Debate: Should the dose or duration of anticoagulants for the prevention of venous thrombosis be increased in patients with COVID‐19 while we are awaiting the results of clinical trials?

Abstract

The World Health Organization declared COVID-19 a pandemic on 12th March 2020. Within a few weeks it became clear that venous thrombosis (VTE) is a frequent complication of COVID-19, particularly in the more severe cases.1 Thrombotic events were occurring despite the use of prophylactic, low-molecular weight heparin (LMWH) at standard doses and significantly contributing to overall morbidity and mortality. Table I lists some of the largest published cohort studies (˃75 patients) of thrombosis rates in COVID-19. There are some caveats to be considered when assessing the results. Thrombosis was not radiologically confirmed in all studies and screening with imaging was used in some, so that asymptomatic cases were included. Thrombosis prevention strategies differed with some later studies using intermediate or VTE treatment doses of LMWH alongside prophylactic doses. Because of the varying methodology, patient characteristics and thromboprophylaxis modifications, it is difficult to summate the results from these studies. We can surmise that in COVID-19 patients admitted to intensive care units (ICUs) on pharmacological thromboprophylaxis the VTE rate ranged from 18–47% and in patients on the general ward it was 3–7%. Two studies reported that these rates were much higher than those previously observed in their ICU patients with non-COVID infective acute respiratory distress syndrome (ARDS) of 6–8%.2, 3 However, the largest prospective study of septic patients on ICU prior to the COVID-19 pandemic showed a VTE rate of 37% in those on thromboprophylaxis.4 A retrospective study of ICU patients with ARDS due to severe acute respiratory syndrome coronavirus (SARS-CoV) showed a VTE rate of 30% on thromboprophylaxis.5 Similarly, a retrospective study of influenza H1N1 patients with ARDS found a VTE rate of 44% in patients on thromboprophylaxis with LMWH or unfractionated heparin.6 It would seem that while there is undoubtedly a high rate of VTE associated with severe COVID-19, the rate is similar to other infective causes of ARDS. Very few studies have reported on the haemorrhage rate and only one of the aforementioned studies has specifically considered this as a primary outcome measure alongside the thrombosis rate.7 In this cohort, just over half the patients received VTE treatment doses of anticoagulation and the rate of significant haemorrhage was 21%. Although, there is currently no published clinical trial data that shows increased doses of anticoagulation to be effective at reducing the thrombosis rate, there is some retrospective data suggesting better survival rates with therapeutic anticoagulation.8, 9 Other studies have not found any benefit, and furthermore, it is not clear whether any benefit in reduction of thrombosis rates is not offset by an increased bleeding risk.10 Several professional organisations have stated that clinical studies of therapeutic options for preventing VTE are of paramount importance in developing effective management strategies to combat COVID-19.11 While the results from clinical trials are awaited, clinicians have been looking for guidance on how to reduce the thrombosis risk. On 21st May 2020 the International Society on Thrombosis and Haemostasis (ISTH) published guidance statements that reflected the opinions of an expert panel.12 The panel agreed that standard dose thromboprophylaxis should be offered to non-ICU hospitalized patients with COVID-19, but 30% felt that an intermediate dose could be considered. Presumably, the remaining 70% did not agree with this view. Half the panel felt that intermediate dose LMWH could be considered in high-risk ICU patients after weighing up the bleeding risk. A different expert panel convened by the American College of Chest Physicians (ACCP) published guidance on 2nd June that disagreed with this view, and suggested that standard dose thromboprophylaxis should be used in preference to intermediate or VTE treatment doses.13 This document also suggested that LMWH was preferred over unfractionated heparin and direct oral anticoagulants for thromboprophylaxis because of the high likelihood of drug interactions and renal impairment in this group of patients. Both the ISTH and ACCP guidance reiterated the lack of evidence for the efficacy and safety of increased intensity anticoagulation and the urgent need for clinical trials. Guidance published in the UK on the website of the Faculty of Intensive Care Medicine on 19th June 202014 stated that patients receiving ward-based care should receive standard thromboprophylaxis, but that those in critical care should receive intermediate doses. This document states that increased doses of LMWH may even be considered for general ward patients with two or more additional risk factors. While the lack of evidence for the role of anti-platelet therapy is pointed out, there is no mention of the lack of evidence for increased doses of anticoagulation nor discussion of the potential bleeding risks. The British Society of Haematology was asked to endorse this guideline but felt that in the absence of the necessary evidence, it could not support these recommendations nor produce consensus guidance of its own. The British Thoracic Society set out a ‘possible approach to LMWH dosing’ that suggested intermediate doses of LMWH for higher risk patients identified by parameters such as D-dimer thresholds.15 In the absence of clear evidence that these approaches led to better clinical outcomes it was acknowledged that there is a need for clinical trials of higher doses of LMWH in COVID-19 patients. A summary of the statements and recommendations on anticoagulation dosing is given in Table II. In the UK, two proposals for standalone studies of anticoagulation in COVID-19 were submitted to the National Institute for Health Research during March 2020, but were, unfortunately, rejected. Fortunately, many similar studies have been implemented globally. A search on the clinicaltrials.gov website of interventional studies of anticoagulation in COVID-19 on 19th September 2020 returned 23 studies. All of these studies are comparing VTE treatment or intermediate doses of anticoagulants [mostly LMWH, but also direct oral anticoagulants (DOACs)] with prophylactic anticoagulation (mostly LMWH but also unfractionated heparin). Some studies include other interventions such as anti-platelet therapy or fondaparinux. Those aiming to enrol 200 or more participants are listed in Table III. Several studies are aiming to complete recruitment by the end of 2020. Currently, the multi-intervention randomised, embedded, multifactorial, adaptive platform trial for community-acquired pneumonia (REMAP-CAP) study is the only open trial of different doses of anticoagulation in the UK. This is the largest COVID-19 study in terms of participant number, and although the trial as a whole is scheduled to close in 2023, outcome data for specific interventions will be released before this date. In the UK, several institutions have introduced local protocols using intermediate or higher doses of LMWH for thromboprophylaxis in COVID-19. While we are awaiting the results of clinical trials, this article debates whether the dose or duration of anticoagulants given for the prevention of VTE should be increased in patients with COVID-19. The spread of COVID-19 in Europe was rapidly followed by a realisation not only that the rate of thrombosis in critically ill COVID-19 patients was exceptionally high, but that thrombosis within the pulmonary vasculature itself was an important part of its pathophysiology. This prompted the question as to whether intensified thromboprophylaxis would be of benefit and several proposals to test this hypothesis in the UK were made but rejected. Faced with a new and important problem with no trial data and no trial available, the appropriate response is to utilise what is known about the disorder and about the available therapies, to formulate a logical therapeutic plan. Many, but not all, of the guidelines published regarding thromboprophylaxis for COVID-19 adhere to existing guidelines for general medical or surgical admissions. The limitation of this approach is that guidelines, like the studies on which they are based, apply to specific groups of patients, and so it is important to ask whether they apply to the patient(s) you are treating. Do hospitalised and critically ill patients with COVID-19 match the database? The major quoted meta-analysis of thromboprophylaxis for critically ill patients contained 7226 patients but only 3000 were in studies comparing thromboprophylaxis with placebo and 1935 of these were from a trial comparing recombinant activated protein C with placebo. Nonetheless, the analysis reported an odds ratio (OR) (95% confidence interval) for deep vein thrombosis (DVT) of 0·51 (0·41–0·63) and pulmonary embolism (PE) of 0·52 (0·28–0·97).16 Notably, it was not significant for symptomatic DVT: there was no increase in bleeding and the PE rates were only 1% in the heparin arm and 1·9% in the placebo arm. The thrombosis risk may be higher in critically ill sepsis patients. The series of 113 patients with sepsis reported by Kaplan et al. did report a high incidence of thrombosis at 37%, but 16 of42 thromboses were catheter-related and symptomatic PE occurred in only 3·5%,4 this was despite receiving standard thromboprophylaxis. Are these figures comparable to COVID-19? Multiple reports have documented very-high rates of thrombosis, particularly PE, in patients with COVID-19 admitted to ICU, despite, at least standard, thromboprophylaxis. Poissy et al. found that 21% of COVID-19 ICU patients had PE compared to 6·1% in the same period the previous year, despite similar severity scores. This was also higher than the incidence of PE in influenza patients admitted a month before (7·5%).3 In a French, multicentre study of 150 consecutive patients admitted to ICU with COVID-19, all patients received some form of anticoagulation therapy (70% prophylactic dose and 30% at therapeutic dose) and yet relevant thrombotic complications occurred in 43% of patients, including 16·7% with PE.2 Matching to non-COVID patients admitted to ICU revealed that thrombotic complications were much more frequent in the COVID patients: OR 2·6 91·1–6.1), (P = 0·035), with significantly more PE, OR 6·2 (1·6–23.4), (P = 0·008). In both these studies the PE were objectively diagnosed by computed tomography pulmonary angiography. In their updated analysis of 184 patients, Klok et al. reported a cumulative incidence of 49% for all thrombotic events and 42% (or 87% of all VTE) were PE, despite all their patients receiving LMWH thromboprophylaxis.17 Excluding subsegmental PE, the figure is still 27% of cases. Middeldorp et al. reported on 198 patients and found the cumulative risk of PE at 21 days to be 15% for ICU patients.18 Once more, all patients had received LMWH and latterly at an increased dose. Several other studies have reported high rates of thrombosis.19-22 Certainly these data are at risk of bias from various factors including counting methods and incomplete follow-up and some thrombosis-in situ may have been mislabelled as embolic. But it seems clear that the frequency of thrombosis, and in particular of PE in patients with COVID-19, is much higher than in any previous reports of ICU patients, with or without sepsis and persists despite the use of standard thromboprophylactic regimens recommended in standard guidelines. A natural response to these data is to conclude that the intensity of thromboprophylaxis should be increased. But when moving beyond trial data it is important to consider what mechanistic and observational data are available to guide such an alternative strategy. It is not necessarily true that more anticoagulation will reduce the rate of thrombosis, some of which may be driven by a variety of inflammatory mechanisms, and secondly, such a move may result in an unacceptable rate of bleeding. However, there is a logical argument for increasing the intensity of heparin. One of the most striking characteristics of COVID-19 has been the remarkably high levels of D-dimer. This been shown to be a powerful (possibly the most powerful) predictor of thrombosis and mortality23 and results from thrombin production; other indicators including prothrombin fragment 1 + 2 and thrombin-antithrombin complexes are also elevated. Heparin is a potent, albeit indirect, inhibitor of thrombin and increased doses have been shown to reduce the progressive rise in D-dimer in these patients.24 As already noted, heparin at standard doses is effective in reducing the rate of thrombosis in acutely unwell patients. Preventing VTE would be a good reason for intensifying thromboprophylaxis, but there is also extensive evidence that small vessel thrombosis in COVID-19 is part of the pathophysiology leading to vascular shunting and hypoxemia. Imaging and postmortem studies have confirmed the presence of widespread, small and large vessel thrombotic occlusions. In keeping with this, we found that tissue plasminogen activator thrombolysis can be successful in restoring oxygenation.25 Although the composition of these thrombi may be complex, including neutrophil extracellular traps, von Willebrand factor and platelets as well as fibrin, inhibition of thrombin is likely to reduce their formation. Intensified anticoagulation may, therefore, reduce thrombosis, improve lung function and improve prognosis; a hypothesis supported by empirical data. Obi et al. recorded a 37% rate of thromboembolic events (29% PE) among patients with H1N1 compared to 6·2% for all other ICU patients over the preceding 5 years.6 They instituted a programme of therapeutic heparinisation to deal with this, and in multivariate analysis, adjusting for H1N1 status, non-anticoagulated patients were 33 times more likely to have any VTE compared with those treated with empirical therapeutic anticoagulation (P = 0.01). More recently, data from Mount Sinai Hospital showed an improved outcome in patients admitted to ICU who received therapeutic anticoagulation.8 A subsequent paper from the same group showed lower (but not significant) mortality on therapeutic compared to prophylactic anticoagulation.26 Our own data using graded thromboprophylaxis are in keeping with this.27 Increasing prophylaxis intensity runs the risk of increasing bleeding problems but not necessarily so, given the highly prothrombotic nature of this infection. The meta-analysis of thromboprophylaxis by Alhazzani et al. found no difference in the risk of major bleeding between heparin prophylaxis and placebo.16 Historical data suggest a moderate or severe bleeding rate of 3·5% in patients receiving therapeutic heparin in hospital.28 These compare well with the thrombosis rates reported above for COVID-19. Moreover, in the studies by Obi et al.,6 Hsu et al.,24 and Paranjpe et al.,8 there was no increase in bleeding events associated with increased anticoagulation intensity. Increasing intensity of thromboprophylaxis, therefore, represents a reasonable approach to a pressing clinical problem and is supported by logic, mechanistic evidence and observational clinical data, without evidence of increased bleeding or other detriment. Establishment of such an approach in guidelines will require randomised clinical trials, which are now under way and should be supported; however, for centres not participating in a relevant trial and for many patients who are ineligible for a trial, intensified thromboprophylaxis may be justified. However, both as an interim measure and in trials it would be a mistake to replace one blanket recommendation with another. It is now clear that the spectrum of COVID-19 disease is much wider than was apparent in March 2020. Many patients have a mild disease not requiring admission and not all those admitted will require ICU support. The focus of the case for intensified anticoagulation is on those patients with a severe and potentially fatal disease who develop or are developing respiratory failure. A graded response is required to identify patients at risk and most likely to benefit. The obvious candidate for this measure is D-dimer, which shows exactly this relationship.23 An alternative marker for intensification may be C-reactive protein.29 Similarly, we should be more sophisticated in the amount of heparin given to the selected patients and some authors have recognised this instituting ‘intensified’ thromboprophylaxis as an intermediate between standard prophylaxis and ‘therapeutic’ We should also consider additional there is evidence that patients require doses of LMWH to the same of and that the inflammatory response the This is not a to formulate an alternative there are data to in the absence of trial data, we should the using available data and to an therapy thrombotic and risks. In critically ill patients with COVID-19, a reasonable will be that higher than doses of anticoagulants are clinical before there is data to support a new is to There have been many medical what has been considered the approach on or has in been to be in used to be recommended for many such as pulmonary embolism and but it is now known that this can be and is to the of this is the use of as primary prophylaxis small studies suggested that it was of benefit and because and patients in was However, large randomised clinical trials showed no benefit and The COVID-19 pandemic has a of to with guidelines and before there has been evidence to support any While there is no the need for of data, many of these have not been the and are of a lower than would be for The guidelines and local protocols that have been were on expert than evidence, in recommendations that This and in clinical the of guideline There is much in recommended dosing of anticoagulation for VTE whether D-dimer results should whether critical care patients should receive higher doses and whether and how thromboprophylaxis should be on COVID-19 that was and many UK implemented for COVID-19 In although are is high with and In although a high rate of thrombosis has been most of the studies did not report data on rates of bleeding. One guideline recommended of in patients with COVID-19 and levels but this was not on evidence and would be to what is recommended in other or Many protocols and guidelines recommended thromboprophylaxis with LMWH or for patients admitted to for COVID-19, as VTE rates were to be However, when rates of VTE were these were lower than at of This not prophylactic particularly when there is a bleeding rate of after Some guidelines also heparin doses on D-dimer The for this has been that D-dimer is associated with outcome in COVID-19 and is a test used in the for VTE as well as a predictor of VTE However, there is no evidence that in patients with high D-dimer the outcomes are because of thrombosis, that anticoagulation can improve the we are all that D-dimer with and patients with severe COVID-19 have of Although some retrospective data has shown an of higher D-dimer levels in patients with VTE and COVID-19, this not to D-dimer levels VTE as D-dimer may than the VTE these other guidelines that also higher intensity anticoagulation have specifically recommended not using D-dimer to guide anticoagulation It may seem logical to anticoagulation thromboprophylaxis for patients with COVID-19 in the same way that considered it logical to patients with pulmonary embolism to However, the of thrombosis in COVID-19 is and direct and to the with vascular and it be that inhibition of thrombin by anticoagulation will be an effective strategy. In some other thrombosis vascular such as therapeutic anticoagulation has efficacy in the absence of The other is that anticoagulation will increase major bleeding to an that any benefit in This has out to be the case when thromboprophylaxis beyond in medical patients. There is a reduction in but also an increase in major so that there is no bleeding in patients with COVID-19 is not in the ICU is that anticoagulation to therapeutic doses for VTE prevention will result in the that there is no need to VTE as is of not true as the duration of anticoagulation would be VTE is diagnosed and VTE in an a in anticoagulation management is It could be that protocols and guidance without the necessary evidence is than no as this subsequent to data in a trial clinical trials are available, some clinicians may not patients because of a that the approach is known and there is no the clinical to patients. As an for the anticoagulation there were two for this The was that clinicians all patients should be on therapeutic anticoagulation and the was that therapeutic anticoagulation was an high-risk for ICU patients. both of these of clinical could not be when were in COVID-19, some clinical to part due to that this would by patients who have infection. randomised trials and meta-analysis have shown survival benefit with doses of All data that is prospective nor randomised is to bias and only can be Although there are retrospective reports of hospitalised patients with COVID-19 receiving therapeutic the results are with many likely data, particularly randomised trials, are the way to the safety and efficacy of a new without good evidence of efficacy and safety Within a clinical trial the potential and are so that patients can an as to whether they to receive an treatment or such safety is to patients receiving local this the to about the role of anticoagulation as as This was in a by the to all in This the use of of a trial, in a trial is of of a trial, was is a to that will benefit In it is to in randomised trials than standard care or guidelines on and We the use of but only within the of a clinical trial as this is the approach that will identify the management There are many trials open and that will be to the efficacy and safety of anticoagulation protocols in hospitalised patients with COVID-19 as well as whether D-dimer results should These trials include to of COVID-19 COVID-19 and COVID-19 with a recruitment to anticoagulation of and an for data to a result as as Our as is to support these studies as to local protocols use that the and the the argument and the the argument and the All authors and the in A of in COVID-19 in COVID-19

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