Full-dose blood thinners have been found to reduce the need for organ support in moderately ill COVID-19 patients, but not in critically ill patients, found a multi-platform trial reported in the New England Journal of Medicine.
"These results make for a compelling example of how important it is to stratify patients with different disease severity in clinical trials. What might help one subgroup of patients might be of no benefit, or even harmful, in another," said National Heart, Lung, and Blood Institute (NHLBI) director and cardiologist Dr Gary H. Gibbons.
Researchers have observed that in some people who died from COVID-19, blood clots had formed throughout their bodies, even in their smallest blood vessels.
Antithrombotics, which include blood thinners or anticoagulants, help prevent clot formation in certain diseases. Doctors did not know which antithrombotic drug, what dose, and at what point during the course of COVID-19, antithrombotics might be effective. To answer these urgent questions, three international partners came together and harmonised their trial protocols to study the effects of using a full, or therapeutic dose, of the blood thinner heparin versus a low, or prophylactic dose, of heparin in moderately and critically ill patients hospitalised with COVID-19.
Researchers defined moderately ill patients as those hospitalised for COVID-19 without the requirement of organ support, and critically ill patients as those hospitalised for COVID-19 requiring intensive care level of support, including respiratory and/or cardiovascular organ support.
In April 2020, hospitalised COVID-19 patients received either a low or full dose of heparin for up to 14 days after enrolment. By December 2020, interim results indicated that full-dose anticoagulation did not reduce the need for organ support and may even cause harm in critically ill patients. However, one month later, interim results indicated that full doses of heparin likely benefited moderately ill patients.
"The formal conclusions from these studies suggest that initiating therapeutic anticoagulation is beneficial for moderately ill patients and once patients develop severe COVID-19, it may be too late for anticoagulation with heparin to alter the consequences of this disease," said Dr Judith Hochman, senior associate dean for Clinical Sciences at New York University, a corresponding author of the moderately ill study and study chair of the NIH-funded trial partner Accelerating COVID-19 Therapeutic Interventions and Vaccines-4 (ACTIV-4) Antithrombotics Inpatient.
"The medication evaluated in these trials is familiar to doctors around the world and is widely accessible, making the findings highly applicable to moderately ill COVID-19 patients."
The final analysis of trial data included 1,074 critically ill and 2,219 moderately ill patients. For both moderately and critically ill patients, researchers looked at how long they were free of organ support up to 21 days after enrolment. Among moderately ill patients, researchers found that the likelihood of full-dose heparin to reduce the need for organ support compared to those who received low-dose heparin was 99%. A small number of patients experienced major bleeding, though this happened infrequently. For critically ill patients, full-dose heparin also decreased the number of major thrombotic events, but it did not reduce the need for organ support or increase their chances of leaving the hospital early after receiving treatment.
The participating trials include: Randomised, Embedded, Multi-factorial Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP- CAP) Therapeutic Anticoagulation; Antithrombotic Therapy to Ameliorate Complications of COVID-19 (ATTACC); and ACTIV-4 Antithrombotics Inpatient.
In the United States, ACTIV-4 Antithrombotics Inpatient is being led by a collaborative effort with several universities, including the University of Pittsburgh, a trial coordinating centre, and New York University, the study chairs' office and a coordinating centre. ACTIV-4 Antithrombotics Inpatient is also conducting another study to test the effects of adding an anti-platelet agent to anticoagulation.
"More work needs to be done to continue to improve outcomes in patients with COVID-19," said Dr Matthew D. Neal, the Roberta G. Simmons Associate Professor of Surgery at the University of Pittsburgh, co-author of the moderately ill study and co-chair of ACTIV-4 Antithrombotics Inpatient. "Given what we know about the type of blood clots in patients with COVID-19, testing anti-platelet agents is a particularly exciting approach."
The collaborative trials are supported by multiple international funding organisations, including the Canadian Institutes of Health Research, the National Institute for Health Research (UK), the National Health and Medical Research Council (Australia), the National Institutes of Health (US), and the PREPARE and RECOVER consortia (EU).
Study details
Therapeutic Anticoagulation with Heparin in Non-critically Ill Patients with Covid-19
Published in New England Journal of Medicine 4 August 2021
Abstract
Background
Thrombosis and inflammation may contribute to the risk of death and complications among patients with coronavirus disease 2019 (Covid-19). We hypothesised that therapeutic-dose anticoagulation may improve outcomes in non-critically ill patients who are hospitalised with COVID-19.
Methods
In this open-label, adaptive, multiplatform, controlled trial, we randomly assigned patients who were hospitalised with Covid-19 and who were not critically ill (which was defined as an absence of critical care–level organ support at enrolment) to receive pragmatically defined regimens of either therapeutic-dose anticoagulation with heparin or usual-care pharmacologic thromboprophylaxis.
The primary outcome was organ support–free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of −1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. This outcome was evaluated with the use of a Bayesian statistical model for all patients and according to the baseline d-dimer level.
Results
The trial was stopped when pre-specified criteria for the superiority of therapeutic-dose anticoagulation were met. Among 2219 patients in the final analysis, the probability that therapeutic-dose anticoagulation increased organ support–free days compared with usual-care thromboprophylaxis was 98.6% (adjusted odds ratio, 1.27; 95% credible interval, 1.03 to 1.58). The adjusted absolute between-group difference in survival until hospital discharge without organ support favouring therapeutic-dose anticoagulation was 4.0 percentage points (95% credible interval, 0.5 to 7.2).
The final probability of the superiority of therapeutic-dose anticoagulation over usual-care thromboprophylaxis was 97.3% in the high d-dimer cohort, 92.9% in the low d-dimer cohort, and 97.3% in the unknown d-dimer cohort. Major bleeding occurred in 1.9% of the patients receiving therapeutic-dose anti-coagulation and in 0.9% of those receiving thromboprophylaxis.
Conclusions
In non-critically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin increased the probability of survival to hospital discharge with reduced use of cardiovascular or respiratory organ support as compared with usual-care thromboprophylaxis
See more from MedicalBrief archives:
Experimental drug to prevent COVID-19 blood clots — Imperial College trial
Preventive blood thinners link to reduced risk of death in COVID-19
Meta-analysis: COVID-19 associated with 74% increased risk of thrombo-embolism mortality