Clozapine-associated cardiotoxicity: Risk factors and long-term cardiovascular outcomes from a multicentre...

Clozapine-associated cardiotoxicity, including myocarditis, is a recognized early complication. Risk factors and long-term cardiovascular consequences remain poorly defined.

To evaluate heart failure, arrhythmia, cardiomyopathy and mortality outcomes among clozapine-treated patients with and without cardiotoxicity.

We conducted a retrospective cohort study using the TriNetX Global Collaborative Network. Adults exposed to clozapine were identified. Adults initiating clozapine were identified and classified by early cardiotoxicity, defined as elevated troponin within 6 weeks and 90 days of initiation. Propensity score matching (1:1) was performed to balance baseline demographics and co-morbidities. Outcomes were assessed over 5 years from index. Cox proportional hazards models were used to identify predictors of early cardiotoxicity. Hazard ratios (HRs) with 95% confidence intervals (CIs) were reported.

After matching, 1203 patients were included in each cohort within the 6-week exposure window. Over 5 years of follow-up, heart failure occurred in 4.7% of patients with early cardiotoxicity compared with 3.8% of those without (HR: 1.76, 95% CI: 1.16-2.68). Arrhythmias occurred in 6.9% vs. 6.2% (HR: 1.54, 95% CI: 1.09-2.18), and cardiomyopathy in 1.9% vs. 1.0% (HR: 2.59, 95% CI: 1.27-5.29). All-cause mortality did not differ significantly between groups (9.9% vs. 10.4%; HR: 1.25, 95% CI: 0.96-1.62). In a secondary analysis using a 90-day exposure window, findings were consistent for cardiovascular outcomes, whereas all-cause mortality was modestly increased (HR: 1.36, 95% CI: 1.06-1.76). Cox regression identified male sex, younger age, obesity, valproate coadministration and concomitant antipsychotic use (risperidone, olanzapine, quetiapine) as independent risk factors, whereas traditional cardiovascular co-morbidities were not significantly associated with outcomes.

Early clozapine cardiotoxicity predicts long-term heart failure, arrhythmias and cardiomyopathy, but not mortality. Risk is higher in males, younger patients, those with obesity and those taking valproate or multiple antipsychotics. Findings support early risk stratification and ongoing cardiovascular surveillance.