It has been announced that the international trials of anticoagulants (blood thinners) have paused enrollment of critically ill COVID-19 patients, however enrollment will continue for patients who do not require ICU care.
Prof Martin Landray, Professor of Medicine & Epidemiology, Nuffield Department of Population Health, University of Oxford, said:
“In the hospital setting, blood thinners are commonly used in low doses to prevent blood clots forming (for example after surgery) and in high doses to treat them if they have done so (usually for deep vein thrombosis and pulmonary embolism).
“Over the past 9 months, there have been many reports that COVID-19 is associated with an increased risk of blood clotting and that this may be a significant contributor to the worst consequences of this disease, including respiratory failure, the need for a mechanical ventilator, and death.
“Consequently, many have advocated that blood thinners such as heparin should be used in high doses for patients with COVID and in some hospitals this has become common practice. However, without properly evaluating the effects through randomised trials it is impossible to know whether, in the context of COVID, the proposed benefits of reducing clotting outweigh the risks of increased bleeding.
“As we have seen many times in this pandemic, randomised clinical trials are essential for establishing the difference between a treatment that ‘should’ work and one which we know actually does so. Does the theory translate into practice? And on balance, are patients more likely to do well if they receive high doses of blood thinners or if they do not?
“The researchers of all 3 trials mentioned in this statement (REMAP-CAP, ACTIV-4, and ATTACC) are to be commended for conducting the randomised trials necessary to address this really important question. As is standard practice, each trial is overseen by an independent group of experts (including people with expert skills in statistics, clinical medicine, and blood clotting) who look at the data to assess if there is clear evidence that the treatment being studied is beneficial or harmful. Those independent committees have now advised that enrolment of critically ill patients, presumably those on intensive care units and similar, should cease. The research teams are now conducting the statistical analyses needed to ensure that the findings are properly understood and can be reliably communicated to those responsible for caring for these types of patients around the world. That process may take a little time but it is critical to get it right. We need to understand the balance of benefits and hazards so that future patients are treated appropriately. Today’s public statement is clear and measured, which is exactly as it should be.
“Nothing in this report alters the ongoing need for randomised clinical trials of blood thinners in patients who have less severe COVID (particularly in hospital) or of other treatments that might reduce blood clotting in different ways (such as aspirin).”
Prof Stephen Evans, Professor of Pharmacoepidemiology, London School of Hygiene & Tropical Medicine, said:
“There are good theoretical reasons to think that the use of blood thinners might improve outcomes for patients in hospital with Covid-19. It is vital that such ideas are tested by randomised controlled trials and the REMAP-CAP collaboration have done a really good job of assessing this treatment.
“As with all similar trials a data-monitoring committee oversees the results in confidence as they come in. Their vigilance has noted that in one subgroup in the trial does not show benefit and may have harm. They say “Among critically ill COVID-19 patients requiring intensive care unit (ICU) support, therapeutic anticoagulation drugs did not improve outcomes”.
“The pausing of this trial is not done lightly, but safety of participants is paramount, and shows that trial monitoring is effective.
“Getting the dose right in anti-coagulation is often difficult. A delicate balance exists between under-dosing and failing to prevent clots, and over-dosing causing excessive bleeding. The authors say “A potential for harm in this sub-group could not be excluded and increased bleeding was noted with full-dose anticoagulation”.
“There will be careful evaluation no doubt to understand reasons why some patients had excessive bleeding. The clotting seen in patients with Covid-19 may have features that are unlike clots usual seen in veins or arteries and these trials may help to elucidate this.”
All our previous output on this subject can be seen at this weblink:
Prof Martin Landray: “- Co-chief investigator of the RECOVERY trial of potential treatments for COVID-19 (funded by UKRI and NIHR; contributions to supply of study treatment from Abbvie, Roche, and Regeneron).
– Research funding to University of Oxford received from Novartis, Boehringer Ingelheim, and Merck Sharp & Dohme.-
– Infrastructure and core funding received from Health Data Research UK, NIHR Oxford Biomedical Research Centre, UK Biobank Ltd, MRC Population Health Research Unit, and British Heart Foundation Centre for Research Excellence.
– Employee of University of Oxford with salary supported by Li Ka Shing Foundation, Health Data Research UK, NIHR Oxford Biomedical Research Centre, Wellcome Trust, and National Health Service.
– I do not accept personal honoraria payments directly or indirectly from the pharmaceutical, biotechnology, or food industries although reimbursement to the University of Oxford for the costs of travel and accommodation to participate in scientific meetings may be accepted. I hold no shares in and receive no consultancy payments directly or indirectly from tobacco, pharmaceutical, biotechnology, or food companies. I comply with the Independence of Research Policy of the Nuffield Department of Population Health, Universityy of Oxford. For details see: https://www.ndph.ox.ac.uk/files/about/ndph-independence-of-research-policy-jun-20.pdf/@@download.”
Prof Stephen Evans: “No conflicts of interest. I am funded (one day per week) by LSHTM. They get funding from various companies, including Astra Zeneca and GSK but I am not funded by them, I have no involvement in obtaining funding from them and I am not an investigator on any grants obtained from them. I am the statistician to the ‘meta-Data Safety and Monitoring Board’ for CEPI. I am paid for my attendance at those meetings and will be paid expenses for travel if that occurs.”