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

Navarese et al., Cardiology Journal, doi:10.5603/CJ.a2022.0072, RECOVERY-SIRIO, NCT04351763, Sep 2022

https://c19early.org/navarese.html

RCT 215 hospitalized non-intensive care COVID-19 patients showing no significant difference in clinical improvement with amiodarone or verapamil. The trial, which aimed to assess the effects of ion channel inhibitors on COVID-19 progression, was prematurely terminated due to slow enrollment.

Important missing comments or errors? Let us know.

Study covers amiodarone and verapamil.

risk of death, 102.8% higher, RR 2.03, p = 0.33, treatment 6 of 71 (8.5%), control 3 of 72 (4.2%).

risk of mechanical ventilation, 52.1% higher, RR 1.52, p = 0.43, treatment 9 of 71 (12.7%), control 6 of 72 (8.3%).

risk of no recovery, 29.9% higher, HR 1.30, p = 0.19, treatment 71, control 72, inverted to make HR<1 favor treatment, clinical category improvement, Kaplan–Meier, day 15.

Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates

Navarese et al., 30 Sep 2022, Randomized Controlled Trial, Poland, peer-reviewed, median age 62.0, 23 authors, study period 20 May, 2020 - 13 May, 2021, trial NCT04351763 (history) (RECOVERY-SIRIO). Contact: elianonavarese@gmail.com, eliano.navarese@cm.umk.pl.

This Paper Amiodarone All

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

MD Eliano P Navarese, Przemysław Podhajski, Felicita Andreotti, Giuseppe La Torre, Robert Gajda, Adrian Radziwanowski, Małgorzata Nowicka, Paweł Bukowski, Jacek Gajda, Maciej Omyła, Piotr Lackowski, Maciej Piasecki, Małgorzata Jasiewicz, Paweł Szymański, Łukasz Pietrzykowski, Piotr Michalski, Aldona Kubica, Iwona Urbanowicz, Nicola Orsini, Max Conte, Jarosław Pinkas, Marc A Brouwer, Jacek Kubica

Cardiology Journal, doi:10.5603/cj.a2022.0072

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 ReCOVeRy-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 739 www.cardiologyjournal.org 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,) and was two-fold higher for every decrement of 100 units in nadir platelet count (HR 2.19,. By cluster analysis, thresholds of 5 mg/dL for peak CRP and 187 × 10 3 /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. (

Conflict of interest: None declared

References

Azar, Shin, Kang, Diagnosis of SARS--CoV-2 infection in the setting of the cytokine release syndrome, Expert Rev Mol Diagn, doi:10.1080/14737159.2020.1830760

Cao, Wang, Wen, A trial of lopinavir-ritonavir in adults hospitalized with severe COVID-19, N Engl J Med, doi:10.1056/NEJMoa2001282

Castaldo, Aimo, Castiglione, Safety and efficacy of amiodarone in a patient with COVID-19, JACC Case reports

Chan, Yuan, Kok, A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to--person transmission: a study of a family cluster, Lancet, doi:10.1016/S0140-6736(20)30154-9

Charlton, Pearson, Hover, Ion channels as therapeutic targets for viral infections: further discoveries and future perspectives, Viruses, doi:10.3390/v12080844

Chen, Sang, Jiang, Longitudinal hematologic and immunologic variations associated with the progression of COVID-19 patients in China, J Allergy Clin Immunol, doi:10.1016/j.jaci.2020.05.003

Dodd, Follmann, Wang, Endpoints for randomized controlled clinical trials for COVID-19 treatments, Clin Trials, doi:10.1177/1740774520939938

Gustine, Jones, Immunopathology of hyperinflammation in COVID-19, Am J Pathol, doi:10.1016/j.ajpath.2020.08.009

Hoffmann, Kleine-Weber, Schroeder, SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor, Cell, doi:10.1016/j.cell.2020.02.052

Hojyo, Uchida, Tanaka, How COVID-19 induces cytokine storm with high mortality, Inflamm Regen, doi:10.1186/s41232-020-00146-3

Hover, Foster, Barr, Viral dependence on cellular ion channels: an emerging anti-viral target?, J Gen Virol, doi:10.1099/jgv.0.000712

Jiang, Huang, Xie, The association between severe COVID-19 and low platelet count: evidence from 31 observational studies involving 7613 participants, Br J Haematol, doi:10.1111/bjh.16817

Lai, Millet, Daniel, The SARS-CoV Fusion Peptide Forms an Extended Bipartite Fusion Platform that Perturbs Membrane Order in a Calcium-Dependent Manner, J Mol Biol

Levi, Thachil, Iba, Coagulation abnormalities and thrombosis in patients with COVID-19, Lancet Haematol, doi:10.1016/S2352-3026(20)30145-9

Maggioni, Andreotti, Gervasoni, COVID-19 trials in Italy: a call for simplicity, top standards and global pooling, Int J Cardiol, doi:10.1016/j.ijcard.2020.06.043

Navarese, Musci, Frediani, Ion channel inhibition against COVID-19: A novel target for clinical investigation, Cardiol J, doi:10.5603/CJ.a2020.0090

Popat, Review and comparative study of clustering techniques, Int J Comp Sci Info Tech

Sanchis-Gomar, Lavie, Morin, Amiodarone in the COVID-19 era: treatment for symptomatic patients only, or drug to prevent infection?, Am J Cardiovasc Drugs, doi:10.1007/s40256-020-00429-7

Socio, Gidari, Sicari, National Early Warning Score 2 (NEWS2) better predicts critical Coronavirus Disease 2019 (COVID-19) illness than COVID-GRAM, a multi-centre study, Infection, doi:10.1007/s15010-021-01620-x

Stadler, Ha, Ciminale, Amiodarone alters late endosomes and inhibits SARS coronavirus infection at a postendosomal level, Am J Resp Cell Mol Biol

Tang, Bidon, Jaimes, Coronavirus membrane fusion mechanism offers a potential target for antiviral development, Antiviral Res, doi:10.1016/j.antiviral.2020.104792

Wood, Neuberg, Thompson, Outcomes of patients with hematologic malignancies and COVID-19: a report from the ASH Research Collaborative Data Hub, Blood Advances

DOI record: { "DOI": "10.5603/cj.a2022.0072", "ISSN": [ "1898-018X", "1897-5593" ], "URL": "http://dx.doi.org/10.5603/CJ.a2022.0072", "author": [ { "affiliation": [], "family": "Navarese", "given": "Eliano P.", "sequence": "first" }, { "affiliation": [], "family": "Podhajski", "given": "Przemysław", "sequence": "additional" }, { "affiliation": [], "family": "Andreotti", "given": "Felicita", "sequence": "additional" }, { "affiliation": [], "family": "La Torre", "given": "Giuseppe", "sequence": "additional" }, { "affiliation": [], "family": "Gajda", "given": "Robert", "sequence": "additional" }, { "affiliation": [], "family": "Radziwanowski", "given": "Adrian", "sequence": "additional" }, { "affiliation": [], "family": "Nowicka", "given": "Małgorzata", "sequence": "additional" }, { "affiliation": [], "family": "Bukowski", "given": "Paweł", "sequence": "additional" }, { "affiliation": [], "family": "Gajda", "given": "Jacek", "sequence": "additional" }, { "affiliation": [], "family": "Omyła", "given": "Maciej", "sequence": "additional" }, { "affiliation": [], "family": "Lackowski", "given": "Piotr", "sequence": "additional" }, { "affiliation": [], "family": "Piasecki", "given": "Maciej", "sequence": "additional" }, { "affiliation": [], "family": "Jasiewicz", "given": "Małgorzata", "sequence": "additional" }, { "affiliation": [], "family": "Szymański", "given": "Paweł", "sequence": "additional" }, { "affiliation": [], "family": "Pietrzykowski", "given": "Łukasz", "sequence": "additional" }, { "affiliation": [], "family": "Michalski", "given": "Piotr", "sequence": "additional" }, { "affiliation": [], "family": "Kubica", "given": "Aldona", "sequence": "additional" }, { "affiliation": [], "family": "Urbanowicz", "given": "Iwona", "sequence": "additional" }, { "affiliation": [], "family": "Orsini", "given": "Nicola", "sequence": "additional" }, { "affiliation": [], "family": "Conte", "given": "Max", "sequence": "additional" }, { "affiliation": [], "family": "Pinkas", "given": "Jarosław", "sequence": "additional" }, { "affiliation": [], "family": "Brouwer", "given": "Marc A.", "sequence": "additional" }, { "affiliation": [], "family": "Kubica", "given": "Jacek", "sequence": "additional" } ], "container-title": "Cardiology Journal", "container-title-short": "Cardiol J.", "content-domain": { "crossmark-restriction": false, "domain": [] }, "created": { "date-parts": [ [ 2022, 8, 1 ] ], "date-time": "2022-08-01T09:14:35Z", "timestamp": 1659345275000 }, "deposited": { "date-parts": [ [ 2022, 10, 5 ] ], "date-time": "2022-10-05T08:31:13Z", "timestamp": 1664958673000 }, "indexed": { "date-parts": [ [ 2024, 8, 23 ] ], "date-time": "2024-08-23T15:43:12Z", "timestamp": 1724427792243 }, "is-referenced-by-count": 4, "issue": "5", "issued": { "date-parts": [ [ 2022, 9, 30 ] ] }, "journal-issue": { "issue": "5", "published-online": { "date-parts": [ [ 2022, 9, 30 ] ] } }, "link": [ { "URL": "https://journals.viamedica.pl/cardiology_journal/article/viewFile/88627/68179", "content-type": "unspecified", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "3595", "original-title": [], "page": "739-750", "prefix": "10.5603", "published": { "date-parts": [ [ 2022, 9, 30 ] ] }, "published-online": { "date-parts": [ [ 2022, 9, 30 ] ] }, "publisher": "VM Media SP. zo.o VM Group SK", "reference-count": 0, "references-count": 0, "relation": {}, "resource": { "primary": { "URL": "https://journals.viamedica.pl/cardiology_journal/article/view/88627" } }, "score": 1, "short-title": [], "source": "Crossref", "subject": [], "subtitle": [], "title": "Ion channel inhibition with amiodarone or verapamil in symptomatic hospitalized nonintensive-care COVID-19 patients: The ReCOVery-SIRIO randomized trial", "type": "journal-article", "volume": "29" }

Late treatment
is less effective

Please send us corrections, updates, or comments. c19early involves the extraction of 100,000+ datapoints from thousands of papers. Community updates help ensure high accuracy. Treatments and other interventions are complementary. All practical, effective, and safe means should be used based on risk/benefit analysis. No treatment or intervention is 100% available and effective for all current and future variants. We do not provide medical advice. Before taking any medication, consult a qualified physician who can provide personalized advice and details of risks and benefits based on your medical history and situation. IMA and WCH provide treatment protocols.

Submit

Post

@CovidAnalysis

FAQ

Public domain CC0 1.0