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The Efficacy of the Mineralcorticoid Receptor Antagonist Canrenone In Journal of Clinical Medicine Article The Efficacy of the Mineralcorticoid Receptor Antagonist Canrenone in COVID-19 Patients 1,2, , 3, , 4 1 2 Marco Vicenzi * y, Massimiliano Ruscica * y , Simona Iodice , Irene Rota , Angelo Ratti , Roberta Di Cosola 2, Alberto Corsini 3,5, Valentina Bollati 4 , Stefano Aliberti 6,7 and Francesco Blasi 6,7 1 Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Cardiovascular Disease Unit, Internal Medicine Department, 20122 Milan, Italy; [email protected] 2 Dyspnea Lab, Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy; [email protected] (A.R.); [email protected] (R.D.C.) 3 Department of Pharmacological and Biomolecular Science, University of Milan, 20133 Milan, Italy; [email protected] 4 EPIGET Lab, Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy; [email protected] (S.I.); [email protected] (V.B.) 5 IRCCS Multimedica, Sesto San Giovanni, 20099 Milan, Italy 6 Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan, Italy; [email protected] (S.A.); [email protected] (F.B.) 7 Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Internal Medicine Department, Respiratory Unit and Cystic Fibrosis Adult Center, 20122 Milan, Italy * Correspondence: [email protected] (M.V.); [email protected] (M.R.); Tel.: +39-02-5032-0512 (M.V.); +39-02-5031-8220 (M.R.) These authors contributed equally to this work. y Received: 19 August 2020; Accepted: 9 September 2020; Published: 11 September 2020 Abstract: Background: In COVID-19 patients, aldosterone via angiotensin-converting enzyme-2 deregulation may be responsible for systemic and pulmonary vasoconstriction, inflammation, and oxidative organ damage. Aim: To verify retrospectively the impact of the mineralcorticoid receptor antagonist canrenone i.v. on the need of invasive ventilatory support and/or all-cause in-hospital mortality. Methods: Sixty-nine consecutive COVID-19 patients, hospitalized for moderate to severe respiratory failure at Fondazione Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca’ Granda Ospedale Maggiore Policlinico of Milan, received two different therapeutic approaches in usual care according to the personal skills and pharmacological management experience of the referral medical team. Group A (n = 39) were given vasodilator agents or renin–angiotensin–aldosterone system (RAAS) inhibitors and group B (n = 30) were given canrenone i.v. Results: Among the 69 consecutive COVID-19 patients, those not receiving canrenone i.v. (group A) had an event-free rate of 51% and a survival rate of 64%. Group B (given a mean dose of 200 mg/q.d. of canrenone for at least two days of continuous administration) showed an event-free rate of 80% with a survival rate of 87%. Kaplan–Meier analysis for composite outcomes and mortality showed log rank statistics of 0.0004 and 0.0052, respectively. Conclusions: The novelty of our observation relies on the independent positive impact of canrenone on the all-cause mortality and clinical improvement of COVID-19 patients ranging from moderate to severe diseases. Keywords: COVID-19; angiotensin-converting enzyme-2; renin–angiotensin–aldosterone system; mineralcorticoid receptor antagonist; aldosterone; canrenone J. Clin. Med. 2020, 9, 2943; doi:10.3390/jcm9092943 www.mdpi.com/journal/jcm J. Clin. Med. 2020, 9, 2943 2 of 10 1. Introduction Since early December 2019, when the first pneumonia cases of unknown origin were identified in Wuhan (China), almost 11.5 million people across the globe have contracted severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). As of 31 August, SARS-CoV-2 has led to 852,758 deaths worldwide [1]. Despite the spread of this global pandemic and the high volume of clinical trials launched, no consensus in a standardized treatment has been reached yet [2,3]. The foremost hypotheses describing the pathway through which SARS-CoV-2 enters the cells is related to the involvement of angiotensin-converting enzyme-2 (ACE2). Although this enzyme has been described as the receptor for coronaviruses [4], upregulation of ACE2 due to ACE inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) has not been consistently demonstrated in human and animal studies (reported in [5]). ACE2 serves a counterbalancing role in the renin–angiotensin–aldosterone system (RAAS), i.e., it cleaves away (i) phenylalanine from angiotensin (Ang) II, converting it to Ang-(1-7), and (ii) leucine from Ang I, converting it to Ang-(1-9). SARS-CoV-2 infection appears to downregulate ACE2, possibly making the enzyme unable to exert protective effects in organs, e.g., a cardioprotective effect [6]. Indeed, besides coronavirus infections, potentially deleterious effects of RAAS have been reported in heart and lung and medical conditions such as hypertension, heart failure, and obesity [7]. Recent evidence from our group and others shows that progressive activation of the Ang II/angiotensin type 1 receptor (AT1R) axis, along with the final effector—aldosterone—may be responsible for systemic and pulmonary vasoconstriction, inflammation, and oxidative organ damage [8–10]. However, in COVID-19 infections, the role of aldosterone has not been disentangled alongside consideration of the beneficial effects observed from anti-aldosterone and RAAS blockers under experimental conditions of pulmonary diseases [11]. In line with the findings that aldosterone levels are associated with severe clinical outcomes in COVID-19 patients [12], we postulated the hypothesis that mineralcorticoid receptor antagonist (MRA) could have a beneficial effect on RAAS activation during SARS-CoV-2 infection. Thus, the present study aimed to verify, in COVID-19 patients, the impact of canrenone i.v. on the need for invasive ventilatory support and/or all-cause in-hospital mortality. 2. Experimental Section 2.1. Population Description, Treatments, and Biochemical Evaluation In this retrospective study (CARDIOVID-19, ID 1676), a series of 69 consecutive patients, enrolled in COVID-19 registry network was considered. All patients were hospitalized for severe respiratory failure due to SARS-CoV-2 infection and were cared for at the Cardiorespiratory Sub-Intensive Unit of Fondazione IRCCS Ca’ Granda Policlinico Hospital of Milan. All patients received usual care treatment according to local protocols (hydroxychloroquine, lopinavir/ritonavir, anakinra, and methylprednisone). However, according to the referral physicians’ experience and their skills in pharmacological management, once arterial hypertension (systolic pressure 140 mmHg or diastolic ≥ pressure 90 mmHg) and/or hypokalemia ([K+] <4.0 mmol/L) were manifested [9], patients could have ≥ received anti-hypertensive agents and potassium supplementation per os or i.v. (group A) or canrenone i.v. associated with anti-hypertensive agents, if necessary (group B). Thus, the choice of treatment was not based on a randomized design and the experimental groups were composed a posteriori. Before treatment and during hospitalization, blood pressure, the partial pressure of oxygen to inspiratory fraction of oxygen ratio (PaO2/FiO2), and alveolar–arterial oxygen gradient (DA-aO2) were recorded. C-reactive protein (CRP), interleukin-6 (IL-6), D-dimer, and ferritin were determined by blood sample collection during routine laboratory analysis. Composite outcomes as invasive ventilatory support and/or all-cause in-hospital mortality were considered during in-hospital follow-up. J. Clin. Med. 2020, 9, 2943 3 of 10 2.2. Statistical Method For normally-distributed demographics and clinical characteristics, data were expressed as the mean and standard deviation; otherwise, they were expressed as the median and interquartile range. Frequencies and percentages were calculated for categorical variables. The differences between the two groups defined as receiving or not receiving canrenone i.v. were compared using Pearson’s chi-square test or Fisher’s exact test for categorical data, or Welsch’s t-test or Mann–Whitney’s U-test for continuous variables, as appropriate. The effect size of MRA treatment was evaluated with Cohen’s d for unequal group sizes. Survival time was calculated starting at the date of hospitalization until the date of the first occurrence of the endpoint (i.e., invasive ventilator support or all-cause in-hospital mortality); in the presence of both events, the latter date was the date of the first event. For each survival outcome, data were censored at the date of hospital discharge for patients who did not experience the events of interest during their follow-up. We compared survival curves for mortality and composite endpoint using Kaplan–Meier estimates and tested statistical significance using the log rank test. Univariate and multivariate Cox proportional hazard models were used to evaluate the estimate of the hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between all variables and the two survival endpoints. Variables that were associated with composite outcome or death (two-sided p-value <0.05) in the univariate analysis were included in the multivariate Cox proportional hazards models. A two-sided p-value <0.05 was considered to be significant. We reported two models for the analyses of the mortality and composite endpoints: model 1: All of the significant variables in the univariate analysis were included as covariates, plus gender—a known risk factor for lethality [13]; model
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