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Table 6a. Anticoagulant Therapy: Selected Clinical Trial Data

Last Updated: February 29, 2024

The clinical trials described in this table do not represent all the trials that the Panel reviewed while developing the recommendations for anticoagulant therapy. The studies summarized below are those that have had the greatest impact on the Panel’s recommendations.

Table 6a. Anticoagulant Therapy: Selected Clinical Trial Data
Methods Results Limitations and Interpretation
ATTACC/ACTIV-4a/REMAP-CAP: Multiplatform, Open-Label RCT of Therapeutic Anticoagulation in Noncritically Ill, Hospitalized Patients With COVID-19 in 9 Countries1

Key Inclusion Criterion

  • Hospitalized with laboratory-confirmed SARS-CoV-2 infection without need for HFNC oxygen, NIV, MV, vasopressors, or inotropes

Key Exclusion Criteria

  • Hospital discharge expected in ≤72 hours
  • Need for therapeutic anticoagulation or dual antiplatelet therapy
  • High bleeding risk

Interventions

  • Therapeutic UFH or LMWH for 14 days or until hospital discharge, whichever came first (n = 1,190) 
  • SOC, which included prophylactic UFH or LMWH (n = 1,054)

Primary Endpoint

  • Organ support-free days by Day 21, as measured by an OS

Key Secondary Endpoints

  • Survival until hospital discharge
  • Hospital LOS
  • Thrombosis or major bleeding events

Participant Characteristics

  • Median age 59 years; 59% men; median BMI 30
  • 52% with HTN; 30% with DM; 11% with CVD 
  • 66% required low-flow oxygen.
  • D-dimer level: 
    • 48.4% <2 times ULN 
    • 28.4% ≥2 times ULN 
    • 23.1% unknown
  • 62% on corticosteroids; 36% on RDV 

Primary Outcomes

  • Therapeutic anticoagulation was superior to SOC for organ support-free days (aOR 1.27; 95% CrI, 1.03–1.58; 99% posterior probability).
  • 4% absolute difference in survival until hospital discharge without organ support that favored therapeutic arm (95% CrI, 0.5–7.2)
  • Outcome was consistent across D-dimer stratum.

Secondary Outcomes

  • Survival until hospital discharge: 92% in both arms
  • No difference between arms in hospital LOS (aOR 1.03; 95% CrI, 0.94–1.13)
  • Thrombosis: 1% in therapeutic arm vs. 2% in SOC arm
  • Major bleeding events: 2% in therapeutic arm vs. 1% in SOC arm

Key Limitations

  • Open-label study
  • Dose for anticoagulation varied in SOC arm (27% received intermediate dose of thromboprophylaxis).
  • Inclusion criteria for hospital LOS and ICU-level care differed across trials.
  • Trial only enrolled 17% of screened patients.

Interpretation

  • Therapeutic heparin increased the number of organ support-free days and decreased the number of patients requiring organ support. 
  • Therapeutic heparin did not significantly affect hospital LOS or the number of major thrombosis events or deaths.
  • Major bleeds occurred 1% more frequently in the therapeutic arm than in the SOC arm.
RAPID: Open-Label RCT of Therapeutic Heparin in Moderately Ill, Hospitalized Patients With COVID-19 in 6 Countries2

Key Inclusion Criteria

  • Hospitalized with COVID-19 and D-dimer level ≥2 times ULN or any elevated D-dimer level and SpO2 ≤93% on room air
  • Hospitalized <5 days

Key Exclusion Criteria

  • Need for therapeutic anticoagulation
  • Receiving dual antiplatelet therapy
  • High bleeding risk

Interventions

  • Therapeutic UFH or LMWH for 28 days or until hospital discharge or death (n = 228) 
  • Prophylactic UFH or LMWH for 28 days or until hospital discharge or death (n = 237)

Primary Endpoint

  • Composite of ICU admission, NIV or MV, or death at 28 days

Key Secondary Endpoints

  • All-cause death at 28 days
  • Mean number of organ support-free days
  • VTE
  • Major bleeding events
  • Mean number of hospital-free days alive

Participant Characteristics

  • Median age 60 years; 57% men; mean BMI 30
  • 48% with HTN; 34% with DM; 7% with CVD
  • 91% with hypoxia; 6% received HFNC oxygen.
  • D-dimer level:
    • 49% <2 times ULN
    • 51% ≥2 times ULN
  • 69% on corticosteroids

Primary Outcome

  • Composite of ICU admission, NIV or MV, or death at 28 days: 16% in therapeutic arm vs. 22% in prophylactic arm (OR 0.69; 95% CI, 0.43–1.10)

Secondary Outcomes

  • All-cause death at 28 days: 2% in therapeutic arm vs. 8% in prophylactic arm (OR 0.22; 95% CI, 0.07–0.65)
  • Mean number of organ support-free days: 26 in therapeutic arm vs. 24 in prophylactic arm (OR 1.41; 95% CI, 0.9–2.21)
  • No difference between arms for VTE (1% in therapeutic arm vs. 3% in prophylactic arm) or major bleeding events (1% in therapeutic arm vs. 2% in prophylactic arm)
  • Mean number of hospital-free days alive: 20 in therapeutic arm vs. 18 in prophylactic arm (OR 1.09; 95% CI, 0.79–1.50)

Key Limitations

  • Open-label study
  • Trial only enrolled 12% of screened patients.

Interpretation

  • Compared to prophylactic heparin, therapeutic heparin reduced mortality (a secondary endpoint) but had no effect on the primary composite endpoint of ICU admission, the need for NIV or MV, or death up to 28 days. 
  • There were no differences between the arms in the percentages of patients who experienced VTE or major bleeding events.
HEP-COVID: Open-Label RCT of Therapeutic Heparin in High-Risk, Hospitalized Patients With COVID-19 in the United States3

Key Inclusion Criteria

  • Hospitalized with COVID-19 and required supplemental oxygen
  • D-dimer level >4 times ULN or sepsis-induced coagulopathy score of ≥4
  • Hospitalized <72 hours

Key Exclusion Criteria

  • Need for therapeutic anticoagulation
  • Receiving dual antiplatelet therapy
  • High bleeding risk
  • CrCl <15 mL/min

Interventions

  • Therapeutic LMWH until hospital discharge or primary endpoint met (n = 129)
  • Usual care of prophylactic or intermediate-dose LMWH until hospital discharge or primary endpoint met (n = 124)

Primary Endpoint

  • Composite of VTE, ATE, or death from any cause within 32 days of randomization

Key Safety Endpoint

  • Major bleeding events within 32 days

Participant Characteristics

  • Median age 67 years; 54% men; mean BMI 30
  • 60% with HTN; 37% with DM; 75% with CVD 
  • 64% received oxygen via nasal cannula; 15% received HFNC oxygen or NIV; 5% received MV.
  • 80% on corticosteroids

Primary Outcomes

  • Composite of VTE, ATE, or death within 32 days: 29% in therapeutic arm vs. 42% in usual care arm (relative risk 0.68; 95% CI, 0.49–0.96)
    • Thrombotic events: 11% in therapeutic arm vs. 29% in usual care arm (relative risk 0.37; 95% CI, 0.21–0.66)
    • Death: 19% in therapeutic arm vs. 25% in usual care arm (relative risk 0.78; 95% CI, 0.49–1.23)
  • Non-ICU stratum composite of VTE, ATE, or death within 32 days: 17% in therapeutic arm vs. 36% in usual care arm (relative risk 0.46; 95% CI, 0.27–0.81)

Safety Outcomes

  • Major bleeding events within 32 days: 5% in therapeutic arm vs. 2% in usual care arm (relative risk 2.88; 95% CI, 0.59–14.02)
    • Non-ICU stratum major bleeding events within 32 days: 2% in both arms

Key Limitations

  • Open-label study
  • Trial only enrolled 2% of screened patients.

Interpretation

  • Compared to usual care, therapeutic LMWH reduced the incidence of VTE, ATE, and death.
  • Among patients who were not in the ICU, therapeutic LMWH significantly reduced the percentage of patients who experienced thrombotic events and did not increase the percentage of patients who experienced major bleeding events. 
ACTION: Open-Label RCT of Therapeutic Rivaroxaban in Hospitalized Patients With COVID-19 in Brazil4

Key Inclusion Criteria

  • Hospitalized with COVID-19 and elevated D-dimer level
  • Symptoms for ≤14 days

Key Exclusion Criteria

  • Need for therapeutic anticoagulation
  • CrCl <30 mL/min
  • Receiving P2Y12 inhibitor therapy or aspirin >100 mg
  • High bleeding risk

Interventions

  • Therapeutic anticoagulation for 30 days: rivaroxaban 15 mg or 20 mg once daily; if clinically unstable, enoxaparin 1 mg/kg twice daily or UFH (n = 311) 
  • Usual care prophylactic anticoagulation with enoxaparin or UFH during hospitalization (n = 304)

Primary Endpoint

  • Hierarchical composite of time to death, hospital duration, or oxygen use duration by Day 30

Key Secondary Endpoints

  • Thrombosis, with and without all-cause death
  • Death by Day 30
  • Bleeding events

Participant Characteristics

  • Median age 57 years; 60% men; mean BMI 30
  • 49% with HTN; 24% with DM; 5% with CAD 
  • Critically ill: 7% in therapeutic arm vs. 5% in usual care arm
  • 75% required oxygen: 60% received low-flow oxygen; 8% received HFNC oxygen; 1% received NIV; 6% received MV.
  • 83% on corticosteroids

Primary Outcome

  • No difference between arms in the composite of time to death, hospital duration, or oxygen use duration by Day 30 (win ratio 0.86; 95% CI, 0.59–1.22)

Secondary Outcomes

  • No difference between therapeutic and usual care arms in:
    • Thrombosis: 7% vs. 10%
    • Death by Day 30: 11% vs. 8%
  • Any bleeding events: 12% in therapeutic arm vs. 3% in usual care arm
  • Major bleeding events: 3% in therapeutic arm vs. 1% in usual care arm
  • Clinically relevant, nonmajor bleeding events: 5% in therapeutic arm vs. 1% in usual care arm

Key Limitations

  • Open-label study
  • Trial only enrolled 18% of screened patients.
  • Therapeutic rivaroxaban was administered for a longer duration than prophylactic anticoagulation (30 days vs. a mean duration of 8 days).

Interpretation

  • When compared with usual care, therapeutic rivaroxaban did not reduce mortality, hospital duration, oxygen use duration, or the percentage of patients who experienced thrombosis. 
  • Patients who received therapeutic rivaroxaban had more clinically relevant, nonmajor bleeding events than those who received usual care.
  • The longer duration of therapy in the therapeutic arm may have influenced the difference in bleeding events.
FREEDOM: RCT of Anticoagulation Strategies in Noncritically Ill Patients Who Were Hospitalized With COVID-19 in 10 Countries5 

Key Inclusion Criterion

  • Hospitalized with symptomatic COVID-19 for <48 hours

Key Exclusion Criteria

  • Need for therapeutic anticoagulation
  • CrCl <30 mL/min
  • Receiving P2Y12 inhibitor therapy or aspirin >100 mg per day
  • Anticipated hospitalization for <72 hours

Interventions

  • Therapeutic apixaban 5 mg twice daily (n = 1,121) 
  • Therapeutic enoxaparin 1 mg/kg twice daily (n = 1,136)
  • Usual care prophylactic enoxaparin (n = 1,141)

Primary Endpoint

  • 30-day composite of all-cause mortality, need for ICU-level care, systemic thromboembolism, or ischemic stroke. Endpoint assessed for the combined therapeutic arms vs. the prophylactic arm.

Key Secondary Endpoints

  • 30-day all-cause mortality
  • BARC type 3 or 5 bleeding events

Participant Characteristics

  • Median age 52 years; 59% men; mean BMI 26
  • 32% with HTN; 19% with DM
  • 22% on corticosteroids; 10% on RDV

Primary Outcome

  • 30-day composite outcome: 11.3% in combined therapeutic arms vs. 13.2% in prophylactic arm (HR 0.85; 95% CI, 0.69–1.04; P = 0.11)
  • Primary endpoint was not statistically significant when therapeutic enoxaparin or apixaban were compared to prophylactic enoxaparin.

Secondary Outcomes

  • 30-day all-cause mortality: 4.9% in therapeutic enoxaparin arm vs. 7.0% in prophylactic enoxaparin arm (HR 0.69; 95% CI, 0.49–0.99)
  • 30-day all-cause mortality: 5.0% in therapeutic apixaban arm vs. 7.0% in prophylactic enoxaparin arm (HR 0.7; 95% CI, 0.49–0.99)
  • BARC type 3 or 5 bleeding events: 0.4% in combined therapeutic arms vs. 0.1% in prophylactic arm (IRR 3.96; 95% CI, 0.50–31.27)

Key Limitations

  • Open-label study
  • Trial was terminated early due to slow recruitment (3,452 of 3,600 planned patients recruited).
  • Minimal treatment with RDV or DEX as SOC for COVID-19

Interpretation

  • When compared with prophylactic enoxaparin, therapeutic apixaban and therapeutic enoxaparin did not reduce 30-day mortality, the need for ICU-level care, or the occurrence of  thromboembolism or ischemic stroke. 
  • Fewer patients died in the therapeutic enoxaparin and therapeutic apixaban arms than in the prophylactic enoxaparin arm.
  • There were no statistically significant differences between the arms in the percentages of patients who experienced severe bleeding events.
COVID-PACT: Open-Label RCT of Full-Dose Versus Prophylactic-Dose Anticoagulation in Adults With COVID-19 Who Were Receiving Intensive Care Unit-Level Care in the United States6

Key Inclusion Criteria

  • Aged ≥18 years
  • Acute SARS-CoV-2 infection
  • Required ICU-level care for ≤96 hours prior to randomization

Key Exclusion Criteria

  • Ongoing or planned use of full-dose anticoagulation or dual antiplatelet therapy
  • High bleeding risk
  • History of HIT
  • Ischemic stroke within 2 weeks

Interventions

  • Full-dose anticoagulation until Day 28 or hospital discharge, whichever came first (n = 197)
  • Prophylactic anticoagulation (n = 193)
  • Eligible patients were also randomized 1:1 to receive clopidogrel or no antiplatelet therapy (n = 292)

Primary Endpoint

  • Composite of VTE or ATE events by hospital discharge or Day 28. Events included death due to VTE or ATE, PE, clinically evident DVT, MI, ischemic stroke, systemic embolic event or acute limb ischemia, and clinically silent DVT.

Key Secondary Endpoint

  • Individual outcomes listed above, with the exception of clinically silent DVT

Key Safety Endpoints

  • Fatal or life-threatening bleeding events
  • Moderate or severe bleeding events

Participant Characteristics

  • Median age 61 years; 41% women; 71% White 
  • 99% received HFNC oxygen, NIV, or MV; 15% received MV.
    • 41% received MV during the study.
  • 31% to 37% crossed over to an alternative study treatment during the study.

Primary Outcome

  • Composite of VTE or ATE events by hospital discharge or Day 28: 12% in full-dose anticoagulation arm vs. 6% in prophylactic anticoagulation arm (win ratio 1.95; 95% CI, 1.08–3.55; P = 0.028)

Secondary Outcome

  • Composite of clinically evident VTE or ATE events by hospital discharge or Day 28: 10% in full-dose anticoagulation arm vs. 6% in prophylactic anticoagulation arm (win ratio 1.79; 95% CI, 0.92–3.47; P = 0.087)

Safety Outcomes

  • No fatal bleeding events occurred.
  • Life-threatening bleeding events: 4 (2.1%) in full-dose anticoagulation arm vs. 1 (0.5%) in prophylactic anticoagulation arm (P = 0.19) 
  • Moderate or severe bleeding events: 15 (7.9%) in full-dose anticoagulation arm vs. 1 (0.5%) in prophylactic anticoagulation arm (P = 0.002)

Key Limitations

  • Open-label study (adjudication committee members were blinded to the study arms).
  • Trial was stopped early because the decreasing number of ICU admissions for patients with COVID-19 made recruitment difficult.
  • There was an unequal crossover between the arms, with a greater crossover from the prophylactic anticoagulation arm to the full-dose anticoagulation arm. 

Interpretation

  • Among patients with COVID-19 who required ICU-level care, patients who received full-dose anticoagulation had fewer VTE or ATE events but no survival benefit compared to those who received prophylactic anticoagulation.
  • The prevalence of moderate or severe bleeding events was higher among patients who received full-dose anticoagulation than among those who received prophylactic anticoagulation.
REMAP-CAP/ACTIV-4a/ATTACC: Multiplatform, Open-Label RCT of Therapeutic Anticoagulation in Critically Ill, Hospitalized Patients With COVID-19 in 20 Countries7

Key Inclusion Criteria

  • Hospitalized with severe COVID-19 and receiving HFNC oxygen, NIV, MV, ECMO, vasopressors, or inotropes 
  • Hospitalized <72 hours (ACTIV-4a, ATTACC) or <14 days (REMAP-CAP)

Key Exclusion Criteria

  • Hospital discharge expected in ≤72 hours
  • Need for therapeutic anticoagulation or dual antiplatelet therapy
  • High bleeding risk

Interventions

  • Therapeutic UFH or LMWH for 14 days or until hospital discharge, whichever came first (n = 534)
  • Usual care thromboprophylaxis (n = 564)

Primary Endpoint

  • Number of organ support-free days by Day 21

Key Secondary Endpoints

  • Survival to hospital discharge
  • Any thrombosis
  • Composite of major thrombotic events or death
  • Bleeding events

Participant Characteristics

  • Median age 60 years; 70% men; median BMI 30
  • 24% with chronic respiratory disease; 33% with DM; 10% with chronic kidney disease; 8% with severe CVD 
  • 32% received HFNC oxygen; 38% received NIV; 29% received MV. 
  • 18% on vasopressors; 82% on corticosteroids; 32% on RDV 

Primary Outcome

  • Median number of organ support-free days by Day 21: 4 in therapeutic arm vs. 5 in usual care arm (aOR 0.83; 95% CrI, 0.67–1.03; 99.9% posterior probability of futility; OR < 1.2)

Secondary Outcomes

  • No difference between therapeutic and usual care arms in:
    • Survival to hospital discharge: 63% vs. 65% (aOR 0.84; 95% CrI, 0.64–1.11)
    • Thrombosis: 6% vs. 10% 
    • Composite of major thrombotic events or death: 41% in both arms
    • Major bleeding events: 4% vs. 2% (aOR 1.48; 95% CrI, 0.75–3.04)

Key Limitations

  • Open-label study
  • Dose of thromboprophylaxis varied in usual care arm (51% received intermediate dose; 2% received subtherapeutic dose; 5% received therapeutic dose).
  • Inclusion criteria for hospital LOS and ICU-level care differed across trials.
  • Trial stopped for futility.

Interpretation

  • In patients who required ICU-level care, therapeutic heparin did not reduce the duration of organ support or mortality.
  • Although the differences were not significant, patients who received therapeutic anticoagulation had more bleeding events and fewer thrombotic events than patients who received usual care.
INSPIRATION: Open-Label RCT of Intermediate-Dose Versus Prophylactic-Dose Anticoagulation in Patients With COVID-19 in Intensive Care Units in Iran8 

Key Inclusion Criteria

  • Admitted to ICU
  • Hospitalized <7 days

Key Exclusion Criteria

  • Life expectancy <24 hours
  • Need for therapeutic anticoagulation
  • Bleeding or high bleeding risk

Interventions

  • Intermediate-dose anticoagulation: enoxaparin 1 mg/kg once daily (n = 276) 
  • Prophylactic-dose anticoagulation (n = 286)

Primary Endpoint

  • Composite of adjudicated acute VTE, ATE, the need for ECMO, or all-cause mortality at 30 days

Key Secondary Endpoints

  • All-cause mortality at 30 days
  • VTE
  • Bleeding events

Participant Characteristics

  • Median age 62 years; 58% men; median BMI 27
  • 44% with HTN; 28% with DM; 14% with CAD 
  • 32% received NIV; 20% received MV.
  • 23% on vasopressors; 93% on corticosteroids; 60% on RDV

Primary Outcome

  • Composite of adjudicated acute VTE, ATE, the need for ECMO, or all-cause mortality at 30 days: 46% in intermediate-dose arm vs. 44% in prophylactic arm (OR 1.06; 95% CI, 0.76–1.48)

Secondary Outcomes

  • No difference between intermediate-dose arm and prophylactic arm in:
    • All-cause mortality at 30 days: 43% vs. 41% 
    • VTE: 3% in both arms
    • Major bleeding events and clinically relevant, nonmajor bleeding events: 6.3% vs. 3.1% (OR 2.02; 95% CI, 0.89–4.61)

Key Limitations

  • Open-label study
  • Not all patients received ICU-level care.

Interpretation

  • Intermediate-dose anticoagulation did not significantly reduce the occurrence of VTE and ATE, the need for ECMO, or mortality. 
  • Although the difference was not significant, patients who received intermediate-dose anticoagulation had more bleeding events than patients who received prophylactic-dose anticoagulation.
ANTICOVID: Open-Label RCT of Therapeutic-Dose Versus Intermediate-Dose Versus Prophylactic-Dose Anticoagulation in Patients With COVID-19 in Intensive Care Units in France9 

Key Inclusion Criterion

  • Hospitalized for <72 hours with hypoxemic COVID-19 pneumonia

Key Exclusion Criteria

  • Weight <40 kg or >100 kg
  • Indication or contraindication for therapeutic anticoagulation
  • Bleeding or high bleeding risk

Interventions

  • Therapeutic-dose anticoagulation: tinzaparin 175 IU/kg once daily or enoxaparin 100 IU/kg twice daily (n = 110)
  • Intermediate-dose anticoagulation: tinzaparin 7,000 IU once daily or enoxaparin 4,000 IU twice daily (n = 110) 
  • Prophylactic-dose anticoagulation: tinzaparin 3,500 IU once daily or enoxaparin 4,000 IU once daily (n = 114)

Primary Endpoint

  • Hierarchical outcome of all-cause mortality or time to clinical improvement of 2 points on a WHO scale by Day 28

Key Secondary Endpoints

  • Net clinical outcome by Day 28, defined as a composite of venous or arterial thrombosis, major bleeding events (as defined by ISTH), or all-cause death
  • Major bleeding events

Participant Characteristics

  • Mean age 58 years; 67% men; median BMI 27–28
  • 31% with HTN; 18% with DM; 4% with CAD 
  • 23% received conventional oxygen; 61% received HFNC oxygen; 7% received NIV; 10% received MV.
  • 92% on corticosteroids; 0.6% on RDV; 34% on tocilizumab; 3% on vasopressors

Primary Outcome

  • No difference between arms for hierarchical outcome of all-cause mortality or time to clinical improvement by Day 28

Secondary Outcomes

  • Net clinical outcome by Day 28: 20.0% in therapeutic-dose arm vs. 16.4% in intermediate-dose arm vs. 29.8% in prophylactic-dose arm
  • Venous or arterial thrombosis: 5% in therapeutic-dose arm vs. 5% in intermediate-dose arm vs. 20% in prophylactic-dose arm
  • Major bleeding events: 4% in therapeutic-dose arm vs. 4% in intermediate-dose arm vs. 3% in prophylactic-dose arm

Key Limitations

  • Open-label study
  • Not all patients received ICU-level care.
  • Study excluded patients weighing >100 kg.
  • Tinzaparin is not available in the United States.

Interpretation

  • The use of intermediate doses of anticoagulants improved the net clinical outcome by reducing the number of thrombosis events.
  • There was no difference between the arms in the occurrence of major bleeding events.
ACTIV-4B: Double-Blind RCT of Anticoagulant and Antiplatelet Therapy in Symptomatic, Nonhospitalized Patients With COVID-19 in the United States10

Key Inclusion Criteria

  • Aged 40–80 years
  • Symptomatic SARS-CoV-2 infection
  • CrCl >30 mL/min
  • PLT >100,000 cells/µL

Key Exclusion Criteria

  • Previously hospitalized with COVID-19
  • Acute leukemia, recent major bleeding events, or indication or contraindication for anticoagulant or antiplatelet therapy

Interventions

  • 558 of 657 randomized patients received study drugs.
  • Aspirin 81 mg PO once daily for 45 days (n = 144)
  • Prophylactic-dose anticoagulation: apixaban 2.5 mg PO twice daily for 45 days (n = 135)
  • Therapeutic-dose anticoagulation:  apixaban 5 mg PO twice daily for 45 days (n = 143)
  • Placebo (n = 136)

Primary Endpoint

  • Composite of all-cause mortality, symptomatic VTE, ATE, MI, stroke, or hospitalization for cardiovascular or pulmonary cause at 45 days

Key Secondary and Safety Endpoints

  • Component events of primary endpoint
  • Major bleeding 

Participant Characteristics

  • Listed characteristics are for all 657 randomized patients.
  • Median age 54 years; 59% women; median BMI 30; 13% Black, 28% Hispanic
  • 18% with DM; 20% with a history of smoking; 35% with HTN

Primary Outcome

  • Composite of all-cause mortality, symptomatic VTE, ATE, MI, stroke, or hospitalization at 45 days: 1 (0.7%) in aspirin arm vs. 1 (0.7%) in apixaban 2.5 mg arm vs. 2 (1.4%) in apixaban 5 mg arm vs. 1 (0.7%) in placebo arm
  • Risk differences compared with placebo:
    • 0.0% (95% CI, not calculable) in aspirin arm
    • 0.7% (95% CI, -2.1% to 4.1%) in 2.5 mg apixaban arm
    • 1.4% (95% CI, -1.5% to 5.0%) in 5 mg apixaban arm 
  • Cumulative incidence of primary outcomes did not significantly differ across treatment arms (log-rank P = 0.78).

Secondary Outcome

  • No differences between all treatment arms and placebo arm in occurrence of individual components of the primary endpoint

Safety Outcome

  • No major bleeding events occurred.

Key Limitation

  • Initial target sample size was 7,000 patients, but trial was terminated after enrolling only 9% of target because of a low event rate.

Interpretation

  • Among symptomatic outpatients with COVID-19 who were clinically stable, treatment with aspirin or a therapeutic or prophylactic dose of apixaban did not reduce the risk of death, symptomatic VTE or ATE, or hospitalization for cardiovascular or pulmonary causes compared to placebo.
OVID: Open-Label RCT of Low-Molecular-Weight Heparin for Thromboprophylaxis in Symptomatic, Nonhospitalized Patients With COVID-19 in Germany and Switzerland11

Key Inclusion Criteria

  • Aged ≥50 years
  • Positive SARS-CoV-2 test result within past 5 days
  • Respiratory symptoms or temperature ≥37.5 °C

Key Exclusion Criteria

  • Severe renal or hepatic dysfunction
  • Severe anemia or recent major bleeding events
  • Receiving dual antiplatelet therapy

Interventions

  • Enoxaparin 40 mg SUBQ once daily for 14 days (n = 234)
  • SOC (n = 238) 

Primary Endpoint

  • Composite of any untoward hospitalization or all-cause death by Day 30 

Key Secondary Endpoint

  • Composite of major arterial and venous cardiovascular events by Day 30
  • Bleeding events

Participant Characteristics

  • Median age 57 years; 46% women; 96% White
  • Median of 3 days from COVID-19 diagnosis to randomization
  • 24% with HTN; 8% with DM; 5% with CVD
  • 9.5% received ≥1 COVID-19 vaccine doses.

Primary Outcome

  • Composite of any untoward hospitalization or all-cause death by Day 30: 8 (3%) in enoxaparin arm vs. 8 (3%) in SOC arm (adjusted relative risk 0.98; 95% CI, 0.37–2.56; P = 0.96)

Secondary Outcomes

  • Composite of major arterial and venous cardiovascular events by Day 30: 2 (1%) in enoxaparin arm vs. 4 (2%) in SOC arm (relative risk 0.51; 95% CI, 0.09–2.74)
  • No major or clinically relevant, nonmajor bleeding events occurred.

Key Limitations

  • Open-label study
  • Trial terminated early due to a low probability that enoxaparin would be superior to the standard of care for the primary outcome.

Interpretation

  • Thromboprophylaxis with enoxaparin did not reduce the risk of hospitalization or death among nonhospitalized, symptomatic patients with COVID-19.
ETHIC: Open-Label RCT of Low-Molecular-Weight Heparin for Thromboprophylaxis in Symptomatic Outpatients With COVID-19 in Belgium, Brazil, India, South Africa, Spain, and the United Kingdom12

Key Inclusion Criteria

  • Aged ≥30 years
  • RT-PCR-confirmed SARS-CoV-2 infection, with symptoms for ≤9 days
  • ≥1 risk factors for severe disease

Key Exclusion Criteria

  • Receipt of a COVID-19 vaccine
  • eGFR <30 mL/min
  • Receiving anticoagulant or antiplatelet therapy, except low-dose aspirin

Interventions

  • Enoxaparin 40 mg SUBQ once daily (for patients weighing <100 kg) or enoxaparin 40 mg SUBQ twice daily (for patients weighing ≥100 kg), self-administered for 21 days (n = 105)
  • SOC (n = 114)

Primary Endpoint

  • Composite of all-cause hospitalization or all-cause mortality by Day 21

Key Secondary Endpoints

  • VTE by Day 90
  • Bleeding events by Day 50

Participant Characteristics

  • Median age 59 years; 56% men
  • Median of 5 days from first symptom to randomization

Primary Outcomes

  • Composite of all-cause hospitalization or all-cause mortality by Day 21: 12 (11%) in enoxaparin arm vs. 12 (11%) in SOC arm (HR 1.09; 95% CI, 0.49–2.43; P = 0.83)
  • Patients who required hospitalization: 12 in enoxaparin arm vs. 12 in SOC arm
    • Hospitalized patients who required acute medical care or ICU admission: 4 in enoxaparin arm vs. 0 in SOC arm

Secondary Outcomes

  • VTE by Day 90: 1 (1%) in enoxaparin arm vs. 2 (2%) in SOC arm
  • Bleeding events by Day 50: 2 (2%) in enoxaparin arm vs. 2 (2%) in SOC arm

Key Limitations

  • Open-label study
  • Study terminated early because of low event rate and lack of efficacy.

Interpretation

  • This study demonstrated no benefit of prophylaxis with LMWH in outpatients with COVID-19 who were at risk of progressing to severe disease.
ACTIV-4C: Double-Blind RCT of 30 Days of Apixaban After Hospital Discharge in Patients With COVID-19 in the United States13

Key Inclusion Criteria

  • Hospitalized >48 hours with confirmed SARS-CoV-2 infection within 2 weeks of admission
  • PLT >50,000 cells/µL and Hgb >8 g/dL

Key Exclusion Criteria

  • Need for therapeutic or prophylactic anticoagulation at hospital discharge
  • Ischemic stroke, intracranial bleed, or neurosurgery within 3 months
  • Bleeding events within past 30 days
  • Major surgery within 14 days
  • Inherited or active acquired bleeding disorder

Interventions

  • Apixaban 2.5 mg PO twice daily for 30 days, starting at hospital discharge (n = 610)
  • Placebo (n = 607)

Primary Endpoint

  • Composite of death, ATE, or VTE by Day 30

Key Safety Endpoint

  • Bleeding events

Participant Characteristics

  • Median age 54 years; 50% men; 27% Black, 17% Hispanic
  • 15% on antiplatelet therapy
  • At hospital discharge, 16% were prescribed antiplatelet therapy; 93% received aspirin.

Primary Outcome

  • Composite of death, ATE, or VTE by Day 30: 13 (2.1%) in apixaban arm vs. 14 (2.3%) in placebo arm (relative risk 0.92; 95% CI, 0.44–1.95; P = 0.85)

Safety Outcomes

  • Major bleeding events: 2 (0.4%) in apixaban arm vs. 1 (0.2%) in placebo arm (relative risk 2.00; 95% CI, 0.18–22.03)
  • Clinically relevant, nonmajor bleeding events: 3 (0.6%) in apixaban arm vs. 6 (1.1%) in placebo arm (relative risk 0.50; 95% CI, 0.13–1.99) 

Key Limitation

  • Trial was terminated early due to a low event rate and because the decreasing number of hospitalizations for people with COVID-19 made recruitment difficult.

Interpretation

  • Incidence of death or thromboembolism was low in this cohort of patients.
  • Because the trial was terminated early, the results were imprecise, and the study was inconclusive.
MICHELLE: Open-Label RCT of Using Rivaroxaban After Hospital Discharge in Patients With COVID-19 Who Were at High Risk of Venous Thromboembolism in Brazil14

Key Inclusion Criteria

  • Hospitalized for ≥3 days with confirmed SARS-CoV-2 infection
  • Increased risk of VTE, defined as an IMPROVE VTE score at hospital discharge of >4 or 2–3 with D-dimer >500 ng/mL 

Key Exclusion Criterion

  • Suspicion or confirmation of a thrombotic event

Interventions

  • Rivaroxaban 10 mg PO once daily for 35 days, starting at hospital discharge (n = 159)
  • No anticoagulation (n = 159)

Primary Endpoint

  • Composite of symptomatic or fatal VTE, asymptomatic VTE on bilateral lower-limb venous ultrasound and CTPA, symptomatic ATE, or cardiovascular death by Day 35

Key Secondary Endpoints

  • Symptomatic or fatal VTE
  • Composite of symptomatic VTE, MI, non-hemorrhagic stroke, or cardiovascular death 

Key Safety Endpoint

  • Bleeding events

Participant Characteristics

  • Median age 57 years; 60% men
  • While hospitalized, 86% received thromboprophylaxis with enoxaparin, 14% received unfractionated heparin, and 5% received antiplatelet therapy.

Primary Outcome

  • Primary composite outcome by Day 35: 5 (3%) in rivaroxaban arm vs. 15 (9%) in no anticoagulation arm (relative risk 0.33; 95% CI, 0.12–0.90; P = 0.03)
    • Difference driven mainly by incidence of PE (2 in rivaroxaban arm vs. 10 in no anticoagulation arm).

Secondary Outcomes

  • Symptomatic or fatal VTE: 1 (0.6%) in rivaroxaban arm vs. 8 (5.0%) in no anticoagulation arm (relative risk 0.13; 95% CI, 0.02–0.99; P = 0.049)
  • Composite of symptomatic VTE, MI, non-hemorrhagic stroke, or cardiovascular death: 1 (0.6%) in rivaroxaban arm vs. 9 (5.7%) in no anticoagulation arm (relative risk 0.11; 95% CI, 0.01–0.87; P = 0.036)

Safety Outcome

  • No major bleeding events occurred.

Key Limitations

  • Open-label study with no placebo
  • Not all patients had the protocol-specified CTPA or Doppler ultrasound during the study. However, a higher number of imaging evaluations occurred among the patients in the rivaroxaban arm.

Interpretation

  • In patients who were at high risk of VTE, the use of thromboprophylaxis with rivaroxaban 10 mg PO once daily for 35 days improved clinical outcomes when compared with no anticoagulation. 

References

  1. ATTACC, ACTIV-4a, and REMAP-CAP Investigators. Therapeutic anticoagulation with heparin in noncritically ill patients with COVID-19. N Engl J Med. 2021;385(9):790-802. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34351721.
  2. Sholzberg M, Tang GH, Rahhal H, 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;375:n2400. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34649864.
  3. Spyropoulos AC, Goldin M, Giannis D, 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 Intern Med. 2021;181(12):1612-1620. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34617959.
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  7. REMAP-CAP, ACTIV-4a, and ATTACC Investigators. Therapeutic anticoagulation with heparin in critically ill patients with COVID-19. N Engl J Med. 2021;385(9):777-789. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34351722.
  8. INSPIRATION Investigators. 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. JAMA. 2021;325(16):1620-1630. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33734299.
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  10. Connors JM, Brooks MM, Sciurba FC, et al. Effect of antithrombotic therapy on clinical outcomes in outpatients with clinically stable symptomatic COVID-19: the ACTIV-4B randomized clinical trial. JAMA. 2021;326(17):1703-1712. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34633405.
  11. Barco S, Voci D, Held U, et al. Enoxaparin for primary thromboprophylaxis in symptomatic outpatients with COVID-19 (OVID): a randomised, open-label, parallel-group, multicentre, Phase 3 trial. Lancet Haematol. 2022;9(8):e585-e593. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35779558.
  12. Cools F, Virdone S, Sawhney J, et al. Thromboprophylactic low-molecular-weight heparin versus standard of care in unvaccinated, at-risk outpatients with COVID-19 (ETHIC): an open-label, multicentre, randomised, controlled, Phase 3b trial. Lancet Haematol. 2022;9(8):e594-e604. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35779560.
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  14. Ramacciotti E, Barile Agati L, Calderaro D, et al. Rivaroxaban versus no anticoagulation for post-discharge thromboprophylaxis after hospitalisation for COVID-19 (MICHELLE): an open-label, multicentre, randomised, controlled trial. Lancet. 2022;399(10319):50-59. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34921756.