Correspondence
Atypical Antipsychotic Drugs and the Risk of Sudden Cardiac Death
N Engl J Med 2009; 360:2136-2138May 14, 2009
- Article
To the Editor:
Ray et al. (Jan. 15 issue)1 report that both typical and atypical antipsychotic drugs were associated with a doubling of the risk of sudden cardiac death, a risk that was dose-dependent and untested for time dependence. The authors state that the likely mechanism of action is an increase in the risk of serious ventricular arrhythmias, although they acknowledge that other mechanisms may be involved. Increased mortality among the severely mentally ill is well known, and although the illnesses themselves are associated with increased mortality,2-4 their undertreatment may lead to even higher mortality.5 An increased risk of cardiac events may be due to the illnesses themselves and associated risk factors or to their treatment, since chronic psychotic disorders are strongly associated with cardiac risk factors, including poor nutrition, obesity, substance abuse, smoking, lack of exercise, poverty, and stress. Moreover, doses of antipsychotic drugs are often higher in patients with more severe illness.
In their study, Ray et al. matched users and nonusers of antipsychotic drugs according to age, sex, timing of treatment exposures, cardiovascular risk scores, and other measures in order to avoid confounding. Nevertheless, patients who received antipsychotic drugs had an increase by a factor of 5.0 in indexes of psychiatric illness and an increase by a factor of 3.5 in exposure to other psychotropic drugs. Prudence requires that we pay close attention to the findings of this study in balancing the risks and benefits of antipsychotic drugs. However, the reported rates of death appear to be of uncertain clinical significance and require study in patients who are matched for psychiatric morbidity.
Ross J. Baldessarini, M.D.
McLean Hospital, Belmont, MA 02478-9106
rjb@mclean.org Dr. Baldessarini reports receiving grant support from the Bruce J. Anderson Foundation, the McLean Private Donors Psychotic Disorders and Psychopharmacology Research Fund, Janssen, Eli Lilly, and Novartis and consulting fees from AstraZeneca, Auritec, Biotrofix, Janssen, Noven, Eli Lilly, Luitpold, NeuroHealing, Novartis, Pfizer, and SK Bio-Pharmaceuticals. No other potential conflict of interest relevant to this letter was reported.
5 References1
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;360:225-235
Full Text | Web of Science | Medline2
Osby U ,Correia N ,Brandt L ,Ekbom A ,Sparen P . Mortality and causes of death in schizophrenia in Stockholm county, Sweden. Schizophr Res 2000;45:21-28
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Baldessarini RJ, Tarazi FI. Pharmacotherapy of psychosis and mania. In: Brunton LL, Lazo JS, Parker KL, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 11th ed. New York: McGraw-Hill, 2005:461-500.
4
Joukamaa M ,Heliovaara M ,Knekt P ,Aromaa A ,Raitasalo R ,Lehtinen V . Schizophrenia, neuroleptic medication and mortality. Br J Psychiatry 2006;188:122-127
CrossRef | Web of Science | Medline5
Tiihonen J ,Wahlbeck K ,Lonnqvist J , et al. Effectiveness of antipsychotic treatments in a nationwide cohort of patients in community care after first hospitalization due to schizophrenia and schizoaffective disorder: observational follow-up study. BMJ 2006;333:224-230
CrossRef | Web of Science | Medline
To the Editor:
In documenting the cardiovascular risks associated with the use of antipsychotic drugs, Ray et al. provide important information to assist the clinician in making an informed assessment of the risks and benefits of these drugs. In their analysis of specific drugs, however, it is surprising that the authors did not present data on the atypical agents ziprasidone and aripiprazole. Concern about the potential cardiac arrhythmogenicity of ziprasidone was raised even before its approval by the Food and Drug Administration.1 In addition, the identification of ziprasidone and aripiprazole as agents that are less likely to have adverse metabolic effects (obesity, hyperglycemia, and dyslipidemia2) than other atypical antipsychotic drugs has led some clinicians to view them as safer and therefore to prefer them. The presentation of data on these agents would substantially enhance the usefulness of this report.
2 ReferencesLawrence H. Price, M.D.
Butler Hospital, Providence, RI 02906
lawrence_price_md@brown.edu 1
Harrigan EP ,Miceli JJ ,Anziano R , et al. A randomized evaluation of the effects of six antipsychotic agents on QTc, in the absence and presence of metabolic inhibition. J Clin Psychopharmacol 2004;24:62-69
CrossRef | Web of Science | Medline2
Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care 2004;27:596-601
CrossRef | Web of Science | Medline
Author/Editor Response
Baldessarini's description of our results as “untested for time dependence” overlooks the analysis that was restricted to the first 365 days of use of antipsychotic drugs, which had findings similar to those in the primary analysis. He also raises the issue of confounding according to antipsychotic indication, which was considered extensively in our report. An important analysis was that of the cohort that excluded patients with a baseline diagnosis of schizophrenia or related psychoses. Control subjects were matched according to a propensity score, which is one method of matching patients for psychiatric morbidity. In this cohort, both users and nonusers of antipsychotic drugs had similar distributions of baseline psychiatric medications, diagnoses, and health care utilization. Findings were very similar to those in the primary cohort. The absence of increased risk among former users of antipsychotic drugs and the marked dose–response relationship for current users provide further evidence that confounding according to indication did not explain our findings.
As noted by Baldessarini, many studies have reported excess mortality among patients with schizophrenia. Given our findings and those of clinical trials1 involving the elderly, which have shown an increase in the rate of death from any cause among users of antipsychotic drugs, one wonders to what extent the excess mortality among patients with schizophrenia reflects the effects of the drugs with which this disease is nearly always treated.
We concur with Price that drug-specific data regarding ziprasidone and aripiprazole would be of interest. To ensure adequate power for individual drug analyses, we had an a priori requirement of at least 3000 person-years of current use, which would provide an expected five cases of sudden cardiac death under the null hypothesis. Neither ziprasidone nor aripiprazole met this criterion. However, both of these drugs were included in the analysis of all atypical antipsychotic drugs. On the basis of the principle that findings for the entire study population should apply to subgroups unless there is convincing evidence to the contrary,2 we believe that these particular atypical antipsychotic drugs should not be considered free of risk for sudden cardiac death until further data become available.
2 ReferencesWayne A. Ray, Ph.D.
Katherine T. Murray, M.D.
C. Michael Stein, M.B., Ch.B.
Vanderbilt University School of Medicine, Nashville, TN 372321
Food and Drug Administration. FDA public health advisory: deaths with antipsychotics in elderly patients with behavioral disturbances. (Accessed April 24, 2009, at http://www.fda.gov/cder/drug/advisory/antipsychotics.htm.)
2
Yusuf S ,Wittes J ,Probstfield J ,Tyroler HA . Analysis and interpretation of treatment effects in subgroups of patients in randomized clinical trials. JAMA 1991;266:93-98
CrossRef | Web of Science | Medline
- Citing Articles (4)
Citing Articles
1
Fariz A. Rani, Patrick Byrne, Noel Cranswick, Macey L. Murray, Ian C.K. Wong. (2011) Mortality in Children and Adolescents Prescribed Antipsychotic Medication. Drug Safety 34:9, 773-781
CrossRef2
Maurizio Pompili, Gianluca Serafini, Marco Innamorati, Elisa Ambrosi, Ludovica Telesforo, Paola Venturini, Gloria Giordano, Michele Battuello, David Lester, Paolo Girardi. (2011) Unmet treatment needs in schizophrenia patients: is asenapine a potential therapeutic option?. Expert Review of Neurotherapeutics 11:7, 989-1006
CrossRef3
Eva Saar, Dimitri Gerostamoulos, Olaf H. Drummer, Jochen Beyer. (2011) Assessment of the stability of 30 antipsychotic drugs in stored blood specimens. Forensic Science International
CrossRef4
(2009) Current awareness: Pharmacoepidemiology and drug safety. Pharmacoepidemiology and Drug Safety 18:11, i-xii
CrossRef
