key: cord-0694037-z6quyvqa
authors: Cullivan, S.; Sholzberg, M.; Áinle, F.Ní; Kevane, B.
title: Anticoagulation as a therapeutic strategy for hospitalised patients with COVID-19
date: 2022-01-12
journal: Thrombosis Update
DOI: 10.1016/j.tru.2022.100097
sha: f06e21e9de29a70c7769d75b1cdc1742aacc478a
doc_id: 694037
cord_uid: z6quyvqa

The COVID-19 pandemic has devastated the global community and continues to cause significant morbidity and mortality worldwide. The development of effective vaccines has represented a major step towards reducing transmission and illness severity but significant challenges remain, particularly in regions where vaccine access has been limited. COVID-19 is associated with hypercoagulability and increased risk of thrombosis, with greatest risk among the critically ill. Interestingly, early observational data suggested that anticoagulant therapy might improve clinical outcomes, aside from thrombotic events, in patients with COVID-19. In this review we summarise data generated from three published randomised clinical trials which have sought to determine the effect of therapeutic heparin anticoagulation on efficacy and safety outcomes in hospitalised patients with COVID-19: the multiplatform REMAP-CAP, ACTIV-4a and ATTACC randomised controlled trials and the RAPID trial. In the multiplatform REMAP-CAP, ACTIV-4a and ATTACC randomised controlled trials, therapeutic heparin was not associated with benefit in critically ill patients with COVID-19 compared with usual care (adjusted proportional odds ratio (OR) for increased organ-support free days up to day 21: 0.83; 95% credible interval, 0.67–1.03, posterior probability of futility 99.9%). Conversely, among hospitalised patients without critical illness, therapeutic heparin was associated with an increased probability of organ support-free days alive (adjusted OR, 1.27; 95% credible interval, 1.03–1.58). The RAPID trial also evaluated the effect of therapeutic heparin compared with prophylactic heparin in non-critically ill patients. In this study, therapeutic heparin did not significantly reduce the odds of the primary composite outcome (death, mechanical ventilation or intensive care unit admission) (OR 0.69; 95% confidence interval [CI], 0.43 to 1.10; p = 0.12) but was associated with a significant reduction in all-cause mortality [OR, 0.22 (95%-CI, 0.07 to 0.65)]. Collectively these studies suggest that therapeutic anticoagulation with heparin may reduce the severity of illness and potentially even confer a survival benefit in hospitalised, non-critically ill patients with COVID-19. No benefit for therapeutic anticoagulation with heparin was evident in critically ill patients with COVID-19. Therefore, while the results of additional studies in this evolving field are pending, it is important to approach decisions regarding therapeutic heparin in moderately ill hospitalised patients with COVID-19 in a measured and individualised manner.

The COVID-19 pandemic has devastated the global community and continues to cause significant morbidity and mortality worldwide. The development of effective vaccines has represented a major step towards reducing transmission and illness severity but significant challenges remain, particularly in regions where vaccine access has been limited. COVID-19 is associated with hypercoagulability and increased risk of thrombosis, with greatest risk among the critically ill.

Interestingly, early observational data suggested that anticoagulant therapy might improve clinical outcomes, aside from thrombotic events, in patients with COVID- 19 . In this review we summarise data generated from three published randomised clinical trials which have sought to determine the effect of therapeutic heparin anticoagulation on efficacy and safety outcomes in hospitalised patients with COVID-19: the multiplatform REMAP-CAP, ACTIV-4a and ATTACC randomised controlled trials and the RAPID trial. In the multiplatform REMAP-CAP, ACTIV-4a and ATTACC randomised controlled trials, therapeutic heparin was not associated with benefit in critically ill patients with COVID-19 compared with usual care (adjusted proportional odds ratio (OR) for increased organ-support free days up to day 21: 0.83; 95% credible interval, 0.67 -1.03, posterior probability of futility 99.9%). Conversely, among hospitalised patients without critical illness, therapeutic heparin was associated with an increased probability of organ support-free days alive (adjusted OR, 1.27; 95% credible interval, 1.03 -1.58). The RAPID trial also evaluated the effect of therapeutic heparin compared with prophylactic heparin in non-critically ill patients. In this study, therapeutic heparin did not significantly reduce the odds of the primary composite outcome (death, mechanical ventilation or intensive care unit admission) (OR 0.69; 95% confidence interval [CI], 0.43 to 1.10; p=0.12) but was associated with a significant reduction in all-cause mortality [OR, 0.22 (95%-CI, 0.07 to 0.65)]. Collectively these studies suggest that therapeutic anticoagulation with heparin may reduce the severity of illness and potentially even confer a survival benefit in hospitalised, noncritically ill patients with COVID-19. No benefit for therapeutic anticoagulation with heparin was evident in critically ill patients with COVID-19. Therefore, while the results of additional studies in this evolving field are pending, it is important to approach decisions regarding therapeutic heparin in moderately ill hospitalised patients with COVID-19 in a measured and individualised manner.

Over 200 million individuals have been infected with the SARS-CoV-2 virus since the emergence of the pandemic in late 2019 and the global death toll now stands at almost 5 million people 1 .

Worryingly, in recent months chronic morbidity has also become increasingly recognised among survivors [2] [3] [4] . The development of effective vaccines has represented a major step towards infection containment but vaccine supply remains challenging for many countries, particularly in lower to middle income countries [5] [6] [7] . Sub-optimal uptake of vaccination is also impacting ability to achieve herd-immunity in some regions [8] [9] [10] . Until these obstacles can be addressed, it is likely that the global community will continue to be faced with outbreaks of infection and emergence of novel variants 11 .

Reducing the risk of progression to severe COVID-19 among infected individuals is vital, not only in order to reduce the mortality rate but also in order to mitigate against the risk of healthcare system collapse 12, 13 . Efforts to improve COVID-19 treatment strategies must therefore continue to be prioritised.

COVID-19 is associated with hypercoagulability and increased risk of thrombosis. Importantly, elevated D-dimer levels have been identified as being predictive of poor clinical outcomes including critical illness and death [14] [15] [16] . The risk of thrombosis appears to be increased in all hospitalised patients with COVID-19 but the risk is greatest among patients with critical illness requiring organ support 15, 17, 18 . In situ pulmonary artery thrombosis and microvascular thrombosis appear to be prominent features of severe COVID-19 and may contribute to the development of the acute respiratory distress syndrome (ARDS) [19] [20] [21] . Furthermore, there is evolving evidence that sustained endotheliopathy and hypercoagulability may be implicated in long COVID syndrome pathogenesis 4, 22 . The observed relationship between inflammatory coagulation activation and COVID-19 severity have prompted a tremendous response from the global scientific community to define the pathobiology of this hypercoagulability 21, 23 .

At an early stage of the pandemic observational data emerged suggesting that anticoagulant therapy might confer survival benefit in COVID-19 24 . Consequently, the role of anticoagulation as a therapeutic strategy for COVID-19 has become an area of immense research interest 25 . Heparin anticoagulation has been of particular interest, due to its known additional anti-inflammatory and possible anti-viral properties 26 . Heparin was discovered over a century ago and was the first anticoagulant used medically. It is a naturally occurring glycosaminoglycan that is produced by mast 

The following trials have recently evaluated the effect of therapeutic heparin as a potential treatment adjunct in hospitalised patients with COVID-19 (Table 1) . These international, multicentre trials evaluated patients with different levels of disease severity as they hypothesized differential heparin effect. Collectively, the results of the RAPID and the multiplatform trials suggest that therapeutic heparin is of benefit in hospitalised patients with moderate illness but not in those with critical illness. It seems plausible therefore that therapeutic-dose heparin modulates the negative effects of thromboinflammation when applied earlier in the course of disease requiring hospitalisation.

The results of the multiplatform trial by the ATTACC, ACTIV-4a, and REMAP-CAP investigators and the RAPID trial are compelling and potentially practice changing, as they suggest that therapeutic heparin is safe and efficacious for patients with moderate COVID-19. A number of key differences exist between these trials however, which warrant discussion. An increase in organ support-free days and increased probability of survival without the requirement for organ-support, irrespective of baseline d-dimer level, was demonstrated in the multiplatform trial. Adherence to protocolassigned anticoagulation dosing regimens differed between trials. Protocol adherence to therapeutic anticoagulation was 88.3% in the multiplatform trial and 97.4% in the RAPID trial, and may have attenuated the results in the former. Adherence to prophylactic anticoagulation was similar at 98.3% and 97.9% respectively. In the multiplatform study, the number of major bleeding events was numerically higher in the therapeutic heparin arm in both the critical care and non-critical care populations, although this observation did not achieve statistical significance. An increased incidence of major bleeding with therapeutic heparin was not observed in the RAPID Study, which focused exclusively on non-critically ill patients. The low incidence of major bleeding overall in these studies is reassuring. As both studies excluded patients at high risk of bleeding, these results may not be generalisable to hospitalised patients with higher bleeding risks.

Individualised, patient-centred treatment decisions regarding the role of therapeutic anticoagulation is vital in ensuring that the potential benefits of such a treatment approach can be appropriately harnessed without exposing patients to unnecessary risks. These data suggest that therapeutic heparin anticoagulation is not appropriate to initiate in the critical care setting for the purposes of attenuating disease severity. Whether it is efficacious and safe to continue therapeutic heparin in moderately ill hospitalised patients who subsequently develop critical illness, necessitating organ support, was not the focus of either of these trials and therefore remains an important unanswered question.

Differing doses of heparin therapy and alternative anticoagulants have also been explored as potential therapeutic strategies for COVID-19. A study comparing intermediate-dose heparin in comparison to fixed-dose standard thromboprophylaxis has also failed to demonstrate a benefit in severe COVID-19, although additional studies are ongoing 30 . Studies evaluating the role of the direct oral anticoagulants have also not shown any evidence of a survival benefit to date or of a diseasemodifying effect 31 . Initial observational data suggested that anti-platelet therapy might be beneficial in COVID-19 although no survival advantage or reduction in disease severity was detected in a recent randomised controlled trial, although the outcomes from other additional studies are also awaited 32, 33 .

The negative results of the multiplatform study in critically ill patients with COVID-19 and positive results of the multiplatform and RAPID trials in the moderately ill suggest that earlier treatment in the course of hospitalization is preferable. It is biologically plausible that early initiation of heparin therapy may modulate dysregulated thrombo-inflammation and mitigate associated pulmonary endothelialitis and alveolar destruction. Later initiation of therapeutic heparin may alter the safety profile, augmenting the risk of major haemorrhage, and attenuate potential for benefit. Furthermore, the ideal treatment duration is unclear. Patients in the multiplatform study were treated for up to 14 days, while patients in the RAPID trial were treated for a maximum of 28 days, with a mean duration of 6.5 days. Patients in these studies received either intravenous or subcutaneous heparin preparations but LMWH was the most frequently used agent. The inhaled route of administration was not examined in these trials and this is the focus of additional studies 36 and acute respiratory distress syndrome 37, 38 . A prospective meta-analysis would be invaluable to facilitate the interpretation of the findings from these clinical trials where clinical characteristics and trial methodology have differed.

Therapeutic anticoagulation with heparin appears to be associated with favourable outcomes among moderately-ill patients admitted to hospital with COVID-19. These potential benefits are not evident in critically ill hospitalised patients with COVID-19. Globally, as the number of people infected with SARS-CoV-2 continues to rise and novel, highly-infectious variants emerge, the search for efficacious, affordable therapeutic interventions persists. The studies described in this review suggest that therapeutic heparin may confer benefit in select hospitalised patients with moderate COVID-19, following careful individualised risk assessment. Additional research is required to guide routine clinical practice in this dynamically evolving field.

BK is supported by a Science Foundation Ireland COVID-19 Rapid Response Award (20/COV/0157).

World Health Organization Coronavirus (COVID-19) Dashboard

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Severe COVID-19 Illness: Risk Factors and Its Burden on Critical Care Resources

Association of Intensive Care Unit Patient Load and Demand With Mortality Rates in US Department of Veterans Affairs Hospitals During the COVID-19 Pandemic

COVID-19 and coagulation: bleeding and thrombotic manifestations of SARS-CoV-2 infection

Risk of venous thromboembolism in patients with COVID-19: A systematic review and meta-analysis

Incidence of venous thromboembolism in hospitalized patients with COVID-19

Incidence of thrombotic complications in critically ill ICU patients with COVID-19

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Endothelial dysfunction and immunothrombosis as key pathogenic mechanisms in COVID-19

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Recent Randomized Trials of Antithrombotic Therapy for Patients With COVID-19: JACC State-of-the-Art Review

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Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19

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