Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19
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Design
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Open-label, adaptive, single multiplatform, randomized, controlled trial
Platforms:
Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP)
Multicenter, Adaptive, Randomized Controlled Platform Trial of the Safety and Efficacy of Antithrombotic Strategies in Hospitalized Adults with COVID-19 (ACTIV-4a)
Antithrombotic Therapy to Ameliorate Complications of COVID-19 (ATTACC)
N= 2,244
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Objective
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To assess if therapeutic-dose anticoagulation may improve outcomes in noncritically ill patients who are hospitalized with Covid-19 |
Study Groups
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Therapeutic-dose anticoagulation (n= 1,181)
Usual-care thromboprophylaxis (n = 1,050)
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Inclusion Criteria
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Hospitalized and moderately ill patients with Covid-19 and no need for ICU-level care, no use of respiratory or cardiovascular organ support (oxygen delivered by high-flow nasal cannula, noninvasive or invasive mechanical ventilation, or the use of vasopressors or inotropes), ICU admission without organ supports (ACTIV-4a)
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Exclusion Criteria
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Expected hospital discharge within 72 hours, therapeutic anticoagulation was indicated, high risk of bleeding, receipt of dual antiplatelet therapy, allergy to heparin, including heparin-induced thrombocytopenia (HIT)
ATTACC and ACTIV-4a: 72 hours since hospital admission for Covid-19 or in-hospital confirmation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); REMAP-CAP: 14 days since admission
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Methods
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Patients enrolled from the three platforms were randomized (1:1) to receive either therapeutic-dose anticoagulation with unfractionated or low-molecular-weight heparin (UFH or LMWH) or usual-care pharmacologic thromboprophylaxis. Anticoagulants dosing regimens and duration were administered based on local protocol and based on the treating physicians' discretion. Therapeutic dosing was defined as used for treating acute venous thromboembolism for up to 14 days or until recovery (discharge or discontinuation of supplemental oxygen for > 24 hours).
The ATTACC and REMAP-CAP adopted the response-adaptive randomization, where group-assignment ratios could be modified and allowed patients to receive the treatment with better outcomes based on interim analyses.
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Duration
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Study enrollment: between April 21, 2020, and January 22, 2021
Follow-up: 90 days
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Outcome Measures
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Primary outcome: organ support–free days evaluated on an ordinal scale combining in-hospital death and the number of days free of cardiovascular or respiratory organ support up to day 21 (higher value = better outcomes)
Any death during hospitalization through 90 days was assigned to the worst score of - 1.
Secondary outcomes: survival until hospital discharge, survival without receipt of organ support, survival without receipt of invasive mechanical ventilation, survival without mechanical respiratory support, length of hospital stay, a major thrombotic event or death (a composite of myocardial infarction, pulmonary embolism, ischemic stroke, systemic arterial embolism, or in-hospital death), and any thrombotic event including deep venous thrombosis
Safety outcome: major bleeding events
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Baseline Characteristics
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Therapeutic-Dose Anticoagulation
(n= 1,181)
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Usual-Care Thromboprophylaxis
(n= 1,050)
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Age, years
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59 ± 14.1 |
58.8 ± 13.9 |
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Male
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713 (60.4%) |
597 (56.9%) |
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Race or ethnic group
White
Asian
Black
First Nations or American Indian
Hispanic or Latino
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622/994 (62.6%)
41/994 (4.1%)
219/994 (22%)
118/965 (12.2%)
574/1,004 (57.2%)
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564/845 (66.7%)
43/845 (5.1%)
162/845 (19.2%)
82/819 (10%)
537/879 (61.1%)
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Median body-mass index (IQR), kg/m2
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29.8 (26.3 to 34.7) |
30.3 (26.7 to 34.9) |
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Preexisting condition
Hypertension
Diabetes Mellitus
Severe cardiovascular disease
Chronic kidney disease
Chronic respiratory disease
Immunosuppressive disease
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546/1,023 (53.4%)
352/1,181 (29.8%)
123/1,165 (10.6%)
83/1,173 (7.1%)
249/1,132 (22%)
105/1,143 (9.2%)
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447/892 (50.1%)
311/1,049 (29.6%)
121/1,038 (11.7%)
69/1,037 (6.7%)
212/988 (21.5%)
103/1,005 (10.2%)
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Treatment
Antiplatelet agent
Remdesivir
Glucocorticoid
Tocilizumab
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148/1,140 (13%)
428/1,178 (36.3%)
479/791 (60.6%)
6/1,178 (0.5%)
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111/1,013 (11%)
383/1,048 (36.5%)
415/656 (63.3%)
7/1,048 (0.7%)
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Respiratory support
None
Low-flow nasal cannula or face mask
High-flow nasal cannula
Noninvasive mechanical ventilation
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156 (13.2%)
789 (66.8%)
25 (2.1%)
21 (1.8%)
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123 (11.7%)
696 (66.3%)
28 (2.7%)
24 (2.3%)
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Median laboratory value (IQR)
Median D-dimer relative to ULN at trial site
Platelets, per mm3
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1.6 (0.9 to 2.6)
221,000 (171,000 to 290,000)
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1.5 (1 to 2.7)
218,000 (172,500 to 289,000)
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Platform of enrollment
ATTACC
ACTIV-4a
REMAP-CAP
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650 (55%)
387 (32.8%)
144 (12.2%)
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509 (48.5%)
392 (37.3%)
149 (14.2%)
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ULN: upper limit of the normal range
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Results
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Endpoint
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Therapeutic-dose anticoagulation (n= 1,181)
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Usual-care thromboprophylaxis (n= 1,050)
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Adjusted difference in risk (95% credible interval)
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Adjusted odds ratio (95% credible interval)
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Probability of superiority of therapeutic-dose anticoagulation
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Patients who survived until hospital discharge without receipt of organ support |
n= 1,171
939 (80.2%)
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n= 1,048
801 (76.4%)
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4 (0.5 to 7.2) |
1.27 (1.03 to 1.58) |
98.6% |
Survival until hospital discharge
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n= 1,171
1,085 (92.7%)
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n= 1,048
962 (91.8%)
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1.3 (-1.1 to 3.2) |
1.21 (0.87 to 1.68) |
87.1% |
Survival without organ support at 28 days
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n= 1,175
932 (79.3%)
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n= 1,046
789 (75.4%)
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4.5 (0.9 to 7.7) |
1.3 (1.05 to 1.61) |
99.1% |
Survival without mechanical respiratory support
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994 (84.2%)
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864 (82.3%)
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- |
1.22 (0.97 to 1.55) |
95.3% |
Length of hospital stay
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-
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-
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- |
1.03 (0.94 to 1.13) |
72.7% |
Major thrombotic event or death
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n= 1,180
94 (8%)
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n= 1,046
104 (9.9%)
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-2.6 (-4.4 to -0.2) |
0.72 (0.53 to 0.98) |
98% |
Any thrombotic event or death
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n= 1,180
96 (8.1%)
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n= 1,046
108 (10.3%)
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- |
0.71 (0.52 to 0.96) |
98.6% |
Major bleeding
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n= 1,180
22 (1.9%)
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n= 1,047
9 (0.9%)
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0.7 (-0.1 to 2.3) |
1.8 (0.9 to 3.74) |
95.5% |
*The authors reported the proportion of patients who survived until hospital discharge without receipt of organ support instead of organ-support free days since the majority of patients in both treatment groups survived until hospital discharge without receiving critical care–level organ support, and the median value for organ support-free days was 22 in both groups.
The proportion of patients who were survival free of invasive mechanical ventilation through 28 days were reported in a graph. There was a larger proportion of patients who were survival free of invasive mechanical ventilation through 28 days in the usual-care thromboprophylaxis group (probability of superiority: 92%).
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Adverse Events
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Common Adverse Events: N/A
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Serious Adverse Events: N/A
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Percentage that Discontinued due to Adverse Events: N/A
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Study Author Conclusions
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In noncritically ill patients with COVID-19, an initial strategy of therapeutic-dose anticoagulation with heparin increased the probability of survival to hospital discharge with reduced use of cardiovascular or respiratory organ support as compared with usual-care thromboprophylaxis.
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InpharmD Researcher Critique
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The open-label design has the potential to introduce bias since physicians in the usual-care thromboprophylaxis group may be more likely to diagnose thrombotic events. The primary outcome of the study was changed and showed superiority for the therapeutic-dose anticoagulation group, however, there was most likely no superiority for this group in the original primary outcome of organ support-free days.
Each platform varied in the classification of illness severity, which may have allowed for inclusion of noncritical patients and confounded the results. Overall, the multiplatform design helps to increase the external validity of the results. Therapeutic-dose anticoagulation for noncritical COVID-19 patients has the potential to increase survival without organ support compared to usual-care thromboprophylaxis based on the results.
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