The primary cohort included 93,300 antipsychotic users and 186,600 matched controls. There were 44,218 and 46,089 users of single typical and atypical antipsychotics at cohort entry. The propensity-score-matched cohort included 67,824 antipsychotic users and 116,069 nonusers.
In the primary cohort, users and nonusers of antipsychotics had comparable baseline demographic characteristics (). The mean age was 46 years, 65% were female, 70% were of white race, and 57% had urban residence. Antipsychotic users were more likely to have Medicaid enrollment related to disability (63%) than were nonusers (37%) but had a slightly lower mean baseline cardiovascular risk score (9.2 versus 9.6). As expected, antipsychotic users had higher prevalence of baseline psychiatric comorbidity; however, there was substantial comorbidity among nonusers as well, particularly for affective disorders. In the propensity-score-matched cohort, antipsychotic users and nonusers had identical propensity scores and comparable baseline psychiatric comorbidity.
Baseline characteristics* of cohort members according to antipsychotic use status at cohort entry.
When compared with users of typical antipsychotics, atypical users were slightly younger, less likely to have Medicaid enrollment related to disability, and had higher baseline cardiovascular risk (). They also had higher antipsychotic doses, in part due to the preponderance of low-dose use for thioridazine (54% low dose). Atypical users also were less likely to have a diagnosis of schizophrenia (14% vs 27% for typical users), but more likely to have diagnosed mood disorders (bipolar: 23% vs 12% for typical agents; other mood: 60% vs 36% for typical agents), except for users of clozapine (indicated for treatment-resistant psychosis24
), for whom 89% had a diagnosis of schizophrenia.
Baseline characteristics* according to antipsychotic type and use of frequently prescribed individual drugs.
During the 1,042,159 person-years of cohort followup, there were 1870 sudden cardiac deaths, or 17.9 per 10,000 person-years. The unadjusted rate increased from 4.7 per 10,000 for those aged 30–34 at baseline to 47.6 per 10,000 for those 70–74 and was more than twice as high for males ( 27.1 per 10,000) as for females (12.9 per 10,000).
Current users of typical antipsychotics had an adjusted rate of sudden cardiac death 2.00 (95% CI, 1.69–2.35) times that of nonusers (). A similar increased risk was present for current users of atypical antipsychotics, who had a rate of sudden cardiac death more than twice that of nonusers (IRR=2.27[1.89–2.73]) and not significantly different from that for the typical agents (IRR=1.14 [.93–1.39]). The rates of sudden cardiac death for both typical and atypical antipsychotic users were greater than those for former antipsychotic users (p<.0001), who had no significantly increased risk of sudden cardiac death (IRR=1.13[0.98–1.30]). A significantly increased rate of sudden cardiac death was present for each of the six frequently prescribed individual antipsychotics ().
Adjusted incidence rate-ratios for sudden cardiac death according to antipsychotic current use status* and frequently prescribed individual drugs.
The risk of sudden cardiac death increased with dose for current users of both typical and atypical antipsychotics (). For the typical agents, the IRRs increased from 1.31 (0.97–1.77) for low doses to 2.42 (1.91–3.06) for high doses (p<.001, test for dose-response). For the atypical drugs, the IRRs increased from 1.59 (1.03–2.46) for low doses to 2.86 (2.25–3.65) for high doses (p=.015, test for dose-response). There was a dose-response trend for each of the six frequently prescribed individual drugs (), which was statistically significant for thioridazine (p=.005) and of borderline significance for risperidone (p=.051). Current users of thioridazine in high doses (≥300mg) had the greatest increased risk, an IRR of 5.05 (3.09–8.27).
Figure 1 Adjusted incidence rate-ratio for sudden cardiac death among current users of antipsychotics, according to antipsychotic type and dose (chlorpromazine equivalents: low, <100mg; moderate, 100mg–299mg; high, ≥300mg). The reference (more ...)
Figure 2 Adjusted incidence rate-ratio for sudden cardiac death among current users of six frequently prescribed individual antipsychotic drugs, according to dose( chlorpromazine equivalents: low, <100mg; moderate, 100mg–299mg; high, ≥300mg). (more ...)
In the propensity-score-matched cohort (), current users of both typical and atypical antipsychotics had increased risk of sudden cardiac death, with respective IRRs of 1.84 (1.50–2.26) and 1.99 (1.61–2.46) and there was a significant dose-response for each class (p<.001, p=.0457, respectively). The IRR for atypical vs typical antipsychotics was 1.08 (0.82–1.43).
Table 3 Propensity-score matched cohort that excludes persons with baseline diagnosis of schizophrenia or related psychoses. Adjusted incidence rate-ratios for sudden cardiac death according to antipsychotic current use status*, dose** and frequently prescribed (more ...)
We performed several additional analyses to further test the robustness of study findings. To assess the influence of the adverse metabolic effects of chronic antipsychotic use,12
analysis was restricted to those with less than 365 days of cumulative duration of use. The respective IRRs for the typical and atypical drugs were 1.73 (1.09–2.72, p=.019) and 1.87 (1.29–2.73, p<.001). To assess possible bias from inclusion of persons with antipsychotic use prior to the beginning of followup, which could preferentially eliminate patients susceptible to pro-arrhythmic effects,33
we analyzed cohort members with no antipsychotic use in the two years preceding t0
. The respective IRRs for current users of typical and atypical antipsychotics were 1.74 (1.14–2.67, p<.001) and 1.86 (1.35–2.57, p<.001). To assess the effects of secular trends in antipsychotic use and incidence of sudden cardiac death, we restricted analysis to 1998–2005; the respective IRRs for current users of typical and atypical antipsychotics were 1.78 (1.35–2.35, p<.001) and 2.03 (1.65–2.50, p<.001).