Typical and atypical antipsychotics
increase risk of sudden cardiac death
Question: What is the risk of sudden cardiac death with
typical and atypical antipsychotics?
People: 279 907 Medicaid enrolees, aged 34–74 years (mean
45.7 years; 65.2% women), who were either currently taking
a single antipsychotic (n=93 307) or no antipsychotics
(n=186 600). Eligible antipsychotic users were those having
at least one qualifying day of use of antipsychotic drugs
during the study period. Two controls were randomly
selected for each antipsychotic user, with matching for age,
gender and first day of follow-up (defined as the first
qualifying day for each antipsychotic user). Controls could
subsequently become users of antipsychotic drugs. As well as
the overall cohort, a subcohort matched for propensity scores
was used in secondary analyses. Follow-up ended at the end
of the study period, death, termination of Medicaid
enrolment or if the participant subsequently met any of the
study exclusion criteria. People could re-enter the study if
they left it. Exclusion criteria: registration with Medicaid for
,2 years; not eligible for full pharmacy benefits; not a regular
user of medical care (,1 filled prescription and ,1 outpatient
visit in each of the preceding 2 years); high risk of death from
non-cardiac causes. Follow-up did not include time spent in
hospital or the 30 days after discharge.
Setting: Tennessee, USA; 1 January 1990 to 31 December 2005.
Atypical or typical antipsychotic use. Current use
of antipsychotic was defined as the days between filling the
prescription until the prescribed medication would have run
out, when the person was most likely to be taking the drugs.
Indeterminate use was the period up to 90 days after finishing
the current drug. Former use was defined as any time after the
first antipsychotic use that was not classified as current or
indeterminate use. Non-use was defined as any days without
antipsychotic prescription and with no antipsychotic use in the
past. Antipsychotic use was categorised by approximate
chlorpromazine dose equivalents, with ,100 mg
chlorpromazine defined as low dose, 100–299 mg as moderate
dose and>300 mg as high dose. Typical antipsychotics assessed
were thioridazine and haloperidol, and atypicals were clozapine,
quetiapine, olanzapine and risperidone. Results were adjusted
for demographic characteristics and comorbid conditions at
baseline. Summary cardiovascular risk scores were calculated
from baseline cardiovascular and somatic variables (score range
0–19, higher score indicating greater risk).
Outcomes: Sudden cardiac death occurring in the
community, identified using death certificates.
Design: Retrospective cohort study.
Follow-up period: 16 years.
There were 1870 sudden cardiac deaths during the study
period, equivalent to 17.9 per 10 000 person years. Current
users of typical and atypical antipsychotics were significantly
more likely to have sudden cardiac death than antipsychotic
non-users (typical antipsychotics: incidence rate ratio (IRR)
1.99, 95% confidence interval (CI) 1.68 to 2.34; atypical
antipsychotics: IRR 2.26, 95% CI 1.88 to 2.72). There was no
significant difference between atypical and typical antipsychotics
in risk of sudden cardiac death (IRR 1.14, 95% CI 0.93
to 1.39). Former users of antipsychotics and non-users did not
differ significantly in risk of sudden cardiac death (IRR 1.13,
95% CI 0.98 to 1.30). Current users of antipsychotics had a
higher risk of sudden cardiac death than former users
(p,0.001). There was a dose–response relationship, with
higher doses of typical or atypical antipsychotics increasing
the risk of sudden cardiac death compared with non-users
(p,0.001 for typical, p=0.01 for atypical antipsychotics).
Similar results were found if the propensity matched
subcohort was used.
Compared with antipsychotic non-users, current users of
typical or atypical antipsychotics have a similarly increased
risk of sudden cardiac death.
Ray WA, Chung CP, Murray KT, et al. Atypical antipsychotic
drugs and the risk of sudden cardiac death. N Engl J Med
Correspondence to: Dr Wayne A Ray, Department of Preventative Medicine, Village
at Vanderbilt, Suite 2600, 1501 21st Avenue South, Nashville, TN 37212, USA;
Source of funding: National Heart, Lung, and Blood Institute and the Agency for
Healthcare Quality and Research.