Why did you (and your colleagues) write this paper? What was its main purpose?

SIMONA COSTANZO AND AUGUSTO DI CASTELNUOVO

A hypercoagulable condition, associated with the presence of microvascular thrombosis, has been described in patients with COVID-19 and proposed as a possible pathogenic mechanism contributing to disease progression and lethality. Therefore, the possibility to improve clinical outcomes of COVID-19 patients by commonly-used and inexpensive antithrombotic drugs has become attractive. Evidence from earlier observational studies appeared insufficient and data on the risk–benefit profile of anticoagulant therapy in COVID-19 were sparse and contradictory.

However, major guidelines promptly supported the potential beneficial effect of anticoagulants, mainly low-molecular weight heparin, in reducing mortality in COVID-19 patients.

The CORIST Collaboration was an observational study launched last March 2020, at the very beginning of the pandemic, when the clinical situation in Italy was quite dramatic and a rapid organization of a randomised controlled clinical trial was considered to be difficult, if not impossible. We therefore decided to evaluate, within the CORIST collaboration, the association between in-hospital administration of heparin and survival in a large cohort of patients with COVID-19 patients hospitalised in 30 centres all over Italy.

What are the main conclusions? 

SIMONA COSTANZO AND AUGUSTO DI CASTELNUOVO

In a large real-life sample of patients with COVID-19 hospitalised throughout Italy, heparin use, mainly low-molecular weight heparin, was associated with a 40% lower overall in-hospital mortality, independently from several possible confounders, taking into account possible differences across centres by either adjustment or stratification.

In particular, in-hospital heparin treatment was associated with lower mortality in severely ill COVID-19 patients and in those with strong coagulation activation.

What are the paper's implications? - to the public? -to medical professionals?

SIMONA COSTANZO AND AUGUSTO DI CASTELNUOVO

In a dramatic scenario as the current pandemic and in the absence of any undoubtedly effective therapy against mortality in COVID-19 patients, data from our large observational study will, on one hand, encourage doctors to use heparin to treat hospitalised patients with COVID-19 and, on the other, help trialists to elaborate better protocols for the expected RCT.

COVID-19 infection has been clinically divided into three phases: a first phase with unspecific symptoms; followed by a second phase with pulmonary impairment and inflammation activation; and a third phase, affecting only a limited number of patients, characterized by a worsening of clinical symptoms and a widespread inflammatory state. The last has been related to a process of "hypercoagulation" that could be potentially controlled by anticoagulant therapy. Therefore, heparin might be useful both in the initial phase as prophylactic treatment in patients with pneumonia, and in advanced stages to contain the thrombotic phenomena originating in the pulmonary circulation as a result of the worsening inflammatory state. Moreover, heparin, and in particular LMWH, may also exert a direct anti-inflammatory effect by inhibiting blood cell functions, such as platelet-leukocyte interactions and the exposure of cellular adhesion molecules, events recognized to play a crucial role in inflammatory responses.

In our CORIST study, heparin was effective in a way unrelated to D-dimer levels, thus suggesting that, besides its anticoagulant property, pleiotropic effects of this drug would play a major role in reducing COVID-19 mortality

Are the findings clinically significant? Should the findings change practice?

SIMONA COSTANZO AND AUGUSTO DI CASTELNUOVO

We are confident that our study, performed all-over Italy in a unique real life situation, will advance the field since it transfers a solid basis of evidence of heparin use in classical thrombotic diseases to a novel, still largely unknown infectious condition, in which both pulmonary and renal problems are considered to determine patient mortality.

In the absence of clear-cut results from controlled, randomised trials, these findings support the use of heparin in hospitalised patients with COVID-19. However, given the observational design of our study, these results should still be treated cautiously.