Cardiac Death Risk Rises With Both Antipsychotic Types

Current users of both first-generation and second-generation antipsychotics appear to have a similar, dose-related increase in sudden cardiac death.

Further, the presumed safety advantage of second-generation antipsychotics (SGAs) over first-generation antipsychotics (FGAs) regarding the adverse effects on cardiac health does not appear to exist, according to results from a retrospective analysis of the incidence of sudden cardiac death among users of FGAs and SGAs and nonusers of antipsychotic medication.

The antipsychotic medications included in the analysis were haloperidol, thioridazine, clozapine, olanzapine, quetiapine, and risperidone.

The study, which appeared in the January 15 New England Journal of Medicine, was conducted by Wayne Ray, Ph.D., and colleagues at Vanderbilt University School of Medicine.

An association between risk for sudden cardiac death and use of FGAs has long been recognized. This new study appears to extend that association to all antipsychotics and to underscore the need for a comprehensive medical and cardiac history before initiating treatment and for careful monitoring of patients.

“The study basically provides additional information to our understanding of something we have known for a long time, which is that there is a very low frequency, but still an increased rate, of deaths from sudden cardiac death,” said Jeffrey Lieberman, M.D., chair of APA's Council on Research, in an interview. “The study also tells us that there is no safety advantage to second-generation drugs. So what it means is that anyone who is treated needs to be evaluated and monitored for any potential effects the drugs could have on their cardiac function. Our practice guidelines already call for a thorough medical, including cardiac, history and for an annual physical exam as part of a patient's general health.”

Lieberman is chair of the Department of Psychiatry at the College of Physicians and Surgeons at Columbia University and director of the New York State Psychiatric Institute.

An APA statement by the Council on Research about the study and its implications for clinicians treating patients with antipsychotic medication is posted on APA's Web site at<www.psych.org/MainMenu/Newsroom/APAMemberDBSAResources/ResearchRecommendations.aspx>.

The statement outlines the methods and results of the NEJM study as well as some methodological concerns.

“[C]linicians should continue to observe extant practice guidelines for the workup and management of psychotic patients,” the statement reads. “With regard to cardiac safety, these include obtaining a medical and medication history, a thorough physical exam, vital signs, and routine laboratory tests.”

The higher rates of early death, metabolic syndrome, and cardiovascular illness among people with serious mental illness are believed to be multifactorial, including socioeconomic status and lifestyle choices involving diet, smoking, and exercise. Antipsychotic drugs, however, are also suspected to contribute to the mix; antipsychotics are believed to block potassium electrical currents in the heart, which may lead to QT-prolongation and the fatal arrhythmia known as torsades de pointes (TdP). The NEJM study appears to bolster the belief that the drugs themselves may be contributing to early risk for death.

But at least one prominent researcher believes that interpretation obscures a more obvious issue confronting clinicians treating patients with severe mental illness: the higher mortality associated with coronary heart disease and the established sources of modifiable risk including smoking, obesity, dislipidemia, hyperglycemia, and hypertension.

“These factors are more than sufficient to explain excess deaths in this population without invoking a drug effect on cardiac conduction to explain the mortality,” said John Newcomer, M.D., a professor of psychiatry at Washington University School of Medicine in St. Louis, in an interview. Newcomer's research has focused on general medical health—especially cardiometabolic health—and medical monitoring of patients with serious mental illness.

“The only thing we can be sure of here is that patients die early, and most patients are treated—but whether and how the treatment plays a role is uncertain,” Newcomer told Psychiatric News. “What we do know is that coronary heart disease—with all its modifiable risk factors—is the leading cause of death among the general population and the leading cause of death among patients with serious mental illness.”

No Drug Had Higher Risk Than Another

In the study researchers analyzed the adjusted incidence of sudden cardiac death in a retrospective cohort study of Medicaid enrollees in Tennessee. The primary analysis included 44,218 baseline users of a single first-generation antipsychotic, 46,089 users of a single second-generation antipsychotic, and 186,600 matched nonusers of antipsychotic drugs between January 1, 1990, and December 31, 2005.

The cohort included every eligible Medicaid enrollee with at least one qualifying day of use of antipsychotic drugs during the study period; the first day of follow-up was defined as the first qualifying day. The cohort also included two controls for each user of antipsychotic drugs, matched for age, sex, and first day of follow-up, and were randomly selected from qualifying nonusers of antipsychotic drugs on the first day of follow-up.

Follow-up extended from the first qualifying day until the end of the study period, the death of the person, the termination of Medicaid enrollment, or the date on which eligibility criteria for inclusion in the cohort were no longer met.

To try to account for the many confounding factors affecting the risk of sudden cardiac death, Ray and colleagues also performed several“ residual confounding analyses” in which they matched users and nonusers according to a “propensity score”—that is, the predicted probability that a person would become a user of antipsychotic medications. This allowed the researchers to achieve cohorts for comparison that were at least roughly balanced with regard to patient characteristics, including psychiatric profile.

They found that current users of both typical and atypical antipsychotic drugs had significantly higher rates of sudden cardiac death than did nonusers of antipsychotic drugs. Of patients treated with any of the first- or second-generation antipsychotics for a total of 166,324 person years, there were 478 sudden cardiac deaths.

That translates to approximately 2.9 events per 1,000 patient years. By comparison, nonusers of antipsychotic medications experienced 1.4 sudden cardiac deaths per 1000 patient years.

There was no statistically significant difference in frequency of death between users of FGAs and SGAs: there were 255 sudden cardiac deaths among patients using FGAs and 223 among those using SGAs. Moreover, no drug had a significantly higher risk for sudden cardiac death than did another.

This risk was dose dependent in both medication classes, with doses equivalent to at least 300 mg of chlorpromazine a day posing the greatest risk, Lieberman explained.

Former users of antipsychotic drugs did not have a significant risk of cardiac death.

An editorial that accompanied the NEJM article argued that an electrocardiogram should be obtained for all patients prior to being prescribed antipsychotic drugs—a recommendation that has not generally been considered cost-effective and that could be impossible with some patients.

“This modest effort could enable each patient starting on a high-dose antipsychotic to be screened for existing or emergent prolongation of the QT interval,” wrote Sebastian Schneeweiss, M.D., Sc.D., and Jerry Avorn, M.D., in the editorial.

But APA, in its guidance document on the findings, questions the wisdom of the recommendation: “Instituting a policy of routine serial measurement of the QTc interval in all patients initiating treatment with antipsychotic medication may be premature. While some antipsychotics are known to substantially prolong the QTc, others do so to only a modest degree. Furthermore, although prolongation of the QTc is the best available clinical surrogate for the development of TdP, it is an imperfect biomarker. The QTc generally has low specificity for predicting arrhythmias, and for some drugs a dissociation exists between QTc prolongation and TdP.”

Teasing Out Effects of Variables Difficult

Ray and colleagues acknowledged in the NEJM study the difficulty of controlling for a large number of possibly confounding factors associated with antipsychotic use that may affect risk for cardiac death.

But they state that a “sensitivity analysis found that residual confounding by smoking had at most a minor effect on estimates of relative risk. Although unmeasured behavioral factors may influence the study findings, the absence of a significantly increased risk of sudden death among former users of antipsychotic drugs and the marked dose-response relationship are evidence of a drug effect per se.”

Still, Newcomer countered that the prevalence of smoking—and other risk factors for cardiovascular disease—is so high in the population of patients with serious mental illness that the analysis may not be able to disentangle those effects from the effects of the drug alone.

He added, “Dose tends to be a proxy for severity of illness, on top of whatever else it may indicate. We know that patients who are sicker get higher doses and that they also tend to get poorer medical care with respect to primary and secondary prevention.”

An abstract of “Atypical Antipsychotics and the Risk of Sudden Cardiac Death” is posted at<http://content.nejm.org/cgi/content/abstract/360/3/225>.▪