Are Heparin and/or steroids effective in avoiding rare COVID-19 Complications when used for severely ill patients?

Authors: Jon Zhou, Pharm.D., MPH

Completed on:  June 17, 2020

Last revised on:  Not yet revised

Reviewed by: Sara Baird MD

Reviewed on: June 20, 2020

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This summary was written as part of the CoRESPOND Earth 2.0 COVID-19 Rapid Response at UC San Diego.  For more information about the project, please visit http://earth2-covid.ucsd.edu

Key findings

• Blood clots in the lungs can compromise oxygenation, leading to worsening clinical outcomes. Some patients may also experience venous and arterial thrombosis in other parts of the circulatory system.
• Several reports suggested that heparin and low molecular weight heparin (LMWH) can reduce inflammation and improve clinical outcomes, but the mechanism for this phenomenon is unknown.
• Therapeutic doses of LMWH should be initiated when thromboembolic complications are suspected. However, despite increasing evidence of the pro-thrombotic state associated with COVID-19, there are no clear recommendations for initiating LMWH for prophylaxis of thromboembolic complications.  LMWH should be initiated in this setting according to institutional and local guidelines.
• Due to the lack of evidence, systemic corticosteroids should not be recommended in patients without COVID-19 related acute respiratory distress syndrome (ARDS). In patients with ARDS, there is still insufficient data to conclusively recommend for or against the use of systemic corticosteroids. Several institutional guidelines consider its use only when indicated for other conditions, although these guidelines may change as more data is published.

Related topics

• none

Summary of information

Use of heparin products

Clinical trials have suggested a high rate of thromboembolic complications among COVID-19 patients in hospital. One study reported a 27% incidence of venous thromboembolism (VTE) and 3.7% incidence of arterial thrombotic events among 184 ICU patients.[1] Another study reported that 25% of 81 severely ill COVID-19 patients had VTE.[2] Another recent study reported cumulative incidences of VTE and pulmonary embolism at 69% and 23%, respectively.[3] Evidence indicates that the prevalence of embolic events is increasing [4], which may be due to a higher level of suspicion and increased diagnostic testing, as opposed to a true change in clinical course.

Additionally, severe COVID-19 patients experience complications that impair gas exchange, which has been suggested to be a result of proinflammatory upregulation.[5] This proinflammatory upregulation then stimulates intrinsic fibrinolysis in the lungs, decreasing pulmonary functions.[6] The evidence indicates the potential anticoagulant and anti-inflammatory effects to reduce inflammation and thrombus formation. In a non-peer-reviewed article, 21 patients received low molecular weight heparin (LMWH) and 21 patients did not. The finding suggested that patients who were treated with LMWH showed a significant reduction of IL-6 levels, indicating an improvement from hyperinflammatory state.[7]

The International Society of Thrombosis and Haemostasis (ISTH) recommends all COVID-19 patients who require hospital admission to receive prophylactic doses of low molecular weight heparin (LMWH).[8] In the absence of proven or suspected thromboembolic complications, there are otherwise no clear guidelines or consensus about administration and dosing of LMWH to prevent those complications. For example, in review of some institutional protocols (available to the public online) some use prophylactic dosing while others use therapeutic dosing for all patients, while others rely on lab findings (ie. D-dimer) to determine dose.[9][10][11]

Use of steroids

Besides heparin, corticosteroid therapy has also been suggested to manage the hyperinflammatory state of COVID-19 infection, especially among COVID-19 patients with acute respiratory distress syndrome (ARDS). Recently, results from the RECOVERY (Randomised Evaluation of COVid-19 thERapY) trial showed that dexamethasone 6 mg PO or IV reduced deaths by ⅓ in patients requiring ventilation and by ⅕ in patients receiving oxygen. The trial press release calculated that 1 death would be prevented in every 8 ventilated patients and in every 25 patients needing oxygen.[12] However, the details of this clinical trial have not been released. Additionally, prior data suggested potential harm from steroid use, including one study showed that every 10-mg increase in dosage (of hydrocortisone equivalents) was associated with 4% mortality risk.[13]  

Currently, systemic steroids are only routinely used if they are indicated for other conditions such as comorbidities (ie. COPD), refractory septic shock and multisystem inflammatory syndrome.[8]

Gaps in knowledge:

More research is needed to establish solid evidence on the use of heparin/low molecular weight heparin and corticosteroid in managing COVID-19 complications. Additionally, the optimal type and dose of corticosteroids should also be evaluated.

References:

1. Klok FA, Kruip MJHA, van der Meer NJM, et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res. 2020;191:145-147. doi:10.1016/j.thromres.2020.04.013.
2. Cui S, Chen S, Li X, Liu S, Wang F. Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia. J Thromb Haemost. 2020;18(6):1421-1424. doi:10.1111/jth.14830.
3. Llitjos JF, Leclerc M, Chochois C, et al. High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients [published online ahead of print, 2020 Apr 22]. J Thromb Haemost. 2020;10.1111/jth.14869. doi:10.1111/jth.14869.
4. Poissy J, Goutay J, Caplan M, et al. Pulmonary Embolism in COVID-19 Patients: Awareness of an Increased Prevalence [published online ahead of print, 2020 Apr 24]. Circulation. 2020;10.1161/CIRCULATIONAHA.120.047430. doi:10.1161/CIRCULATIONAHA.120.047430.
5. Xiong TY, Redwood S, Prendergast B, Chen M. Coronaviruses and the cardiovascular system: acute and long-term implications. Eur Heart J. 2020;41(19):1798-1800. doi:10.1093/eurheartj/ehaa231.
6. Idell S. Coagulation, fibrinolysis, and fibrin deposition in acute lung injury. Crit Care Med. 2003;31(4 Suppl):S213-S220. doi:10.1097/01.CCM.0000057846.21303.AB.
7. Shi C, Wang C, Wang H, et al. The potential of low molecular weight heparin to mitigate cytokine storm in severe COVID-19 patients: a retrospective clinical study. medRxiv 2020.03.28.20046144; doi: https://doi.org/10.1101/2020.03.28.20046144.
8. Thachil J, Tang N, Gando S, et al. ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J Thromb Haemost. 2020;18(5):1023-1026. doi:10.1111/jth.14810.
9. COVID-19 treatment adult algorithm and appendices. Yale New Haven Hospital. Available at: https://files-profile.medicine.yale.edu/documents/337c3b98-bce9-40f0-a142-b56fce324879. Accessed June 19, 2020.
10. Mount Sinai Health System Treatment Guidelines for SARS-CoV-2 Infection. Mount Sinai Health System. Available at: https://www.mountsinai.org/files/MSHealth/Assets/HS/About/Coronavirus/MSHS-Treatment-Guidelines-COVID.pdf. Accessed June 19, 2020.
11. Massachusetts General Hospital (MGH) COVID-19 Treatment Guidance. The General Hospital Corporation. Available at: https://www.massgeneral.org/assets/MGH/pdf/news/coronavirus/mass-general-COVID-19-treatment-guidance.pdf. Accessed June 18, 2020.
12. Low-cost dexamethasone reduces death by up to one third in hospitalised patients with severe respiratory complications of COVID-19. Oxford University News Release. Available at: https://www.recoverytrial.net/files/recovery_dexamethasone_statement_160620_v2final.pdf. Accessed June 18, 2020.
13. Lu X, Chen T, Wang Y, Wang J, Yan F. Adjuvant corticosteroid therapy for critically ill patients with COVID-19. Crit Care. 2020;24(1):241. Published 2020 May 19. doi:10.1186/s13054-020-02964-w.