A data-driven approach to identify risk profiles and protective drugs in COVID-19

A study performed in Ticino between Ente Ospedaliero Cantonale (EOC), USI Universitą della Svizzera italiana and Universitą Vita-Salute San Raffaele (UniSR, Milan, Italy) has shown how drugs against hypertension can reduce by more than 60% the risk of mortality in COVID-19 patients. The multidisciplinary study concerned 576 patients admitted to the EOC during the first wave of the epidemic, and was published in the prestigious journal Proceedings of the National Academy of Sciences (PNAS).

The study, based on data from 576 patients admitted to the EOC between March 1 and May 1, 2020 with an average age of 72 years, brought together a multidisciplinary team of clinicians and statistical researchers from the EOC, USI, and UniSR. The team work has revealed, through advanced statistical analysis of patient demographic and clinical data integration, that common anti-hypertensive therapies with renin-angiotensin system inhibitors - the so-called "RAASi" drugs - reduce by more than 60% the risk of mortality in COVID-19 patients considered at higher risk of death because they are older and/or have renal and cardiovascular diseases.

For the first time using a sophisticated statistical approach, researchers derived different risk profiles to assess the effect of drugs, analyse dependencies between different risk factors, and the impact of treatments on survival. The observed effect of RAASi is likely to be attributed to the interaction between the coronavirus and the renin-angiotensin system itself. In fact, it is known that SARS-CoV-2 enters host cells after binding to the angiotensin-converting enzyme (ACE2), whose function it "blocks", causing an excess of angiotensin and an increase in inflammation in the body, inflammation that is reduced by RAASi drugs.

EOC Chief Medical Officer and USI Faculty of Biomedical Sciences Professor Paolo Ferrari comments, "This study teaches us three important lessons. First, that a known and safe drug, commonly used and routinely prescribed by primary care physicians for the treatment of hypertensive patients, turns out to reduce mortality among people affected by COVID-19 when they are treated with these drugs. Second, that only with sophisticated biostatistical methods can one "unmask" information that would go unnoticed with a conventional approach. Third, that even in the context of our Canton Ticino, great teamwork can lead to important discoveries."

"It was immediately clear that the age and coexistent medical conditions of the patients played an important role in the progress of the COVID-19 disease," says Pietro Cippą , director of the EOC Department of Medicine who developed the study, "but the inevitable overlap of anagraphic, clinical and pharmacological elements made it extremely difficult to appreciate their impact in a complex and new context such as the one we had to face in the past months. Thanks to a precise data collection and to the application of advanced statistical methods, it was possible to develop a multifactorial risk profile and to evaluate the impact of drug therapies taken by patients before and during hospitalisation".

Clelia Di Serio , Full professor of Medical Statistics at UniSR and Adjunct professor at USI explains: "The main difficulty in analysing the data of this pandemic lies in the nature of the collection on an emergency basis, so statistical-computational techniques are needed to balance numerically unbalanced risk groups and to consider confounding effects. With researchers Federica Cugnata and Chiara Brombin, we applied a combination of non-parametric and machine learning techniques to derive the complex dependency structure between treatments, comorbidities, risk factors and clinical response. The interaction between all researchers involved allowed a thorough reading of the models, based on reproducibility principles, and confirmed generalizable results: we consider the result on RAASi protection very solid."  

Alessandro Ceschi, Head of the Istituto di Scienze Farmacologiche della Svizzera Italiana and Director of the EOC Clinical Trial Unit (EOC-CTU) and Professor at the USI Faculty of Biomedical Sciences adds: "With an innovative and rigorous approach, this study has analysed the effect of different classes of drugs on the course of COVID-19 disease in hospitalized patients, obtaining important results quickly and, as regards the protective effect observed for RAASi, contributing to shedding light on a topic controversially debated at the international level. These data may contribute to the design of randomised-controlled clinical trials that will definitively clarify the role of these drugs in COVID-19, to the benefit of patient care."

The study  is available online at >>  www.pnas.org/content/early/2020/12/09/2016877118