In large clinical trial conducted worldwide, full dose anti-coagulation treatments given to moderately ill patients hospitalised for COVID-19 reduced the requirement of vital organ support – such as the need for ventilation. A trend in possible reduction of mortality was also observed and is being further studied. With large numbers of COVID-19 patients requiring hospitalisation, these outcomes could also help reduce the overload on intensive care units around the world.
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 hospitalised patients would be safe and effective was unknown at that time.
Three clinical trial platforms spanning five continents in more than 300 hospitals have been working together to test whether there is a greater benefit of full doses of heparin to treat moderately ill hospitalised adults with COVID-19 compared to the lower heparin dose typically administered to prevent blood clots in hospitalised patients. Moderately ill patients are those not in intensive care and who did not receive organ support such as mechanical ventilation at trial enrolment.
Based on the interim results of more than 1,000 moderately ill patients admitted to hospital, findings showed that full doses of blood thinners, in addition to being safe, were superior to the doses normally given to prevent blood clots in hospitalised patients – with regard to the primary endpoint which is the need for ventilation or other organ supportive interventions. The trial investigators are now working as fast as possible to make the full results of the study available so clinicians can make informed decisions about treating their COVID-19 patients.
As is normal for clinical trials, these trials are overseen by independent boards that routinely review the data and are composed of experts in ethics, biostatistics, clinical trials, and blood clotting disorders. Informed by the deliberations of these oversight boards, all the trial sites have stopped enrolment.
However, research questions remain about how to further improve the clinical care of COVID-19 patients. This adaptive protocol has been designed to allow different drugs to be started, stopped or combined during the study in response to emerging scientific data. This approach enables the rapid testing of additional agents without compromising safety and the study will evolve accordingly.
The trial results complement the group’s findings announced in December that routine use of full-dose anti-coagulation when started in the ICU in critically ill COVID-19 patients was not beneficial and may have been harmful in some patients.
The three international trials include: the Randomised, Embedded, Multi-factorial Adaptive Platform Trial for Community-Acquired Pneumonia (RAMAP-CAP) Therapeutic Anticoagulation; Accelerating COVID-19 Therapeutic Interventions and Vaccines-4 Antithrombotics Inpatient; and Antithrombotic Therapy to Ameliorate Complications of COVID-19.
The trials, which span four continents have the common goal of assessing the benefit of full doses of blood thinners to treat moderately ill or critically ill adults hospitalised for COVID-19, compared to a lower dose often used to prevent blood clots in hospitalised patients.
To meet the challenge of this pandemic, investigators worldwide joined forces to answer this question as rapidly as possible. In the US, the ACTIV-4 trial is being led by a collaborative effort with several universities, including the University of Pittsburgh and New York University, New York City.
The trials are supported by multiple international funding organisations including Canadian Institutes of Health Research (CAN), the National Institutes of Health’s National Heart, Lung, and Blood Institute (US), the Translational Breast Cancer Research Consortium and the University of Pittsburgh Medical Centre Learning While Doing Program (US), the LifeArc Foundation, National Institutes of Health Research (UK), National Health and Medical Research Council (AUS), Minderoo Foundation (AUS), and the PREPARE and RECOVER consortia (EU).
Commenting on the NIH report, Dr Amesh Adalja an infectious disease physician and senior scholar at Johns Hopkins University said: “It appears that there's a window of time – before ICU admission – in which full dose anticoagulation is beneficial. This illustrates the nuanced treatment that is needed for COVID-19 based on the severity and phase of illness.”
Forbes reports that during the early months of the pandemic, it was not uncommon for health care providers to place patients on protective or prophylactic doses of anticoagulants (as opposed to full-dose) upon admission to the hospital. Anticoagulants such as low molecular weight heparin or unfractionated heparin, reduce the risk for forming blood clots, a common and potentially deadly condition that became quite evident during the early months of treating patients with COVID-19.
South Africa’s Health Department has issued a warning against the treatment of critically ill COVID-19 patients using high-dosage blood thinners. The Times reports that the department cited evidence from a large randomised controlled clinical trial which was a collaborative effort between three international groups. It revealed that high-dose, compared to low-dose blood thinners, did not help critically ill ICU patients.
“The clinical trial design is strong and the National Essential Medicines List subcommittee on COVID-19 recommends against the use of high-dose blood thinners in critically ill patients with COVID-19.
According to a report by the NIH, the clinical trial has been halted for critically ill COVID-19 patients in intensive care but is continuing for moderately ill patients.
The Times quotes the NIH as saying the trial was launched after clinicians observed that COVID-19 patients, including ones who died, formed blood clots throughout their bodies. This unusual clotting can result in a number of health complications including stroke, heart attack and lung failure.
[link url="https://www.nih.gov/news-events/news-releases/full-dose-blood-thinners-decreased-need-life-support-improved-outcome-hospitalized-covid-19-patients"]NIH material[/link]
[link url="https://www.remapcap.org/"]REMAP-CAP trial[/link]
[link url="https://www.clinicaltrials.gov/ct2/show/NCT04372589"]ATTACC trial[/link]
[link url="https://www.forbes.com/sites/robertglatter/2021/01/23/full-dose-blood-thinners-reduced-need-for-respiratory-support-and-improved-outcomes-in-non-icu-covid-19-patients-study-finds/?sh=a60edea66964"]Full Forbes report (Open access)[/link]
[link url="https://www.timeslive.co.za/news/south-africa/2021-01-20-high-dosage-blood-thinners-may-harm-critically-ill-covid-19-patients-health-department-warns/"]Full report in The Times (Open access)[/link]