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.

Immunomodulating Therapies in Acute Myocarditis and Recurrent/Acute Pericarditis

“…From a recent international retrospective case collection of AM presenting with left ventricular (LV) systolic dysfunction, the prevalence of lymphocytic AM has been estimated to be ~72%, being the most frequently diagnosed form both in fulminant myocarditis [FM], a clinical entity defined by the need of circulatory support, and non-FM ( 11 ). The etiology of lymphocytic AM is broad and includes heterogeneous pathogens, drugs or autoimmune-mediated injury in the setting of systemic inflammatory diseases ( 10 , 13 , 14 ). The role of viruses in myocarditis etiology has been historically recognized, with Parvovirus (PV)B-19, adenoviruses, Human Herpesvirus (HHV)-6, enteroviruses being the most common agents identified in the myocardium of patients with AM ( 15 , 16 ).…”

“…One of the largest case series of 122 patients with ICI-associated myocarditis had early onset of symptoms (median 30 days after initial exposure to ICI), and up to 50% of deaths ( 9 ). A systematic analysis of the World Health Organization pharmacovigilance database confirmed a 32.5% of mortality in patients who had myocarditis associated with the administration of ICIs with a median time-to-onset of 33 days ( 10 ). The increased reports of cases in the last years are perhaps consistent with growing recognition of this new clinical syndrome, as well as the more widespread use of ICIs.…”

“…Historically, the vaccine that is most associated with myocarditis is the anti-smallpox ( 10 , 126 ). Smallpox vaccine was associated with eosinophilic myocarditis, while almost all the present cases of mRNA COVID-19 vaccine are not associated with eosinophilia.…”

“…Conversely, EMB is at risk of thromboembolism if ventricular thrombi are present, and can yield false-negative findings when endomyocardial fibrosis is prominent and eosinophil infiltration has partially or completely vanished ( 138 ). Eosinophil-related heart involvement can be encountered within the full spectrum of eosinophil-associated diseases ( 137 ), including drug hypersensitivity (even in the absence of skin manifestations) ( 10 ), parasitic infections (namely toxocariasis, trichinosis, filarial infections or sarcocystosis), aspirin-exacerbated respiratory disease, eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg-Strauss syndrome), hypereosinophilic syndromes (HES) (mainly idiopathic and FIP1L1-PDGFRA -associated HES, formerly chronic eosinophilic leukemia) and high-grade hematological malignancies [e.g., Hodgkin and angioimmunoblastic T-cell lymphomas, as well as B-cell acute lymphoblastic lymphoma with t ( 5 , 14 ) (q31;q32); IGH-IL3 rearrangement ( 140 ). In a review of 179 cases of biopsy-proven eosinophilic myocarditis, the main identified causes were drug hypersensitivity, EPGA, HES and parasitic infection, accounting for 34%, 13% and 8% of cases, respectively, while 36% of cases were idiopathic or eosinophilic myocarditis with undefined cause ( 137 ).…”

State-of-the-Art of Endomyocardial Biopsy on Acute Myocarditis and Chronic Inflammatory Cardiomyopathy

“…It is widely accepted that viruses can induce myocarditis, both through a direct myocardial injury and/or triggering abnormal hyperactivity of the immune system against the myocardium [ 4 ••]. Autoimmune disorders are among other common causes of myocarditis, like exposure to toxic, or drugs (i.e., the new anticancer class of immune checkpoint inhibitors (ICI) [ 5 , 6 ]). A genetic susceptibility has been more recently recognized [ 7 •, 8 , 9 ].…”