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Randomized Controlled Trial
. 2022;29(5):739-750.
doi: 10.5603/CJ.a2022.0072. Epub 2022 Aug 1.

Ion channel inhibition with amiodarone or verapamil in symptomatic hospitalized nonintensive-care COVID-19 patients: The ReCOVery-SIRIO randomized trial

Eliano P Navarese  1   2   3 , Przemysław Podhajski  4 , Felicita Andreotti  5   6 , Giuseppe La Torre  7 , Robert Gajda  8 , Adrian Radziwanowski  4 , Małgorzata Nowicka  4 , Paweł Bukowski  8 , Jacek Gajda  8 , Maciej Omyła  8 , Piotr Lackowski  4 , Maciej Piasecki  4 , Małgorzata Jasiewicz  4 , Paweł Szymański  9 , Łukasz Pietrzykowski  4 , Piotr Michalski  4 , Aldona Kubica  10 , Iwona Urbanowicz  4 , Nicola Orsini  11 , Max Conte  12 , Jarosław Pinkas  13 , Marc A Brouwer  14 , Jacek Kubica  4
Affiliations
Randomized Controlled Trial

Ion channel inhibition with amiodarone or verapamil in symptomatic hospitalized nonintensive-care COVID-19 patients: The ReCOVery-SIRIO randomized trial

Eliano P Navarese et al. Cardiol J. 2022.

Abstract

Background: Ion channel inhibition may offer protection against coronavirus disease 2019 (COVID-19). Inflammation and reduced platelet count occur during COVID-19 but precise quantification of risk thresholds is unclear. The Recov ery-SIRIO study aimed to assess clinical effects of amiodarone and verapamil and to relate patient phenotypes to outcomes.

Methods: RECOVERY-SIRIO is a multicenter open-label 1:1:1 investigator-initiated randomized trial with blinded event adjudication. A sample of 804 symptomatic hospitalized nonintensive-care COVID-19 patients, follow-up for 28 days was initially planned.

Results: The trial was stopped when a total of 215 patients had been randomized to amiodarone (n = 71), verapamil (n = 72) or standard care alone (n = 72). At 15 days, the hazard ratio (hazard ratio [HR], 95% confidence interval [CI]) for clinical improvement was 0.77 (0.52-1.14) with amiodarone and 0.97 (0.81-1.17) with verapamil as compared to usual care. Clinically relevant associations were found between mortality or lack of clinical improvement and higher peak C-reactive protein (CRP) levels or nadir platelet count at 7, 10 and 15 days. Mortality rate increased by 73% every 5 mg/dL increment in peak CRP (HR 1.73, 95% CI 1.27-2.37) and was two-fold higher for every decrement of 100 units in nadir platelet count (HR 2.19, 95% CI 1.37-3.51). By cluster analysis, thresholds of 5 mg/dL for peak CRP and 187 × 103/mcL for nadir platelet count identified the phenogroup at greatest risk of dying.

Conclusions: In this randomized trial, neither amiodarone nor verapamil were found to significantly accelerate short-term clinical improvement. Peak CRP and nadir platelet counts were associated with increased mortality both in isolation and by cluster analysis.

Keywords: COVID-19; amiodarone; ion-channel inhibition; randomized trial; verapamil.

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Conflict of interest statement

Conflict of interest: None declared

Figures

Figure 1
Figure 1
Randomization and treatment assignment.
Figure 2
Figure 2
Clinical improvement at 15 days among patients treated with amiodarone or verapamil versus usual care alone; A. Kaplan-Meier curves of the time to clinical improvement in the intention-to-treat population; B. Distribution of clinical status according to the percentage of clinical categories; CI — confidence interval; HR — hazard ratio.
Figure 3
Figure 3
A. Mortality hazard ratios (HRs) according to peak C-reactive protein (CRP). Data were fitted with a restricted cubic spline Cox regression model. The background histograms in light blue represent the percent of density distribution of peak CRP in the study population. Heavy central lines represent HRs with shaded ribbons denoting 95% confidence intervals. The value of 1 (median) served as reference value in presenting the estimated mortality HRs; B. Mortality HRs according to nadir platelet count. Data were fitted with a restricted cubic spline Cox regression model. The background histograms in light blue represent the percent of density distribution of nadir platelet count in the study population. Heavy central lines represent HRs with shaded ribbons denoting 95% confidence intervals. The value of 250 (median) served as reference value in presenting the estimated mortality HRs.
Figure 4
Figure 4
A. Violin plots of peak C-reactive protein (CRP) values and CRP levels at 7, 10 and 15 days after randomization in patients who survived or died during the study. The width of each region corresponds to the frequency of data points in each part of the violin. Densities are accompanied by an overlaid box plot to provide additional information. The circle denotes the median and the box limits the 25th and 75th percentiles; B. Violin plots of nadir platelet count values and platelet counts at 7, 10 and 15 days after randomization in patients who survived or died during the study. The width of each region corresponds to the frequency of data points in each part of the violin. Densities are accompanied by an overlaid box plot to provide additional information. The circle denotes the median and the box limits the 25th and 75th percentiles.
Figure 5
Figure 5
A. Kaplan-Meier mortality curves of patients belonging to 4 distinct biomarker phenotypes generated by cluster analysis. Patient median values of peak C-reactive protein (CRP) and nadir platelet count are shown stratified by phenogroup; B. Algorithm plot of the optimal number of clusters using the sum of squares method. The location of a bend (knee) in the plot is generally considered an indicator of the appropriate number of clusters; PLT — platelet count.
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