Antipsychotic Drugs and the Risk of Ventricular Arrhythmia and/or Sudden Cardiac Death: A Nation‐wide Case‐Crossover Study

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Abstract

Background

Antipsychotics have been linked to prolongation of the QT interval. However, little is known about the risk of ventricular arrhythmia (VA) and/or sudden cardiac death (SCD) associated with individual antipsychotic drug use. This study was designed to investigate the association between specific antipsychotic drugs and the risk of VA and/or SCD.

Methods and Results

We conducted a case‐crossover study using a nation‐wide population‐based sample obtained from Taiwan's National Health Insurance Research Database. A total of 17 718 patients with incident VA and/or SCD were enrolled. Conditional logistic regression models were applied to examine the effects of antipsychotic drug use on the risk of VA/SCD during various case and control time windows of 7, 14, and 28 days. The effect of the potency of a human ether‐à‐go‐go‐related gene (hERG) potassium channel blockade was also assessed. Antipsychotic drug use was associated with a 1.53‐fold increased risk of VA and/or SCD. Antipsychotic drugs with increased risk included clothiapine, haloperidol, prochlorperazine, thioridazine, olanzapine, quetiapine, risperidone, and sulpiride. The association was significantly higher among those with short‐term use. Antipsychotics with a high potency of the hERG potassium channel blockade had the highest risk of VA and/or SCD.

Conclusion

Use of antipsychotic drugs is associated with an increased risk of VA and/or SCD. Careful evaluations of the risks and benefits of antipsychotic treatment are highly recommended.

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Most cited references 26

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Atypical antipsychotic drugs and the risk of sudden cardiac death.

Wayne Ray, Cecilia P Chung, Katherine T Murray … (2009)

Users of typical antipsychotic drugs have an increased risk of serious ventricular arrhythmias and sudden cardiac death. However, less is known regarding the cardiac safety of the atypical antipsychotic drugs, which have largely replaced the older agents in clinical practice. We calculated the adjusted incidence of sudden cardiac death among current users of antipsychotic drugs in a retrospective cohort study of Medicaid enrollees in Tennessee. The primary analysis included 44,218 and 46,089 baseline users of single typical and atypical drugs, respectively, and 186,600 matched nonusers of antipsychotic drugs. To assess residual confounding related to factors associated with the use of antipsychotic drugs, we performed a secondary analysis of users of antipsychotic drugs who had no baseline diagnosis of schizophrenia or related psychoses and with whom nonusers were matched according to propensity score (i.e., the predicted probability that they would be users of antipsychotic drugs). Current users of typical and of atypical antipsychotic drugs had higher rates of sudden cardiac death than did nonusers of antipsychotic drugs, with adjusted incidence-rate ratios of 1.99 (95% confidence interval [CI], 1.68 to 2.34) and 2.26 (95% CI, 1.88 to 2.72), respectively. The incidence-rate ratio for users of atypical antipsychotic drugs as compared with users of typical antipsychotic drugs was 1.14 (95% CI, 0.93 to 1.39). Former users of antipsychotic drugs had no significantly increased risk (incidence-rate ratio, 1.13; 95% CI, 0.98 to 1.30). For both classes of drugs, the risk for current users increased significantly with an increasing dose. Among users of typical antipsychotic drugs, the incidence-rate ratios increased from 1.31 (95% CI, 0.97 to 1.77) for those taking low doses to 2.42 (95% CI, 1.91 to 3.06) for those taking high doses (P<0.001). Among users of atypical agents, the incidence-rate ratios increased from 1.59 (95% CI, 1 .03 to 2.46) for those taking low doses to 2.86 (95% CI, 2.25 to 3.65) for those taking high doses (P=0.01). The findings were similar in the cohort that was matched for propensity score. Current users of typical and of atypical antipsychotic drugs had a similar, dose-related increased risk of sudden cardiac death. 2009 Massachusetts Medical Society

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Sudden cardiac death in the United States, 1989 to 1998.

Zhi-Jie Zheng, Janet B Croft, Wayne Giles … (2001)

Sudden cardiac death (SCD) is a major clinical and public health problem. United States (US) vital statistics mortality data from 1989 to 1998 were analyzed. SCD is defined as deaths occurring out of the hospital or in the emergency room or as "dead on arrival" with an underlying cause of death reported as a cardiac disease (ICD-9 code 390 to 398, 402, or 404 to 429). Death rates were calculated for residents of the US aged >/=35 years and standardized to the 2000 US population. Of 719 456 cardiac deaths among adults aged >/=35 years in 1998, 456 076 (63%) were defined as SCD. Among decedents aged 35 to 44 years, 74% of cardiac deaths were SCD. Of all SCDs in 1998, coronary heart disease (ICD-9 codes 410 to 414) was the underlying cause on 62% of death certificates. Death rates for SCD increased with age and were higher in men than women, although there was no difference at age >/=85 years. The black population had higher death rates for SCD than white, American Indian/Alaska Native, or Asian/Pacific Islander populations. The Hispanic population had lower death rates for SCD than the non-Hispanic population. From 1989 to 1998, SCD, as the proportion of all cardiac deaths, increased 12.4% (56.3% to 63.9%), and age-adjusted SCD rates declined 11.7% in men and 5.8% in women. During the same time, age-specific death rates for SCD increased 21% among women aged 35 to 44 years. SCD remains an important public health problem in the US. The increase in death rates for SCD among younger women warrants additional investigation.

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Antipsychotic drugs: prolonged QTc interval, torsade de pointes, and sudden death.

J Bigger, Peter A. Glassman (2001)

The authors review the mechanisms and establish the risk of torsade de pointes and sudden death with antipsychotic drugs. They present a review of original concepts, the distinction between familial and drug-induced cases of torsade de pointes, and the recognition of the role of noncardiac drugs in torsade de pointes and sudden death. They review the evidence linking QTc interval prolongation, potassium channels, and torsade de pointes from both the long QT syndrome and drugs. They examine the risk for torsade de pointes from antipsychotic drugs and estimate the frequency of sudden death on the basis of epidemiological data in normal and schizophrenic populations. All drugs that cause torsade de pointes prolong the QTc interval and bind to the potassium rectifier channel, but the relationships are not precise. Prediction of torsade de pointes and sudden death can be improved by examining dose dependency, the percent of QTc intervals higher than 500 msec, and the risk of drug-drug interactions. Although sudden unexpected death occurs almost twice as often in populations treated with antipsychotics as in normal populations, there are still only 10-15 such events in 10,000 person-years of observation. Although pimozide, sertindole, droperidol, and haloperidol have been documented to cause torsade de pointes and sudden death, the most marked risk is with thioridazine. There is no association with olanzapine, quetiapine, or risperidone. Ziprasidone does prolong the QT interval, but there is no evidence to suggest that this leads to torsade de pointes or sudden death. Only widespread use will prove if ziprasidone is entirely safe. To date, all antipsychotic drugs have the potential for serious adverse events. Balancing these risks with the positive effects of treatment poses a challenge for psychiatry.

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Author and article information

Journal

Journal ID (nlm-ta): J Am Heart Assoc

Journal ID (iso-abbrev): J Am Heart Assoc

Journal ID (hwp): ahaoa

Journal ID (publisher-id): jah3

Title: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease

Publisher: Blackwell Publishing Ltd

ISSN (Electronic): 2047-9980

Publication date Collection: February 2015

Publication date (Electronic): 23 February 2015

Volume: 4

Issue: 2

Electronic Location Identifier: e001568

Affiliations

Department of Psychiatry, Far Eastern Memorial Hospital, New Taipei City, Taiwan (C.S.W.)

College of Public Health, National Taiwan University, Taipei, Taiwan (C.S.W.)

Department of Psychiatry, National Taiwan University Hospital, Taipei, Taiwan (C.S.W.)

Division of Biostatistics and Bioinformatics, Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan (Y.T.T., H.J.T.)

Department of Public Health, China Medical University, Taichung, Taiwan (H.J.T.)

Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL (H.J.T.)

Author notes

Correspondence to: Hui‐Ju Tsai, MPH, PhD, Division of Biostatistics and Bioinformatics, Institute of Population Health Sciences, National Health Research Institutes, 35 Keyan Road Zhunan, Miaoli County 350, Taiwan. E‐mails: tsaihj@ 123456nhri.org.tw , h-tsai@ 123456northwestern.edu

Accompanying Tables S1 through S3 are available at http://jaha.ahajournals.org/content/1/5/e001568/suppl/DC1

Article

Publisher ID: jah3870

DOI: 10.1161/JAHA.114.001568

PMC ID: 4345877

PubMed ID: 25713294

SO-VID: 10e5da3c-8771-4739-a206-d9381bf76569

License:

This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

History

Date received : 23 December 2014

Date accepted : 24 January 2015

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Antipsychotic Drugs and the Risk of Ventricular Arrhythmia and/or Sudden Cardiac Death: A Nation‐wide Case‐Crossover Study

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Abstract

Background

Methods and Results

Conclusion

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Cardiovascular Innovations and Applications

Most cited references 26

Atypical antipsychotic drugs and the risk of sudden cardiac death.

Sudden cardiac death in the United States, 1989 to 1998.

Antipsychotic drugs: prolonged QTc interval, torsade de pointes, and sudden death.

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