Collaborative international clinical trials testing full dose anticoagulation with heparin (a blood thinner) in both moderately ill and critically ill patients has found the treatment improves outcomes and reduces the need for vital organ support such as mechanical ventilation in moderately ill patients.
The trials found heparin does not yield the same positive outcomes among critically ill patients already requiring life support, according to two international studies published on 4 August 2021 in the prestigious New England Journal of Medicine.
Senior author on the studies, Ryan Zarychanski, MD, MSc, Associate Professor of Internal Medicine at University of Manitoba and hematologist, critical care physician and senior scientist at Cancer Care 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 trial were Therapeutic Anticoagulation; 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) platform. 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 or not providing increased doses of blood thinners routinely administered to hospitalized patients would be safe and effective was unknown at that time.
"The goal 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-4 a 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 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 those not in ICU and who did not receive 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, accessible and affordable standard of care for moderately ill hospitalized Covid-19 patients around the world using a familiar drug. As such the results of the trial can be immediately applied."
Ewan Goligher, MD, PhD, Critical Care Physician and Scientist at Toronto General Hospital
Goligher is the 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.
Lead REMAP-CAP investigator in Ireland, Director of the Irish Critical Care Clinical Trials Network and Professor of Critical Care Medicine in UCD School of Medicine, Professor Alistair Nicholsaid: "Patients with Covid-19 in Irish ICUs contributed to these findings, which will allow us to improve treatments for future Covid-19 patients in Ireland and elsewhere. It is a testament to the dedication of researchers in Ireland and around the world who worked closely and collaboratively during a very difficult time in the health service that we were able to discover treatments to improve their recovery and outcomes. Our REMAP-CAP study has already discovered that steroids and IL6 receptor antaganists such as Tocilizumab improve outcomes in critically ill patients with Covid-19. Through these discoveries we are taking great strides to improve the outcomes of the sickest patients who require ICU care."
In Ireland, the trials were supported by the Health Research Board under its Irish Critical Care-Clinical Trails Network at UCD. Trial management and data coordination in Ireland was led by Alistair Nichol, Professor of Critical Care Medicine at UCD and Intensivist at St Vincent's University Hospital.
The REMAP-CAP, ACTIV-4a, and ATTACC Investigators (2021) Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19. The New England Journal of Medicine. doi.org/10.1056/NEJMoa2103417.