What is the most recent literature regarding VTE prophylaxis in critically ill patients with COVID-19?

What is the most recent literature regarding the utility of enhanced VTE prophylaxis in critically ill patients with COVID-19?

Comment by InpharmD Researcher

Guidelines do not recommend an intermediate or therapeutic dose of anticoagulation over prophylactic doses for hospitalized COVID-19 patients. Some studies have observed positive impacts on patient prognosis with intermediate and therapeutic anticoagulation dosing; however, these studies are limited by small sample sizes or retrospective designs.

Background

The U.S. National Institute of Health (NIH) guidelines for antithrombotic therapy in patients with COVID-19 recommend prophylactic dose anticoagulation for nonpregnant adults hospitalized with COVID-19. Anticoagulant or antiplatelet therapy should not be used to prevent arterial thrombosis outside of the usual standard of care for patients without COVID-19. The guidelines do not make a recommendation for or against higher than prophylactic doses of anticoagulation due to insufficient data. Based on a meta-analysis by the American Society of Hematology, patients treated with intermediate or therapeutic doses of anticoagulation versus prophylactic doses did not confer a benefit in VTE and mortality in critically=ill patients. While there were lower odds of pulmonary embolism (odds ratio [OR] 0.09; 95% CI 0.02 to 0.57), intermediate and therapeutic doses were also associated with higher odds of major bleeding (OR 3.84; 95% CI 1.44 to 10.21). Data for therapeutic doses to prevent VTE is insufficient to form a conclusion. [1]

The American Society of Hematology guidance statement recommends prophylactic-intensity over intermediate or therapeutic-intensity anticoagulation in critically-ill COVID-19 patients due to lack of direct, high-quality evidence. However, they do not recommend against providers administering higher intensities of anticoagulation if they choose to. Patients should be individually assessed to determine anticoagulation intensity. [2], [3]

Per Interim Guidelines from the Anticoagulation Forum published in May 2020, critically ill patients (i.e. ICU) with confirmed for highly-suspected COVID-19 are recommended to receive increased doses of VTE prophylaxis. Examples include enoxaparin 40 mg SubQ BID, enoxaparin 0.5 mg/kg SubQ BID, heparin 7500 units SubQ TID, or low-intensity heparin infusion. Doses should be adjusted based on renal function and extreme weight. This recommendation is based largely on expert opinion. [4]

Given the emerging evidence of clinical benefits, the Scientific and Standardization Committee (SSC) of the International Society on Thrombosis and Haemostasis (ISTH) suggests approximately 4 weeks of extended-duration VTE prophylaxis (at least 2 weeks and up to 6 weeks post-hospital discharge) either with prophylactic-dose LMWH (e.g., enoxaparin, dalteparin, tinzaparin) or a DOAC (e.g., rivaroxaban, betrixaban) for selected hospitalized COVID-19 patients who meet high VTE risk criteria (e.g., advanced age, ICU stay, cancer, history of VTE, thrombophilia, severe immobility, elevated D-diver of >2 times ULN, IMPROVE VTE score >4) with low bleed risk. [5]

Unlike the clinical guidance discussed above, the CHEST expert panel only recommends inpatient VTE prophylaxis due to the uncertainty around the true incidence of post-discharge VTE and potential major bleeding in COVID-19 patients with extended thromboprophylaxis. The panel observed potential net benefit of extended thromboprophylaxis only when the patient has low bleed risk, and the risk of symptomatic VTE is above 1.8% at 35-42 days post-discharge. [6]

The Interim Guideline from The Anticoagulation Forum recommends a full 3-month course of anticoagulation therapy for COVID-19 patients even with presumed but unconfirmed hospital-associated VTE events unless at a high risk of bleed or with a recent history of bleed. The SSC and CHEST expert panel also concur with a minimum duration of 3-month therapeutic anticoagulation therapy for VTE treatment. [5], [6]

While inpatient treatment typically involves heparin, some authors suggest direct oral anticoagulants (DOACs) may be preferred for outpatients due to the ease of administration. [7]

Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

What is the most recent literature regarding the utility of enhanced VTE prophylaxis in critically ill patients with COVID-19?

Please see Tables 1-3 for your response.

Therapeutic versus prophylactic anticoagulation for severe COVID-19: a randomized phase II clinical trial (HESACOVID)
Design	Randomized, open-label, phase II trial N=20
Objective	To evaluate whether therapeutic anticoagulation could improve gas exchange compared to the standard anticoagulant thromboprophylaxis, reducing the need to maintain mechanical ventilation in severe COVID-19 patients
Study Groups	Prophylactic anticoagulation (n=10) Therapeutic anticoagulation (n=10)
Inclusion Criteria	Aged >18 years, SARS-CoV-2 infection confirmed by reverse transcriptase-polymerase chain reaction (RT-PCR), acute respiratory distress syndrome (ARDS) per the Berlin definition, severe respiratory failure requiring mechanical ventilation, D-dimer >1,000 μg/L; prothrombin time (PT)/INR <1.5; activated partial thromboplastin time (aPTT)/ratio < 1.5, platelets >100,000/mm³
Exclusion Criteria	Age >85 years, creatinine clearance (CrCl) <10 mL/min, severe circulatory shock with a dose of norepinephrine >1.0 μg/kg/min, chronic renal failure in renal replacement therapy, liver disease (Child-Pugh B or C), other advanced disease (e.g., active cancer, heart failure NYHA class III or IV, COPD), cardiorespiratory arrest, pregnant women, recent major surgery or severe trauma in the last 3 weeks, recent stroke in the last 3 months, active bleeding, blood dyscrasia (e.g., hemophilia, von Willebrand factor deficiency), indication for therapeutic anticoagulation
Methods	Patients were randomized 1:1 to receive prophylactic or therapeutic anticoagulation. The prophylactic anticoagulation group received subcutaneous unfractionated heparin (UFH) at a dose of 5000 IU TID (if weight < 120 kg) and 7500 IU TID (if weight > 120 kg) or enoxaparin at a dose of 40 mg daily (if weight < 120 kg) and 40 mg BID (if weight > 120 Kg) according to the doctor's judgment. Therapeutic anticoagulation consisted of subcutaneous (SC) enoxaparin dosed according to age and CrCl (1 mg/kg BID if aged <75 years with CrCl >50 mL/min). If the patient's CrCl worsened to <10 mL/min during the study period, then UFH was given adjusted to an activated partial thromboplastin time (aPTT) between 1.5 and 2.0. Therapeutic enoxaparin was given for at least 96 hours, but was ideally given for 14 days. Anticoagulation could be suspended at any time if there was evidence of clinical bleeding.
Duration	Recruitment: April to July 2020 Follow-up: up to 28 days
Outcome Measures	Primary: PaO2/FiO2 ratio at days 7 and 14 Secondary: time until removed from ventilation; ventilator-free days (of the 28-day study period); D-Dimer levels; mortality
Baseline Characteristics		Prophylactic anticoagulation (n=10)	Therapeutic anticoagulation (n=10)	P-value
	Age, years	58 ± 16	55 ± 10	0.529
	Male	70%	90%	0.264
	Time from symptom onset to hospitalization, days Time in ICU before enrollment, days (IQR)	6 ± 3 1 (0-2)	7 ± 2 0 (0-2)	0.464 0.496
	Body mass index, kg/m²	34 ± 8	33 ± 8	0.828
	Previous anticoagulation use Prophylactic Therapeutic	70% 0	40% 0	0.137 1.000
	Concomitant medications* Norepinephrine Corticosteroids Hydroxychloroquine Macrolide antibiotic	60% 70% 10% 90%	60% 70% 40% 90%	1.00 1.00 0.121 1.00
	SOFA score (IQR)	10 (8-11)	10 (7-11)	0.877
	Baseline PaO2/FiO2 ratio	184 ± 53	163 ± 41	0.336
	*No patients received remdesivir, any interleukin-6 inhibitors, or antiplatelet agents; all patients received neuromuscular blocking agents. Therapeutic anticoagulation was prescribed for a median of 14 days, which may be considered excessive for these patients. IQR=interquartile range; SOFA=sequential organ failure assessment
Results		Prophylactic anticoagulation (n=10)	Therapeutic anticoagulation (n=10)	P-value
	PaO2/FiO2 ratio (95% confidence interval) Day 0 Day 7 Day 14	184 (146–222) 168 (142–195) 195 (128–262)**	163 (133–193) 209 (171–247) 261 (230–293)**	0.336 0.060 0.057
	Ventilator-free days (IQR) ICU-free days (IQR)	0 (0−11) 0 (0−10)	15 (6-16) 12 (2-12)	0.028 0.067
	All-cause 28-day mortality In-hospital mortality	30% 50%	10% 20%	0.264 0.160
	D-dimer, µg/L (95% CI) Baseline After anticoagulation Days between measurements	3408 (1283–5532) 4878 (2291–7465) 4.3 ± 1.2	4176 (1986–6365] 1469 (1034–1904) 3.9 ± 1.2
	Length of hospital stay, days (IQR)	30 (23-38)	31 (22-35)	0.838
	Thrombotic events	20%	20%	1.000
	**An intergroup analysis showed a significant increase from baseline to 14 days in PaO2/FiO2 ratio with the therapeutic group (P=0.0004), but not with the prophylactic group (P=0.487).
Adverse Events		Prophylactic anticoagulation (n=10)	Therapeutic anticoagulation (n=10)
	Major bleeding	0	0
	Minor bleeding	0	20%
	Bleeding requiring medical attention	20%	40%
	Drop in hemoglobin >5.0 g/dL	20%	40%
Study Author Conclusions	This open-label, controlled, randomized clinical trial demonstrated that therapeutic enoxaparin improved gas exchange over time and increased the ratio of successful liberation from mechanical ventilation. After these results, a larger clinical trial is urgently needed to evaluate the anticoagulant therapy in severe COVID-19 patients.
InpharmD Researcher Critique	This study is limited by its single-center design and small sample size, which was not large enough to power for mortality. Instead, the primary endpoint (PaO2/FiO2 [P/F] ratio) is limited in quantifying pulmonary dysfunction improvement. Additionally, this study was conducted relatively early in the pandemic (April to July 2020), which may represent different practices for patients with COVID-19.

References:

Lemos ACB, do Espírito Santo DA, Salvetti MC et al. Therapeutic versus prophylactic anticoagulation for severe COVID-19: a randomized phase II clinical trial (HESACOVID). Thromb Res. 2020;196:359–366.

Intermediate-dose anticoagulation, aspirin, and in-hospital mortality in COVID-19: a propensity score-matched analysis
Design	Retrospective, propensity score-matched, observational study N=2785
Objective	To examine the impact of intermediate-dose anticoagulation and aspirin on in-hospital mortality in COVID-19
Study Groups	Alive (n=2402) Dead (n=383)
Inclusion Criteria	Diagnosis of COVID-19 via PCR test
Exclusion Criteria	Age < 18 years, multiple inpatient hospital encounters, missing data
Methods	Patient medical records were extracted from the analytics team and analyzed. Patients were categorized into one of six anticoagulation intensity groups based on the criteria. 1. Prophylaxis dose: received a maximum enoxaparin dose of 30–40 mg at a weight-adjusted concentration of < 0.7 mg/kg every 24 hours, enoxaparin 30–40 mg at a weight-adjusted concentration of < 0.4 mg/kg every 12 hours, subcutaneous unfractionated heparin (UFH) 5000 units up to three times per day, or subcutaneous UFH 5000 or 7500 units up to three times per day with a BMI ≥ 40 kg/m2, and who did not receive any other type of documented anticoagulant during their hospitalization 2. Intermediate dose: received a maximum enoxaparin dose of ≥ 0.4 and < 0.7 mg/kg every 12 hours or subcutaneous UFH 7500 U at any frequency with a BMI < 40 kg/m2, and who did not receive any other type of anticoagulant during their hospitalization. 3. Therapeutic dose: received a maximum enoxaparin dose ≥ 0.7 mg/kg every 12 hours, enoxaparin ≥ 0.7 mg/kg every 24 hours with creatinine clearance < 30 mL/min, enoxaparin ≥ 1.4 mg/kg every 24 hours, intravenous UFH, or intravenous bivalirudin. 4. Alternative dose: received any other dose of enoxaparin and who did not receive a direct oral anticoagulant (DOAC) or any other therapeutic-dose anticoagulant. 5. DOAC: received a DOAC and no other type of therapeutic-dose anticoagulation 6. No documented anticoagulation: All other patients. Propensity score-matching calculated using multivariable regression analysis was performed to adjust for disease severity and other clinical covariates. These were individually reported as hazard ratio (HR) for death based on the individual covariates.
Duration	March 2020 to June 2020
Outcome Measures	Primary outcome: In-hospital death Secondary outcome: Multivariable analysis of in-hospital death in the propensity-score matched anticoagulation cohort for the intermediate dose anticoagulation versus prophylactic dose.
Baseline Characteristics		Total	Alive (n=2402)	Dead (n=383)	p-value
	Age, years 18 to 40 >40 to 50 >50 to 60 >60 to 70 >70 to 80 >80 to 90 >90 to 110	359 298 501 553 492 421 161	356 (99.2%) 285 (95.6%) 467 (93.2%) 499 (90.2%) 389 (79.1%) 301 (71.5%) 105 (65.2%)	3 (0.8%) 13 (4.4%) 34 (6.8%) 54 (9.8%) 103 (20.9%) 120 (28.5%) 56 (34.8%)	<0.001
	Female	1389	1212 (87.3%)	177 (12.7%)	0.12
	Race Caucasian African-american Asian-merican Others	1300 746 62 677	1074 (82.6%) 650 (87.1%) 51 (82.3%) 627 (92.6%)	226 (17.4%) 96 (12.9%) 11 (17.7%) 50 (7.4%)	<0.001
	Cardiovascular disease	1683	1406 (83.5%)	277 (16.5%)	<0.001
	Home antiplatelet prior to hospitalization	804	650 (80.8%)	154 (19.2%)	<0.001
	In-hospital aspirin use	964	811 (84.1%)	153 (15.9%)
Results	Endpoint	Total	Alive (n=2402)	Dead (n=383)	p-Value
	Anticoagulation during hospitalization Prophylactic Intermediate Therapeutic Alternative enoxaparin dose DOAC No documented anticoagulation	1395 229 531 162 233 235	1291 (92.5%) 189 (82.5%) 386 (72.7%) 141 (87.0%) 206 (88.4%) 189 (80.4%)	104 (7.5%) 40 (17.5%) 145 (27.3%) 21 (13.0%) 27 (11.6%) 46 (19.6%)	<0.001
		Hazard ratio for death		95% confidence interval	p-value
	Multivariable analysis of in-hospital death for anticoagulation when comparing intermediate dose anticoagulation with prophylactic dose	0.518		0.308 to 0.872	0.013
Study Author Conclusions	In this propensity score-matched, observational study of COVID-19, intermediate-dose anticoagulation and aspirin were each associated with a lower cumulative incidence of in-hospital death.
InpharmD Researcher Critique	This article is a preprint and must be interpreted with caution. Nevertheless, this is one of newer studies that attempted to control for baseline characteristics. Observational studies are investigational by nature but the propensity score-matching strengthens the applicability of the results.

References:

Meizlish ML, Goshua G, Liu Y, et al. Intermediate-dose anticoagulation, aspirin, and in-hospital mortality in COVID-19: a propensity score-matched analysis. Preprint. medRxiv. 2021;2021.01.12.21249577. Available 2021 Jan 15. doi:10.1101/2021.01.12.21249577

Beneficial Effects of Intermediate Dosage of Anticoagulation Treatment on the Prognosis of Hospitalized COVID-19 Patients: The ETHRA Study
Design	Retrospective analysis N=95
Objective	To study the potential beneficial effects of different dosages of anticoagulation treatment on the prognosis of COVID-19 inpatients and on coagulation and inflammatory biomarkers as well as to evaluate the safety profile of this therapeutic strategy
Study Groups	No prophylaxis (n=15) Prophylaxis (n=26) Intermediate (n=42) Therapeutic (n=12)
Inclusion Criteria	Hospitalized in general COVID-19 wards, anticoagulation within first 5 days post-admission
Exclusion Criteria	Contraindication to anticoagulation therapy (e.g. active bleeding), venous thromboembolism (VTE) or intubation or death within the first 24 hours post-admission
Methods	Medical records of patients were obtained and analyzed. On March 11, 2020, the hospital adopted the Enhanced dose THRomboprophylaxis (intermediate dose) in all COVID-19 Admissions (ETHRA). This protocol was revised on March 25, 2020. The intermediate and therapeutic doses were not described but consisted of LMWH or fondaparinux. Patients received intermediate doses by default and therapeutic doses if there is radiological deterioration, clinical deterioration with hypoxemia and/or unexplained fever, clinical suspicion for DVT/PE, or increasing D-dimers. They were compared with patients who received prophylaxis and no prophylaxis treatment (possibly denoting a group of patients deviating from the ETHRA hospital protocol. But, once again, this was unspecified).
Duration	Not specified
Outcome Measures	Primary outcome: Incidence of intubations or VTE, pulmonary embolism (PE), and deep vein thrombosis (DVT) confirmed with imaging Secondary outcome: Inflammatory biomarkers in patients treated with intermediate dosages, safety
Baseline Characteristics		No prophylaxis (n=15)	Prophylaxis (n=26)	Intermediate (n=42)	Therapeutic (n=12)
	Age, years	53.7	56.8	58.5	76
	Males	8 (53.3%)	14 (53.8%)	30 (71.4%)	6 (50%)
	Smoking Hypertension Diabetes	20% 13.3% 0	26.9% 19.2% 11.5%	21.4% 35.7% 7.1%	8.3% 33.3% 16.7%
	Charlson Comorbidity Index*	1 (0 to 3)	2 (0 to 3.3)	2 (0 to 3)	5 (5 to 7.5)
	Hydroxychloroquine Axithromycin Other antibiotics Lopniavir/Ritonavir Remdesivir	60% 80% 73% 20% 0	81% 88% 88% 8% 0	79% 90% 83% 14% 2%	58% 67% 83% 17% 0
	*p-value for Charlson Comorbidity index was <0.001 indicating a significant difference between groups (due to the high score in the therapeutic group).
Results	Endpoint	No prophylaxis (n=15)	Prophylaxis (n=26)	Intermediate (n=42)	Therapeutic (n=12)
	Incidence of primary outcome Death	6 (40%) 1	5 (19%) 1	6 (14%) 0	4 (33%) 2
	Regression analysis of reduction of events compared to the no prophylaxis and prophylaxis group, hazard ratio (95% confidence interval [CI]; p-value)	-	-	0.16 (0.05 to 0.52; p=0.002)	0.17 (0.04 to 0.71; p=0.015)
	Intermediate group (n=15) ferritin increased before initiation of LMWH and decreased to similar levels of untreated controls > 3 days after. No other biomarkers were significantly different between treatment group
Adverse Events	Hemorrhagic complications: n=2 in the intermediate group and n=1 in the prophylactic group. None required discontinuation.
Study Author Conclusions	Anticoagulation treatment (particularly intermediate dosage) appears to have positive impact on COVID-19 inpatients’ prognosis by inhibiting both coagulation and inflammatory cascades.
InpharmD Researcher Critique	Retrospective studies are exploratory and need to be verified in subsequent studies. There were a lack of frequent measurements of clinical markers. The therapeutic group also had a higher Charlson Comorbidity Index which may be the cause of higher incidences or morbidity and mortality.

References:

Poulakou G, Dimakakos E, Kollias A, et al. Beneficial Effects of Intermediate Dosage of Anticoagulation Treatment on the Prognosis of Hospitalized COVID-19 Patients: The ETHRA Study. In Vivo. 2021;35(1):653-661. doi:10.21873/invivo.12305