Systematic analysis of drug-associated myocarditis reported in the World Health Organization pharmacovigilance database

Abstract

While multiple pharmacological drugs have been associated with myocarditis, temporal trends and overall mortality have not been reported. Here we report the spectrum and main features of 5108 reports of drug-induced myocarditis, in a worldwide pharmacovigilance analysis, comprising more than 21 million individual-case-safety reports from 1967 to 2020. Significant association between myocarditis and a suspected drug is assessed using disproportionality analyses, which use Bayesian information component estimates. Overall, we identify 62 drugs associated with myocarditis, 41 of which are categorized into 5 main pharmacological classes: antipsychotics (n = 3108 reports), salicylates (n = 340), antineoplastic-cytotoxics (n = 190), antineoplastic-immunotherapies (n = 538), and vaccines (n = 790). Thirty-eight (61.3%) drugs were not previously reported associated with myocarditis. Antipsychotic was the first (1979) and most reported class (n = 3018). In 2019, the two most reported classes were antipsychotics (54.7%) and immunotherapies (29.5%). Time-to-onset between treatment start and myocarditis is 15 [interquartile range: 10; 23] days. Subsequent mortality is 10.3% and differs between drug classes with immunotherapies the highest, 32.5% and salicylates the lowest, 2.6%. These elements highlight the diversity of presentations of myocarditis depending on drug class, and show the emerging role of antineoplastic drugs in the field of drug-induced myocarditis.

Fig. 1. Drugs associated with myocarditis in VigiBase(r), from 1967 to Janunary 2020.

Information component and its 95% lower-end credibility interval (IC₀₂₅) (represented by the error bar) for each drug significantly associated with myocarditis (IC₀₂₅ > 0). Related raw data are available in the Source Data file.

Fig. 2. Overlap between drugs associated with myocarditis.

Overlap between drug classes in the dataset (A), between drug substances in the antipsychotic group (B) and salicylate group (C), between subclasses in immunotherapy (D) and cytotoxic (E), and types of vaccines in the vaccine group (F). DTPP diphteria, tetanus, pertussis, and/or polio vaccine, HepA/HepB hepatitis A and/or hepatitis B vaccine. Subclasses in immunotherapy regroup anti-PD1 (cemiplimab, nivolumab, and pembrolizumab), anti-PDL1 (atezolizumab, avelumab, and durvalumab), anti-CTLA4 (ipilimumab), and interleukin-2 (aldesleukin). Subclasses in cytotoxic regroup alkylating agents (busulfan and cyclophosphamide), anthracyclines (daunorubicin, doxorubicin, epirubicin, and idarubicin), and antimetabolites (cytarabine and fluorouracil). Due to graphical limitations, some overlaps cannot be displayed. Exact combinations are presented with UpSetR plots in the Supplementary Information file.

Fig. 3. Evolution of reporting across time, by drug classes.

Evolution of cumulative number of reports per year (A); of cases per year, by drug class (B); of proportion of each drug class by half-decade (C); and time to onset between first treatment intake and myocarditis event (D). In B, are also mentioned all drugs with more than 80 reports over time, and corresponding year when the information component (IC) became significant with an IC₀₂₅ > 0. In D, intergroup comparison represents the comparison between all groups, regarding the time to onset between first treatment intake and myocarditis event (using Kruskal–Wallis methods). DTPP diphteria, tetanus, pertussis and/or poliomyelitis vaccine.

Fig. 4. Evolution of mortality across time, by drug classes.

Mortality associated with myocarditis cases, by drug class (A) and mortality by quartile of time, for each drug class (B–F). Intergroup comparisons assessed by χ² test were performed to assess mortality differences over time, for which results are as follow: A p = 2.1e–90 (significant), B p = 2.8e–05 (significant), C p = 0.2 (not significant), D p = 0.018 (significant), E p = 0.003 (significant), and F p = 5.2e–08 (significant).