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Table 7a. Anticoagulant Therapy: Selected Clinical Data

Last Updated: September 26, 2022

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

Table 7a. Anticoagulant Therapy: Selected Clinical 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:

  • Discharge expected ≤72 hours
  • Requirement for therapeutic anticoagulation or dual antiplatelet therapy
  • High bleeding risk

Interventions:

  • Therapeutic UFH or LMWH for 14 days or until discharge, whichever comes first (n = 1,190)
  • SOC (n = 1,054)

Primary Endpoint:

  • Organ support-free days at Day 21, evaluated on an ordinal scale

Key Secondary Endpoints:

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

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:
    • 48.4% <2 times ULN
    • 28.4% ≥2 times ULN
    • 23.1% unknown
  • 62% on corticosteroids; 36% on RDV

Primary Outcomes:

  • Organ support-free days: therapeutic anticoagulation superior to SOC (aOR 1.27; 95% CrI, 1.03–1.58; 99% posterior probability)
  • Survival until hospital discharge without organ support: 4% absolute difference favoring therapeutic anticoagulation arm (95% CrI, 0.5–7.2)
  • Outcome consistent across D-dimer stratum

Secondary Outcomes:

  • Survival until hospital discharge: 92% in both arms
  • Hospital LOS: no difference between arms (aOR 1.03; 95% CrI, 0.94–1.13)
  • Thrombosis: 1% in therapeutic arm vs. 2% in SOC arm
  • Major bleeding: 2% in therapeutic arm vs. 1% in SOC arm
Key Limitations:
  • Open-label study
  • Anticoagulation dose varied in SOC arm (27% received intermediate-dose thromboprophylaxis).
  • Studies had different criteria for ICU care and expected hospital LOS.
  • Only enrolled 17% of screened patients

Interpretation:

  • Therapeutic heparin increased 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 therapeutic arm than in 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 ≥2 times ULN or any elevated D-dimer level and SpO2 ≤93% on room air
  • Hospitalized <5 days

Key Exclusion Criteria:

  • Indication for therapeutic anticoagulation
  • Dual antiplatelet therapy
  • High bleeding risk

Interventions:

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

Primary Endpoint:

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

Key Secondary Endpoints:

  • All-cause death
  • Mean organ support-free days
  • VTE
  • Major bleeding event
  • Mean 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% had hypoxia; 6% received HFNC oxygen
  • D-dimer:
    • 49% <2 times ULN
    • 51% ≥2 times ULN
  • 69% on corticosteroids

Primary Outcome:

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

Secondary Outcomes:

  • All-cause death: 2% in therapeutic arm vs. 8% in prophylactic arm (OR 0.22; 95% CI, 0.07–0.65)
  • Mean organ support-free days: 26 days in therapeutic arm vs. 24 days 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 (1% in therapeutic arm vs. 2% in prophylactic arm)
  • Mean hospital-free days alive: 20 days in therapeutic arm vs. 18 days in prophylactic arm (OR 1.09; 95% CI, 0.79–1.50)
Key Limitations:
  • Open-label study
  • Only enrolled 12% of screened patients

Interpretation:

  • Compared to prophylactic heparin, therapeutic heparin reduced mortality (a secondary endpoint) but had no effects on the composite primary 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 proportions of patients who experienced major bleeding events or VTE.
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 supplemental oxygen
  • D-dimer >4 times ULN or sepsis-induced coagulopathy score of ≥4
  • Hospitalized <72 hours

Key Exclusion Criteria:

  • Indication for therapeutic anticoagulation
  • 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 of any cause within 32 days of randomization

Key Safety Endpoint:

  • Major bleeding

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 high-flow oxygen or NIV; 5% received MV
  • 80% on corticosteroids

Primary Outcomes:

  • Composite of VTE, ATE, and death within 32 days: 29% in therapeutic arm vs. 42% in usual care arm (relative risk 0.68; 95% CI, 0.49–0.96)
    • Death: 19% in therapeutic arm vs. 25% in usual care arm (relative risk 0.78; 95% CI, 0.49–1.23)
    • Thrombotic events: 11% in therapeutic arm vs. 29% in usual care arm (relative risk 0.37; 95% CI, 0.21–0.66)
  • 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)

Key Safety Outcomes:

  • Major bleeding: 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: 2% in both arms
Key Limitations:
  • Open-label study
  • Only enrolled 2% of screened patients

Interpretation:

  • Compared to usual care, therapeutic LMWH reduced the incidence of VTE, ATE, and death.
  • For patients not in the ICU, therapeutic LMWH significantly reduced thrombotic events and did not increase major bleeding.
ACTION: Open-Label RCT of Therapeutic Oral Anticoagulation (Rivaroxaban) in Hospitalized Patients With COVID-19 in Brazil4
Key Inclusion Criteria:
  • Hospitalized for COVID-19 with elevated D-dimer level
  • Symptoms for ≤14 days
Key Exclusion Criteria:
  • Indication for therapeutic anticoagulation
  • CrCl <30 mL/min
  • P2Y12 inhibitor therapy or aspirin >100 mg
  • High bleeding risk

Interventions:

  • Therapeutic anticoagulation for 30 days: rivaroxaban 15 mg or 20 mg 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, and oxygen use duration through Day 30

Key Secondary Endpoints:

  • Thrombosis, with and without all-cause death
  • Mortality
  • Bleeding events

Participant Characteristics:

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

Primary Outcomes:

  • Composite of time to death, hospital duration, and oxygen use duration: no difference between arms (win ratio 0.86; 95% CI, 0.59–1.22)

Secondary Outcomes:

  • No difference between therapeutic and prophylactic arms:
    • Mortality: 11% vs. 8%
    • Thrombosis: 7% vs. 10%
  • Any bleeding: 12% in therapeutic arm vs. 3% in usual care arm
  • Major bleeding: 3% in therapeutic arm vs. 1% in usual care arm
  • Clinically relevant, nonmajor bleeding: 5% in therapeutic arm vs. 1% in usual care arm
Key Limitations:
  • Open-label study
  • Only enrolled 18% of screened patients
  • Longer duration of anticoagulation in the rivaroxaban arm (30 days) than the prophylactic anticoagulation arm (mean duration of 8 days)

Interpretation:

  • When compared with usual care, therapeutic rivaroxaban did not reduce mortality, hospital duration, oxygen use duration, or thrombosis.
  • Patients who received therapeutic rivaroxaban had more clinically relevant nonmajor bleeding than those who received usual care.
  • The longer duration of therapy in the rivaroxaban arm may have influenced the difference in bleeding events.
REMAP-CAP/ACTIV-4a/ATTACC: Multiplatform, Open-Label RCT of Therapeutic Anticoagulation in Critically Ill, Hospitalized Patients With COVID-19 in 20 Countries5
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:
  • Discharge expected within 72 hours
  • Requirement for therapeutic anticoagulation or dual antiplatelet therapy
  • High bleeding risk

Interventions:

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

Primary Endpoint:

  • Organ support-free days at 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% required HFNC oxygen; 38% required NIV; 29% required MV
  • 18% on vasopressors; 82% on corticosteroids; 32% on RDV

Primary Outcome:

  • Median organ support-free days at Day 21: 4 days in therapeutic arm vs. 5 days 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:
    • Survival to hospital discharge: 63% vs. 65% (aOR 0.84; 95% CrI, 0.64–1.11)
    • Thrombosis: 6% vs. 10%
    • Major thrombotic events or death: 41% both arms
    • Major bleeding events: 4% vs. 2% (aOR 1.48; 95% CrI, 0.75–3.04)
Key Limitations:
  • Open-label study
  • Anticoagulation dose varied in usual care arm (i.e., 51% intermediate, 2% subtherapeutic, 5% therapeutic).
  • Inclusion criteria for hospital LOS and ICU-level care differed across trials.
  • Trial stopped for futility.

Interpretation:

  • In patients requiring ICU care, therapeutic heparin did not reduce the duration of organ support or mortality.
  • Although the differences were nonsignificant, 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 Anticoagulant in Patients in Intensive Care With COVID-19 in Iran6
Key Inclusion Criteria:
  • Admitted to ICU
  • Hospitalized <7 days
Key Exclusion Criteria:
  • Life expectancy <24 hours
  • Indication for therapeutic anticoagulation
  • Overt bleeding

Interventions:

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

Primary Endpoint:

  • Composite of adjudicated acute VTE, ATE, ECMO, or all-cause mortality within 30 days

Key Secondary Endpoints:

  • All-cause mortality
  • VTE
  • Bleeding event

Participant Characteristics:

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

Primary Outcome:

  • Composite of adjudicated acute VTE, ATE, ECMO, or all-cause mortality: 46% in therapeutic arm vs. 44% in prophylactic arm (OR 1.06; 95% CI, 0.76–1.48)

Secondary Outcomes:

  • No difference between therapeutic and prophylactic arms:
    • All-cause mortality: 43% vs. 41%
    • VTE: 3% both arms
    • Major bleeding and clinically relevant nonmajor bleeding: 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 VTE and ATE, the need for ECMO, or mortality.
  • Although the difference was nonsignificant, patients who received intermediate-dose anticoagulation had more bleeding events than patients who received usual care.
OVID: Open-Label RCT of Low-Molecular-Weight Heparin for Thromboprophylaxis in Symptomatic, Nonhospitalized Patients With COVID-19 in Germany and Switzerland7
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
  • Receiving dual antiplatelet treatment

Interventions:

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

Primary Endpoint:

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

Key Secondary Endpoints:

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

Participant Characteristics:

  • Median age 57 years; 46% women; 96% White
  • Median time from COVID-19 diagnosis to randomization: 3 days
  • 24% with HTN; 8% with DM; 5% with CVD
  • 9.5% received at least 1 dose of a COVID-19 vaccine

Primary Outcome:

  • Composite of any untoward hospitalization and 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)

Key Secondary Outcomes:

  • Composite of major arterial and venous cardiovascular events at 30 days: 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
  • Study terminated early because of the very low probability that enoxaparin would show superiority 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 UK8
Key Inclusion Criteria:
  • Aged ≥30 years
  • RT-PCR-confirmed SARS-CoV-2 infection, with symptoms for ≤9 days
  • ≥1 risk factor for severe disease
Key Exclusion Criteria:
  • Receipt of COVID-19 vaccination
  • eGFR <30 mL/min
  • Receiving anticoagulant or antiplatelet therapy, except low-dose aspirin

Interventions:

  • Enoxaparin 40 mg SUBQ 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 and all-cause mortality by Day 21

Key Secondary Endpoints:

  • VTE by Days 21, 50, and 90
  • Bleeding events by Days 21 and 50

Participant Characteristics:

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

Primary Outcomes:

  • Composite of all-cause hospitalization and 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

Key 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.

References

  1. ATTACC Investigators, ACTIV-4a Investigators, REMAP-CAP Investigators, et al. 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.
  4. Lopes RD, de Barros ESPGM, Furtado RHM, et al. 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. Lancet. 2021;397(10291):2253-2263. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34097856.
  5. REMAP-CAP Investigators, ACTIV-4a Investigators, ATTACC Investigators, et al. 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.
  6. INSPIRATION Investigators, Sadeghipour P, Talasaz AH, 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. JAMA. 2021;325(16):1620-1630. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33734299.
  7. 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.
  8. 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.