Heparin dose sufficient to prevent COVID-19 deaths four times higher than WHO recommended dose

The anti-coagulant heparin reduces the likelihood of death from COVID-19 by 78% when administered in therapeutic doses to patients with signs of respiratory failure on admission to hospital, according to a study reported on October 14 in the British Medical Journal.

The World Health Organization (WHO) currently recommends only prophylactic use of heparin for such patients. The prophylactic dose of the drug, prescribed mainly to prevent blood clots, is only a quarter of the therapeutic dose. Prophylactic administration did not prove beneficial in the randomized clinical trial described in the article. The study involved 465 patients treated at 28 hospitals in six countries, including Brazil.

"We believe these results should change clinical practice," Elnara Negri, a co-author of the article, told Agência FAPESP. Negri is a professor and physician at São Paulo's Syrian-Lebanese Hospital and Hospital das Clínicas (HC), the hospital complex run by the University of São Paulo's Medical school (FM-USP).

The treatment is not recommended for everyone diagnosed with COVID-19. "It's only indicated for patients admitted to hospital and only under medical supervision," Negri stressed. "Anyone who takes an anti-coagulant without needing to or without proper supervision may bleed to death."

The clinical trial involved male and female patients with an average age of 60 and admitted to hospital with oxygen saturation of 93% or less. It was designed to observe the effect of heparin on outcomes of infection by SARS-CoV-2. In addition to reducing mortality, the aim was to find out whether the treatment reduced the need for non-invasive ventilation (with a high-flow catheter or oxygen mask), intubation, and admission to an intensive care unit (ICU).

The volunteers were divided into two groups. One group was given the therapeutic dose. The other served as the control group and received only the prophylactic dose. The effect on outcomes was evaluated 28 days after the drug was administered.

"We found no significant difference in terms of a need for ICU admission, non-invasive ventilation or intubation, but the mortality rate was significantly lower for the group given a therapeutic dose, and substantial bleeding, the main adverse effect observed in the study, was very low. In other words, the therapy is safe," Negri said.

The results also showed that in order for heparin to be beneficial, it must be administered between seven and 14 days after the onset of symptoms. Previous research had already shown that treatment with the anti-coagulant did not produce significant benefits when administered after ICU admission.

Benefits were observed during this stage of the disease only when heparin was injected. Orally administered heparin had no effect. "This may be because the drug also has anti-viral and anti-inflammatory effects that have been confirmed in the context of COVID-19. The good news is that the drug is cheap and available via the SUS [Brazil's national health service]," Negri said.

First evidence

Working in partnership with colleagues at FM-USP's Department of Pathology, Marisa Dolhnikoff and Paulo Saldiva, Negri was one of the first people in the world to raise the hypothesis that blood clotting disorders could be responsible for some of the most severe symptoms of COVID-19, such as respiratory failure and pulmonary fibrosis. The group published the first article in the scientific literature to describe "pathological evidence of pulmonary thrombotic phenomena in severe COVID-19" (more at: agencia.fapesp.br/33233).

"The virus enters the body via the respiratory system, and some organisms manage to contain it before it reaches the pulmonary alveoli. But when it invades the capillaries that irrigate the lungs, it starts to make holes in the endothelium [the layer of cells that line the interior of blood vessels], and this leads to blood clotting. Microthrombi are formed and prevent the passage of blood to the pulmonary structures in which gas exchange occurs," Negri explained.

Heparin helps avert this process via two mechanisms. It dissolves the microthrombi that prevent oxygen from flowing from the alveoli to the small blood vessels in the lungs, and it contributes to regeneration of the vascular endothelium.

Studies published last year show that roughly 15% of people infected by the novel coronavirus develop blood clotting disorders. "This is the population that can benefit from treatment with heparin, but timing is vitally important," Negri said.