Collaborative international clinical trials testing full-dose anticoagulation with heparin (a blood thinner) in hospitalized patients with COVID-19 has found the treatment improves survival and reduces the need for vital organ support such as mechanical ventilation in moderately ill patients, but does not yield the same positive outcomes among critically ill patients already requiring life support, according to two Canadian-led studies published August 4 in the prestigious New England Journal of Medicine.
Senior author on the studies, Ryan Zarychanski, MD, M.Sc., 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, US 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 Patrick Lawler MD, MPH 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 Ewan Goligher, MD, PhD, 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).
Study: Therapeutic Anticoagulation in Critically Ill Patients with Covid-19 – Preliminary Report. DOI: 10.1056/NEJMoa2103417
Study: Therapeutic Anticoagulation in Non-Critically Ill Patients Hospitalized for Covid-19. DOI: 10.1056/NEJMoa2105911
ClinicalTrials.gov Identifier(s): NCT04359277, NCT02735707, NCT04505774.