The average QTc interval for all of the patients while on cisapride vs while off cisapride was 443 vs 441 ms (P=0.39). A change in the QTc interval of >75 ms has been characterized by some investigators as ‘abnormal’ [16]. In the patient who expired from cardiac arrest shortly after discontinuing cisapride, the average QTc on vs off cisapride was 487 vs 462 ms—a statistically significant difference (P=0.0066), but well within a change of 75 ms.

The maximum QTc interval that is considered ‘abnormal’ is somewhat controversial. After applying other standards for prolonged QTc [1618], we found that none of the patients included in the study had evidence of prolonged QTc while on cisapride.

The major limitation in this study is that it was retrospective. In addition, only a relatively small number of subjects fit the inclusion criteria. Although the power analysis shows that 21 patients were necessary to detect a significant difference in QT interval, a much larger data set may be required to detect a difference in the rate of severe cardiac events, including torsades de pointes. It may have been more appropriate to study only those individuals with a QT interval prolonged at baseline. However, given that this study was retrospective, it was not possible to assign a baseline QT interval. In addition, if this were possible, the number of subjects eligible for study would have further decreased.

Another limitation to this study includes the problem associated with QT and QTc interval measurements, including computer error in reading the QT interval (failure to detect the end of the T wave leading to overestimation of the QT interval) [19], diurnal variation in the QT interval which is associated with changes in the autonomic nervous system tone [19,20], and the HR correction formula used to calculate the QTc interval [20] (the Bazett method was used for all of the ECGs in the study).

Due to the limitations, this study cannot be used as evidence to support the earlier contraindication to cisapride use in ESRD patients or the de facto removal from the market. A large retrospective study of the safety of cisapride is necessary if those conclusions are to be made.

Although this study did not find ESRD patients to be at risk of QT or QTc interval prolongation while on cisapride, we do advocate that all available treatment alternatives be tried before cisapride therapy is implemented. For those patients who fail all other alternative treatments and have quality-of-life issues, cisapride should be considered if there are no other risk factors for development of QT prolongation or torsades de pointes. Those factors include history of hypokalaemia/hypomagnesaemia, bradycardia, atrioventricular (AV) block, and myocardial ischaemia [16]. Atrial arrhythmias and coronary heart disease have also been cited as being possible indicators of increased risk for cisapride-induced arrhythmias [2].

When cisapride use is being considered, a preliminary ECG should be done to rule out any underlying QT prolongation. Subsequent ECGs every 3–6 months should be obtained after implementation of cisapride. Total daily dose in the ESRD patient should not exceed 60 mg. Diligent monitoring of concomitant medications should be done to ensure that medications that could potentially inhibit cisapride metabolism or induce QT prolongation themselves are not added to a patient's drug therapy regimen.



   Acknowledgments
 
This work was supported in part by a grant from the National Kidney Foundation of the Upper Midwest. The authors wish to thank Joseph P. Roel MPH MHA for his assistance with the statistical analysis and Wendy L. St.Peter, PharmD FCCP BCPS for her assistance with the manuscript.



   Notes
 
Correspondence and offprint requests to: Matthew J. Lewis PharmD BCPS, Division of Nephrology (D5), Hennepin County Medical Center, 914 South 8th Street, Minneapolis, MN 55404, USA. Back



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 30.11.99
Revision received 6. 7.00.



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