Clozapine-associated myocarditis in the World Health Organization's pharmacovigilance database: Focus on reports from various countries

Abstract

Introduction: The incidence of clozapine-associated myocarditis varies by country. These variations are explored in VigiBase, the World Health Organization’s global database which has >25 million spontaneously reported adverse drug reaction (ADR) reports from the drug agencies of 145 countries. Methods: On January 15, 2021, a search of Vigibase since inception focused on myocarditis in clozapine patients. The 3572 individual reports were studied suing the standard VigiBase logarithmic measure of disproportionality called the information component (IC). The IC measures the disproportionality between the expected and the reported rates. After duplicates were eliminated there were 3274 different patients with myocarditis studied in logistic regression models. Results: The first myocarditis case was published in 1980 but since 1993 the VigiBase clozapine-myocarditis IC has been significant; moreover, currently it is very strong (IC=6.0, IC005IC995=5.9-6.1) and statistically significantly different from other antipsychotics. Of the 3274 different patients with myocarditis, 43.4% were non-serious cases, 51.8% were serious but non-fatal, and 4.8% were fatal. More than half (1621/3274) of the reports came from Australia, of which 69.2 % were non-serious, 27.7% serious but non-fatal, and 4.8% fatal. There were 41 cases of myocarditis from Asian countries through the end of 2020. Conclusions: In pharmacovigilance studies, confounding factors may explain statistical associations, but the strength and robustness of these results are compatible with the theory that myocarditis is definitively associated with early clozapine treatment. Myocarditis reports from Australia reports are over-represented to a major degree. Asian countries may be underreporting myocarditis to their drug agencies.