Clozapine-associated cardiotoxicity: Risk factors and long-term cardiovascular outcomes from a multicentre propensity-matched analysis - 25/09/26

Doi : 10.1016/j.acvd.2026.07.004

Eric Yalley ^a,⁎ , Beloved Adenuga ^a, Ayomide Ogunsakin ^a, Raenique Doran ^a, Miriam Michael ^b,^c

^a Howard University College of Medicine, Washington, DC 20059, USA

^b Department of Internal Medicine, Howard University, Washington, DC 20060, USA

^c Department of Internal Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA

^* Corresponding author. Howard University College of Medicine, 520 W St., NW, Washington, DC 20059, USA. Howard University College of Medicine 520 W St., NW, Washington DC 20059 USA

Sous presse. Épreuves corrigées par l'auteur. Disponible en ligne depuis le Friday 25 September 2026

Graphical abstract

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Highlights

•	Early clozapine cardiotoxicity increases the long-term risk of heart failure.
•	Early clozapine cardiotoxicity increases the long-term risk of arrhythmias.
•	Early clozapine cardiotoxicity increases the long-term risk of cardiomyopathy.
•	Male sex, younger age and obesity raise the cardiovascular risk.
•	Valproate and concomitant antipsychotics raise the cardiovascular risk.
•	Traditional cardiovascular co-morbidities do not predict cardiotoxicity.
•	Findings support early risk stratification and ongoing cardiovascular surveillance.

Le texte complet de cet article est disponible en PDF.

Abstract

Background

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

Aim

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

Methods

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.

Results

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.

Conclusions

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.

Le texte complet de cet article est disponible en PDF.

Keywords : Clozapine, Cardiotoxicity, Cardiomyopathy, Heart failure, Arrhythmia