May 6, 2020

expert reaction to study looking at blood thinners in hospitalised patients with COVID-19

Research, published in the Journal of the American College of Cardiology, reports on the impact of blood thinners on hospitalised patients with COVID-19.

Prof Philip Bath, Stroke Association Professor of Stroke Medicine, Chair & Head Division of Clinical Neuroscience, NIHR Senior Investigator, University of Nottingham, said:

“Many medical illnesses, including pneumonia and COVID-19, are associated with stickier (pro-coagulant) blood so giving blood thinners (anticoagulants) to those hospitalised makes sense and benefit has been shown in many randomised controlled trials.  At lower doses, typically as an injection under the skin (subcutaneous), they are used to prevent the development of clots in the legs (deep vein thrombosis) and the moving of these into the lungs (pulmonary embolism, which is often fatal).  In more ill patients, they may be used at higher doses to reduce blood clotting, again as an injection under the skin or into a vein as an intravenous infusion.

“The Mount Sinai publication is not a randomised trial but rather an observational study which means it is open to confounding factors, some which they accounted for and others that will not have been measured.  Nevertheless, the report describes what we would consider to be best practice and since trials have shown benefit, it is unsurprising that the New York group have found better outcomes.  In this respect, there is really little to suggest that COVID-19 would be any different from any other serious infection.  There are caveats – blood thinners would not be given to patients with overt bleeding or to those with acute stroke.  In stroke, the risk of bleeding, including into the brain, matches any benefit so intermittent pneumatic compression sleeves around the leg (rather than drugs) are used to prevent clots in the leg.”

Prof Stuart Pocock, Professor of Medical Statistics, London School of Hygiene & Tropical Medicine, said:

“Firstly, the hypothesis that anticoagulants may be of value in COVID-19 patients is a reasonable one, because the virus does seem to have pro-thrombotic properties.

“The concern is that this study is not randomised – there are problems of observational selection regarding who got given anticoagulants and who didn’t.  This is a potential selection bias.  The authors have attempted to adjust for differences in the type of patients, but you can’t expect to explain away all the reasons why one patient gets anticoagulants and another does not.

“The main result in this study for all patients does not show a difference in survival between those on anticoagulants and those on control.  Therefore, overall the study would be judged to be neutral.

“It is in the patients who go on to require mechanical ventilation, which are a subgroup, where there appears to be an association between anticoagulant use and increased survival.  But that is a post-hoc selected subgroup so cannot provide reliable evidence.

“At best, this study is hypothesis-generating, therefore would provide motivation for randomised trials to be carried out.  Patients who require anticoagulants for other reasons could not enter the trial.  The trial would need to be in patients for which it is not mandated that they get anticoagulants, so they can be randomised.”

Dr Riyaz Patel, Associate Professor of Cardiology, UCL, said:

“It is certainly evident that hospitalised COVID19+ patients tend to have increased blood clotting problems and this may be contributing to worse outcomes, particularly where clotting occurs in the blood vessels in the lungs and stops blood being adequately supplied with oxygen.

“Although it is common practice to give low dose anti clotting medicines to patients in hospital, to stop clots forming in the legs, it remains unclear whether giving higher doses of blood thinners to COVID19+ is beneficial or harmful, especially as sudden bleeding could in itself cause more problems.

“This study provide useful data adding to that story and indicating there may be some benefit from this strategy with perhaps not as many harms.  However it is only observational data which means we don’t know if the differences observed are due to the treatment or because of other factors that were not available to the researchers.  For example, it is possible more frail patients were not given the blood thinners in preference to healthier patients who may have been more likely to survive anyway and with fewer bleeding complications.

“What we are waiting for are well conducted clinical trials where patients are allocated one blood thinning treatment strategy or another randomly.  These are in progress and hopefully we will have definitive answers on this important issue very soon.”

Prof Paolo Madeddu, Professor of Experimental Cardiovascular Medicine, University of Bristol, said:

“The paper is from an excellent center specialized in cardiovascular disease.  The study shows a lower mortality rate and prolonged survival in a cohort of hospitalized patients receiving different type of anticoagulant therapy as compared with other patients who did not receive such a treatment.  Interestingly, however, the group on anti-coagulant therapy needed more ventilation assistance, which then was associated with a more evident benefit on mortality in the anticoagulant therapy patients.

“Anti-coagulant therapy should prevent / treat thrombotic events that are responsible for heart attacks and cerebrovascular complications.  The authors did not provide an explanation on the clinical laboratory basis a patient was assigned to the therapy or not.  Therefore, the study has a potential bias in recruitment criteria, which could influence the conclusion.  They do not provide an explanation why the anticoagulant group needed ventilation.  An association between the clinical indication or use of ventilation and anticoagulant therapy is likely.

“On the one hand, microvascular pulmonary thrombosis plays an important pathophysiological role in pulmonary embolism (PE), whose initial symptom is intense dyspnea requiring ventilation.  Anti-coagulant therapy could have prevented PE.  Unfortunately, the authors do not report the cause of death in the two groups and whether thrombotic events prevailed in untreated group.

“On the other hand, patients admitted to the Intensive Care Unit (ICU) are known to be at risk for thrombo-embolic events.  A prolonged mechanical ventilation together with the hemodynamic effects of this ventilation with a high positive and expiratory pressure, the presence of central venous catheters, the immobilization of these patients and the presence of obesity or other comorbidities can attribute to the occurrence of a deep venous thrombosis (DVT) in patients admitted at ICU.  This could explain (without detracting but rather highlighting the importance) the benefit of anticoagulation reported in the study.”

Prof Saad Shakir, Director of the Drug Safety Research Unit (DSRU) near Southampton, said:

“Obviously any treatment for patients with Covid-19 infection, including anticoagulation known as blood thinners is new, so studies such as this one are needed.  It is a good quality observational study, the researchers accounted for possible bias and confounders.

“The implication for the real world is that Covid-19 illness can increase the viscosity of blood, cause blood clots in the lung and other organ dysfunction, which indicates that blood thinners have a place in the treatment of some patients with Covid-19 infection.  These are patients with severe disease, many of whom will be ventilated.  As expected, bleeding is the main adverse drug reaction which happens in 3% of patients given blood thinners versus 1.9% in those who are not.

“Criteria for major bleeding, which is the concern, are defined in the paper.  I agree with the authors who state that while their study is informative, further studies, such as randomised controlled clinical trials are needed to further evaluate the use of blood thinners in patients with Covid-19.  Not only to better measure the benefit but also to describe in more detail issues such as the criteria of which patients will benefit from blood thinners, the most advantageous timing and the level of anticoagulation.  The best approach to put the bleeding adverse drug reactions in perspective is to conduct a structured benefit-risk balance.”

Prof Robin Ferner, Honorary Professor of Clinical Pharmacology at the University of Birmingham, Honorary Consultant Physician at City Hospital Birmingham, Director Emeritus of the West Midlands Centre for Adverse Drug Reactions, and a series editor of The BMJ’s Therapeutic Series, said:

“Deranged blood clotting is an important and poorly understood feature of severe COVID-19. Large clots on the lung (pulmonary emboli) can occur in all patients who are confined to bed with pneumonia, and are dangerous and potentially fatal because they block the flow of blood through the lungs.  They most often start with clots in the deep veins in the legs.  Some of the features of pulmonary emboli, such as very poor oxygen uptake in the lungs, are seen in severe COVID-19, but clots in the deep veins and large pulmonary emboli are rare.  However, it seems that the lungs are damaged by small clots (microthrombi) that form within the lung’s blood vessels.  There is also an increased risk of bleeding, for example, bleeding into the brain, in COVID-19.  There are good treatments that reduce the risk of deep vein thrombosis, but these do not seem to prevent the microthrombi.  One possibility is that patients would do better if they were given higher doses of anticoagulant.

“This paper reports what happened to 2773 patients admitted to hospital with COVID-19, 786 of whom were given systemic anticoagulants at some point during their illness by their physicians, who determined the treatment.  The anticoagulant could be given by mouth or by injection.  The authors give us no information on which anticoagulants were used, or the intensity of anticoagulation.

“Overall, 23% of each group died.  Patients who were anticoagulated were much more likely (30%) to be mechanically ventilated than those who were not (8%), but if they were ventilated, anticoagulated patients were much less likely to die in hospital (29%) than patients who were ventilated but not systemically anticoagulated (63%).  There was a possible increase in bleeding events in the patients who were anticoagulated (3% -v- 2%).

“The results are confusing.  Doctors believe it’s best to avoid ventilation if at all possible.  This paper shows that the people who were given an anticoagulant were also more likely to be ventilated.  The authors claim that these patients have a better chance of surviving.  However, it is impossible to tell whether this effect is causal because we don’t know when the anticoagulants were given.

“Overall, the ‘probability of being ventilated × the probability of dying’ was 0.3 × 0.29 (9%) in the anticoagulated group, but 0.08 × 0.63 (5%) in the group without anticoagulants.  This doesn’t quite fit with the authors’ suggestion that systemic anticoagulation ‘may be associated with improved outcomes,’ but it certainly underlines their conclusion that ‘Prospective randomized trials are needed to determine whether systemic [anticoagulation] confers a survival benefit in hospitalized patients with COVID-19.’

“It is standard practice to give low-dose anticoagulants to prevent deep vein thrombosis in patients in hospital with pneumonia.  This trial will not alter that.  And there is still no therapeutic intervention, which has been reported, that clearly reduces mortality in COVID-19.”

Prof Stephen Evans, Professor of Pharmacoepidemiology, London School of Hygiene & Tropical Medicine, said:

“This paper is an observational study that attempts to relate administration of anti-coagulants (AC) to outcomes in patients in hospital with Covid-19.

“While there is some scientific reasoning to support the idea that blood clots may be a an important factor related to poor prognosis in Covid-19 [https://blogs.bmj.com/bmj/2020/05/01/covid-19-a-complex-multisystem-clinical-syndrome/], this paper must be treated with caution.

“Patients were not randomised to anti-coagulants or no anti-coagulants and so there can be a number of differences in patient selection that could affect the outcome.

“The authors have used duration of anti-coagulants treatment as a possible predictive factor when analysing the data. This is probably a mistake. If a patient dies within say 24 hours, they cannot have a duration of treatment greater than 24 hours!

“When they say “In a multivariate proportional hazards model, longer duration of AC treatment was associated with a reduced risk of mortality (adjusted HR of 0.86 per day, 95% confidence interval 0.82-0.89, p<0.001)”, on the face of it this is not sensible. It is a general rule of epidemiology that you do not use information from the future (when you start anti-coagulants treatment you don’t know how long it will be given for, and when you use it at the start of treatment you are using information from the future) when analysing data that involves following up patients over time.

“It may well be that anti-coagulants treatment could be beneficial, but this paper provides very little reliable evidence on this question. A well-designed and analysed observational can shed some light, though in most instances a carefully conducted randomised trial is necessary to give convincing evidence of efficacy. The authors do note the limitations of observational studies in this context and say “Prospective randomized trials are needed to determine whether systemic AC confers a survival benefit in hospitalized patients with COVID-19”, but the paper has more limitations than its authors may realise.”

Prof Kevin McConway, Emeritus Professor of Applied Statistics, The Open University, said:

“On the face of it, this research looks as if it might be heralding an important advance in treating hospitalised patients with COVID-19 – but in fact the findings are presented quite cautiously. The claim is only that blood thinners (anticoagulants) may improve survival, and the researchers say very clearly that more research is needed before we can be sure about the potential benefits from this treatment. Why the caution? I’ll explain – though in my view the caution is very necessary.

“The researchers themselves explain several reasons for caution, in the research report (penultimate paragraph). Overall, the main problem is that the study was observational – that is, the research is reporting what went on in these hospitals, on the basis of choices that the medical teams made, rather than deliberately trying to change treatments in a controlled manner. As a result, there will inevitably be many differences between the patients who were treated with blood thinners and those who weren’t, apart from the blood thinners. These other differences might, in part at least, be what led to any differences in survival. In one of their statistical analyses, the researchers adjusted their results to take into account several factors that might affect the risks of mortality, but one can never be sure that everything important has been accounted for. Also, my reading of the report is that these adjustments were used only in looking at the relationship between duration of anticoagulant treatment and risk of death, where they found that longer anticoagulant treatment was associated with reduced mortality risk, in a statistically significant manner. I don’t think that the adjustments were used in the simpler calculations of death rates and of lengths of hospital stay, that are most prominently mentioned in the press release. That isn’t necessarily a big problem, but it does make the picture rather less clear.

“Other issues are that detailed information is not available on all aspects of how the doctors chose which patients should get anticoagulant treatment. (Remember that almost three-quarters of patients were not treated with blood thinners.) I am certainly not claiming that these choices would have been made inappropriately or irrationally, but lack of knowledge about how patients were chosen for this treatment does make the interpretation of the findings harder. There are indications in the report that anticoagulants were more likely to be used for patients that appeared to be more at risk of blood clots, but perhaps these patients would have (on average) different levels of seriousness of COVID-19 disease than those that were not given anticoagulants. That may have affected their survival in a way that wasn’t allowed for by the statistical adjustments and that can’t really be determined from this study. (This issue is essentially what is referred to as ‘indication bias’ in the research paper.) This could go either way. Maybe the patients given anticoagulants were more seriously ill on average. Or maybe even the treatment was given to patients that the doctors thought were most likely to benefit, and that could even mean that really extremely ill patients were not given blood thinners. We just don’t know for sure, not until more research has been done.

“Some aspects of the numbers perhaps need further explanation. The press release points out that, of patients who unfortunately did not survive, those on anticoagulants spent about a week longer in hospital before their deaths than did those who were not on anticoagulants, and that’s quite a big difference. However, the research report also points out that there was hardly any difference between the percentages of patients who died, out of those receiving and not receiving anticoagulants (22.5% compared to 22.8%). Furthermore, the average lengths of hospital stay for patients who died, whether or not they had anticoagulants, 21 and 14 days respectively, are much longer than the average (median) length of stay in hospital for all patients, which was 5 days. It’s not at all surprising that patients who died were in hospital for a relatively long time, given the likely severity of their illness, but again this shows that a comparison of the lengths of stay for the patients who died does not give the whole picture.

“The position on patients who required mechanical ventilation is complicated too. Patients who received anticoagulants were much more likely to need ventilation – about 30% of them did, compared to only 8% of those who had not had anticoagulants. That’s a big difference. Just looking at ventilated patients, those who received anticoagulants were considerably less likely to die than those who did not receive anticoagulants – 29% compared to 63%. That’s a big difference too. But taking both of these differences in account, the picture perhaps looks different. Of patients who received anticoagulants, almost 9% required ventilation and also subsequently died. Of patients not receiving anticoagulants, the corresponding percentage is considerably lower, at 5%. Again, this difference is probably due to differences in disease severity between the two groups, but again this complicates the overall interpretation, and is another reason why more research is needed to see more precisely where anticoagulants are useful in this awful disease.

“There are certainly positive points about the research. Using anticoagulants can be problematic, because they make it more likely that serious bleeds will occur in the body. It’s reassuring that the proportion of bleeding events in patients receiving blood thinners was not significantly higher than in those who did not receive blood thinners – though again this is difficult to interpret fully because of other differences between the patient groups.”

‘Association of Treatment Dose Anticoagulation with In-Hospital Survival Among Hospitalized Patients with COVID-19’ by Ishan Paranjpe et al. was published in the Journal of the American College of Cardiology at 19:00 UK time on Wednesday 6 May 2020.

Declared interests

Prof Philip Bath: “No conflicts of interest.”

Dr Riyaz Patel: “No conflicts.”

Prof Saad Shakir: “The Drug Safety Research Unit is an independent charity (No. 327206), which works in association with the University of Portsmouth.  It receives unconditional donations from pharmaceutical companies.  The companies have no control on the conduct or the publication of the studies conducted by the DSRU.  Saad Shakir is an employee of Drug Safety Research Unit, an independent charity (No. 327206), which works in association with the University of Portsmouth.  He has no conflicts of interest to declare.”

Prof Robin Ferner: “None.”

Prof Stephen Evans: “No conflicts of interest.  I am funded (1 day/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 or any grants obtained from them.  I am the statistician to the “meta-Data Safety and Monitoring Board” for CEPI [https://cepi.net/].  I will probably be paid for my attendance at meetings and expenses for travel.”

Prof Kevin McConway: “Prof McConway is a member of the SMC Advisory Committee, but his quote above is in his capacity as a professional statistician.”

None others received.