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Do atypical antipsychotics increase the risk of sudden cardiac death similar to typical antipsychotics?

Background
For years, there has been concern regarding an association between antipsychotic medications and a negative impact on mortality. In 2001, a retrospective cohort study of 281,744 Tennessee Medicaid enrollees, covering 1,282,996 person-years of follow-up, revealed moderate doses of typical antipsychotics (>100 mg thioridazine equivalents) result in an increased risk of sudden cardiac death.^1,2 In the study, 1487 sudden cardiac deaths were reported, and moderate dose users of typical antipsychotics had a significant 2.4-fold increase in the rate of sudden cardiac death as compared to nonusers.

In 2005, a meta-analysis of 15 randomized, placebo-controlled trials of atypical antipsychotics in dementia found an increased risk of death in general, not sudden cardiac death in particular, with atypical antipsychotic use as compared to placebo.³ That same year, the Food and Drug Administration (FDA) issued a “talk paper” alerting health care professionals to this higher death rate among elderly patients being treated for dementia (an off-label use).⁴ All manufacturers of atypical antipsychotics were required to add a boxed warning to their labeling describing this risk and noting the off-label nature of this use. Typical antipsychotics were required to make similar safety-related changes to prescribing information in 2008.⁵

Current Issue
On January 15, 2009, Ray and colleagues published a retrospective cohort study in the New England Journal of Medicine that further evaluated the risk of sudden cardiac death with antipsychotics.⁶ This time, the risk with atypical antipsychotics was the investigational target. The study enrolled 44,218 users of single typical antipsychotics, 46,089 users of single atypical antipsychotics, and 186,600 matched nonusers of antipsychotic medications among Tennessee Medicaid enrollees. Only individuals between 30 to 74 years of age were enrolled as persons younger than 30 rarely suffer from sudden cardiac death, and death certificates of older individuals can be less reliable with regard to a definitive diagnosis of sudden cardiac death. In addition, enrolled patients had to have been eligible for full pharmacy benefits, consistently made use of medical care, and were new users of an antipsychotic medication. Patients with a high risk of noncardiac-related death were excluded from the analysis. Patient follow-up extended from the initial qualifying day of antipsychotic drug use until the end of the study period (study period ran from January 1, 1990 to December 31, 2005), termination of Medicaid participation, date at which the patient no longer met eligibility criteria for the study, or upon death of the patient.

The primary study endpoint was community-occurring sudden cardiac death.^6,7 This was defined as a sudden, fatal pulseless condition, consistent with ventricular tachyarrhythmia, but without any known noncardiac etiology. Results are presented in Table 1. As seen in the table, current users of atypical and typical antipsychotics had a significantly higher risk of sudden cardiac death as compared to the reference group of nonusers. In addition, former users of antipsychotics were not at a significantly increased risk indicating that simply taking an antipsychotic at any timepoint in the past does not result in an increased risk of sudden cardiac death in the future.

Table 1. Adjusted incidence-rate ratios for sudden cardiac death according to user status.^6,7

CI=confidence interval

Higher doses of typical and atypical antipsychotics were associated with an increased risk of sudden cardiac death as well.^6,7 In the study, doses were reported as chlorpromazine equivalents; low doses were <100 mg, moderate doses between 100 to 299 mg, and high doses were >300 mg. The incidence-rate ratios for sudden cardiac death increased from 1.31 (95% confidence interval [CI]: 0.97 to 1.77) at low doses of typical antipsychotics to 2.42 (95% CI: 1.91 to 3.06) at high doses. For atypical agents, a similar dose-response was observed: 1.59 (95% CI: 1.03 to 2.46) at low doses to 2.86 (95% CI: 2.25 to 3.65) at high doses. No individual antipsychotic in the study was immune to this dose-response phenomenon. The authors concluded that current users of both typical and atypical antipsychotics had an increased risk of sudden cardiac death that was dose-related.

Implications
In an accompanying editorial, Schneeweiss and Avorn note the importance of this well-designed pharmacoepidemiologic study.⁸ Since their introduction, the atypical antipsychotics have reached far beyond their labeled indications to include new and particularly vulnerable patient populations including the elderly and children. This increase in use has driven olanzapine (Zyprexa), risperidone (Risperdal), and quetiapine (Seroquel) into the list of top 10 selling drugs globally with a combined sales volume of $14.5 billion in 2007. Although the effects of typical antipsychotics on the heart have been widely known for years, the article by Ray and colleagues is the first to directly link the use of atypical antipsychotics to an increased risk of sudden cardiac death despite the fact that the first atypical (i.e. clozapine) was approved for use in 1989.

Shneeweiss and Avorn state that this new data should help to curb the prescribing of these agents, particularly among children and the elderly, 2 populations for which clear evidence of efficacy is lacking.⁸ In addition, the authors emphasize that physicians should continue to be allowed to prescribe these medications in patients where benefit is proven such as schizophrenia and bipolar disorders. However, if an antipsychotic is necessary, obtaining an electrocardiogram (EKG) before and shortly after initiation of the medication may be prudent in order to identify patients with potential cardiac issues from the onset of high dose antipsychotic therapy.

References

1. Ray WA, Meredith S, Thapa PB, Meador KG, Hall K, Murray KT. Antipsychotics and the risk of sudden cardiac death. Arch Gen Psychiatry. 2001;58(12):1161-1167.
2. Heartwire. Antipsychotic drugs associated with increase in risk of sudden cardiac death. Available at http://www.theheart.org/article/186397.do. January 16, 2009.
3. Schneider LS, Dagerman KS, Insel P. Risk of death with atypical antipsychotic drug treatment for dementia. JAMA. 2005;294(15):1934-1943.
4. Food and Drug Administration. FDA issues public health advisory for antipsychotic drugs used for treatment of behavioral disorders in elderly patients. Available at http://www.fda.gov/bbs/topics/ANSWERS/2005/ANS01350.html. January 21, 2009.
5. Food and Drug Administration. FDA requests boxed warnings on older class of antipsychotic drugs. Available at http://www.fda.gov/bbs/topics/NEWS/2008/NEW01851.html. January 21, 2009.
6. Ray WA, Chung CP, Murray KT, Hall K, Stein CM. Atypical antipsychotic drugs and the risk of sudden cardiac death. N Engl J Med. 2009;360(3):225-235.
7. Heartwire. Newer antipsychotics have same risk of sudden cardiac death as older ones. Available at http://www.theheart.org/article/933903.do. January 16, 2009.
8. Schneeweiss S, Avorn J. Antipsychotic agents and sudden cardiac death – how should we manage the risk? N Engl J Med. 2009;360(3):294-296.