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PubMed2005

QTc interval prolongation and antipsychotic drug treatments: focus on sertindole.

Since the 1960s, physicians have been aware of electrocardiographic (ECG) abnormalities and cases of sudden death associated with the use of antipsychotic drugs in patients with schizophrenia. Explanations for such deaths have traditionally focused on drug-induced prolongation of the QT interval leading to the development of life-threatening ventricular arrhythmias such as torsade de pointes (TdP). It is now apparent that most conventional and atypical antipsychotics can cause dose-related prolongation of the corrected QT interval (QTc), although there are important differences in the potency of individual agents. This review discusses potential mechanisms underlying QTc prolongation and arrhythmogenesis and examines the evidence for a relationship between antipsychotic drugs and prolongation of the QTc interval. New electrophysiological and epidemiological data are presented which suggest there may not be a clear-cut cause-effect relationship between QTc prolongation and the development of ventricular tachyarrhythmias for all atypical antipsychotics. For at least one of these agents (sertindole), counterbalancing mechanisms may act to reduce the risk of proarrhythmic activity arising as a result of QTc prolongation.

Antipsychotic Agents↗
PubMed2003

QTc interval prolongation is a predictor of future strokes in patients with type 2 diabetes mellitus.

BACKGROUND AND PURPOSE: QTc interval prolongation is a predictor of cardiovascular morbidity and mortality in general populations and in patients with diabetes. The aim of this study was to investigate the predictors of stroke in patients with type 2 diabetes, with particular emphasis on the independent role of QT interval parameters. METHODS: We carried out a long-term follow-up study with 471 type 2 diabetics. Several clinical, laboratory, ECG, and echocardiographic variables were recorded at baseline. Predictive factors for stroke were evaluated by Kaplan-Meier estimation of survival curves and by univariate and multivariate Cox survival analyses. RESULTS: After a median follow-up of 57 months (range, 2 to 84 months), 40 incident strokes were observed. QTc interval prolongation (>or=470 ms1/2) was an independent predictor of stroke, with adjusted hazard ratios ranging from 2.2 to 2.9 (95% confidence intervals, 1.1 to 6.0). Other independent factors associated with stroke were older age; the presence of cerebrovascular disease at baseline; increased 24-hour proteinuria, serum triglycerides, and left ventricular mass; and decreased high-density lipoprotein cholesterol. Excluding patients with previous cerebrovascular disease from the analysis did not change the results significantly. CONCLUSIONS: QTc interval prolongation is a predictor of future stroke in patients with type 2 diabetes. Intervention studies are needed to assess whether this factor could be modified.

Adult↗
PubMed2004

[QTc-interval prolongation in therapy with atypical antipsychotics--results of an open, non-randomized survey].

The introduction of Ziprasidone stimulated discussion about frequency and importance of QTc-interval prolongations with antipsychotic therapy. In an open non-randomized study we collected data about QTc-interval, electrolytes, vital parameters and associated clinical symptoms in patients treated with atypical antipsychotics. 33 patients were scanned and some moderate QTc-interval prolongations but no clinical events were seen. Due to scarcity of such events existing data should be completed by large scale clinical studies and by registration of severe QTc-interval prolongations and torsades de pointes in central drug monitoring systems.

Antipsychotic Agents↗
PubMed2000

Greater quinidine-induced QTc interval prolongation in women.

BACKGROUND: Prolongation of the electrocardiographic QT interval by drugs is associated with the occurrence of a potentially lethal form of polymorphic ventricular tachycardia termed torsades de pointes. Women are at greater risk than men for development of this adverse event when taking drugs that prolong the QT interval. To determine whether this may be the result of gender-specific differences in the effect of quinidine on cardiac repolarization, we compared the degree of quinidine-induced QT interval lengthening in healthy young men and women. METHODS: Twelve women and 12 men received a single intravenous dose of quinidine (4 mg/kg) or placebo in a single-blind, randomized crossover trial. Total plasma and protein-free concentrations of quinidine and 3-hydroxyquinidine were measured in serum. QT intervals were determined and corrected for differences in heart rate with use of the method of Bazett (QTc = QT/RR1/2). RESULTS: As expected, the mean QTc interval at baseline was longer for women than for men (mean +/- SD; 407 +/- 7 versus 395 +/- 9 ms, P < .05). The slope of the relationship between change in the QTc interval (delta QTc) from baseline to the serum concentration of quinidine was 44% greater for women than for men (mean +/- SE; 42.2 +/- 3.4 versus 29.3 +/- 2.6 ms/microg per mL, P < .001). These results were not influenced by analysis of 3-hydroxyquinidine, free concentrations of quinidine and 3-hydroxyquinidine, or the JT interval. CONCLUSIONS: Quinidine causes greater QT prolongation in women than in men at equivalent serum concentrations. This difference may contribute to the greater incidence of drug-induced torsades de pointes observed in women taking quinidine and has implications for other cardiac and noncardiac drugs that prolong the QTc interval. Adjustment of dosages based on body size alone are unlikely to substantially reduce the increased risk of torsades de pointes in women.

Adult↗
PubMed1995

QTc interval prolongation during infusion with dipyridamole or adenosine.

The aim of our study was to discover whether there was a relationship between the QTc interval prolongation on the standard 12-lead electrocardiogram (ECG) and provoked myocardial ischemia. Since the increase of adenosine plasma levels, obtained either with adenosine or dipyridamole (an adenosine reuptake inhibitor) infusion, has been used to test the coronary artery reserve in patients affected by coronary artery disease, the QTc interval modifications during dipyridamole or adenosine echocardiographic stress test were evaluated. Twenty-five patients admitted to our Institute for evaluation of chest pain of suspected myocardial origin underwent an echocardiographic dipyridamole stress test (0.84 mg/kg over 10 min) after discontinuation of antianginal treatment. Of these patients, 10 underwent an echocardiographic adenosine stress test (scalar doses of 50, 75, 100, 140 micrograms/kg/min) after 48-72 h. The Bazett formula was used to evaluate the QTc interval. After dipyridamole and adenosine administration, a significant prolongation of the QTc interval was observed only in those patients who had positive test results. Our data suggested that QTc interval prolongation during pharmacological stress tests might be considered a marker of myocardial ischemia.

Adenosine↗
PubMed2001

Prolonged QTc interval predicts mortality in patients with Type 1 diabetes mellitus.

AIMS: To evaluate prolonged QTc interval and QT dispersion as predictors of all-cause and cardiovascular mortality after adjustment for well-established risk factors in Type 1 diabetic patients. METHODS: From a cohort of all adult Type 1 diabetic patients, duration of diabetes >or= 5 years, attending the clinic in 1984 and followed in an observational study for 10 years (n = 939), all subjects with resting baseline electrocardiograms were identified (n = 697, 360 males). The QT length was measured and corrected for heart rate (QTc). Maximal QTc length (QTc max) and QT dispersion were determined. RESULTS: At baseline, 431 had normoalbuminuria (< 30 mg/24 h), 138 had microalbuminuria (30-299 mg/24 h) and 128 had macroalbuminuria (>or= 300 mg/24 h) of whom 66 (15%), 35 (25%) and 61 (48%) died during follow-up, respectively (26 (6%), 14 (10%), 21 (16%) from cardiovascular disease). QTc max. was 442 (1.2) ms (mean (SEM)) for survivors and 457 (3.7) in patients who died (P < 0.001). In a Cox proportional hazards model including baseline values of putative risk factors, independent predictors of death were QTc max (P = 0.03), age (P < 0.001), presence of hypertension (P = 0.001), male sex (P < 0.001), log urinary albumin excretion (P < 0.001), smoking (P = 0.04), log serum-creatinine (P < 0.001), height (P < 0.001), low social class (P = 0.04), whereas QT dispersion, heart rate, and HbA1c were not included. In the subgroup with macroalbuminuria, but not for all patients, QTc max was an independent risk factor for cardiovascular mortality. CONCLUSION: QTc prolongation, but not increased QT dispersion, is an independent marker of increased mortality in patients with Type 1 diabetes mellitus.

Adult↗
PubMed2005

Renin-angiotensin polymorphisms and QTc interval prolongation in end-stage renal disease.

BACKGROUND: Polymorphisms of renin-angiotensin system (RAS) genes in patients with end-stage renal disease (ESRD) on chronic hemodialysis may be associated with QTc interval prolongation, leading to fatal arrhythmias. The objective of this study was to determine (1) the prevalence of QTc prolongation in hemodialysis patients, and (2) the association of a prolonged QTc in these patients with RAS polymorphisms [angiotensin-converting enzyme-insertion/deletion (ACE-I/D), angiotensin type 1 receptor-A1166C (AT1R-A1166C), and angiotensinogen-M235T (AGT-M235T)]. METHODS: Twelve-lead electrocardiograms (ECGs), serum electrolytes (sodium, potassium, and calcium), and ACE and angiotensin II levels were obtained 10 to 12 hours after a hemodialysis session in 43 patients with ESRD on chronic hemodialysis [mean age (+/-SD), 55 +/- 14 years]. Using polymerase chain reaction (PCR), the presence of polymorphisms of the ACE-I/D, AT1R-A1166C, and AGT-M235T genes was determined from the buccal cells. A maximum QT interval in patients with sinus rhythm and normal QRS duration was corrected for heart rate using Hodges' formula. RESULTS: Fifty-eight percent of the patients had QTc interval prolongation (>440 msec). The ACE-DD genotype (P = 0.002) and the C allele of the AT1R-A1166C gene (P = 0.004), but not the AGT-M235T gene, contributed to QTc prolongation. CONCLUSION: Polymorphisms of ACE and AT1R genes additively contribute to QTc prolongation found in a great majority of ESRD patients. Therefore, ESRD patients with both or one of these polymorphisms may be at a higher risk for sudden cardiac death.

Adult↗
PubMed1993

Measurement of the QT interval and the risk associated with QTc interval prolongation: a review.

The accurate measurement of the QT interval and its correction or adjustment for cycle length, age, and gender have been topics of increasing interest over the course of the past 70 years. The availability of digitized electrocardiographic recordings on large normal populations together with statistical adjustment for pertinent covariates has provided useful data for defining QT interval prolongation. Data from the International Long QT Syndrome Registry indicate that the probabilistic risk of developing malignant arrhythmias in patients with QT prolongation is exponentially related to the length of the QTc interval. The risk is further accentuated by the development of T-wave alternans, particularly at very prolonged QTc intervals.

Adolescent↗
PubMed2003

Prolonged QTc intervals in medicated patients with schizophrenia.

Psychotropic drugs have been associated with sudden deaths and the lengthening of corrected-QT interval (QTc) on the electrocardiogram which may be a precursor of life-threatening arrhythmias as reported with some of these drugs. The objectives of this study were to measure the frequency of QTc lengthening in patients with schizophrenia receiving psychotropic drugs, and to assess whether QTc lengthening was associated with certain psychotropic drugs and other risk factors. One hundred and sixty three patients with schizophrenia (104 males and 59 females) were included in the study. Clinical and demographic data were collected from the case records. One hundred healthy volunteers were recruited to establish values for upper limits of normal for measurement of QTc interval and dispersion. Eleven (6.7%) of the patients had a prolonged QTc interval. The significant predictors obtained from a logistic regression modelling were chlorpromazine, flupenthixol decanoate and fluphenazine decanoate. Caution should be exercised and monitoring with ECG should be considered in patients prescribed chlorpromazine and depot antipsychotic medications even at recommended doses.

Aged↗
PubMed2004

Prolonged QTc interval and risks of total and cardiovascular mortality and sudden death in the general population: a review and qualitative overview of the prospective cohort studies.

BACKGROUND: In certain subgroups of patients, prolongation of the QTc interval may increase total and cardiovascular mortality due to life-threatening ventricular arrhythmias and sudden death. Nonetheless, whether modest prolongation of the QTc interval in the general population has clinical importance remains unclear. METHODS: We conducted a literature search from 1990 forward to identify all published prospective cohort studies evaluating the association between prolonged QTc interval and risks of total and cardiovascular mortality as well as sudden death. We reviewed each of the studies individually and then conducted a qualitative overview. RESULTS: The 7 prospective cohort studies identified included 36 031 individuals. There were 2677 (8.7%) individuals with prolonged QTc interval, defined as 440 milliseconds or greater. Whereas 1 study reported no association between prolonged QTc interval and mortality (relative risk, 1.02; 95% confidence interval, 0.70-1.49), the other 6 reported inconsistent associations overall as well as across subgroups defined by various characteristics including age, sex, and comorbidities. The reported associations for both cardiovascular mortality and sudden death were also inconsistent. In the overview, the only consistent findings were for the subgroup of patients with prior cardiovascular disease, in which relative risks ranged from 1.1 to 3.8 for total mortality, from 1.2 to 8.0 for cardiovascular mortality, and from 1.0 to 2.1 for sudden death. Further, in individuals without prior cardiovascular disease, associations were either absent or greatly attenuated; specifically, relative risks ranged from 0.9 to 1.6 for total mortality, from 1.2 to 1.7 for cardiovascular mortality, and from 1.3 to 2.4 for sudden death. CONCLUSIONS: There was no consistent evidence for increased risks of total or cardiovascular mortality or of sudden death, except perhaps for patients with prior cardiovascular disease. In the general population, if QTc interval prolongation is associated with any increase in mortality, that risk is likely to be small and difficult to detect reliably.

Cardiovascular Diseases↗
PubMed1998

Prolonged QTc interval, impaired pulmonary function, and a very lean body mass jointly predict all-cause mortality in elderly men.

PURPOSE: Assess the joint impact of prolonged QTc interval (QT interval corrected for heart rate), impaired lung function, and low body weight on all-cause mortality. METHODS: This is a population-based, prospective study of the Honolulu Heart Program cohort, performed in Oahu Island, Hawaii, during the 1991-1993 fourth examination of cohort survivors. The participants were 3056 Japanese-American men, 71 to 93 years of age. The measurement consisted of: 1) instrument calculated, heart rate corrected QT interval; 2) one second forced expiratory volume (FEV1) as a percentage of age- and height-predicted FEV1; and 3) body mass index (BMI, kg/m2). Relations of subsequent 3 1/2 year, on average, mortality rates with high risk states of these variables are determined. High risk states are QTc > 440 msec, percent predicted FEV1 < or = 80%, and BMI < or = 21 kg/m2. RESULTS: Mortality rates synergistically increase among groups with one, two, or three high risk states. Men having all three high risk states are seven times more likely to die in the follow-up period than men with no high risk conditions. Very thin men having one other high risk state, pulmonary impairment or prolonged QTc, are four times more likely to die. Excluding diabetics, active smokers, or men taking drugs affecting QT interval does not alter findings. Excluding prevalent coronary heart disease decreases mortality rates among joint high risk groups. CONCLUSION: Results are consistent with clinical studies identifying an autonomic neuropathy associated with wasting chronic lung disease, prolonged QTc, and mortality. Aging populations in developed nations will increase the prevalence of diseases associated with these conditions in decades to come.

Aged↗
PubMed2006

Prolonged QTc interval and risk of sudden cardiac death in a population of older adults.

OBJECTIVES: This study sought to investigate whether prolongation of the heart rate-corrected QT (QTc) interval is a risk factor for sudden cardiac death in the general population. BACKGROUND: In developed countries, sudden cardiac death is a major cause of cardiovascular mortality. Prolongation of the QTc interval has been associated with ventricular arrhythmias, but in most population-based studies no consistent association was found between QTc prolongation and total or cardiovascular mortality. Only very few of these studies specifically addressed sudden cardiac death. METHODS: This study was conducted as part of the Rotterdam Study, a prospective population-based cohort study that comprises 3,105 men and 4,878 women aged 55 years and older. The QTc interval on the electrocardiogram was determined during the baseline visit (1990 to 1993) and the first follow-up examination (1993 to 1995). The association between a prolonged QTc interval and sudden cardiac death was estimated using Cox proportional hazards analysis. RESULTS: During an average follow-up period of 6.7 years (standard deviation, 2.3 years) 125 patients died of sudden cardiac death. An abnormally prolonged QTc interval (>450 ms in men, >470 ms in women) was associated with a three-fold increased risk of sudden cardiac death (hazard ratio, 2.5; 95% confidence interval, 1.3 to 4.7), after adjustment for age, gender, body mass index, hypertension, cholesterol/high-density lipoprotein ratio, diabetes mellitus, myocardial infarction, heart failure, and heart rate. In patients with an age below the median of 68 years, the corresponding relative risk was 8.0 (95% confidence interval 2.1 to 31.3). CONCLUSIONS: Abnormal QTc prolongation on the electrocardiogram should be viewed as an independent risk factor for sudden cardiac death.

Aged↗
PubMed2005

Prolongation of QTc interval after postoperative nausea and vomiting treatment by droperidol or ondansetron.

BACKGROUND: At dosages above 0.1 mg/kg, droperidol induces a dose-dependent QTc interval prolongation. Although subject to controversy, low-dose droperidol has recently been suspected to induce cardiac arrhythmias. Hence, 5-hydroxytryptamine type 3 antagonists have become the first-line drug for management of postoperative nausea and vomiting. These drugs are also known to prolong the QTc interval at high dosages. This study describes QTc interval changes associated with postoperative nausea and vomiting treatment by droperidol or ondansetron at low doses. METHODS: Eighty-five patients with postoperative nausea and vomiting were included in this prospective, single-blind study. Patients received either 0.75 mg intravenous droperidol (n = 43) or 4 mg intravenous ondansetron (n = 42). Electrocardiographic recordings were obtained before administration of antiemetic drug and then 1, 2, 3, 5, 10, and 15 min after. Electrocardiographic monitoring was maintained for 3 h in eight patients in each group. RESULTS: The QTc interval was prolonged (> 450 ms in men, > 470 ms in women) in 21% of the patients before antiemetic drug administration. This was significantly correlated with lower body temperature and longer duration of anesthesia. Compared with predrug QTc measurement, both antiemetics were associated with a significant QTc interval prolongation (P < 0.0001). The mean maximal QTc interval prolongation was 17 +/- 9 ms after droperidol occurring at the second minute and 20 +/- 13 ms after ondansetron at the third minute (both P < 0.0001). Compared with predrug measurement, the QTc interval was significantly lower after the 90th minute in both groups. CONCLUSIONS: Droperidol and ondansetron induced similar clinically relevant QTc interval prolongations. When used in treatment of postoperative nausea and vomiting, a situation where prolongation of the QTc interval seems to occur, the safety of 5-hydroxytryptamine type 3 antagonists may not be superior to that of low-dose droperidol.

Adult↗
PubMed2001

Prolonged QTc interval and its relationship to autonomic cardiovascular reflexes in patients with cirrhosis.

BACKGROUND/AIMS: We have previously shown that an abnormality in cardiac autonomic reflexes (AN) is an independent predictor of mortality in patients with chronic liver disease. Aim of this study was to determine whether there was an association between prolonged QTc interval and cardiac AN. METHODS: Cardiac AN and QTc interval were determined in 130 patients (Child A 42, B 53, C 35) with alcoholic and non-alcoholic liver disease. RESULTS: Prolonged QTc (>440ms) was seen in 58 (Child A 30%, B 46%, C 60%, P=0.04) patients. Autonomic tests were normal in 21%, borderline abnormal in 36% and definitely abnormal in 43%. QTc correlated with albumin (P<0.001), prothrombin time (P=0.003) and Child-Pugh score (P<0.001), but not with Valsalva ratio, heart rate variation with 6 breath/min breathing, tilt table or isometric exercise. By logistic regression analysis, QTc correlated only with Child-Pugh score (P<0.001). Mean QTc of 34 who died during the follow up was higher than survivors. Cox regression analysis showed that only Child-Pugh score and AN were independent predictors of mortality. CONCLUSIONS: Prolonged QTc seen in liver disease is independent of their cardiac autonomic function, but is related to the severity of the liver disease.

Adult↗
PubMed2005

Drugs, QTc interval prolongation and final ICH E14 guideline : an important milestone with challenges ahead.

Regulatory concerns on the ability of an ever-increasing number of non-antiarrhythmic drugs to delay ventricular repolarisation, prolong the corrected QT (QTc) interval and induce potentially fatal ventricular tachyarrhythmias have culminated in the adoption of two, internationally harmonised, regulatory guidelines. On 12 May 2005, the International Conference on Harmonisation (ICH) reached an important milestone when it adopted the final texts for clinical (ICH topic E14) and non-clinical (ICH topic S7B) strategies by which drugs should be investigated for their potential to induce these effects during their development.ICH E14 provides recommendations to sponsors concerning the design, conduct, analysis and interpretation of clinical studies to assess the potential of a drug to delay cardiac repolarisation. Specifically, it calls for a clinical 'thorough QT/QTc study' (typically conducted in healthy volunteers), which is intended to determine whether a drug has a threshold pharmacological effect on cardiac repolarisation, as detected by QT/QTc interval prolongation. The E14 recommendations are generally applicable not only to new drugs that have systemic bioavailability but also to approved drugs when a new dose, route of administration or target population that may result in an increased risk is explored. The guideline provides for exceptions when this study may not be required.Recognising the fractious relationship between ICH E14 and ICH S7B, and the persistence of a number of issues that may require clarity and/or the emergence of other new scientific issues in the future, the ICH Steering Committee has formed an Implementation Working Group that is charged with providing clarity on aspects of the guideline that are ambiguous and responding to issues on which the sponsors are uncertain. This paper provides a commentary on some of the challenges that are likely to be faced by the sponsors of drugs during the next few years of application of these two guidelines. The adoption of these guidelines has left a number of questions unanswered and raised some new ones. When in doubt, the sponsor should seek formal regulatory clarity before making key decisions that may impact further development, assessment and approval of a new chemical entity. Although the goal of developing drugs with much lower torsadogenic potential and without inappropriate restriction in the use (or even rejection) of potentially beneficial drugs is within sight, it is questionable whether the risk of drug-induced pro-arrhythmia will be eliminated completely.

Clinical Trials as Topic↗
PubMedDate not supplied

QTc interval prolongation associated with citalopram overdose: a case report and literature review.

Citalopram is a member of the selective serotonin reuptake inhibitor class of antidepressants. In 1998, citalopram was approved by the US Food and Drug Administration for the treatment of major depression. Like the other selective serotonin reuptake inhibitors, citalopram enjoys a relatively benign side effect profile compared with the tricyclic antidepressants and the monoamine oxidase inhibitors. However, citalopram has been associated with electrocardiographic changes and seizures at doses greater than 600 mg per day. Fatalities have occurred with citalopram-only overdoses. We report the case of a healthy 21-year-old woman who developed QTc interval prolongation after ingestion of approximately 400 mg citalopram. We discuss the cardiac effects of citalopram, review previous cases of citalopram overdose, and discuss treatment recommendations.

Adult↗
PubMed2005

QTc interval prolongation in patients on long-term methadone maintenance therapy.

OBJECTIVE: The aim of the present study was to assess the incidence of abnormal QTc interval values in a population of subjects on a long-term methadone maintenance treatment, as a single therapy, and with methadone dosages ranging between 10 and 600 mg/daily (mean+/-SD=87+/-76). METHOD: Basal ECG recordings were carried out in 83 former heroin addicts on long-term successful methadone maintenance therapy for at least 6 months, while no other known QT-prolonging agent was being administered. RESULTS: Eighty-three percent of the subjects had a more prolonged QT interval than the reference values for persons of the same sex and age. Only 2 patients displayed a QTc interval of >500 ms. No correlation emerged between QTc values and methadone dosages. CONCLUSION: Patients on long-term methadone maintenance treatment show longer than expected QTc interval values. This data, associated with the finding that methadone is a rather potent inhibitor of HERG potassium channels and that it may induce torsade de pointes in predisposed subjects, supports the recommendation that patients entering methadone treatment (MT) are screened for cardiac risk factors. ECG might be considered in ongoing MT patients especially before starting QT-prolonging medications.

Adult↗