olanzapine and Death--Sudden

Alterations of electrocardiogram results and cases of sudden cardiac death have been reported since the beginning of neuroleptic treatment. In particular, a temporal association exists between some antipsychotics and prolongation of the heart rate-corrected QT interval (QTc), an event that may increase the risk for developing a potentially fatal ventricular tachycardia arrhythmia known as torsades de pointes if it significantly exceeds normal intraindividual and interindividual variation. Although the incidence of serious adverse cardiac events in response to antipsychotic medications is relatively low, any possibility for the occurrence of cardiotoxicity warrants continued study. The present article reviews important differences among antipsychotic drugs in the potential for, and occurrence of, serious adverse cardiac outcomes and suggests that olanzapine, as therapeutically administered to patients with schizophrenia and related psychoses, does not contribute significantly to a QTc prolongation that could result in potentially fatal ventricular arrhythmias.

Topics: Acute Disease; Antipsychotic Agents; Arrhythmias, Cardiac; Benzodiazepines; Death, Sudden; Female; Humans; Long QT Syndrome; Male; Olanzapine; Pirenzepine; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Torsades de Pointes

The Ziprasidone Observational study of car DIAC Outcomes (ZODIAC), a large simple trial comparing ziprasidone versus olanzapine in real-world use, showed no difference in risk of sudden death. Upon the request of the US Food and Drug Administration, 205 fatal events were readjudicated applying ICD-10 coding rules for sudden death.. A readjudication committee coded three domains (witness to death, time of symptom onset to death, and most likely cause of death) for use within algorithms consistent with ICD-10 rules. Relative risks (RR) and corresponding 95%CI were calculated for persons randomized to ziprasidone versus olanzapine, comparing 1-year incidence of sudden death, using multiple definitions.. Data on symptom onset to death and diagnosis of specific cardiac arrhythmias required by the ICD-10 rules were often lacking. Sensitivity analyses were conducted to explore the impact of cases suggestive of cardiac origin but missing data required by ICD-10 sudden death codes. Overall, the readjudicated data matched the study's initial findings, with no significant difference in 1-year mortality between ziprasidone and olanzapine for sudden death not otherwise specified and sudden cardiac death (R96.0 or R96.1 or I46.1; RR = 1.11, 95%CI 0.45- 2.77).. After outcome readjudication, ZODIAC found no difference in the risk of sudden death among those randomized to ziprasidone versus olanzapine. However, unlike hospital-based studies, fatal events in general population studies often occur outside hospital and often lack the clinical detail needed for the exact determination of symptom onset and event. Epidemiological evaluations of sudden death need to consider the limitations of the available data.

Topics: Antipsychotic Agents; Benzodiazepines; Cause of Death; Clinical Coding; Death, Sudden; Death, Sudden, Cardiac; Endpoint Determination; Follow-Up Studies; Heart; Humans; Incidence; International Classification of Diseases; Olanzapine; Piperazines; Product Surveillance, Postmarketing; Research Design; Risk; Schizophrenia; Sensitivity and Specificity; Surveys and Questionnaires; Thiazoles; Time Factors; United States; United States Food and Drug Administration

Topics: Adult; Aggression; Antipsychotic Agents; Autopsy; Benzodiazepines; Bipolar Disorder; Catatonia; Death, Sudden; Female; Humans; Hypothyroidism; Incidence; Lorazepam; Obesity; Olanzapine; Ovarian Neoplasms; Patient Admission; Patient Transfer; Pulmonary Embolism; Restraint, Physical; Risk; Valproic Acid; Venous Thrombosis

To establish the instantaneous relative risk (RR) associated with the dispensing of individual antipsychotic drugs, carbamazepine and valproate for those > or = 65 years who resided in an aged care facility.. The risk of death for incident users of antipsychotic drugs, carbamazepine and valproate in 2003 or 2004 who resided in an aged care facility was established using mortality rates and Cox proportional hazards models over two time periods. The regression models were adjusted for age, gender, medical and psychotropic drug dispensing, and a measure of overall medical comorbidity. Olanzapine users formed the referent group.. Haloperidol and chlorpromazine use were associated with the highest death rates. The instantaneous RR for those dispensed haloperidol was 1.67 (95% confidence intervals (CI) = 1.50-1.84, p < 0.001) and for chlorpromazine it was 1.75 (95%CI = 1.31-2.34, p < 0.001). The RR of death for haloperidol and chlorpromazine was higher in the regression model restricted to 60 days follow up (haloperidol RR = 2.17, 95%CI = 1.86-2.53, p < 0.001, chlorpromazine RR = 2.72, 95%CI = 1.84-4.01).. The increased risk associated with haloperidol and chlorpromazine dispensing should be interpreted cautiously because confounding by medical illness cannot be excluded despite adjusting the model for multiple variables. This study supports the findings from other data linkage studies that atypical antipsychotic medications are not associated with increased risk of death compared with conventional antipsychotic drugs.

Topics: Aged; Anticonvulsants; Antipsychotic Agents; Australia; Benzodiazepines; Carbamazepine; Cause of Death; Chlorpromazine; Comorbidity; Cross-Sectional Studies; Death, Sudden; Female; Haloperidol; Homes for the Aged; Humans; Male; Nursing Homes; Olanzapine; Risk; Valproic Acid; Veterans

Sertindole (Serdolect), an atypical antipsychotic, was voluntarily suspended in the European Union in 1998 following regulatory concerns over reports of serious cardiac dysrhythmias and sudden unexpected deaths. The reported causes of death, their frequency, prolongation of the rate corrected QT interval (QTc) and cardiac dysrhythmias in patients prescribed sertindole were compared with those for patients treated with two other atypical antipsychotics. All patients in England, prescribed atypical antipsychotics by general practitioners during each drug's immediate post-marketing period, were identified using an observational cohort technique, prescription-event monitoring. Mortality rates in the sertindole cohort were compared with those in a comparator cohort using standardized mortality ratios and incidence rate ratios. Cardiovascular events were reviewed and followed up to identify cases of prolongation of QTc interval. There was no statistically significant difference in mortality rates between sertindole and the comparator cohort, although confidence intervals (CI) were wide due to small numbers in the sertindole cohort. A much smaller number of patients were prescribed sertindole than the other antipsychotics. Six cases of prolongation of QTc interval were identified in 462 patients (1.3%, 95% CI 0.5-2.8) treated with sertindole and one with unspecified electrocardiogram changes in the comparator cohort of 16,542 patients. This study contributes to the understanding of the occurrence of prolongation of QTc interval during clinical use of sertindole, the incidence of which was similar to that in clinical trials. Although no statistically significant difference was shown in mortality rates between sertindole and comparator cohort, the sertindole cohort was too small to rule out an association between the use of this drug and cardiovascular deaths.

Topics: Adult; Aged; Aged, 80 and over; Antipsychotic Agents; Arrhythmias, Cardiac; Benzodiazepines; Cohort Studies; Death, Sudden; Electrocardiography; European Union; Female; Humans; Imidazoles; Indoles; Long QT Syndrome; Male; Middle Aged; Olanzapine; Pirenzepine; Product Surveillance, Postmarketing; Risperidone; Sex Factors