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Disentangling the Association of Hydroxychloroquine Treatment with Mortality in Covid-19 Hospitalized Patients through Hierarchical Clustering

Di Castelnuovo et al., Journal of Healthcare Engineering, doi:10.1155/2021/5556207 (date from preprint)
Jan 2021  
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HCQ for COVID-19
1st treatment shown to reduce risk in March 2020
*, now known with p < 0.00000000001 from 422 studies, recognized in 42 countries.
No treatment is 100% effective. Protocols combine complementary and synergistic treatments. * >10% efficacy in meta analysis with ≥3 clinical studies.
4,000+ studies for 60+ treatments.
Retrospective 4,396 hospitalized patients in Italy showing significantly lower mortality with HCQ treatment, and identifying greater efficacy for a subgroup of patients in clustering analysis.
risk of death, 40.0% lower, RR 0.60, p < 0.001, treatment 3,270, control 1,000, odds ratio converted to relative risk, multivariate Cox proportional hazards model 4, control prevalence approximated with overall prevalence.
Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates
Di Castelnuovo et al., 29 Jan 2021, retrospective, Italy, peer-reviewed, 111 authors.
This PaperHCQAll
Disentangling the Association of Hydroxychloroquine Treatment with Mortality in Covid-19 Hospitalized Patients through Hierarchical Clustering
Augusto Di Castelnuovo, Alessandro Gialluisi, Andrea Antinori, Nausicaa Berselli, Lorenzo Blandi, Marialaura Bonaccio, Raffaele Bruno, Roberto Cauda, Simona Costanzo, Giovanni Guaraldi, Lorenzo Menicanti, Marco Mennuni, Ilaria My, Giustino Parruti, Giuseppe Patti, Stefano Perlini, Francesca Santilli, Carlo Signorelli, Giulio Stefanini, Alessandra Vergori, Walter Ageno, Antonella Agodi, Piergiuseppe Agostoni, Luca Aiello, Samir Al Moghazi, Rosa Arboretti, Filippo Aucella, Greta Barbieri, Martina Barchitta, Paolo Bonfanti, Francesco Cacciatore, Lucia Caiano, Francesco Cannata, Laura Carrozzi, Antonio Cascio, Giacomo Castiglione, Arturo Ciccullo, Antonella Cingolani, Francesco Cipollone, Claudia Colomba, Crizia Colombo, Annalisa Crisetti, Francesca Crosta, Gian Battista Danzi, Damiano D'ardes, Katleen De Gaetano Donati, Francesco Di Gennaro, Giuseppe Di Tano, Gianpiero D'offizi, Francesco Maria Fusco, Carlo Gaudiosi, Ivan Gentile, Francesco Gianfagna1, Gabriele Giuliano, Emauele Graziani, Gabriella Guarnieri, Valerio Langella, Giovanni Larizza, Armando Leone, Gloria Maccagni, Federica Magni, Stefano Maitan, Sandro Mancarella, Rosa Manuele, Massimo Mapelli, Riccardo Maragna, Rossella Marcucci, Giulio Maresca, Silvia Marongiu, Claudia Marotta, Lorenzo Marra, Franco Mastroianni, Alessandro Mengozzi, Marianna Meschiari, Jovana Milic, Filippo Minutolo, Roberta Mussinelli, Cristina Mussini, Maria Musso, Anna Odone, Marco Olivieri, Antonella Palimodde, Emanuela Pasi, Raffaele Pesavento, Francesco Petri, Carlo A Pivato, Venerino Poletti, Claudia Ravaglia, Giulia Righetti, Andrea Rognoni, Marco Rossato, Ilaria Rossi, Marianna Rossi, Anna Sabena, Francesco Salinaro, Vincenzo Sangiovanni, Carlo Sanrocco, Nicola Schiano Moriello, Laura Scorzolini, Raffaella Sgariglia, Paola Giustina Simeone, Michele Spinicci, Enrica Tamburrini, Carlo Torti, Enrico Maria Trecarichi, Roberto Vettor, Andrea Vianello, Marco Vinceti, Agostino Virdis, Raffaele De Caterina, Licia Iacoviello
Journal of Healthcare Engineering, doi:10.1155/2021/5556207
e 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. ese 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. e 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 < 0.001). is 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]). ese effects survived adjustments for additional medications in use and were concordant with associations with disease severity and outcome. ese 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.
Conflicts of Interest e authors declare that they have no conflicts of interest. Authors' Contributions e raw data analyzed in the present work may be made available under approval by each local center involved in the study, in a way which does not affect patients' privacy. ADiC, RDC, and LI conceived the CORIST study. AG, ADiC, and LI conceptualized the present work. AG performed statistical analyses and wrote the first draft of the manuscript, under the supervision of ADiC and LI. All the co-authors contributed to collection, curation, and elaboration of the analyzed data, and/or to a critical review and editing of the manuscript. Di Castelnuovo and Gialluisi contributed equally to this manuscript. Supplementary Materials Figure S1 . Cross-patient dissimilarity matrix based on Gower distance. Figure S2 . Optimal number of clusters (k) to apply in the hierarchical clustering analysis. Figure S3 . Check for basic assumptions of Cox PH models. Table S1
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Late treatment
is less effective
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