The US National Institutes of Health (NIH) ACTIV-4 Trial of blood thinners has paused enrolment of critically ill COVID-19 patients, reports MedicalBrief.
There are three clinical trial platforms working together to test the effects of full doses of anticoagulants in COVID-19 patients.The NIH paused enrolment for one group of patients.
Among critically ill COVID-19 patients requiring intensive care unit (ICU) support, therapeutic anticoagulation drugs did not reduce the need for organ support. Enrolment continues for moderately ill hospitalised COVID-19 patients in the trials.
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 paused enrolment of the most critically ill hospitalised patients with COVID-19. A potential for harm in this sub-group could not be excluded. Increased bleeding is a known complication of full-dose anticoagulation. The trials are working urgently to undertake additional analyses which will be made available as soon as possible.
At the recommendation of the oversight boards, patients who do not require ICU care at the time of enrolment will continue to be enrolled in the trial. Whether the use of full-dose compared to low-dose blood thinners leads to better outcomes in hospitalizsed patients with less COVID-19 severe disease remains a very important question. Patients who require full-dose blood thinners for another medical indication are not included in these trials.
COVID-19 is associated with significant inflammation and clinical and pathologic evidence of widespread blood clots. These trials were launched because clinicians have observed that many patients ill with COVID-19, including those who have died from the disease, formed blood clots throughout their bodies, even in their smallest blood vessels. This unusual clotting can cause multiple health complications, including lung failure, heart attack, and stroke.
Three international partners have come together in an unprecedented collaboration resulting in a multiple platform randomised controlled trial. The three international trials include: the Randomized, Embedded, Multi-factorial Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) Therapeutic Anticoagulation; Accelerating COVID-19 Therapeutic Interventions and Vaccines-4 (ACTIV-4) Antithrombotics Inpatient; and Antithrombotic Therapy to Ameliorate Complications of COVID-19 (ATTACC).
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 United States, 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 the Canadian Institutes of Health Research, the National Institute for Health Research (U.K.), the National Health and Medical Research Council (Australia), the National Institutes of Health (U.S.), and the PREPARE and RECOVER consortia (EU).
Interim data from other multiplatform trials REMAP-CAP and ATTACC informed the decision by ACTIV-4 trial leaders, but no results or changes have been announced for those other trials. The three trials "harmonise platforms" to look at therapeutic anticoagulation with heparin.
While the specifics weren't disclosed, decades of experience with heparin suggest those concerns would likely relate to excess bleeding – major bleeds, clinically relevant bleeds, and intracranial haemorrhage – or thrombocytopenia, commented Dr Behnood Bikdeli of Brigham and Women's Hospital and Harvard Medical School, on MedPage Today. Bikdeli is not part of ACTIV-4 but has been involved in COVID-19 anticoagulation consensus recommendations and other similar trials.
Observational data available so far have been all over the map, with some noting a survival advantage to therapeutic anticoagulation in the ICU, but others finding harm. A pilot trial suggested that therapeutic dosing of enoxaparin (Lovenox) improved respiratory outcomes in severe COVID-19, but was far from conclusive.
"The academic community is so split on how they've been thinking about this," he said. "Many of the hospitals made acute changes to their protocols and treatment guidelines. Some of them considered some form of intensified antithrombotic therapy as standard of care. Some of them even went above and beyond for sicker patients, considering thrombolytic therapy as standard of care."
[link url="https://www.medpagetoday.com/infectiousdisease/covid19/90351?"]Full MedPage Today report[/link]