In-perspective: the ARAMIS double-blind randomized placebo-controlled trial of anakinra for the treatment of acute myocarditis

Abstract

Acute myocarditis is an inflammatory condition of the myocardium that in its most severe manifestation can result in fulminant presentations with life-threatening dysrhythmias and cardiogenic shock.1 There are few data to guide evidence-based management of this often-morbid acute cardiovascular illness. Common immunosuppressive therapies, such as corticosteroids, cyclosporine A, azathioprine, and immunoglobulin, are not recommended due to neutral or minimal effects in clinical trials among patients with acute or chronic myocarditis.2,3 Blockade of interleukin-1β, a crucial step in the NLRP3 inflammasome pathway, has favourable effects in other inflammatory non-cardiac and cardiac conditions.4 Moreover, translational research has pointed to a central role of the inflammasome in the pathobiology of acute myocarditis. Therefore, it was rational to study the potential role of anakinra, a recombinant non-glycosylated form of human interleukin-1 receptor antagonist that blocks the action of both IL-1α and IL-1β, in acute myocarditis.5 The aim of the Anakinra vs. placebo double-blind, Randomized controlled trial for the treatment of Acute MyocarditIS’ (ARAMIS) trial (ClinicalTrials.gov identifier: NCT03018834) was to investigate the efficacy and safety of anakinra for the treatment of acute myocarditis through 28 days after hospital discharge.6 The ARAMIS trial was a phase 2b multicenter, double-blind, randomized, and placebo-controlled trial.6 Eligible patients with chest pain due to suspected acute myocarditis, confirmed by cardiac magnetic resonance (CMR) imaging and serum cardiac troponin levels, were randomized within 72 h of hospitalization in a 1:1 fashion to anakinra 100 mg subcutaneously once daily during the hospitalization (up to 14 days) or matched placebo. The primary endpoint was the number of days alive free of any myocarditis complications, defined as the presence of ventricular arrhythmia, hospitalization for heart failure, chest pain requiring medication, or occurrence of ventricular dysfunction (defined as left ventricular ejection fraction <50%), from randomization to 28 days after hospital discharge.6 Adult patients with a diagnosis of acute myocarditis were eligible. The diagnosis of acute myocarditis was based on the presence of acute symptoms (chest pain, dyspnoea, palpitations, shock, or sudden death), elevated cardiac troponin >1.5x the upper limit of normal, and the presence of original Lake Louise criteria on CMR imaging.6 Additional selected inclusion criteria included: age ≥18 years; the presence of normal coronary arteries on angiography or on coronary computed tomography in patients aged ≥40 years or in the presence of risk factors or previous cardiovascular disease. Selected exclusion criteria: Presence of coronary artery disease; clinical suspicion or evidence of any of the following: COVID-19 associated myocarditis, chronic inflammatory or autoimmune disease; antiphospholipid antibodies; Lyme disease; trypanosomiasis diseases; myositis; sarcoidosis; giant-cell myocarditis; tuberculosis; and infection with human immunodeficiency virus, hepatitis B virus or hepatitis C virus; suspected drug-induced myocarditis; malignancy; renal failure (estimated creatinine clearance <30 mL/min); Child-Pugh Class C hepatic impairment. All patients were to be treated with standard of care with beta-blockers and ACE inhibitors. The investigators considered a priori that an augmentation of >1.5 days free from myocarditis complication would be clinically meaningful. They estimated that the inclusion of 60 patients in each group would provide 80% power to demonstrate a 1.5-day difference between the two groups at a 5% two-sided significance level. The trial was funded by a research grant from the French Ministry of Health, Programme Hospitalier de Recherche Clinique (PHRC) 2015, and ACTION Coeur.6 A total of 120 patients were randomized across six centres in France and 117 were analysed. The median age of the population was 28 years and the majority (∼90%) were men. Notably, most participants presented with chest pain and ST-elevation (65%) in the absence of other severe manifestations of myocarditis. The median ejection fraction by echo was 60% with only ∼10% of participants with an EF < 50%. The median duration of study therapy was only 2 days (25th, 75th percentiles: 1, 3 days). There was only 1 crossover from placebo to anakinra. Follow-up was complete. Overall, the rate of the composite endpoint of myocarditis complications occurred in 13.7% of patients. However, there were no heart failure events and only one patient with ventricular arrhythmia in each group, with the majority of events consisting of chest pain requiring medication or a modest decrease in ejection fraction. The primary endpoint was 30 days (30–32 days) alive without a complication of myocarditis among patients treated with anakinra and 31 days (30–32 days) among patients treated with placebo (P = 0.168). The proportion of patients with serious adverse events within 28 days after discharge was 12.1% in the anakinra group and 10.2% in the placebo group, with no significant difference between groups (Odds ratio 1.21; 95% confidence interval 0.37–3.94). No severe infections were observed. ARAMIS is the largest randomized therapeutic study in patients with acute myocarditis, reflecting the limited evidence available in this field. Execution of this pragmatic, academically sponsored trial demonstrated the feasibility of conducting trials of acute myocarditis with diagnosis based on cardiac troponin and CMR. A very short course of anakinra during the hospitalization appeared safe but did not reduce myocarditis complications as assessed in this trial. The trial was well-designed and executed. Nevertheless, it was designed with relatively low statistical power (80%) with a very broad set of complications contributing to the endpoint. Moreover, because of the low risk of the population enrolled in the trial, severe complications were infrequent. In this context, with the short duration of therapy in the population that was studied, there was no signal of benefit to suggest that a slightly larger sample size would have resulted in a different conclusion. It is reasonable to consider additional studies with larger sample size and with different selection criteria, including a focus on higher-risk patients such as those with acute heart failure or cardiogenic shock. Such trials are ongoing (e.g. ClinicalTrials.gov Identifier: NCT05150704). In addition, because the causes of myocarditis are diverse, it is possible that selection of patients with more narrow aetiological profile could be important to the opportunity for a beneficial effect of specific anti-inflammatory therapies. Such personalization of therapy for acute myocarditis may be necessary to achieve optimal outcomes but will require validation of such a hypothesis in future studies. None declared.

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