A New Monitoring Protocol for Clozapine-Induced Myocarditis Based on an Analysis of 75 Cases and 94 Controls

• Published in: Australian and New Zealand journal of psychiatry 2011-06, Vol.45 (6), p.458-465
• Main Authors: Ronaldson, Kathlyn J., Fitzgerald, Paul B., Taylor, Andrew J., Topliss, Duncan J., McNeil, John J.
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antipsychotic Agents - adverse effects; Antipsychotic Agents - therapeutic use; Biological and medical sciences; C-Reactive Protein; Case-Control Studies; Clinical Protocols; Clozapine; Clozapine - adverse effects; Clozapine - therapeutic use; Diseases; Drug monitoring; Drug Monitoring - methods; Drug toxicity and drugs side effects treatment; Echocardiography; Female; Humans; Male; Medical sciences; Middle Aged; Myocarditis - blood; Myocarditis - chemically induced; Myocarditis - diagnosis; Myocardium; Pharmacology. Drug treatments; Toxicity: cardiovascular system; Troponin - blood
• ISSN: 0004-8674; 1440-1614
• DOI: 10.3109/00048674.2011.572852

Objective: To develop an evidence-based monitoring protocol for clozapine-induced myocarditis. Methods: Potential cases of clozapine-related myocarditis occurring between January 1994 and January 2009 and a comparative group of patients taking clozapine for at least 45 days without cardiac disease were documented from the patients’ medical records. Results: A total of 75 cases and 94 controls were included. Nine cases died. The time to onset was 10–33 days with 83% of cases developing between days 14 and 21 inclusive. At least twice the upper limit of normal troponin was found in 90% of cases, but 5 cases had C-reactive protein more than 100 mg/L and left ventricular impairment by echocardiography without a clinically significant rise in troponin. The proposed monitoring protocol recommends obtaining baseline troponin I/T, C-reactive protein and echocardiography, and monitoring troponin and C-reactive protein on days 7, 14, 21 and 28. Mild elevation in troponin or C-reactive protein, persistent abnormally high heart rate or signs or symptoms consistent with infective illness should be followed by daily troponin and C-reactive protein investigation until features resolve. Cessation of clozapine is advised if troponin is more than twice the upper limit of normal or C-reactive protein is over 100 mg/L. Combining these two parameters has an estimated sensitivity for symptomatic clozapine-induced myocarditis of 100%. The sensitivity for asymptomatic disease is unknown. Conclusion: This protocol recommends active monitoring for 4 weeks, relying predominantly on troponin and C-reactive protein results. It encourages continuation of clozapine in the presence of mild illness, but defines a threshold for cessation.