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20th April 2022
Heart failure (HF) is typically described as either left ventricular systolic or diastolic dysfunction and multiple studies have correlated the elevation of pro-inflammatory cytokines with a worse prognosis. In fact, increased levels of plasma interleukin-6 (IL-6) concentrations are frequently observed in patients with acute heart failure and which have prognostic value. Additionally, other work suggests that a modestly elevated CRP level upon discharge had unique long-term prognostic implications among hospitalised patients with acute heart failure. However, whether the use of anti-inflammatory agents is of value in those with heart failure is uncertain, although some evidence suggests that, despite suppression of the inflammatory markers CRP and IL-6, anti-inflammatory agents, such as infliximab, do not improve the clinical condition of patients with moderate-to-severe chronic heart failure.
Using data from the Epidemiology of Acute Heart Failure in the Emergency Departments (EAHFE) registry, researchers examined the outcomes for a subset of patients whose blood results were suggestive of inflammation, i.e., N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels > 300pg/ml and CRP levels > 5mg/ml. The team then divided patients into two groups based on whether they received systemic corticosteroids in the ED or not. For the analysis, the primary outcome was 30-day all-cause mortality with secondary outcomes including in-hospital, all-cause mortality and a 30-day post-discharge composite of ED revisits, hospitalisation or death. They also undertook a subgroup analysis based on CRP levels.
Corticosteroid use and HF outcomes
A total of 1109 patients with an overall mean age of 81.2 years (45% male) were included in the study, of whom, 121 (10.9%) received at least one IV bolus of corticosteroids during their ED stay.
In patients with CRP levels > 5mg/l and NT-proBNP levels > 300pg/ml, the cumulative risk of 30-day all-cause mortality was not significantly different to those who did not receive corticosteroids (HR = 1.26, 95% CI 0.75 – 2.09, p = 0.38).
However, as levels of CRP increased and after adjustment for the EAHFE score (which predicts short-term prognosis), the hazard ratios reduced, although remained non-significant. For example, in patients with highly elevated CRP levels (> 40mg/l and NT-proBNP levels > 300) the adjusted HR for 30-day all-cause mortality was 0.56 (95% CI 0.20 – 1.55, p = 0.27) and, while not significant, this was 7.7% lower in corticosteroid-treated patients.
The authors concluded that their analysis suggested that corticosteroid use in those with acute heart failure might have the potential to improve outcomes, especially among those with inflammatory activation, but further larger, prospective studies should be considered to assess any potential in patients with the highest degree of inflammation.
Miro O et al. Effect of systemic corticosteroid therapy for acute heart failure patients with elevated C‐reactive protein ESC Heart Fail 2022
9th December 2021
RoActemra (tocilizumab) has received approval from the EMA for the treatment of adults with severe COVID-19 and who are in receipt of systemic treatment with corticosteroids and requiring supplemental oxygen or mechanical ventilation.
Until the COVID-19 approval, RoActemra was already approved for use in the management of inflammatory conditions including rheumatoid arthritis, systemic juvenile idiopathic arthritis, juvenile idiopathic polyarthritis, giant cell arteritis and cytokine release syndrome (CRS).
Tocilizumab is a monoclonal antibody that works by inhibiting the binding of interleukin-6 (IL-6) to its receptor and in doing so, Inhibits IL-6 signal transduction of inflammatory mediators in rheumatic diseases. However, emerging evidence has indicated a role for IL-6 signalling in patients hospitalised with severe COVID-19, especially those who are critically ill.
The approval for RoActemra was based on data from three phase III trials. In COVACTA, patients hospitalised with severe COVID-19 pneumonia were randomised, 2:1 to either a single intravenous infusion of tocilizumab (at a dose of 8mg per kilogram of body weight) or placebo. The primary outcome was clinical status at day 28 on an ordinal scale which ranged from 1 (discharged or ready for discharge) to 7 (death). In the published results of the trial, tocilizumab did not result in a significantly better clinical status or lower mortality than placebo at 28 days.
In EMPACTA, hospitalised patients with COVID-19 pneumonia, not receiving mechanical ventilation, were randomised to receive standard care plus one or two doses of either tocilizumab (8 mg per kilogram of body weight intravenously) or placebo. The primary outcome was mechanical ventilation or death by day 28 and the results showed that although tocilizumab reduced the likelihood of progression to the composite outcome of mechanical ventilation or death, it did not improve survival.
In the REMDACTA study, patients were again randomised (2:1) to tocilizumab plus remdesivir or placebo plus remdesivir. The primary outcome was the time from randomisation to hospital discharge or “ready for discharge” (category 1 on a 7-category ordinal scale of clinical status) to day 28. As with the other trials, when published, the authors concluded that ‘tocilizumab plus remdesivir did not shorten time to hospital discharge or “ready for discharge” to day 28 compared with placebo plus remdesivir.’
However, despite these somewhat negative findings, a systemic review assessing the efficacy of IL-6 antagonists in patients hospitalised for COVID-19, in nearly 11,000 patients, concluded that ‘administration of IL-6 antagonists, compared with usual care or placebo, was associated with lower 28-day all-cause mortality.’
Details of the revised indicated use in COVID-19 can be found in the summary of product characteristics.