Senior author on the studies (Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19 and Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19), Dr. Ryan Zarychanski, associate professor of internal medicine, University of Manitoba, and hematologist, critical care physician and senior scientist at CancerCare Manitoba, Canada, said, “We had an unprecedented opportunity to work with colleagues across Canada, the United States and around the world to test the benefit of full-dose blood thinners on hospitalized COVID-19 patients. Therapeutic heparin improved survival and decreased progression to severe disease, thus reducing the pressure on intensive care units globally.”

The participating trial platforms that contributed to the global trial were Antithrombotic Therapy to Ameliorate Complications of COVID-19 (ATTACC); Randomized, Embedded, Multi-factorial Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP); and Accelerating COVID-19 Therapeutic Interventions and Vaccines-4 (ACTIV-4) platforms. The worldwide multiplatform trial spanned five continents in over 300 hospitals to urgently test blood thinners on both sets of patients.

Early in the pandemic, physicians around the world observed increased rates of blood clots and inflammation among COVID-19 patients which affected multiple organs and led to complications such as lung failure, heart attack and stroke. Whether providing increased doses of blood thinners routinely administered to hospitalized patients would be safe and effective was unknown at that time.

“The goal [of our trials] was to improve survival and prevent patients from requiring ICU-level care or developing multi-organ failure,” said Dr. Patrick Lawler, cardiologist at the University of Toronto and Peter Munk Cardiac Centre at University Health Network, who was co-principal investigator of ATTACC, a member of the international trial steering committee for REMAP-CAP and on the ACTIV-4a protocol development committee.

In December 2020, results indicated that full dose anticoagulation with heparin was not beneficial and appeared to be harmful among critically ill patients – but the findings were completely different in non-critically ill patients. In January 2021, results of the treatment among moderately ill COVID patients showed full doses of heparin reduced the need for life support with improved survival.

Moderately ill patients are defined as hospitalized COVID-19 patients who were not in ICU and who were not receiving organ support such as mechanical ventilation at trial enrollment.

Trial data analysis involved 1,074 critically ill and 2,219 moderately ill patients. Physician investigators gauged how long participants were free of organ support up to 21 days after enrolling in the clinical trial. The investigators discovered that in moderately ill patients full-dose heparin reduced the need for organ support compared to those who received lower-dose heparin. By contrast, for critically ill patients, full-dose heparin was associated with a high probability of a worse outcome.

“Our conclusions have set a new standard of care for moderately ill hospitalized COVID-19 patients around the world using an affordable, accessible and familiar drug. As such the results of the trial can be immediately applied,” said Dr. Ewan Goligher, critical care physician and scientist at Toronto General Hospital, co-chair of the therapeutic anticoagulation domain in REMAP-CAP, co-principal investigator of the ATTACC platform.

“While the trial results will immediately impact care around the world, it is the methods of collaboration created that will be an enduring contribution of this first of a kind clinical trial that paves the way for future multiplatform clinical trial collaborations on a global scale,” said Zarychanski, senior author, chair of the ATTACC trial and the REMAP-CAP anticoagulation domain and member of the ACTIV-4a protocol development committee.

“We were excited to provide leadership on these innovative, large scale clinical trials – especially at a critical time during the COVID-19 pandemic – and our findings demonstrate the value of international multiplatform collaboration and the future possibilities for continuing to study ways to improve health outcomes in COVID-19 and possibly other diseases,” said Lawler.

“It is a testament to the dedication of researchers around the world who worked closely and collaboratively during a very difficult time that we were able to discover a treatment that can prevent patients from becoming severely ill and improve their recovery and outcomes, but our work is not over yet,” added Goligher.

“The Manitoba government is proud to have been an early supporter of this ground-breaking, life-saving research led out of our province,” Manitoba Premier Brian Pallister said. “The $5 million COVID-19 research fund announced last spring through Research Manitoba allowed local clinician-scientists to embed clinical trials into clinical care and collaborate in new ways so that their research findings can have global impact by advancing COVID-19 treatments.”

In Canada, the trials were supported by multiple international funding organizations including Canadian Institutes of Health Research (CAN), LifeArc, the Provinces of Ontario and Manitoba, the Peter Munk Cardiac Centre, the Thistledown Foundation, CancerCare Manitoba Foundation, and the Victoria General Hospital Foundation; trial management and data coordination was provided by Ozmosis Research and Socar Research. Internationally, the trials were supported by the NIH National Heart, Lung & Blood Institute, Translational Breast Cancer Research Consortium and the UPMC Learning While Doing Program (US), National Institute for Health Research (UK), National Health and Medical Research Council (AUS), Health Research Council of New Zealand, and the PREPARE and RECOVER consortia (EU).

There has been a high incidence of thrombosis, or blood clots, associated with COVID-19 infections worldwide, causing death by pulmonary embolism or stroke.

Dr. Ryan Zarychanski

“It is believed the drug heparin could help COVID-19 patients survive,” says Dr. Ryan Zarychanski, co-principal investigator of the clinical trial, and an associate professor of internal medicine and community health sciences, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba.

“As we rapidly learn more and more about COVID-19, it’s becoming clear that clotting is a very important feature of the disease,” says Dr. Ewan Goligher, an assistant professor of medicine, Interdepartmental Division of Critical Care Medicine, University of Toronto, and clinician-scientist at the Toronto General Hospital Research Institute, University Health Network.

Dr. Ewan Goligher

“High-dose blood thinners have a very high chance of saving many lives and preventing the need for intubation and mechanical ventilation for many patients.”

Heparin is an anticoagulant, or blood thinner, that is inexpensive, familiar, and widely available.

“This trial could lead to an immediately deployable clinical therapy in both high and low income settings, given its universal availability,” says Dr. Patrick Lawler, an assistant professor at the University of Toronto and clinician-scientist at the Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network.

Dr. Patrick Lawler

The project, entitled “The Antithrombotic Therapy to Ameliorate Complications of COVID-19 (ATTACC)” trial is a collaboration between co-principal investigators Drs. Zarychanski, Goligher, and Lawler.

The randomized clinical trial is set to run at 30 sites in Canada, the United States, Mexico and Brazil. More countries and sites are preparing to participate as well including the United Kingdom.

The plan is to enroll up to 3,000 people with COVID-19 who have been admitted to hospital. In a second, related trial, the team will evaluate the impact of heparin on patients requiring life support and who are in an intensive care unit.

The trial organization is a model of Canadian collaboration in a time when everyone has been called upon to work together toward a common goal. The University of Manitoba and the University Health Network are working together to make this large international trial a reality.

Dr. Zarychanski has been studying heparin for the last eight years and has led a clinical trial for the past year-and-a-half called HALO. The seven-country trial was studying heparin in people with severe infections. As evidence of coaguloapathy in COVID-19 emerged, Zarychanski brought that experience to bear in working with Lawler and Goligher to design the ATTACC trial.

“Because of the high incidence of blood clots and high levels of inflammation in COVID-19, blood thinners offer immense potential benefit for patients with COVID-19 disease,” says Zarychanski.

ATTACC was started with funding from a COVID-19 Fast Grant from the Thistledown Foundation, and an Innovation Award from the Peter Munk Cardiac Centre Innovation Committee.