Long-term clozapine monotherapy significantly elevates heart failure risk, often without metabolic complications

Clozapine remains the only antipsychotic approved for treatment-resistant schizophrenia, a severe mental illness. Despite its efficacy, clozapine carries a significant risk of lethal adverse reactions, including cardiotoxicity. Traditionally, the focus has been on acute myocarditis and cardiomyopathy developing within weeks or months of initiation. However, the long-term risk of cardiac adverse events, particularly asymptomatic heart failure, has not been fully elucidated, leaving a critical gap in understanding the full spectrum of its cardiotoxic profile and guiding long-term patient management.

This multicenter retrospective cohort study analyzed patients with schizophrenia receiving clozapine monotherapy in Japan and China. Researchers included cases where serum NT-proBNP concentration and left ventricular ejection fraction (LVEF) from echocardiography were available. A total of 315 patients were enrolled, comprising 99 Japanese patients with a clozapine exposure duration of 57.5 ± 4.0 months and 216 Chinese patients with a significantly longer exposure of 208.1 ± 11.0 months. Blood examinations, including those from the Japanese Clozaril Patient Monitoring Service, were statistically analyzed as independent variables to identify risk factors for cardiotoxicity.

Among the 315 enrolled cases, the age-standardized prevalence of heart failure among clozapine-prescribed patients was significantly higher compared to the general population in both countries. In Japan, the odds ratio was 3.2 (95%CI: 1.4-6.4), while in China, it was 6.9 (95%CI: 3.6-12.0). This indicates a substantially increased risk of heart failure with long-term clozapine use. Key risk factors identified for stage-B heart failure associated with clozapine included prolonged exposure duration to the medication, higher plasma levels of clozapine, and increasing monocyte counts. Unexpectedly, a significant proportion of affected individuals did not present with typical metabolic complications.

Over 70% of cases with stage-B heart failure associated with clozapine in this study did not have metabolic complications, challenging prior assumptions about clozapine's cardiotoxicity pathways. Furthermore, aside from patients with pre-existing cardiomyopathy, myocardial infarction, ileus, or chronic renal failure, no cases with an ejection fraction below 50% were observed. This finding strongly suggests that the clozapine-associated stage-B heart failure observed is likely indicative of heart failure with preserved ejection fraction (HFpEF), rather than systolic dysfunction.