What I did before
COVID-19 is associated with increased risk of venous, arterial, and microvascular thrombosis. Early reports documented high rates of venous thromboembolism (VTE) in hospitalized patients with COVID-19, with pooled incidences of 20-30%, despite standard-dose thromboprophylaxis.1-2
Patients hospitalized with COVID-19 carry traditional provoking factors for VTE, including immobility and acute systemic inflammation. Beyond this, SARS-CoV-2 infection stimulates procoagulant pathways and provokes endothelial damage, resulting in microangiopathy and in-situ thrombosis.3 Thrombogenicity correlates with disease severity, and this is demonstrated by higher documented VTE rates in intensive care unit (ICU) patients (22.7%, 95%CI 18.1-27.6) compared to non-ICU patients (7.9%, 95%CI 5.1-11.2).1 In turn, diagnosis of VTE in patients with COVID-19 is associated with poor prognosis.2
Beyond its role in the prevention and treatment of VTE, heparin harbours anti-inflammatory and anti-viral properties.3 Accordingly, it has been hypothesized that pharmacologic VTE prophylaxis with heparin agents at higher than conventional dosing may improve clinical outcomes for hospitalized patients with COVID-19. Until recently, however, this practice was not supported by clinical trials. In fact, up to early 2021, most major guidelines recommended conventional over high-dose VTE prophylaxis in hospitalized patients with COVID-19.4-6
What changed my practice
Multiple randomized control trials (RCTs) have sought to determine the safety and efficacy of therapeutic anticoagulation in both critically ill and non-critically ill hospitalized patients with COVID-19. Patients with high bleeding risk, contraindication to anticoagulation, an established indication for anticoagulation, concurrent use of dual antiplatelet therapy, pregnancy, or imminent death were excluded.
1. ATTACC, ACTIV4-a, REMAP-CAP (NEJM, August 2021)7, 8
In this multiplatform RCT, 3317 adult patients hospitalized with COVID-19 were randomized to receive therapeutic-dose low molecular weight heparin (LMWH)/unfractionated heparin (UFH) or either standard or intermediate-dose thromboprophylaxis based on local practice. Treatment duration was 14 days or until recovery, which was defined as hospital discharge or discontinuation of oxygen support for over 24 hours. The primary outcome was a composite of organ support–free days and all-cause mortality, evaluated by a Bayesian statistical model.
Patients were grouped into those requiring and not requiring ICU-level support. Results from each cohort were published separately.
Non-critically ill patients (n=1098) who received therapeutic-dose LMWH/UFH were more likely to survive to discharge without the need for organ support (80.2%) compared to controls (76.4%), with a probability of superiority of 98.6%. The benefit was independent of D-dimer levels. Rates of major bleeding were infrequent but trended to be higher in the treatment group (1.9% vs 0.9%).7
In critically ill patients (n=2219), therapeutic-dose LMWH/UFH did not increase the probability of survival to hospital discharge or the number of days free of organ support, with a 99.9% probability of futility. There was also a trend for more major bleeding with therapeutic anticoagulation (3.8% vs. 2.3%).8
2. INSPIRATION (JAMA, May 2021)9
562 adult patients admitted to the ICU with COVID-19 were randomized to receive enoxaparin at either intermediate dosing (1 mg/kg daily) or standard thromboprophylaxis dosing (40 mg daily). Patients with weight less than 40 kg were excluded. There was no difference in the composite primary efficacy outcome of venous or arterial thrombosis, ECMO use, or 30-day mortality between the groups (45.7% vs. 44.1%; p=0.70). There was no significant difference in major bleeding (2.5% vs. 1.4%; p=0.33).
3. RAPID (BMJ, October 2021)10
465 non-critically ill patients hospitalized with COVID-19 and elevated D-dimer were randomized to receive therapeutic-dose LMWH/UFH (n=237) vs standard-dose thromboprophylaxis (n=237). Anticoagulation was continued until the first of 28 days or hospital discharge. The primary composite outcome of death, mechanical ventilation, or ICU admission was not significantly lower in patients receiving therapeutic anticoagulation (16.2% vs. 21.9%; p= 0.12). However, therapeutic dosing was associated with a significant reduction in all-cause mortality (1.8% vs. 7.6%, p = 0.006). Rates of major bleeding were similar and infrequent in both groups (0.9% vs. 1.7%; p= 0.69).
4. HEP-COVID (JAMA, October 2021)11
253 hospitalized adults with COVID-19 were randomized to receive therapeutic-dose enoxaparin (1mg/kg twice daily) vs standard prophylactic or intermediate-dose heparins as per institutional protocol. Inclusion criteria were requirement for supplemental oxygen and either D-dimer levels more than 4 times the upper limit of normal or a sepsis-induced coagulopathy score of 4 or greater. Patients with gastrointestinal or intracranial cancer, bronchiectasis or pulmonary cavitation, hepatic dysfunction with INR greater than 1.5, or creatinine clearance less than 15 mL/min/1.73 m2 were excluded.
The primary efficacy outcome of VTE, arterial thrombosis, or death from any cause was significantly reduced in the therapeutic anticoagulation arm compared to controls (28.7% vs. 41.9% respectively; p=0.03), and this was driven by a reduction in thromboembolism (10.9% vs 29.0%; p<0.001). This benefit was observed in patients without critical illness and not in those with critical illness, which was defined as mechanical ventilation, non-invasive positive pressure ventilation or high-flow nasal cannula, vasopressors, or vital sign monitoring at least every 4 hours. There was no significant difference in major bleeding between groups, although there was a trend towards more bleeding in the critically ill stratum who received therapeutic enoxaparin (8.0% vs. 0%; p= 0.12).
What I do now
In summary, therapeutic-dose LMWH/UFH improves clinical outcomes, and possibly survival, in non-critically ill hospitalized patients with COVID-19. This benefit comes at the cost of slightly increased, although infrequent, rates of major bleeding. In contrast, therapeutic-dose thromboprophylaxis does not improve outcomes, and in fact may cause harm, in critically ill patients.
Our practice mirrors the most recent guidelines from the BC Center for Disease Control (BCCDC)12 and American Society of Hematology (ASH)6. We initiate therapeutic-dose LMWH/UFH for non-critically ill hospitalized COVID-19 patients without high bleeding risk and we provide standard-dose thromboprophylaxis for patients needing ICU-level care.
The preferred anticoagulant is LMWH; UFH is an alternative if LMWH is contraindicated. We do not use DOACs for thromboprophylaxis, as the current literature does not support this13 and LMWH/UFH has lower risk of drug-drug interactions with COVID-19 therapeutic agents. We initiate thromboprophylaxis immediately upon admission and continue until hospital discharge. In accordance with ASH14 and BCCDC12 guidelines, we do not extend thromboprophylaxis routinely beyond hospital discharge because the risk of symptomatic VTE is low.
- Nopp S, Moik F, Jilma B, Pabinger I, Ay C. Risk of venous thromboembolism in patients with COVID‐19: a systematic review and meta‐analysis. Res Pract Thromb Haemost 2020 Sep 25;4(7):1178-1191. DOI: 10.1002/rth2.12439. (View)
- Malas MB, Naazie IN, Elsayed N, Mathlouthi A, Marmor R, Clary B. Thromboembolism risk of COVID-19 is high and associated with a higher risk of mortality: A systematic review and meta-analysis. EClinicalMedicine. 2020 Dec 1;29:100639. DOI: 10.1016/j.eclinm.2020.100639. (View)
- Iba T, Levy JH, Levi M, Thachil J. Coagulopathy in COVID‐19. J Thromb Haemost. 2020 Sep;18(9):2103-9. DOI: 10.1111/JTH.14975. (View)
- Spyropoulos AC, Levy JH, Ageno W, Connors JM, Hunt BJ, Iba T, et al. Scientific and standardization committee communication: Clinical guidance on the diagnosis, prevention and treatment of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost. 2020 Aug;18(8):1859-1865. DOI: 10.1111/JTH.14929. (View)
- Moores LK, Tritschler T, Brosnahan S, Carrier M, Collen JF, Doerschug K, et al. Prevention, diagnosis, and treatment of VTE in patients with coronavirus disease 2019: CHEST guideline and expert panel report. Chest. 2020 Sep 1;158(3):1143-63. DOI: 10.1016/j.chest.2020.05.559. (View)
- Cuker A, Tseng EK, Nieuwlaat R, Angchaisuksiri P, Blair C, Dane K, et al. American Society of Hematology 2021 guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19. Blood Adv. 2021 Feb 9;5(3):872-88. DOI:10.1182/bloodadvances.2020003763. (View)
- Lawler PR, Goligher EC, Berger JS, Neal MD, McVerry BJ, Nicolau JC, et al. Therapeutic anticoagulation with heparin in noncritically ill patients with Covid-19. N Engl J Med. 2021 Aug 26; 385(9):790-802. DOI:10.1056/NEJMoa2105911. (View)
- REMAP-CAP, ACTIV-4a, and ATTACC Investigators. Therapeutic anticoagulation with heparin in critically ill patients with Covid-19. N Engl J Med. 2021 Aug 26;385(9):777-89. DOI: 10.1056/NEJMoa2103417. (View)
- Mazloomzadeh S, Khaleghparast S, Ghadrdoost B, Mousavizadeh M, Baay MR, Noohi F, et al. Effect of intermediate-dose vs standard-dose prophylactic anticoagulation on thrombotic events, extracorporeal membrane oxygenation treatment, or mortality among patients with COVID-19 admitted to the intensive care unit: the INSPIRATION randomized clinical trial. 2021 Apr 27;325(16):1620-30. DOI: 10.1001/jama.2021.4152. (View)
- Sholzberg M, Tang GH, Rahhal H, AlHamzah M, Kreuziger LB, Áinle FN, et al. Effectiveness of therapeutic heparin versus prophylactic heparin on death, mechanical ventilation, or intensive care unit admission in moderately ill patients with covid-19 admitted to hospital: RAPID randomised clinical trial. BMJ 2021 Oct 14;375:n2400. DOI: 10.1136/bmj.n2400. (View)
- Spyropoulos AC, Goldin M, Giannis D, Diab W, Wang J, Khanijo S, et al. Efficacy and safety of therapeutic-dose heparin vs standard prophylactic or intermediate-dose heparins for thromboprophylaxis in high-risk hospitalized patients with COVID-19: the HEP-COVID randomized clinical trial. JAMA Internal Medicine. 2021 Dec 1;181(12):1612-20. DOI: 10.1001/jamainternmed.2021.6203. (View)
- The British Columbia Center for Disease Control. Antimicrobial and immunomodulatory therapy for adult patients with COVID-19. Updated February 6th, 2022. Accessed February 10th, 2022. (View)
- Lopes RD, Furtado RH, Macedo AV, Bronhara B, Damiani LP, Barbosa LM, de Aveiro Morata J, Ramacciotti E, de Aquino Martins P, de Oliveira AL, Nunes VS. Therapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID-19 and elevated D-dimer concentration (ACTION): an open-label, multicentre, randomised, controlled trial. The Lancet. 2021 Jun 12;397(10291):2253-63 (View)
- Cuker A, Tseng EK, Nieuwlaat R, Angchaisuksiri P, Blair C, Dane K, et al. American Society of Hematology living guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19: July 2021 update on postdischarge thromboprophylaxis. Blood Adv. 2022 Jan 25;6(2):664-671. DOI: 10.1182/bloodadvances.2021005945. (View)