Thromb Haemost 2021; 121(08): 1054-1065
DOI: 10.1055/a-1347-6070
Coagulation and Fibrinolysis

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

Augusto Di Castelnuovo**
1   Mediterranea Cardiocentro, Napoli, Italy
,
Simona Costanzo**
2   Department of Epidemiology and Prevention, IRCCS Neuromed, Pozzilli, Isernia, Italy
,
Andrea Antinori
3   UOC Immunodeficienze Virali, National Institute for Infectious Diseases “L. Spallanzani,” IRCCS, Rome, Italy
,
Nausicaa Berselli
4   Section of Public Health, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy
,
Lorenzo Blandi
5   Università di Pavia, Pavia, Italy
,
Marialaura Bonaccio
2   Department of Epidemiology and Prevention, IRCCS Neuromed, Pozzilli, Isernia, Italy
,
Roberto Cauda
6   Fondazione Policlinico Universitario A, Gemelli IRCCS, Rome, Italy
7   Dipartimento di Sicurezza e Bioetica Sede di Roma, Università Cattolica del Sacro Cuore, Rome, Italy
,
Giovanni Guaraldi
8   Infectious Disease Unit, Department of Surgical, Medical, Dental and Morphological Sciences, University of Modena and Reggio Emilia, Modena, Italy
,
Lorenzo Menicanti
9   IRCCS Policlinico San Donato, San Donato, Milanese (MI), Italy
,
Marco Mennuni
10   University of Eastern Piedmont, Maggiore della Carità Hospital, Novara, Italy
,
Giustino Parruti
11   Department of Infectious Disease, Azienda Sanitaria Locale (AUSL) di Pescara, Pescara, Italy
,
Giuseppe Patti
10   University of Eastern Piedmont, Maggiore della Carità Hospital, Novara, Italy
,
Francesca Santilli
12   Department of Medicine and Aging, Clinica Medica, “SS. Annunziata” Hospital and University of Chieti, Chieti, Italy
,
Carlo Signorelli
13   School of Medicine, Vita-Salute San Raffaele University, Milan, Italy
,
Alessandra Vergori
14   Department of HIV/AIDS, National Institute for Infectious Diseases “Lazzaro Spallanzani”-IRCCS, Rome, Italy
,
Pasquale Abete
15   Dipartimento di Scienze Mediche Traslazionali, Università degli studi di Napoli “Federico II,” Napoli, Italy
,
Walter Ageno
16   Department of Medicine and Surgery, University of Insubria, Varese, Italy
,
Antonella Agodi
17   Department of Medical and Surgical Sciences and Advanced Technologies “G.F. Ingrassia,” University of Catania; AOU Policlinico “G. Rodolico - San Marco,” Catania, Italy
,
Piergiuseppe Agostoni
18   Centro Cardiologico Monzino IRCCS, Milan, Italy
19   Section of Cardiovascular, Department of Clinical Sciences and Community Health, University of Milano, Milan, Italy
,
Luca Aiello
20   UOC, Anestesia e Rianimazione, Dipartimento di Chirurgia Generale Ospedale Morgagni-Pierantoni, Forlì, Italy
,
Samir Al Moghazi
21   UOC Infezioni Sistemiche dell'Immunodepresso, National Institute for Infectious Diseases L. Spallanzani, IRCCS, Rome, Italy
,
Rosa Arboretti
22   Department of Civil Environmental and Architectural Engineering, University of Padova, Padova, Italy
,
Marinella Astuto
23   Department of General Surgery and Medical-Surgical Specialties, University of Catania, U.O. Anestesia, Rianimazione 1. P.O. “G. Rodolico,” AOU Policlinico “G. Rodolico - San Marco,” Catania, Italy
,
Filippo Aucella
24   Fondazione I.R.C.C.S “Casa Sollievo della Sofferenza,” San Giovanni Rotondo, Foggia, Italy
,
Greta Barbieri
25   Department of Surgical, Medical and Molecular Medicine and Critical Care, Azienda Ospedaliera Universitaria Pisana, University of Pisa, Pisa, Italy
,
Alessandro Bartoloni
26   Department of Experimental and Clinical Medicine, University of Florence and Azienda Ospedaliero-Universitaria Careggi, Firenze, Italy
,
Paolo Bonfanti
27   UOC Malattie Infettive, Ospedale San Gerardo, ASST Monza, Monza, Italy
28   School of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy
,
Francesco Cacciatore
15   Dipartimento di Scienze Mediche Traslazionali, Università degli studi di Napoli “Federico II,” Napoli, Italy
,
Lucia Caiano
16   Department of Medicine and Surgery, University of Insubria, Varese, Italy
,
Laura Carrozzi
29   Cardiovascular and Thoracic Department, Azienda Ospedaliero-Universitaria Pisana and University of Pisa, Pisa, Italy
,
Antonio Cascio
30   Infectious and Tropical Diseases Unit, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy
,
Arturo Ciccullo
6   Fondazione Policlinico Universitario A, Gemelli IRCCS, Rome, Italy
,
Antonella Cingolani
6   Fondazione Policlinico Universitario A, Gemelli IRCCS, Rome, Italy
7   Dipartimento di Sicurezza e Bioetica Sede di Roma, Università Cattolica del Sacro Cuore, Rome, Italy
,
Francesco Cipollone
12   Department of Medicine and Aging, Clinica Medica, “SS. Annunziata” Hospital and University of Chieti, Chieti, Italy
,
Claudia Colomba
30   Infectious and Tropical Diseases Unit, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy
,
Crizia Colombo
10   University of Eastern Piedmont, Maggiore della Carità Hospital, Novara, Italy
,
Francesca Crosta
11   Department of Infectious Disease, Azienda Sanitaria Locale (AUSL) di Pescara, Pescara, Italy
,
Gian Battista Danzi
31   Department of Cardiology, Ospedale di Cremona, Cremona, Italy
,
Damiano D'Ardes
12   Department of Medicine and Aging, Clinica Medica, “SS. Annunziata” Hospital and University of Chieti, Chieti, Italy
,
Katleen de Gaetano Donati
6   Fondazione Policlinico Universitario A, Gemelli IRCCS, Rome, Italy
,
Francesco Di Gennaro
32   Medical Direction, IRCCS Neuromed, Pozzilli, Isernia, Italy
,
Giuseppe Di Tano
31   Department of Cardiology, Ospedale di Cremona, Cremona, Italy
,
Gianpiero D'Offizi
33   UOC Malattie Infettive-Epatologia, National Institute for Infectious Diseases L, Spallanzani, IRCCS, Roma, Italy
,
Massimo Fantoni
6   Fondazione Policlinico Universitario A, Gemelli IRCCS, Rome, Italy
7   Dipartimento di Sicurezza e Bioetica Sede di Roma, Università Cattolica del Sacro Cuore, Rome, Italy
,
Francesco Maria Fusco
34   UOC Infezioni Sistemiche e dell'Immunodepresso, Azienda Ospedaliera dei Colli, Ospedale Cotugno, Napoli, Italy
,
Ivan Gentile
35   Department of Clinical Medicine and Surgery, University of Naples Federico II, Napoli, Italy
,
Francesco Gianfagna
1   Mediterranea Cardiocentro, Napoli, Italy
16   Department of Medicine and Surgery, University of Insubria, Varese, Italy
,
Elvira Grandone
24   Fondazione I.R.C.C.S “Casa Sollievo della Sofferenza,” San Giovanni Rotondo, Foggia, Italy
,
Emauele Graziani
36   Medicina Interna, Ospedale di Ravenna, AUSL della Romagna, Ravenna, Italy
,
Leonardo Grisafi
10   University of Eastern Piedmont, Maggiore della Carità Hospital, Novara, Italy
,
Gabriella Guarnieri
37   Division of Respiratory Pathophysiology, Department of Cardiologic, Thoracic and Vascular Sciences, University of Padova, Padova, Italy
,
Giovanni Larizza
38   COVID-19 Unit, EE Ospedale Regionale F. Miulli, Acquaviva delle Fonti, Bari, Italy
,
Armando Leone
39   UOC di Pneumologia, P.O. San Giuseppe Moscati, Taranto, Italy
,
Gloria Maccagni
31   Department of Cardiology, Ospedale di Cremona, Cremona, Italy
,
Ferruccio Madaro
38   COVID-19 Unit, EE Ospedale Regionale F. Miulli, Acquaviva delle Fonti, Bari, Italy
,
Stefano Maitan
20   UOC, Anestesia e Rianimazione, Dipartimento di Chirurgia Generale Ospedale Morgagni-Pierantoni, Forlì, Italy
,
Sandro Mancarella
40   ASST Milano Nord, Ospedale Edoardo Bassini Cinisello Balsamo, Milan, Italy
,
Massimo Mapelli
18   Centro Cardiologico Monzino IRCCS, Milan, Italy
19   Section of Cardiovascular, Department of Clinical Sciences and Community Health, University of Milano, Milan, Italy
,
Riccardo Maragna
18   Centro Cardiologico Monzino IRCCS, Milan, Italy
19   Section of Cardiovascular, Department of Clinical Sciences and Community Health, University of Milano, Milan, Italy
,
Rossella Marcucci
26   Department of Experimental and Clinical Medicine, University of Florence and Azienda Ospedaliero-Universitaria Careggi, Firenze, Italy
,
Giulio Maresca
41   UOC di Medicina - Presidio Ospedaliero S. Maria di Loreto Nuovo. ASL Napoli 1 Centro. Napoli. Italy
,
Silvia Marongiu
42   P.O. Santissima Trinità di Cagliari, Cagliari, Italy
,
Claudia Marotta
32   Medical Direction, IRCCS Neuromed, Pozzilli, Isernia, Italy
,
Lorenzo Marra
39   UOC di Pneumologia, P.O. San Giuseppe Moscati, Taranto, Italy
,
Franco Mastroianni
38   COVID-19 Unit, EE Ospedale Regionale F. Miulli, Acquaviva delle Fonti, Bari, Italy
,
Maria Mazzitelli
43   Infectious and Tropical Diseases Unit, Department of Medical and Surgical Sciences “Magna Graecia” University, Catanzaro, Italy
,
Alessandro Mengozzi
44   Department of Clinical and Experimental Medicine, Azienda Ospedaliera Universitaria Pisana, University of Pisa, Pisa, Italy
,
Francesco Menichetti
44   Department of Clinical and Experimental Medicine, Azienda Ospedaliera Universitaria Pisana, University of Pisa, Pisa, Italy
,
Marianna Meschiari
8   Infectious Disease Unit, Department of Surgical, Medical, Dental and Morphological Sciences, University of Modena and Reggio Emilia, Modena, Italy
,
Jovana Milic
8   Infectious Disease Unit, Department of Surgical, Medical, Dental and Morphological Sciences, University of Modena and Reggio Emilia, Modena, Italy
,
Filippo Minutolo
45   Dipartimento di Farmacia, Università di Pisa, Pisa, Italy
,
Beatrice Molena
37   Division of Respiratory Pathophysiology, Department of Cardiologic, Thoracic and Vascular Sciences, University of Padova, Padova, Italy
,
Arturo Montineri
46   U.O. C. Malattie Infettive e Tropicali, P.O. “San Marco.” AOU Policlinico “G. Rodolico - San Marco,” Catania, Italy
,
Cristina Mussini
8   Infectious Disease Unit, Department of Surgical, Medical, Dental and Morphological Sciences, University of Modena and Reggio Emilia, Modena, Italy
,
Maria Musso
47   UOC Malattie Infettive-Apparato Respiratorio, National Institute for Infectious Diseases “L. Spallanzani,” IRCCS, Rome, Italy
,
Daniela Niola
12   Department of Medicine and Aging, Clinica Medica, “SS. Annunziata” Hospital and University of Chieti, Chieti, Italy
,
Anna Odone
5   Università di Pavia, Pavia, Italy
,
Marco Olivieri
48   Computer Service, University of Molise, Campobasso, Italy
,
Antonella Palimodde
42   P.O. Santissima Trinità di Cagliari, Cagliari, Italy
,
Roberta Parisi
2   Department of Epidemiology and Prevention, IRCCS Neuromed, Pozzilli, Isernia, Italy
,
Emanuela Pasi
36   Medicina Interna, Ospedale di Ravenna, AUSL della Romagna, Ravenna, Italy
,
Raffaele Pesavento
49   Clinica Medica 3, Department of Medicine – DIMED, University hospital of Padova, Padova, Italy
,
Francesco Petri
27   UOC Malattie Infettive, Ospedale San Gerardo, ASST Monza, Monza, Italy
,
Biagio Pinchera
35   Department of Clinical Medicine and Surgery, University of Naples Federico II, Napoli, Italy
,
Venerino Poletti
50   UOC Pneumologia, Dipartimento di Malattie Apparato Respiratorio e Torace, Ospedale Morgagni-Pierantoni, Forlì, Italy
51   Department of Respiratory Diseases and Allergy, Aarhus University Hospital, Aarhus, Denmark
,
Claudia Ravaglia
50   UOC Pneumologia, Dipartimento di Malattie Apparato Respiratorio e Torace, Ospedale Morgagni-Pierantoni, Forlì, Italy
,
Andrea Rognoni
10   University of Eastern Piedmont, Maggiore della Carità Hospital, Novara, Italy
,
Marco Rossato
49   Clinica Medica 3, Department of Medicine – DIMED, University hospital of Padova, Padova, Italy
,
Marianna Rossi
27   UOC Malattie Infettive, Ospedale San Gerardo, ASST Monza, Monza, Italy
,
Vincenzo Sangiovanni
34   UOC Infezioni Sistemiche e dell'Immunodepresso, Azienda Ospedaliera dei Colli, Ospedale Cotugno, Napoli, Italy
,
Carlo Sanrocco
11   Department of Infectious Disease, Azienda Sanitaria Locale (AUSL) di Pescara, Pescara, Italy
,
Laura Scorzolini
52   UOC Malattie Infettive ad Alta Intensità di Cura, National Institute for Infectious Diseases “L. Spallanzani,” IRCCS, Rome, Italy
,
Raffaella Sgariglia
40   ASST Milano Nord, Ospedale Edoardo Bassini Cinisello Balsamo, Milan, Italy
,
Paola Giustina Simeone
11   Department of Infectious Disease, Azienda Sanitaria Locale (AUSL) di Pescara, Pescara, Italy
,
Eleonora Taddei
6   Fondazione Policlinico Universitario A, Gemelli IRCCS, Rome, Italy
,
Carlo Torti
43   Infectious and Tropical Diseases Unit, Department of Medical and Surgical Sciences “Magna Graecia” University, Catanzaro, Italy
,
Roberto Vettor
49   Clinica Medica 3, Department of Medicine – DIMED, University hospital of Padova, Padova, Italy
,
Andrea Vianello
37   Division of Respiratory Pathophysiology, Department of Cardiologic, Thoracic and Vascular Sciences, University of Padova, Padova, Italy
,
Marco Vinceti
4   Section of Public Health, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy
53   Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts, United States
,
Alexandra Virano
16   Department of Medicine and Surgery, University of Insubria, Varese, Italy
,
Laura Vocciante
41   UOC di Medicina - Presidio Ospedaliero S. Maria di Loreto Nuovo. ASL Napoli 1 Centro. Napoli. Italy
,
Raffaele De Caterina
29   Cardiovascular and Thoracic Department, Azienda Ospedaliero-Universitaria Pisana and University of Pisa, Pisa, Italy
,
Licia Iacoviello
2   Department of Epidemiology and Prevention, IRCCS Neuromed, Pozzilli, Isernia, Italy
16   Department of Medicine and Surgery, University of Insubria, Varese, Italy
› Author Affiliations
Funding None.

Abstract

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.

Author Contributions

Prof. Iacoviello and Di Castelnuovo had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: Di Castelnuovo, Costanzo, Iacoviello, and De Caterina. Acquisition, analysis, or interpretation of data: all authors. Drafting of the manuscript: Iacoviello, Di Castelnuovo and Costanzo. Critical revision of the manuscript for important intellectual content: Iacoviello, Di Castelnuovo, De Caterina, and de Gaetano Donati. Statistical analysis: Costanzo, Di Castelnuovo, and Arboretti. Administrative, technical, or material support: all authors. Supervision: Iacoviello and Di Castelnuovo.


* THE COVID-19 RISK and Treatments (CORIST) collaboration.


** These authors contributed equally to this work.


Supplementary Material



Publication History

Received: 14 December 2020

Accepted: 06 January 2021

Accepted Manuscript online:
07 January 2021

Article published online:
28 February 2021

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