Use of hydroxychloroquine in hospitalised COVID-19 patients is associated with reduced mortality: Findings from the observational multicentre Italian CORIST study

Background: Hydroxychloroquine (HCQ) was proposed as potential treatment for COVID-19. Objective: We set-up a multicenter Italian collaboration to investigate the relationship between HCQ therapy and COVID-19 in-hospital mortality. Methods: In a retrospective observational study, 3,451 unselected patients hospitalized in 33 clinical centers in Italy, from February 19, 2020 to May 23, 2020, with laboratory-confirmed SARS-CoV-2 infection, were analyzed. The primary end-point in a time-to event analysis was in-hospital death, comparing patients who received HCQ with patients who did not. We used multivariable Cox proportional-hazards regression models with inverse probability for treatment weighting by propensity scores, with the addition of subgroup analyses. Results: Out of 3,451 COVID-19 patients, 76.3% received HCQ. Death rates (per 1,000 person-days) for patients receiving or not HCQ were 8.9 and 15.7, respectively. After adjustment for propensity scores, we found 30% lower risk of death in patients receiving HCQ (HR=0.70; 95%CI: 0.59 to 0.84; E-value=1.67). Secondary analyses yielded similar results. The inverse association of HCQ with inpatient mortality was particularly evident in patients having elevated C-reactive protein at entry. Conclusions: HCQ use was associated with a 30% lower risk of death in COVID-19 hospitalized patients. Within the limits of an observational study and awaiting results from randomized controlled trials, these data do not discourage the use of HCQ in inpatients with COVID-19

Common cardiovascular risk factors and in-hospital mortality in 3,894 patients with COVID-19: survival analysis and machine learning-based findings from the multicentre Italian CORIST Study

Background and aims: There is poor knowledge on characteristics, comorbidities and laboratory measures associated with risk for adverse outcomes and in-hospital mortality in European Countries. We aimed at identifying baseline characteristics predisposing COVID-19 patients to in-hospital death. Methods and results: Retrospective observational study on 3894 patients with SARS-CoV-2 infection hospitalized from February 19th to May 23rd, 2020 and recruited in 30 clinical centres distributed throughout Italy. Machine learning (random forest)-based and Cox survival analysis. 61.7% of participants were men (median age 67 years), followed up for a median of 13 days. In-hospital mortality exhibited a geographical gradient, Northern Italian regions featuring more than twofold higher death rates as compared to Central/Southern areas (15.6% vs 6.4%, respectively). Machine learning analysis revealed that the most important features in death classification were impaired renal function, elevated C reactive protein and advanced age. These findings were confirmed by multivariable Cox survival analysis (hazard ratio (HR): 8.2; 95% confidence interval (CI) 4.6\u201314.7 for age 6585 vs 18\u201344 y); HR = 4.7; 2.9\u20137.7 for estimated glomerular filtration rate levels <15 vs 65 90 mL/min/1.73 m2; HR = 2.3; 1.5\u20133.6 for C-reactive protein levels 6510 vs 64 3 mg/L). No relation was found with obesity, tobacco use, cardiovascular disease and related-comorbidities. The associations between these variables and mortality were substantially homogenous across all sub-groups analyses. Conclusions: Impaired renal function, elevated C-reactive protein and advanced age were major predictors of in-hospital death in a large cohort of unselected patients with COVID-19, admitted to 30 different clinical centres all over Italy

Disentangling the association of hydroxychloroquine treatment with mortality in covid-19 hospitalized patients through hierarchical clustering

none111The efficacy of hydroxychloroquine (HCQ) in treating SARS-CoV-2 infection is harshly debated, with observational and experimental studies reporting contrasting results. To clarify the role of HCQ in Covid-19 patients, we carried out a retrospective observational study of 4,396 unselected patients hospitalized for Covid-19 in Italy (February–May 2020). Patients’ characteristics were collected at entry, including age, sex, obesity, smoking status, blood parameters, history of diabetes, cancer, cardiovascular and chronic pulmonary diseases, and medications in use. These were used to identify subtypes of patients with similar characteristics through hierarchical clustering based on Gower distance. Using multivariable Cox regressions, these clusters were then tested for association with mortality and modification of effect by treatment with HCQ. We identified two clusters, one of 3,913 younger patients with lower circulating inflammation levels and better renal function, and one of 483 generally older and more comorbid subjects, more prevalently men and smokers. The latter group was at increased death risk adjusted by HCQ (HR [CI95%] = 3.80[3.08-4.67]), while HCQ showed an independent inverse association (0.51[0.43-0.61]), as well as a significant influence of cluster∗HCQ interaction (p &lt; 0.001). This was driven by a differential association of HCQ with mortality between the high (0.89[0.65-1.22]) and the low risk cluster (0.46[0.39-0.54]). These effects survived adjustments for additional medications in use and were concordant with associations with disease severity and outcome. These findings suggest a particularly beneficial effect of HCQ within low risk Covid-19 patients and may contribute to clarifying the current controversy on HCQ efficacy in Covid-19 treatment.noneDi Castelnuovo A.; Gialluisi A.; Antinori A.; Berselli N.; Blandi L.; Bonaccio M.; Bruno R.; Cauda R.; Costanzo S.; Guaraldi G.; Menicanti L.; Mennuni M.; My I.; Parruti G.; Patti G.; Perlini S.; Santilli F.; Signorelli C.; Stefanini G.; Vergori A.; Ageno W.; Agodi A.; Agostoni P.; Aiello L.; Moghazi S.A.; Arboretti R.; Aucella F.; Barbieri G.; Barchitta M.; Bonfanti P.; Cacciatore F.; Caiano L.; Cannata F.; Carrozzi L.; Cascio A.; Castiglione G.; Cicullo A.; Cingolani A.; Cipollone F.; Colomba C.; Colombo C.; Crisetti A.; Crosta F.; Danzi G.B.; D'Ardes D.; de Gaetano Donati K.; Di Gennaro F.; Di Tano G.; D'Offizi G.; Fusco F.M.; Gaudiosi C.; Gentile I.; Gianfagna F.; Giuliano G.; Graziani E.; Guarnieri G.; Langella V.; Larizza G.; Leone A.; Maccagni G.; Magni F.; Maitan S.; Mancarella S.; Manuele R.; Mapelli M.; Maragna R.; Marcucci R.; Maresca G.; Marongiu S.; Marotta C.; Marra L.; Mastroianni F.; Mengozzi A.; Meschiari M.; Milic J.; Minutolo F.; Mussinelli R.; Mussini C.; Musso M.; Odone A.; Olivieri M.; Palimodde A.; Pasi E.; Pesavento R.; Petri F.; Pivato C.A.; Poletti V.; Ravaglia C.; Righetti G.; Rognoni A.; Rossato M.; Rossi I.; Rossi M.; Sabena A.; Salinaro F.; Sangiovanni V.; Sanrocco C.; Moriello N.S.; Scorzolini L.; Sgariglia R.; Simeone P.G.; Spinicci M.; Tamburrini E.; Torti C.; Trecarichi E.M.; Vettor R.; Vianello A.; Vinceti M.; Virdis A.; de Caterina R.; Iacoviello L.Di Castelnuovo, A.; Gialluisi, A.; Antinori, A.; Berselli, N.; Blandi, L.; Bonaccio, M.; Bruno, R.; Cauda, R.; Costanzo, S.; Guaraldi, G.; Menicanti, L.; Mennuni, M.; My, I.; Parruti, G.; Patti, G.; Perlini, S.; Santilli, F.; Signorelli, C.; Stefanini, G.; Vergori, A.; Ageno, W.; Agodi, A.; Agostoni, P.; Aiello, L.; Moghazi, S. A.; Arboretti, R.; Aucella, F.; Barbieri, G.; Barchitta, M.; Bonfanti, P.; Cacciatore, F.; Caiano, L.; Cannata, F.; Carrozzi, L.; Cascio, A.; Castiglione, G.; Cicullo, A.; Cingolani, A.; Cipollone, F.; Colomba, C.; Colombo, C.; Crisetti, A.; Crosta, F.; Danzi, G. B.; D'Ardes, D.; de Gaetano Donati, K.; Di Gennaro, F.; Di Tano, G.; D'Offizi, G.; Fusco, F. M.; Gaudiosi, C.; Gentile, I.; Gianfagna, F.; Giuliano, G.; Graziani, E.; Guarnieri, G.; Langella, V.; Larizza, G.; Leone, A.; Maccagni, G.; Magni, F.; Maitan, S.; Mancarella, S.; Manuele, R.; Mapelli, M.; Maragna, R.; Marcucci, R.; Maresca, G.; Marongiu, S.; Marotta, C.; Marra, L.; Mastroianni, F.; Mengozzi, A.; Meschiari, M.; Milic, J.; Minutolo, F.; Mussinelli, R.; Mussini, C.; Musso, M.; Odone, A.; Olivieri, M.; Palimodde, A.; Pasi, E.; Pesavento, R.; Petri, F.; Pivato, C. A.; Poletti, V.; Ravaglia, C.; Righetti, G.; Rognoni, A.; Rossato, M.; Rossi, I.; Rossi, M.; Sabena, A.; Salinaro, F.; Sangiovanni, V.; Sanrocco, C.; Moriello, N. S.; Scorzolini, L.; Sgariglia, R.; Simeone, P. G.; Spinicci, M.; Tamburrini, E.; Torti, C.; Trecarichi, E. M.; Vettor, R.; Vianello, A.; Vinceti, M.; Virdis, A.; de Caterina, R.; Iacoviello, L

Heparin in COVID-19 Patients Is Associated with Reduced In-Hospital Mortality: The Multicenter Italian CORIST Study *

Introduction A hypercoagulable condition was described in patients with coronavirus disease 2019 (COVID-19) and proposed as a possible pathogenic mechanism contributing to disease progression and lethality. Aim We evaluated if in-hospital administration of heparin improved survival in a large cohort of Italian COVID-19 patients. Methods In a retrospective observational study, 2,574 unselected patients hospitalized in 30 clinical centers in Italy from February 19, 2020 to June 5, 2020 with laboratory-confirmed severe acute respiratory syndrome coronavirus-2 infection were analyzed. The primary endpoint in a time-to event analysis was in-hospital death, comparing patients who received heparin (low-molecular-weight heparin [LMWH] or unfractionated heparin [UFH]) with patients who did not. We used multivariable Cox proportional-hazards regression models with inverse probability for treatment weighting by propensity scores. Results Out of 2,574 COVID-19 patients, 70.1% received heparin. LMWH was largely the most used formulation (99.5%). Death rates for patients receiving heparin or not were 7.4 and 14.0 per 1,000 person-days, respectively. After adjustment for propensity scores, we found a 40% lower risk of death in patients receiving heparin (hazard ratio = 0.60; 95% confidence interval: 0.49-0.74; E-value = 2.04). This association was particularly evident in patients with a higher severity of disease or strong coagulation activation. Conclusion In-hospital heparin treatment was associated with a lower mortality, particularly in severely ill COVID-19 patients and in those with strong coagulation activation. The results from randomized clinical trials are eagerly awaited to provide clear-cut recommendations

RAAS inhibitors are not associated with mortality in COVID-19 patients: Findings from an observational multicenter study in Italy and a meta-analysis of 19 studies

none109Objective: The hypothesis that been set forward that use of Renin Angiotensin Aldosterone System (RAAS) inhibitors is associated with COVID−19 severity. We set-up a multicenter Italian collaboration (CORIST Project, ClinicalTrials.gov ID: NCT04318418) to retrospectively investigate the relationship between RAAS inhibitors and COVID−19 in-hospital mortality. We also carried out an updated meta-analysis on the relevant studies. Methods: We analyzed 4069 unselected patients with laboratory-confirmed SARS-CoV-2 infection and hospitalized in 34 clinical centers in Italy from February 19, 2020 to May 23, 2020. The primary end-point in a time-to event analysis was in-hospital death, comparing patients who received angiotensin-converting–enzyme inhibitors (ACE[sbnd]I) or angiotensin-receptor blockers (ARB) with patients who did not. Articles for the meta-analysis were retrieved until July 13th, 2020 by searching in web-based libraries, and data were combined using the general variance-based method. Results: Out of 4069 COVID−19 patients, 13.5% and 13.3% received ACE-I or ARB, respectively. Use of neither ACE-I nor ARB was associated with mortality (multivariable hazard ratio (HR) adjusted also for COVID−19 treatments: 0.96, 95% confidence interval 0.77–1.20 and HR = 0.89, 0.67–1.19 for ACE-I and ARB, respectively). Findings were similar restricting the analysis to hypertensive (N = 2057) patients (HR = 1.00, 0.78–1.26 and HR = 0.88, 0.65–1.20) or when ACE-I or ARB were considered as a single group. Results from the meta-analysis (19 studies, 29,057 COVID−19 adult patients, 9700 with hypertension) confirmed the absence of association. Conclusions: In this observational study and meta-analysis of the literature, ACE-I or ARB use was not associated with severity or in-hospital mortality in COVID−19 patients.noneDi Castelnuovo A.; Costanzo S.; Antinori A.; Berselli N.; Blandi L.; Bonaccio M.; Cauda R.; Gialluisi A.; Guaraldi G.; Menicanti L.; Mennuni M.; Mussinelli R.; My I.; Parruti G.; Patti G.; Perlini S.; Santilli F.; Signorelli C.; Stefanini G.G.; Vergori A.; Abete P.; Ageno W.; Agostoni P.; Aiello L.; Al Moghazi S.; Arboretti R.; Aucella F.; Barbieri G.; Barchitta M.; Bartoloni A.; Bonfanti P.; Cacciatore F.; Caiano L.; Carrozzi L.; Cascio A.; Castiglione G.; Cianfrone S.; Ciccullo A.; Cingolani A.; Cipollone F.; Colomba C.; Colombo C.; Cozzi O.; Crisetti A.; Crosta F.; Danzi G.B.; D'Ardes D.; de Gaetano Donati K.; Di Gennaro F.; Di Tano G.; D'Offizi G.; Fusco F.M.; Gentile I.; Graziani E.; Guarnieri G.; Larizza G.; Leone A.; Lio V.; Lucia M.B.; Maccagni G.; Madaro F.; Maitan S.; Mancarella S.; Manuele R.; Mapelli M.; Maragna R.; Marcucci R.; Maresca G.; Marongiu S.; Marotta C.; Marra L.; Mastroianni F.; Mazzitelli M.; Mengozzi A.; Menichetti F.; Meschiari M.; Milic J.; Minutolo F.; Molena B.; Mussini C.; Musso M.; Odone A.; Olivieri M.; Palimodde A.; Pasi E.; Pesavento R.; Petri F.; Pinchera B.; Pivato C.A.; Poletti V.; Ravaglia C.; Rossato M.; Rossi M.; Sabena A.; Salinaro F.; Sangiovanni V.; Sanrocco C.; Scoppettuolo G.; Scorzolini L.; Sgariglia R.; Simeone P.G.; Trecarichi E.M.; Vettor R.; Vianello A.; Vinceti M.; Virano A.; Vocciante L.; De Caterina R.; Iacoviello L.Di Castelnuovo, A.; Costanzo, S.; Antinori, A.; Berselli, N.; Blandi, L.; Bonaccio, M.; Cauda, R.; Gialluisi, A.; Guaraldi, G.; Menicanti, L.; Mennuni, M.; Mussinelli, R.; My, I.; Parruti, G.; Patti, G.; Perlini, S.; Santilli, F.; Signorelli, C.; Stefanini, G. G.; Vergori, A.; Abete, P.; Ageno, W.; Agostoni, P.; Aiello, L.; Al Moghazi, S.; Arboretti, R.; Aucella, F.; Barbieri, G.; Barchitta, M.; Bartoloni, A.; Bonfanti, P.; Cacciatore, F.; Caiano, L.; Carrozzi, L.; Cascio, A.; Castiglione, G.; Cianfrone, S.; Ciccullo, A.; Cingolani, A.; Cipollone, F.; Colomba, C.; Colombo, C.; Cozzi, O.; Crisetti, A.; Crosta, F.; Danzi, G. B.; D'Ardes, D.; de Gaetano Donati, K.; Di Gennaro, F.; Di Tano, G.; D'Offizi, G.; Fusco, F. M.; Gentile, I.; Graziani, E.; Guarnieri, G.; Larizza, G.; Leone, A.; Lio, V.; Lucia, M. B.; Maccagni, G.; Madaro, F.; Maitan, S.; Mancarella, S.; Manuele, R.; Mapelli, M.; Maragna, R.; Marcucci, R.; Maresca, G.; Marongiu, S.; Marotta, C.; Marra, L.; Mastroianni, F.; Mazzitelli, M.; Mengozzi, A.; Menichetti, F.; Meschiari, M.; Milic, J.; Minutolo, F.; Molena, B.; Mussini, C.; Musso, M.; Odone, A.; Olivieri, M.; Palimodde, A.; Pasi, E.; Pesavento, R.; Petri, F.; Pinchera, B.; Pivato, C. A.; Poletti, V.; Ravaglia, C.; Rossato, M.; Rossi, M.; Sabena, A.; Salinaro, F.; Sangiovanni, V.; Sanrocco, C.; Scoppettuolo, G.; Scorzolini, L.; Sgariglia, R.; Simeone, P. G.; Trecarichi, E. M.; Vettor, R.; Vianello, A.; Vinceti, M.; Virano, A.; Vocciante, L.; De Caterina, R.; Iacoviello, L

Lopinavir/ritonavir and darunavir/cobicistat in hospitalized covid-19 patients: Findings from the multicenter italian corist study

109nononeBackground: Protease inhibitors have been considered as possible therapeutic agents for COVID-19 patients. Objectives: To describe the association between lopinavir/ritonavir (LPV/r) or darunavir/cobicistat (DRV/c) use and in-hospital mortality in COVID-19 patients. Study Design: Multicenter observational study of COVID-19 patients admitted in 33 Italian hospitals. Medications, preexisting conditions, clinical measures, and outcomes were extracted from medical records. Patients were retrospectively divided in three groups, according to use of LPV/r, DRV/c or none of them. Primary outcome in a time-to event analysis was death. We used Cox proportional-hazards models with inverse probability of treatment weighting by multinomial propensity scores. Results: Out of 3,451 patients, 33.3% LPV/r and 13.9% received DRV/c. Patients receiving LPV/r or DRV/c were more likely younger, men, had higher C-reactive protein levels while less likely had hypertension, cardiovascular, pulmonary or kidney disease. After adjustment for propensity scores, LPV/r use was not associated with mortality (HR = 0.94, 95% CI 0.78 to 1.13), whereas treatment with DRV/c was associated with a higher death risk (HR = 1.89, 1.53 to 2.34, E-value = 2.43). This increased risk was more marked in women, in elderly, in patients with higher severity of COVID-19 and in patients receiving other COVID-19 drugs. Conclusions: In a large cohort of Italian patients hospitalized for COVID-19 in a real-life setting, the use of LPV/r treatment did not change death rate, while DRV/c was associated with increased mortality. Within the limits of an observational study, these data do not support the use of LPV/r or DRV/c in COVID-19 patients.noneDi Castelnuovo A.; Costanzo S.; Antinori A.; Berselli N.; Blandi L.; Bonaccio M.; Bruno R.; Cauda R.; Gialluisi A.; Guaraldi G.; Menicanti L.; Mennuni M.; My I.; Parruti A.; Patti G.; Perlini S.; Santilli F.; Signorelli C.; Stefanini G.G.; Vergori A.; Ageno W.; Aiello L.; Agostoni P.; Moghazi S.A.; Arboretti R.; Aucella F.; Barbieri G.; Barchitta M.; Bartoloni A.; Bologna C.; Bonfanti P.; Caiano L.; Carrozzi L.; Cascio A.; Castiglione G.; Chiarito M.; Ciccullo A.; Cingolani A.; Cipollone F.; Colomba C.; Colombo C.; Crosta F.; Dalena G.; Dal Pra C.; Danzi G.B.; D'ardes D.; Donati K.G.; Di Gennaro F.; Di Tano G.; D'offizi G.; Filippini T.; Fusco F.M.; Gaudiosi C.; Gentile I.; Gini G.; Grandone E.; Guarnieri G.; Lamanna G.L.F.; Larizza G.; Leone A.; Lio V.; Losito A.R.; Maccagni G.; Maitan S.; Mancarella S.; Manuele R.; Mapelli M.; Maragna R.; Marra L.; Maresca G.; Marotta C.; Mastroianni F.; Mazzitelli M.; Mengozzi A.; Menichetti F.; Milic J.; Minutolo F.; Molena B.; Mussinelli R.; Mussini C.; Musso M.; Odone A.; Olivieri M.; Pasi E.; Perroni A.; Petri F.; Pinchera B.; Pivato C.A.; Poletti V.; Ravaglia C.; Rossato M.; Rossi M.; Sabena A.; Salinaro F.; Sangiovanni V.; Sanrocco C.; Scorzolini L.; Sgariglia R.; Simeone P.G.; Spinicci M.; Trecarichi E.M.; Veronesi G.; Vettor R.; Vianello A.; Vinceti M.; Visconti E.; Vocciante L.; Caterina R.D.; Iacoviello L.Di Castelnuovo, A.; Costanzo, S.; Antinori, A.; Berselli, N.; Blandi, L.; Bonaccio, M.; Bruno, R.; Cauda, R.; Gialluisi, A.; Guaraldi, G.; Menicanti, L.; Mennuni, M.; My, I.; Parruti, A.; Patti, G.; Perlini, S.; Santilli, F.; Signorelli, C.; Stefanini, G. G.; Vergori, A.; Ageno, W.; Aiello, L.; Agostoni, P.; Moghazi, S. A.; Arboretti, R.; Aucella, F.; Barbieri, G.; Barchitta, M.; Bartoloni, A.; Bologna, C.; Bonfanti, P.; Caiano, L.; Carrozzi, L.; Cascio, A.; Castiglione, G.; Chiarito, M.; Ciccullo, A.; Cingolani, A.; Cipollone, F.; Colomba, C.; Colombo, C.; Crosta, F.; Dalena, G.; Dal Pra, C.; Danzi, G. B.; D'Ardes, D.; Donati, K. G.; Di Gennaro, F.; Di Tano, G.; D'Offizi, G.; Filippini, T.; Fusco, F. M.; Gaudiosi, C.; Gentile, I.; Gini, G.; Grandone, E.; Guarnieri, G.; Lamanna, G. L. F.; Larizza, G.; Leone, A.; Lio, V.; Losito, A. R.; Maccagni, G.; Maitan, S.; Mancarella, S.; Manuele, R.; Mapelli, M.; Maragna, R.; Marra, L.; Maresca, G.; Marotta, C.; Mastroianni, F.; Mazzitelli, M.; Mengozzi, A.; Menichetti, F.; Milic, J.; Minutolo, F.; Molena, B.; Mussinelli, R.; Mussini, C.; Musso, M.; Odone, A.; Olivieri, M.; Pasi, E.; Perroni, A.; Petri, F.; Pinchera, B.; Pivato, C. A.; Poletti, V.; Ravaglia, C.; Rossato, M.; Rossi, M.; Sabena, A.; Salinaro, F.; Sangiovanni, V.; Sanrocco, C.; Scorzolini, L.; Sgariglia, R.; Simeone, P. G.; Spinicci, M.; Trecarichi, E. M.; Veronesi, G.; Vettor, R.; Vianello, A.; Vinceti, M.; Visconti, E.; Vocciante, L.; Caterina, R. D.; Iacoviello, L

RAAS inhibitors are not associated with mortality in COVID-19 patients: findings from an observational multicenter study in Italy and a meta-analysis of 19 studies

Objective: The hypothesis that been set forward that use of Renin Angiotensin Aldosterone System (RAAS) inhibitors is associated with COVID-19 severity. We set-up a multicenter Italian collaboration (CORIST Project, ClinicalTrials.gov ID: NCT04318418) to retrospectively investigate the relationship between RAAS inhibitors and COVID-19 in-hospital mortality. We also carried out an updated meta-analysis on the relevant studies. Methods: We analyzed 4,069 unselected patients with laboratory-confirmed SARS-CoV-2 infection and hospitalized in 34 clinical centers in Italy from February 19, 2020 to May 23, 2020. The primary end-point in a time-to event analysis was in-hospital death, comparing patients who received angiotensin-converting\u2013enzyme inhibitors (ACE-I) or angiotensin-receptor blockers (ARB) with patients who did not. Articles for the meta-analysis were retrieved until July 13th, 2020 by searching in web-based libraries, and data were combined using the general variance-based method. Results: Out of 4,069 COVID-19 patients, 13.5% and 13.3% received ACE-I or ARB, respectively. Use of neither ACE-I nor ARB was associated with mortality (multivariable hazard ratio (HR) adjusted also for COVID-19 treatments: 0.96, 95% confidence interval 0.77-1.20 and HR=0.89, 0.67-1.19 for ACE-I and ARB, respectively). Findings were similar restricting the analysis to hypertensive (N=2,057) patients (HR=1.00, 0.78-1.26 and HR=0.88, 0.65-1.20) or when ACE-I or ARB were considered as a single group. Results from the meta-analysis (19 studies, 29,057 COVID-19 adult patients, 9,700 with hypertension) confirmed the absence of association. Conclusions: In this observational study and meta-analysis of the literature, ACE-I or ARB use was not associated with severity or in-hospital mortality in COVID-19 patients

RAAS inhibitors are not associated with mortality in COVID-19 patients: Findings from an observational multicenter study in Italy and a meta-analysis of 19 studies

Objective: The hypothesis that been set forward that use of Renin Angiotensin Aldosterone System (RAAS) inhibitors is associated with COVID-19 severity. We set-up a multicenter Italian collaboration (CORIST Project, ClinicalTrials.gov ID: NCT04318418) to retrospectively investigate the relationship between RAAS inhibitors and COVID-19 in-hospital mortality. We also carried out an updated meta-analysis on the relevant studies.Methods: We analyzed 4069 unselected patients with laboratory-confirmed SARS-CoV-2 infection and hospitalized in 34 clinical centers in Italy from February 19, 2020 to May 23, 2020. The primary end-point in a time-to event analysis was in-hospital death, comparing patients who received angiotensin-converting-enzyme inhibitors (ACEeI) or angiotensin-receptor blockers (ARB) with patients who did not. Articles for the meta-analysis were retrieved until July 13th, 2020 by searching in web-based libraries, and data were combined using the general variance-based method.Results: Out of 4069 COVID-19 patients, 13.5% and 13.3% received ACE-I or ARB, respectively. Use of neither ACE-I nor ARB was associated with mortality (multivariable hazard ratio (HR) adjusted also for COVID-19 treatments: 0.96, 95% confidence interval 0.77-1.20 and HR = 0.89, 0.67-1.19 for ACE-I and ARB, respectively). Findings were similar restricting the analysis to hypertensive (N = 2057) patients (HR = 1.00, 0.78-1.26 and HR = 0.88, 0.65-1.20) or when ACE-I or ARB were considered as a single group. Results from the meta-analysis (19 studies, 29,057 COVID-19 adult patients, 9700 with hypertension) confirmed the absence of association.Conclusions: In this observational study and meta-analysis of the literature, ACE-I or ARB use was not associated with severity or in-hospital mortality in COVID-19 patients