Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

Lawler, 2021

Integrated REMAPCAP, ATTACC and ACTIV-4a trial.

Type of study: open-label, international, adaptive, multiplatform RCT (mpRCR)

Setting and country:

121 sites in 9

countries (the United States, Canada, the United

Kingdom, Brazil, Mexico, Nepal, Australia, the

Netherlands, and Spain).

Funding and conflicts of interest:

The trial was supported by multiple international funding organizations who had no role in the design, analysis or reporting of the trial result, apart from the ACTIV-4a

protocol, which received input on design from

professional staff members at the National Institutes

of Health and from peer reviewers.

See publication for funding details.

Inclusion criteria:

Patients hospitalized with COVID-19 and who were not critically ill* (absence of critical care–level organ support at enrollment).

Exclusion criteria:

Patients were ineligible for enrollment if 72 hours

had elapsed since hospital admission for Covid-19

or since in-hospital confirmation of the presence

of severe acute respiratory syndrome coronavirus

2 (SARS-CoV-2) (ATTACC and ACTIV-4a) or if 14 days had elapsed since admission (REMAP-CAP).

Patients were also excluded if

hospital discharge was expected within 72 hours

or if they had a clinical indication for therapeutic

anticoagulation, a high risk of bleeding, receipt of dual antiplatelet therapy, or a known heparin allergy, including heparin-induced thrombocytopenia (HIT)

For inclusion criteria per sub trial, see bottom of column with outcomes

N total at baseline:

N = 2244 randomized; primary analysis involved 2219 patients. After exclusion:

Intervention: 1181

Control: 1050

Important characteristics:

Age, mean (SD)

I: 59.0 y (14.1)

C: 58.8 y (13.9)

Sex, n/N (%) male

I: 713/1181 (60.4%)

C: 597/1050 (56.9%)

Country, n (%) (i/C)

Canada 102 (8.6) / 83 (7.9)

Brazil 234 (19.8) / 209 (19.9)

Other§§ 177 (15.0) / 148 (14.1)

BMI, median (IQR)

I: 29.8 (26.3–34.7)

C: 30.3 (26.7–34.9)

Respiratory support, n/N (%)

None

I: 156 (13.2)

C: 123 (11.7)

Low-flow nasal cannula or face mask

I: 789 (66.8)

C: 696 (66.3)

High-flow nasal cannula

I: 25 (2.1)

C: 28 (2.7)

Noninvasive mechanical ventilation

I: 21 (1.8)

C: 24 (2.3)

Unspecified**; In REMAP-CAP, levels of oxygen support (including no support) below the level of high-flow nasal cannula were not

reported.

I: 190 (16.1)

C: 179 (17.0)

Preexisting condition — no./total no. (%)

Hypertension

I: 546/1023 (53.4)

C: 447/892 (50.1)

Diabetes mellitus

I: 352/1181 (29.8)

C: 311/1049 (29.6)

Severe cardiovascular disease

I: 123/1165 (10.6)

C: 121/1038 (11.7)

Chronic kidney disease

I: 83/1173 (7.1)

C: 69/1037 (6.7)

Chronic respiratory disease

I: 249/1132 (22.0)

C: 212/988 (21.5)

Immunosuppressive disease

I: 105/1143 (9.2)

C: 103/1005 (10.2)

Treatment — no./total no. (%)

Antiplatelet agent

I: 148/1140 (13.0)

C: 111/1013 (11.0)

Remdesivir

I: 428/1178 (36.3)

C: 383/1048 (36.5)

Glucocorticoid

I: 479/791 (60.6)

C: 415/656 (63.3)

Tocilizumab

I: 6/1178 (0.5)

C: 7/1048 (0.7)

Median laboratory value (IQR)

Median d-dimer level relative to ULN at trial site

I: 1.6 (0.9–2.6)

C: 1.5 (1.0–2.7)

Platelets — per mm3

I: 221,000 (171,000–290,000)

C: 218,000 (172,500–289,000)

Lymphocytes — per mm3

I: 900 (700–1300)

C: 1000 (700–1400)

Creatinine — mg/dl

I: 0.9 (0.7–1.1)

C: 0.9 (0.7–1.1)

Groups comparable at baseline.

Therapeutic-dose anticoagulation with unfractionated or low-molecular-weight heparin up to 14 days or to hospital discharge.

Dose:
low heparine: according to patient weight (for ACTIV-4a and ATTACC platforms also according to creatinine clearance)

Unfractionated heparine:
for REMAP-CAP and ATTACC suggested target for aPTT of 1.5 to 2.5 times the upper limit of normal or therapeutic anti-Xa levels; for ACTIV 4a suggested target of anti-Xa of 0.7 to 0.7 IU/ml or aPTT 1.5 to 2.5 times the upper limit of normal.

Usual-care pharmacologic thromboprophylaxis up to 14 days or hospital discharge. After this period, decisions regarding thromboprophylaxis are at discretion of treating clinician.

For REMAP-CAP and ATTACC: Standard venous thromboprophylaxis according to local guidelines or usual practice. In case of REMAP-CAP, dose should not be sufficient to result in therapeutic anticoagulation and in case of ATTACC, dose of chosen agent should not be more than half of the approved therapeutic dose for the treatment of venous thromboembolism.

For ACTIV 4a any one of enoxaparin, dalteparin, tinzaparin, fondaparinux, or heparin according to local preference. Dose of agent specified to be consistent with guidelines for low dose thromboprophylaxis.

Length of follow-up: 28 to 90 days

Loss-to-follow-up:

Intervention:

19 (1.6%)

Reasons

9 did not have confirmed COVID-19

9 withdrew consent

1 did not have outcome data available

Control:

6 (0.6%)

Reasons

1 withdrew consent

2 did not have outcome data available

3 did not have confirmed COVID-19

Mortality:

Death in hospital

I: 86/1180 (7.3%)

C: 86/1046 (8.2%)

Length of hospital stay:

Hospital length of stay (time-to-event endpoint truncated at 28 days) in the total group of patients

Hazard ratio

(95% CI) 1.03 (0.94-1.13); the overall median (interquartile

range) hospital length of stay following randomization was 5 (3, 10) days.

ICU-admission

Nothing reported

Organ support free days

Evaluated on an ordinal scale that combined in-hospital death and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge

I: 939/1171 patients (80.2%)

C: 801/1048 patients (76.4%)

Of the in the usual-care

Adjusted odds ratio 1.27 (95% Credible Interval 1.03 to 1.58).

Adjusted for age, sex, trial site, d-dimer cohort, and enrollment period

Survival without intubation through 28 days

I: 1052/1181 (89.1%) C: 923/1050 (87.9%)

Venous thromboembolism (VTE)

Number of patients with VTE not specifically reported.

Pulmonary embolism events

I: 10

C: 19

Deep venous thrombosis events

I: 6

C: 7

Number of patients with an in-hospital thrombotic event (defined as pulmonary embolism, myocardial infarction, ischemic cerebrovascular event, systemic arterial thromboembolism, and deep venous thrombosis).

I: 16/1180 (1.5%) patients

C: 28/1046 (2.7%) patients

Major bleeding

I: 22 out of 1180 (1.9%) patients

C: 9 out of 1047 (0.86%) patients

------------------------------------

Inclusion criteria per sub trial:

REMAP-CAP:

• Known or suspected previous adverse reaction to unfractionated heparin or low molecular weight heparin including HIT
• Intention to continue or commence dual antiplatelet therapy
• Death is deemed to be imminent and inevitable during the next 24 hours AND one or more of the patient, substitute decision maker, or attending physician are not committed to full active treatment
• Enrollment in a trial evaluating anticoagulation for proven or suspected COVID-19 infection, where the protocol of that trial requires continuation of the treatment assignment specified in that trial
• Clinical and/or laboratory bleeding risk or both that is sufficient to contraindicate therapeutic anticoagulation
• Treating physician does not feel trial participation is in the best interest of the patient

ACTIV-4a:

• Platelet count < 50x 109/L
• Hemoglobin <80 g/L (8 g/dL)
• History of heparin-induced thrombocytopenia (HIT) or other heparin allergy including hypersensitivity
• Patient on dual antiplatelet therapy, when one of the agents cannot be stopped safely
• Chronic mechanical ventilation via tracheostomy prior to hospitalization
• Imminent death
• Co-enrollment in other trials is permitted as long as the other trial does not test agents with antithrombotic properties and there is no other scientific contraindication
• Contraindication to anticoagulation
• Pregnancy

ATTACC:

• Platelet count <50 x109/L, INR >2.0, or baseline aPTT >50 seconds
• Hemoglobin <80 g/L (8 g/dL)
• History of heparin-induced thrombocytopenia (HIT) or other heparin allergy including hypersensitivity
• Current use of dual antiplatelet therapy
• Chronic mechanical ventilation via tracheostomy prior to hospitalization
• Patients in whom imminent demise is anticipated and there is no commitment to active ongoing intervention
• Enrollment in other trials related to anticoagulation or antiplatelet therapy
• Bleeding risk

Definitions:

* Moderate disease severity was defined as hospitalization

for Covid-19 without the need for ICU-level care. ICU-level care was defined as the use of respiratory or cardiovascular organ support (oxygen delivered by high-flow nasal cannula,

non-invasive or invasive mechanical ventilation,

or the use of vasopressors or inotropes) in an ICU. [In ACTIV-4a, in which investigators found

that ICU-level care was challenging to define during the pandemic, receipt of organ support, regardless of hospital setting, was used to define ICU-level care. Patients who were admitted to an ICU but without receiving qualifying organ support

were considered to be moderately ill.]

Definitions of major thrombotic and any thrombotic events are described in the study protocol.

Remarks:

The trial was stopped when prespecified criteria for the superiority of therapeutic dose anticoagulation were met.

Authors conclusion:

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.

Spyropoulos, 2021

HEP-COVID Randomized Clinical Trial

AND

corresponding

Trial protocol design paper

(Goldin, 2021)

Type of study:

Randomized controlled trial

Setting and country:

Multicenter study in the US (12 centers)

Funding and conflicts of interest:

Support from

Feinstein Institutes for Medical Research, the

Broxmeyer Fellowship in Clinical Thrombosis, and

grant R24AG064191 from the National Institute on

Aging. The funders had no

role in the design and conduct of the study;

collection, management, analysis, and

interpretation of the data; preparation, review, or

approval of the manuscript; and decision to submit the manuscript for publication.

Inclusion criteria:

• Hospitalized patients
• Nonpregnant patients
• Adults 18 years or older
• COVID-19 diagnosed by nasal swab or serologic testing
• Requirement for supplemental oxygen per investigator judgment
• Plasma D-dimer levle greater than 4 times the upper limit of normal based on local laboratory criteria or a sepsis-induced coagulopathy score of 4 or greater.

Exclusion criteria:

• Physician-determined need for full-dose anticoagulation or dual antiplatelet therapy
• bleeding within the past month
• active gastrointestinal or intracranial cancer
• bronchiectasis or pulmonary cavitation
• hepatic dysfunction with baseline international

normalized ratio greater than 1.5

• creatinine clearance

(CrCl) less than 15mL/min/1.73m2

• Platelet count less than

25 000/μL

• a history of heparin-induced thrombocytopenia

(HIT) within 100 days

• hypersensitivity/intolerance to study drug or components

Patients were stratified into two subgroups: non-intensive care unit patients and intensive care unit patients. ICU status was defined by mechanical ventilation, noninvasive positive pressure ventilation or high-flow nasal cannula, vasopressors, or vital sign monitoring more often than every 4 hours.

ICU: 83 patients (32.8%)

Non-ICU: 170 patients (67.2%)

N total at baseline:

N = 257 participants randomized (130 to the intervention group and 127 to the control group) at baseline.

Important prognostic factors²:

Age, mean (SD):

I: 65.8 (13.9)

C: 67.7 (14.1)

Sex, No./total No. (%) male

I: 68/129 (52.7%)

C: 68/124 (54.8%)

BMI, mean (SD)

I: 31.2 (9.3)

C: 29.8 (13.6)

Race and ethnicity, No. (%) (I/C)

Asian 11 (8.5) / 14 (11.3)

Black 33 (25.6) / 37 (29.8)

White 56 (43.4) / 46 (37.1)

Multiracial/unknown 29 (22.5) / 27 (21.8)

ICU, No./total No. (%)

I: 45/129 (34.9)

C: 38/124 (30.6)

Comorbidities, No./total No. (%) (I/C)

Hypertension 81/129 (62.8) / 70/123 (56.9)

Heart failure 0 / 2/124 (1.6)

Diabetes mellitus 51/128 (39.8) / 43/124 (34.7)

Dyslipidemia 48/129 (37.2) / 39/124 (31.5)

Coronary artery disease 7/129 (5.4) / 11/124 (8.9)

Valvular heart disease 1/129 (0.8) / 3/124 (2.4)

History of ischemic stroke 5/129 (3.9) / 3/124 (2.4)

History of carotid occlusive disease 0 / 0

Peripheral artery disease 4/129 (3.1) / 1/124 (0.8)

Chronic kidney disease 5/129 (3.9) / 4/124 (3.2)

Chronic lung disease 9/129 (7.0) / 8/124 (6.5)

Chronic liver disease/cirrhosis 2/129 (1.6) / 1/124 (0.8)

Pulmonary hypertension 1/127 (0.8) / 2/124 (1.6)

VTE risk factors,, No./total No. (%) (I/C)

Personal history of VTE 6/129 (4.7) / 2/124 (1.6)

History of cancer 16/129 (12.4) / 10/124 (8.1)

Active cancer 1/129 (0.8) / 4/124 (3.2)

Autoimmune disease 1/128 (0.8) / 2/124 (1.6)

Hormonal therapy/oral contraceptives 1/129 (0.8) / 1/124 (0.8)

Known thrombophilia 0 / 0

Recent stroke with paresis 1/129 (0.8) / 1/124 (0.8)

Clinical scores, mean (SD) (I/C)

IMPROVEDD VTE risk score 4.33 (1.48) / 4.22 (1.36)

Sepsis-induced coagulopathy score 2.35 (0.73) / 2.31 (0.85)

Laboratory parameters, mean (SD) (I/C)

White blood cell count, /μL 9600 (5800) / 9800 (8200)

Platelets, ×103/μL 287.7 (119.8) / 269.7 (108.2)

Serum creatinine, mg/dL 0.94 (0.45) / 1.00 (0.50)

Prothrombin time, s 13.5 (1.6) /13.6 (2.6)

D-dimer, ng/mL 3837 (6166) / 3183 (5409)

Medications prior to randomization, No./total No. (%)(I/C)

Low-molecular-weight heparin 106/128 (82.8) / 97/124 (78.2)

Unfractionated heparin 18/127 (14.2) / 23/121 (19.0)

Remdesivir 93/129 (72.1) / 85/124 (68.6)

Glucocorticoids 111/127 (87.4) / 93/123 (75.6)

Antiplatelets 40/129 (31.0) / 24/124 (19.4)

Oxygen therapy, No./total No. (%) (I/C)

Nasal cannula 80/129 (62.0) / 83/124 (66.9)

Nonrebreather mask 12/129 (9.3) / 11/124 (8.9)

Ventilation mask 4/129 (3.1) / 2/124 (1.6)

High-flow or noninvasive positive-pressure ventilation 20/129 (15.5) / 19/124 (15.3)

Invasive mechanical ventilation 8/129 (6.2) / 5/124 (4.0)

Length of hospital stay, mean (SD), d

I: 12.2 (9.3)
C: 11.6 (8.2)

Groups comparable at baseline?

Yes

Describe intervention (treatment/procedure/test):

Patients in the therapeutic dose group received enoxaparin at a dose of 1 mg/kg subcutaneously twice daily if CrCl was 30 L/min/1.73m2 or greater or 0.5 mg/kg twice daily if CrCl was 15-29 mL/min/1.73m2. Study drug was administered for the

duration of hospitalization, including patient transfers to ICU settings.

Study protocol (Goldin, 2021):

Individual dose modification is not permitted unless the CrCl falls below 15 mL/min in the treatment arm (arm 0). In that case, conversion to dose-adjusted intravenous (IV) UFH is acceptable. The investigator is encouraged to convert back to treatment-dose enoxaparin as per protocol once the CrCl returns to values higher than or equal to 15 mL/min.

Describe control (treatment/procedure/test):

Patients in the standard-dose group received prophylactic or intermediate-dose heparin regimens per local institutional standard and could include UFH, up to 22500 IU subcutaneously (divided twice or thrice daily); enoxaparin, 30

mg or 40 mg subcutaneously once or twice daily (weight based

enoxaparin 0.5mg/kg subcutaneously twice daily was permitted but strongly discouraged); or dalteparin, 2500 IU or 5000 IU subcutaneously daily. If CrCl fell below15 mL/min/

1.73 m2, enoxaparin was converted to treatment-dose intravenous UFH until kidney function improved to CrCl greater than 15 mL/min/1.73 m2, when blinded-dose subcutaneous enoxaparin was resumed. Study drug was administered for the

duration of hospitalization, including patient transfers to ICU settings.

In the standard dose

group, 76 patients (61.3%) received prophylactic doses of

heparin (enoxaparin, ≤40mg daily), while 48 patients (38.7%)

received intermediate doses of heparin (enoxaparin, 30 mg

twice daily, 3 patients [2.4%]; enoxaparin, 40mg twice daily,

43 patients [34.7%]; enoxaparin, 0.5mg/kg twice daily, 2 patients

[1.6%]).

Goldin, 2021:

Dose modification is allowed in the prophylactic/intermediate group (arm 1) if the CrCl falls below15 mL/min so that UFH up to 22,500 U daily (i.e., UFH 5,000 U SQ BID or TID or 7,500 IU SQ BID or TID) can be used. The investigator is encouraged to convert back to prophylactic-/intermediate dose LMWH/UFH as per protocol once the CrCl returns to values higher than or equal to 15 mL/min.

Length of follow-up:

Until 30 + 2 days after randomization.

Loss-to-follow-up:

4 patients did not receive study drug (2 withdrew consent and 2 reached end points prior to the first dose). That resulted in 253 patients in the modified intention-to-treat population for analysis:

Intervention: 129

Control: 124

The primary analysis was based on the modified intention to-treat population, followed by the per-protocol population.

Clinical Outcomes During the 30-Day, stratified for ICU and non-ICU:

Mortality

Not reported

Length of hospital stay

Not reported

ICU-admission

Not reported

Organ support free days

Not reported

Venous thromboembolism

Not reported

Major bleeding
No./total No. (%)

Non-ICU patients:

I: 2/84 (2.4)

C: 2/86 (2.3)

RR (95% CI): 1.02 (0.15-7.10)

ICU patients:

I: 4/45 (8.9)

C: 0

RR (95% CI): 7.62 (0.42-137.03)

Author’s conclusions:

Therapeutic dose LMWH reduced

the composite of thromboembolism and

death compared with standard heparin thromboprophylaxis

without increased major bleeding among hospitalized patients

with COVID-19 with very elevated D-dimer levels. The treatment effect was not seen in ICU patients.

Sholzberg, 2021

RAPID trial

Type of study:

Randomized controlled, adaptive, open label clinical

trial.

Setting and country:

28 hospitals in Brazil, Canada, Ireland, Saudi Arabia,

United Arab Emirates, and US.

Funding and conflicts of interest:

Funding limitations and covid-19 restrictions

interfered with our ability to involve patient partners in setting the research question and in developing plans

for recruitment, design, and implementation of the

results of this study.

Inclusion criteria:

Moderately ill* patients admitted to hospital wards for covid-19.

1) Laboratory confirmed COVID-19 (diagnosis of SARS-CoV-2 via reverse transcriptase polymerase chain reaction as per the World Health Organization protocol or by nucleic acid based isothermal amplification) prior to hospital admission OR within first 5 days (i.e. 120 hours) after hospital admission;

2) Admitted to hospital for COVID-19;

3) One D-dimer value above the upper limit of normal (ULN) (within 5 days (i.e. 120 hours) of hospital admission) AND EITHER:

a. D-Dimer ≥2 times ULN OR

b. D-Dimer above ULN and Oxygen saturation ≤ 93% on room air;

4) > 18 years of age;

5) Informed consent from the patient (or legally authorized substitute decision maker).

Exclusion criteria:

1) pregnancy;

2) hemoglobin <80 g/L in the last 72 hours

3) platelet count <50 * 10^9/L in the last 72 hours

4) known fibrinogen <1.5 g/L (if testing deemed clinically indicated by the treating physician prior to the initiation of anticoagulation);

5) known INR >1.8 (if testing deemed clinically indicated by the treating physician prior to the initiation of anticoagulation);

6) patient already prescribed intermediate dosing of LMWH that cannot be changed (determination of what constitutes an intermediate dose is to be at the discretion of the treating clinician taking the local institutional thromboprophylaxis protocol for high risk patients into consideration);

7) patient already prescribed therapeutic anticoagulation at the time of screening [low or high dose nomogram UFH, LMWH, warfarin, direct oral anticoagulant (any dose of dabigatran, apixaban, rivaroxaban, edoxaban)];

8) patient prescribed dual antiplatelet therapy, when one of the agents cannot be stopped safely;

9) known bleeding within the last 30 days requiring emergency room presentation or hospitalization;

10) known history of a bleeding disorder of an inherited or active acquired bleeding disorder;

11) known history of heparin-induced thrombocytopenia;

12) known allergy to UFH or LMWH; 1

3) admitted to the intensive care unit at the time of screening;

14) treated with non-invasive positive pressure ventilation or invasive mechanical ventilation at the time of screening;

15) Imminent death according to the judgement of the most responsible physician;

16) enrollment in another clinical trial of antithrombotic therapy involving hospitalized patients.

N total at baseline:

465 were randomized.

Intervention: 228

Control: 237

Important prognostic factors²:

Age, mean (SD):

I: 60.4 (14.1)

C: 59.6 (15.5)

Sex, n (%), Male:

I: 123 (53.9%)

C: 141 (59.5%)

Body mass index, mean (SD)

I: 30.3 (6.4)

C: 30.2 (7.0)

Duration of symptoms before hospital admission (days), mean (SD)

I: 7.1 (5.1)

C: 7.1 (5.2)

Duration of hospital admission before randomization (days), mean (SD)

I: 1.5 (1.1)

C: 1.4 (1.0)

Hypoxaemia at baseline, n (%)

I: 190 (90.9)

C: 203 (93.1)

High flow nasal cannula oxygen use, n (%)

I: 14 (6.2)
C: 13 (5.5)

Pre-existing conditions, n (%):

Hypertension

I: 108 (47.4)

C: 117 (49.4)

Diabetes mellitus

I: 83 (36.4)

C: 77 (32.5)

Coronary artery disease

I: 16 (7.0)

C: 18 (7.6)

Heart failure

I: 9 (3.9)

C: 6 (2.5)

Atrial fibrillation

I: 0 (0.0)

C: 2 (0.8)

Cerebrovascular disease

I: 10 (4.4)

C: 9 (3.8)

Peripheral vascular disease

I: 0 (0.0)

C: 1 (0.4)

History of venous thromboembolism

I: 3 (1.3)

C: 2 (0.8)

Chronic pulmonary disease

I: 36 (15.8)

C: 27 (11.4)

Chronic kidney disease

I: 20 (8.8)

C: 13 (5.5)

Chronic liver disease

I: 5 (2.2)

C: 9 (3.8)

Cancer

I: 13 (5.7)

C: 19 (8.0)

Immunodeficiency

I: 1 (0.4)

C: 2 (0.8)

Autoimmune disease

I: 6 (2.6)

C: 11 (4.6)

Cognitive impairment

I: 12 (5.3)

C: 11 (4.6)

Mental illness

I: 18 (7.9)

C: 13 (5.5)

Active smoking

I: 5 (2.2)

C: 7 (3.0)

Drug history, n (%):

Systemic corticosteroids

I: 161 (70.6)

C: 162 (68.4)

Antiplatelet agent

I: 24 (10.5)

C: 29 (12.2)

Previous covid-19 vaccine, n (%)

I: 1 (0.4)

C: 2 (0.8)

D-dimer distribution, n (%):

<2.ULN

I: 115 (50.4)

C: 112 (47.3)

≥2-3.ULN

I: 61 (26.8)

C: 55 (23.2)

≥3-4.ULN

I: 25 (11.0)

C: 27 (11.4)

≥4.ULN

I: 27 (11.8)

C: 43 (18.1)

Groups comparable at baseline?

Yes

Describe intervention (treatment/procedure/test):

Unfractionated heparin as used for the treatment of

venous thromboembolism. Unfractionated heparin was administered using a weight based nomogram

(bolus plus continuous infusion) with activated partial

thromboplastin time or unfractionated heparin anti-

Xa titration according to the centre specific protocols

(that is, high dose nomogram).

Study treatment was

started within 24 hours after randomization and

continued until the first of hospital discharge, day 28,

study withdrawal, or death. If a participant was admitted to ICU, continuation of the

allocated treatment was recommended.

Describe control (treatment/procedure/test):

Dose capped prophylactic

subcutaneous heparin (low molecular weight heparin

or unfractionated heparin) adjusted for body mass

index and creatinine clearance (see supplementary

file for dosing).

Study treatment was

started within 24 hours after randomization and

continued until the first of hospital discharge, day 28,

study withdrawal, or death. If a participant was admitted to ICU, continuation of the

allocated treatment was recommended.

Length of follow-up:

28 days

Loss-to-follow-up:

Intervention:

Out of 228 who were assigned to the intervention group, 6 did not receive the allocated intervention (clinician discretion and patient refusal). 4 were lost to follow-up after hospital discharge.

There were 216 patients left for per protocol analysis (6 did not receive allocated intervention and 6 had a negative D-dimer result).

Control:

Out of 237 who were assigned to the control group, 5 did not receive the allocated intervention (clinician discretion and patient refusal). 7 were lost to follow-up after hospital discharge.

There were 227 patients left for per protocol analysis (5 did not receive allocated intervention and 5 had a negative D-dimer result).

Outcome measures and effect size (include 95%CI and p-value if available):

Mortality

Death from any cause, follow-up 28 days

I: 4 of 228 (1.8%) patients

C: 18 of 237 (7.6%) patients

Length of hospital stay

The mean number of hospital-free days.

I: 19.8 days (SD 7.3)

C: 18.4 days (SD 9.2)

Mean difference: 1.40 days (95%CI -0.11 to 2.91)

ICU admission

I: 33 out of 228 (14.5%)

C: 42 out of 237 (17.7%)

RR (95%CI): 0.82 (0.54 to 1.24)

Mean (SD) ICU-free days:

I: 26.0 (6.1)

C: 24.2 (8.8)

Mean difference: 1.80 days (95%CI 0.43 to 3.17)

Organ support free days

Mean (SD) organ support-free days

I: 25.8 (6.2)

I: 24.1 (8.8)

Mean difference: 1.70 (95%CI 0.32 to 3.08)

Mean (SD) ventilator-free days

I: 26.5 (5.6)

C: 24.7 (8.5)

Mechanical ventilation

I: 11/228 (4.8)

C: 16/237 (6.8)

Venous thromboembolism

Consisting of deep vein thrombosis and pulmonary embolism

I: 2 (0.9)

C: 6 (2.5)

RR 0.35; 95%CI 0.07 to 1.70)

ATE (myocardial infarction)

I: 0 (0%)

C: 1 (0.4%)

Major bleeding

ISTH major bleeding

I: 2 (0.9)

C: 4 (1.7)

Notes:

* Moderate illness was defined as admission

to hospital ward level of care (ie, not to ICU), not

already mechanically ventilated, and not imminently

requiring mechanical ventilation or critical care.

Author’s conclusions:

The primary composite outcome of death, mechanical

ventilation, or ICU admission with therapeutic

heparin. However, therapeutic heparin was associated

with a substantially decreased odds of all cause death

and low risk of major bleeding. In conjunction with the recently published multiplatform trial,19 the RAPID

trial therefore suggests that therapeutic heparin is beneficial in moderately ill patients with covid-19 admitted to hospital wards.

Marcos, 2021

Type of study:

open-label, multicenter, randomized, controlled trial

Setting and country:

The study was conducted at 5 Spanish hospitals

Funding and conflicts of interest:

RL reports investigation grants from Rovi, consultant fees from Aspen and Leo-Pharma and lecture fees from BMS,

Boehringer Ingelheim, Daiichi-Sankyo, Leo Pharma, Rovi and Sanofi, outside of the submitted work. PRA reports investigation grants

from Rovi, consultant fees from Viatris, BMS, Pfizer and Leo Pharma and lecture fees from BMS, Daiichi-Sankyo, Leo Pharma, Viatris and

Rovi, outside of the submitted work. All other authors declare no competing interests.

Inclusion criteria:

- Age > 18 years-old

- Hospitalization at the conventional ward due to mild or moderate (CURB65< 2 points and Sat. O2>90%) COVID-19 pneumonia. Maximum allowed time between hospitalization

and randomization is 48 hours

- 3-4 points according to the WHO ordinal scale

- Confirmed COVID-19 diagnosis by PCR or other validated test.

- Baseline D-Dimer >500 ng/mL

- Signed informed consent

- The patient, according to investigator’s opinion, is able to deal with all the requirements

of the clinical trial

Exclusion criteria:

Patients who meet any of the following criteria cannot be included in the clinical trial:

- Need of intensive care unit admission

- Moderate or severe adult respiratory distress syndrome

- Body weight <50Kg

- Creatinine clearance (Cockroft-Gault) <30ml/min

- Severe liver disease (elevation of hepatic enzymes 3 times above the upper limit of

normal)

- Thrombocytopenia <75,000/mm3

- History of coagulopathy or thrombocytopathy

- Active bleeding of increased bleeding risk due to impairment of haemostasis

- Recent (1 month) central nervous system o gastrointestinal bleeding

- Lesions of surgery involving central nervous system, eyes or inner ear in the last 2

months

- Presence of organic lesions with high bleeding risk (e.g. active peptic ulcer, hemorragic

stroke, brain aneurism o tumor)

- Planned surgery or interventional procedure requiring regional anesthesia

- Uncontrolled arterial hypertension

- Acute or subacute bacterial endocarditis

- Need of therapeutic anticoagulation for other reasons (e.g. atrial fibrillation, valvular

prosthesis, venous thromboembolism)

- Need of antiplatelet therapy

- Simultaneous participation in another clinical trial (use of drugs against COVID-19 in the

setting of local clinical management protocols is allowed)

- Previous history of heparin-induced thrombocytopenia

- Hypersensitivity or allergy to sodic bemiparin, heparin, compounds of porcine origin or

any of the excipients

N total at baseline:

72 patients were enrolled. 6 were excluded due to consent withdrawal or not meeting eligibility criteria.

Intervention: 33

Control: 33

Important prognostic factors²:

Age, mean (SD):

I: 62.3 (12.2)

C: 63.0 (13.7)

Sex, n (%), Male:

I: 24 (72.2%)

C: 17 (53.1%)

BMI (kg/m2), median (IQR)

I: 26.1 (24.1-28.8)

C: 25.8 (24.0-29.4)

BMI >30; n (%)

I: 4 (12.1)

C: 5 (15.6)

Comorbidities, n (%)

Hypertension

I: 12 (36.3%)

C: 10 (31.2%)

Diabetes mellitus

I: 3 (9.1)

C: 2 (6.3)

Chronic pulmonary disease

I: 6 (18.2)

C: 5 (15.6)

Cardiopathy

I: 1 (3.0)

C: 3 (9.3)

Previous arterial or venous thrombosis

I: 0

C: 0

Current or former smoking habit

I: 10 (30.3)

C: 16 (50.0)

Cancer

I: 1 (3.0)

C: 1 (3.1)

Days since COVID-19 diagnosis, median (IQR)

I: 6 (3-8)

C: 5 (2-8)

Days since symptoms onset, median (IQR)

I: 8 (6-10)

I: 8 (7-10)

Status at inclusion

Oxygen requirement; n (%)

I: 18 (54.5)

C: 20 (62.5)

D-dimer; median (IQR)

I: 770 (590-1030)

C: 780 (600-1125)

Ferritin; median (IQR)

I: 1093 (514-1751)

C: 518 (287-1248)

IL-6; median (IQR)

I: 24.8 (5.1-57.9)

C: 34.1 (15.7-77.7)

Brescia COVID-19 Score ≥2; n (%)

I: 3 (9.1)

C: 1 (3.1)

Sepsis-induced coagulopathy Score ≥4; n (%)

I: 1 (3.0)

C: 0

COVID-19 therapy, n (%)

Steroids

I: 30 (90.9)

C: 32 (100)

Statins

I: 20 (60.6)

C: 23 (71.9)

Remdesivir

I: 5 (15.2)

C: 4 (12.5)

Tocilizumab

I: 8 (24.2)

C: 7 (21.9)

Extended prophylaxis

after end of study treatment; n (%)

I: 21 (63.6)

C: 23 (71.9)

Duration (days); median (IQR)

I: 10 (7-14)

C: 10 (8-14)

Groups comparable at baseline?

Yes

Describe intervention (treatment/procedure/test):

Therapeutic-dose bemiparin (115 IU/Kg

daily) for 10 days independently

of early hospital discharge, adjusted to body weight (7,500 IU for patients between 50-70 Kg; 10,000

IU for patients weighing >70-100 Kg; 12,500 IU for patients who weighed >100

Kg).

Describe control (treatment/procedure/test):

Standard prophylaxis with subcutaneous bemiparin 3,500 IU once

daily for 10 days independently

of early hospital discharge

Length of follow-up:

On site study follow-up visits, that included laboratory assessments, were

scheduled in days 5 (+ 1 day) and 10 (+ 1 day). A final follow-up visit was performed on day

30 (+ 2 days) either on site or by telephone interview.

Loss-to-follow-up:

33 were allocated to standard thromboprophylaxis and 33 to therapeutic-dose bemiparin. A patient in

the therapeutic-dose arm did not start the assigned treatment due to ICU transfer before its first administration, and was excluded from primary analysis.

Outcome measures and effect size (include 95%CI and p-value if available):

Mortality

Death (day 10), n (%)

I: 0

C: 0

Death (day 30), n (%)

I: 2 (6.3)

C: 1 (3.0)

Length of hospital stay

Hospital discharge in first 10 days, n (%)

I: 21 (65.6)

C: 26 (78.8)

ICU-admission

Need of ICU (day 10), n (%)

I: 4 (12.5)

C: 4 (12.1)

Need of ICU (day 30), n (%)

I: 5 (15.6)

C: 4 (12.1) 5 (15.6)

Organ support free days

Marcos reported the need of mechanical ventilation support and the development of moderate/severe acute respiratory distress syndrome as a part of the primary composite outcome at day 10

I: 7 out of 32 patients (21.9%)

C: 6 out of 33 patients (18.2%)

RR 1.20 (95%CI 0.45 to 3.19).

Venous and arterial thromboembolism

ATE/VTE (day 10), n (%)

I: 0

C: 1 (3.0)

ATE/VTE (day 30), n (%)

I: 0

C: 2 (6.1)

Major bleeding

Major or clinically

relevant bleeding (day

10), n (%)

I: 0

C: 0

Notes:

Author’s conclusions:

In COVID-19 patients hospitalized with non-severe pneumonia

but elevated D-dimer, the use of a 10-day course of therapeutic-dose bemiparin

does not seem to improve clinical outcomes compared to prophylactic doses.

Lopes, 2021

ACTION-trial

Type of study:

A pragmatic, open-label (with blinded adjudication), multicentre, randomized, controlled trial.

Setting and country:

Brazil, 31 hospitals

Funding and conflicts of interest:

The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

Inclusion criteria:

1. Patients with confirmed diagnosis of COVID-19 admitted to hospital

2. Duration of symptoms related to hospitalisation ≤14 days

3. Patients ≥ 18 years old

4. D-dimer above the ULN

5. Agreement to participate by providing the informed consent form.

Exclusion criteria:

1. Patients with indication for therapeutic anticoagulation during inclusion (e.g, diagnosis of VTE, AF, mechanical valve prosthesis)

2. Platelets <50,000/mm3

3. Use of ASA >100 mg

4. Use of P2Y12 inhibitor (clopidogrel, prasugrel, ticagrelor)

5. Chronic use of NSAIDs

6. Sustained uncontrolled systolic BP ≥180 mm Hg or diastolic BP ≥100 mm Hg

7. INR >1·5

8. Patients contraindicated to therapeutic anticoagulation (active bleeding, liver failure, blood dyscrasia or prohibitive haemorrhage risk as evaluated by the investigator)

9. Patients with DIC 10. History of haemorrhagic stroke or any intracranial bleeding at any time in the past or current intracranial neoplasm (benign or malignant), cerebral metastases, arteriovenous malformation, or aneurysm

11. Active cancer (excluding non-melanoma skin cancer) defined as cancer not in remission or requiring active chemotherapy or adjunctive therapies such as immunotherapy or radiotherapy

12. Hypersensitivity to rivaroxaban

13. Use of strong inhibitors of cytochrome P450 (CYP) 3A4 and/or P-gp (e.g., protease inhibitors, ketoconazole, itraconazole) and/or use of P-gp and strong CYP3A4 inducers (including, but not limited to, rifampin/rifampicin, rifabutin, rifapentine, phenytoin, phenobarbital, carbamazepine, or St. John's Wort)

14. Known HIV infection

15. Creatinine clearance.

N total at baseline:

Intervention: 331

Control: 304

Important prognostic factors²:

For example

Age, mean (SD):

I: 56.7 (14.1)

C: 56.6 (14.5)

Sex, n (%), Male:

I: 192 (62%)

C: 176 (58%)

Body mass index, mean (SD), kg/m2:

I: 30.3 (6.0)

C: 30.3 (6.1)

Comorbidities, n (%)

Asthma
I: 18 (6%)
C: 11 (4%)

Chronic lung disease

I: 7 (2%)

C: 12 (4%)

Malignant neoplasm

I: 12 (4%)

C: 4 (1%)

Diabetes 8

I: 3 (27%)

C: 67 (22%)

Hypertension

I: 151 (49%)

C: 151 (50%)

Heart failure

I: 8 (3%)

C: 5 (2%)

Coronary disease I: 12 (4%)

C: 16 (5%)

History of thromboembolism I: 2 (1%)

C: 4 (1%)

Smoking habits, n (%)

Never smoked

I: 255 (82%)

C: 241 (79%)

Current or former smoker

I: 56 (18%)

C: 63 (21%)

Clinical condition, n (%)

Unstable

I: 23 (7%)

C: 16 (5%)

Stable

I: 288 (93%)

C: 288 (95%)

Time from symptom onset to randomization, days, median (IQR)

I: 10.0 (9·0–12.0)

C: 10.0 (8·0–12.0)

Time from symptom onset to hospital admission, days, median (IQR)

I: 8.0 (6.0–10.0)

C: 7.0 (6.0–9.0)

Time from hospital admission to randomization, days, median (IQR)

I: 2.0 (1.0–3.0)

C: 2.0 (1.0–3.0)

Oxygen support required, n (%)

I: 236 (76%)

C: 224 (74%)

Catheter or oxygen mask, n (%)

I: 185 (59%)

C: 184 (61%)

High-flow nasal cannula, n (%)

I: 26 (8%)

C: 22 (7%)

Tracheal intubation, n (%)

I: 23 (7%)

C: 15 (5%)

Non-invasive ventilation, n (%)

I: 2 (1%)

C: 3 (1%)

Disease state at baseline, n (%)

Mild

I: 30 (10%)

C: 39 (13%)

Moderate

I: 257 (83%)
C: 249 (82%)

Severe

I: 24 (8%)

C:16 (5%)

Anticoagulation before randomization, n (%)

I: 285 (92%)

C: 275 (90%)

Standard prophylactic dose, n (%)

I: 175 (56%)

C: 187 (62%)

Greater than standard prophylactic dose, n (%)

I: 110 (35%)

C: 88 (29%)

Baseline medication, n (%)

Antiplatelet

I: 22 (7%)

C: 26 (9%)

Vasopressor

I: 16 (5%)

C: 8 (3%)

Systemic corticosteroids

I: 257 (83%)

C: 253 (83%)

D-dimer concentration, n (%)

≥1 ×upper limit of normal

I: 311 (100%)

C: 304 (100%)

≥3 ×upper limit of normal

I: 84 (27%)

C: 83 (27%)

Creatinine clearance, mL/min, median (IQR)

I: 106.6 (82.9–143.4)

C: 105.7 (76.9–145.1)

Groups comparable at baseline?

Yes

Describe intervention (treatment/procedure/test):

Therapeutic anticoagulation for 30 days (rivaroxaban if clinically stable or enoxaparin if clinically unstable).

Clinically stable patients assigned to receive therapeutic anticoagulation were given oral rivaroxaban at a dose of 20 mg once daily. A reduced dose of 15 mg once daily was used in patients with a creatinine clearance of 30–49 mL/min or those taking azithromycin. Patients were considered to be in a clinically unstable condition if they had COVID-19-related critical illness, a lifethreatening condition, a requirement for mechanical ventilation or vasopressors, or were unable (based on investigator assessment) to take oral medication. Those in an unstable condition received subcutaneous enoxaparin at a dose of 1 mg/kg twice per day, or intravenous unfractionated heparin at a dose to achieve a target anti-Xa concentration (0·3–0·7 IU/mL) or a corresponding target activated partial thromboplastin time (1·5–2·5 times the mean normal value). Unfractionated heparin was the preferred option for patients with renal dysfunction or disseminated intravascular coagulation. When these patients became stable, they were transitioned to oral rivaroxaban (20 mg or 15 mg, as described above). All patients in the therapeutic anticoagulation group continued treatment to day 30 with the same dose of rivaroxaban.

Describe control (treatment/procedure/test):

In-hospital prophylactic anticoagulation (enoxaparin or unfractionated heparin).

Patients assigned to receive prophylactic anticoagulation were given standard venous thromboembolism prophylaxis with enoxaparin or unfractionated heparin during hospitalisation and could receive extended prophylaxis at the discretion of the treating physician (appendix p 7). Patients in this group could receive therapeutic anticoagulation if they developed a definitive clinical indication (eg, objectively confirmed deep vein thrombosis) or at the discretion of the investigator if a high clinical suspicion of a thromboembolic event was raised and a confirmatory test was not available.

Length of follow-up:

30 days for study outcomes, and 60 days for additional safety information.

Loss-to-follow-up:

Of 331 in intervention group, 1 was lost to follow-up before 30 days (withdrew consent, so 310 were included in primary analysis.

Of 304 in the control group, 1 received therapeutic coagulation, but 304 were still included in primary analysis.

Outcome measures and effect size (include 95%CI and p-value if available):

During hospitalisation, data were collected daily.

Mortality

Death, n/total (%)

I: 35/310 (11%)

C: 23/304 (8%)

RR 1·49 (0·90–2·46)

Length of hospital stay at the end of 30 days, mean (SD)

I: 8.1 days (SD 7.2) C: 7.8 days (SD 7.5)

ICU-admission

Not reported

Organ support free days

Not reported

Organ support

The number of patients hospitalised with invasive mechanical ventilation without additional support.

I: 1/310 (0.3%)

C: 4/304 (1.3%)

Venous thromboembolism
VTE (consisting of deep vein thrombosis and pulmonary embolism)

I: 11 (4%)

C: 18 (6%)

RR (95%CI): RR 0.60 (0.29–1.25)

Number of patients that reported the composite thrombotic outcome (consisting of venous thromboembolism – deep vein thrombosis and pulmonary embolism, myocardial infarction, stroke, and major adverse limb event).

I: 23 out of 310 (7%) patients

C: 30 out of 304 (10%) patients

RR 0.75, 95%CI 0.45 to 1.26

Major bleeding, n (%)

I: 10 (3%)

C: 4 (1%)

RR (95%CI): 2.45 (0.78-7.73)

Notes:

** Clinically unstable was defined as the presence of a COVID-19-related critical illness with an immediately life-threatening condition that would typically lead to intensive care unit admission

Author’s conclusion:

in patients hospitalised with COVID-19 with elevated D-dimer concentration, initial in-hospital therapeutic anticoagulation with rivaroxaban for stable patients or enoxaparin for unstable patients followed by rivaroxaban through 30 days did not improve clinical outcomes and increased bleeding compared with in-hospital prophylactic anticoagulation. Thus, the use of therapeutic-dose rivaroxaban, and other direct oral anticoagulants, should be avoided in hospitalised patients with COVID-19 who do not have an evidence-based indication for oral anticoagulation.

Study reference

(first author, publication year)

Was the allocation sequence adequately generated? ^a

Definitely yes

Probably yes

Probably no

Definitely no

Was the allocation adequately concealed?^b

Definitely yes

Probably yes

Probably no

Definitely no

Blinding: Was knowledge of the allocated

interventions adequately prevented?^c

Were patients blinded?

Were healthcare providers blinded?

Were data collectors blinded?

Were outcome assessors blinded?

Were data analysts blinded?

Definitely yes

Probably yes

Probably no

Definitely no

Was loss to follow-up (missing outcome data) infrequent?^d

Definitely yes

Probably yes

Probably no

Definitely no

Are reports of the study free of selective outcome reporting?^e

Definitely yes

Probably yes

Probably no

Definitely no

Was the study apparently free of other problems that could put it at a risk of bias?^f

Definitely yes

Probably yes

Probably no

Definitely no

Overall risk of bias

If applicable/necessary, per outcome measure^g

LOW

Some concerns

HIGH

Lawler, 2021

Probably yes;

Reason: Central Internet-based systems to randomly

assign patients were used. Treatments were initially randomly assigned in a 1:1 ratio. The ATTACC and REMAP-CAP designs specified the possibility of response-adap tive randomization, in which group-assignment ratios could be modified in a blinded fashion during the trial on the basis of response-adaptive interim analyses to favor the assignment of patients to the treatment group showing greater benefit. However, we did not think this influenced the prognostic balance between the two groups at baseline.

Definitely yes;

Reason: Central Internet-based systems to randomly

assign patients were used

Definitely no;

Reason: open label trial

Definitely yes;

Reason: Exclusion rate 1.6% and 0.6% in intervention group and control group respectively. Only 3 participants had no available outcome data. Data was not imputed, but patients were excluded from the analysis.

Definitely yes;

Reason: Protocol adhered, relevant outcomes reported

Definitely no;

Reason: enrollment

was discontinued on the advice of the data and safety monitoring boards after a planned adaptive analysis of data from 1398 patients showed

that the prespecified stopping criteria for superiority

of therapeutic-dose anticoagulation had

been reached

Intention to treat analysis is not clearly mentioned.

HIGH (all outcome measures)

Reasons:

- prespecified stopping criteria

- no mentioning of ITT analysis

- open label trial

Spyropoulos, 2021

Definitely yes

Reason:

Randomization well-described and well-performed

Study protocol

The Feinstein Institutes Biostatistics Unit (Northwell Health) developed and implemented the randomization procedure using the Biostatistics Randomization Management System (BRMS). BRMS is a secure, HIPAA-compliant, web-based application that allows investigators to randomize subjects into randomized clinical trials (RCTs) using their personal computer. BRMS allows for multicenter, stratified, and single/double-blinded RCTs, using permuted blocks. Eligible patients will be stratified according to whether their level of care corresponds to intensive care unit (ICU) care or not. Subjects will be randomly assigned to the treatment arm (arm 0: treatment dose of LMWH) or the prophylactic-/ intermediate-dose arm (arm 1: prophylactic/intermediate dose of LMWH or UFH) in a 1:1 ratio.

Spyropoulos, 2021:

Randomization was performed using a secure web application

and was stratified based on noncritical care (non– intensive care unit [ICU]) or critical care (ICU) status at the time of randomization. Participants were

randomly assigned 1:1 to therapeutic-dose enoxaparin or institutional

standard prophylactic or intermediate-dose heparins.

Definitely yes

Reason:

Study protocol

BRMS is a secure, HIPAA-compliant, web-based application that allows investigators to randomize subjects into randomized clinical trials (RCTs) using their personal computer.

Spyropoulos, 2021:

The study pharmacists as well as data abstractors and designated randomization personnel (i.e., research coordinators and/or research nurses performing the randomization process) will be unblinded.

Were patients blinded?

Definitely yes

Were healthcare providers blinded?

Definitely no

Were data collectors blinded?

Definitely yes

Were outcome assessors blinded?

Unknown

Were data analysts blinded?

Unknown

Reason:

Study protocol (Goldin, 2021):

Due to the pragmatic nature of this study and pseudoblinded trial design, at the time of randomization the study subject and corresponding site PIs will be blinded (unaware of specific treatment arm to which the patient is assigned). The study pharmacists as well as data abstractors and designated randomization personnel (i.e., research coordinators and/or research nurses performing the randomization process) will be unblinded.

Spyropoulos, 2021:

Patients and investigators were blinded to treatment assignment

as much as possible.

Data were collected and adjudicated locally by blinded investigators via imaging, laboratory, and health record data.

Discussion part: Although both investigators

and patients were blinded to study drug regimen,

other unblinded personnel may have introduced bias affecting

outcome ascertainment.

Probably yes

Reason:

There was no loss to follow-up. However, the primary analysis was based on the modified intention to-treat population, followed by the per-protocol population. We assumed that the modified ITT did not have an influence on the risk of bias, as the number of patients that was different between the ITT and modified ITT population was very small (1 in the intervention group and 3 in the control group).

Definitely yes

Reason:

Study protocol available, all reported outcomes in study protocol reported in trial.

Probably yes

Reason:

Funding/Support: This work was supported by the Feinstein Institutes for Medical Research, the Broxmeyer Fellowship in Clinical Thrombosis, and

grant R24AG064191 from the National Institute on Aging.

Role of the funder/Sponsor: The funders had no role in the design and conduct of the study;

collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit

the manuscript for publication.

Modified intention-to-treat analysis performed. However, only 1 and 3 patients in the intervention and control group, respectively, were not analysed.

LOW (mortality, length of hospital stay, ICU-admission, organ support free days)

Reasons:

- patients and data collections blinded, but all other personnel including the healthcare providers were not blinded and could therefore have influenced the ‘soft’ outcome measures

Sholzberg, 2021

Definitely yes

Reason:

We used web based central randomization with a

computer generated random sequence of variable

block sizes stratified by site and age (≤65 v >65

years) to assign patients in a 1:1 ratio to therapeutic

heparin or prophylactic heparin.

Definitely yes

Reason:

Use of central randomization.

Were patients blinded?

Definitely no

Were healthcare providers blinded?

Definitely no

Were data collectors blinded?

Definitely no

Were outcome assessors blinded?

Definitely no

Were data analysts blinded?

Definitely yes

Reasons:

Outcomes were blindly

adjudicated.

An independent

event adjudication committee, which was unaware of

treatment assignments, adjudicated the components

of the primary outcome, bleeding, thrombotic events,

and cause of death. The event adjudication was not

prespecified in the protocol.

Definitely yes

Infrequent loss to follow-up (4 in intervention group and 7 in control group). Primary outcomes were analysed with ITT analysis.

Definitely yes

Study protocol available, most reported outcomes in study protocol reported in trial. Clear mentioning of components of the primary composite that were not included in the protocol but were prespecified as secondary outcomes in the statistical analysis plan; transparent.

IIT principle for primary outcomes.

Definitely yes

The funders had no role

in the trial design; conduct, collection, management, analysis, or

interpretation of data; or in preparation or review of the manuscript or

the approval of the manuscript for submission.

LOW (mortality, length of hospital stay, ICU-admission, organ support free days)

Reasons:

- open-label trial, could possibly have influenced the ‘soft’ outcome measures

Marcos, 2021

Definitely yes

Reason:

Randomization was performed in a 1:1 ratio using a central, electronic,

automated system with permuted blocks of 4.

Definitely yes

Reason:

Randomization was performed in a 1:1 ratio using a central, electronic,

automated system with permuted blocks of 4.

Were patients blinded?

Definitely no

Were healthcare providers blinded?

Unknown

Were data collectors blinded?

Definitely no (assuming these are the researchers)

Were outcome assessors blinded?

Unknown

Were data analysts blinded?

Unknown

Reason:

There was no blinding of patients

or investigators to group allocation.

However, no blinding likely did not affect the outcome measures we’re interested in, since these are ‘hard’ outcome measures.

Definitely yes

Reason:

There was 1 patient that did not start the assigned treatment due to transfer before its first administration and this patient was excluded from primary analysis. There was no other patient lost to follow-up.

Probably yes

Reasons:

Study protocol available, although some figures missing. Study protocol describes the reported outcomes.

Efficacy and safety were

evaluated in the modified intention to treat population (mITT), including all randomized

patients that received at least one dose of the allocated treatment.

è modified intention to treat analysis is doubtful. Not clearly described.

Definitely yes

Reason:

RL reports investigation grants from Rovi, consultant fees from Aspen and Leo-

Pharma and lecture fees from BMS, Boehringer Ingelheim, Daiichi-Sankyo, Leo

Pharma, Rovi and Sanofi, outside of the submitted work. PRA reports

investigation grants from Rovi, consultant fees from Viatris, BMS, Pfizer and

Leo Pharma and lecture fees from BMS, Daiichi-Sankyo, Leo Pharma, Viatris

and Rovi, outside of the submitted work. All other authors declare no competing

interests.

LOW (mortality, length of hospital stay, ICU-admission, organ support free days)

Reasons:

- open-label trial, could possibly have influenced the ‘soft’ outcome measures

Lopes, 2021

Definitely yes

Reason:

Randomization was done in a 1:1 ratio in permuted blocks of variable size, stratified according to clinical condition (stable or unstable), using a central, concealed, web-based, automated randomization system.

Definitely yes

Reason:

Randomization was done in a 1:1 ratio in permuted blocks of variable size, stratified according to clinical condition (stable or unstable), using a central, concealed, web-based, automated randomization system.

Were patients blinded?

Definitely no

Were healthcare providers blinded?

Definitely no

Were data collectors blinded?

Definitely no

Were outcome assessors blinded?

Definitely no

Were data analysts blinded?

Definitely yes

Reason:

There was no masking of patients or investigators to group allocation.

However, there was a blinded adjudication process for the secondary outcomes using standard definitions, as well as regular site training and monitoring and sensitive triggers based on laboratory values, reports of adverse events, unknown causes of death, or changes in antithrombotic therapy, to ensure that no relevant events were missed.

Definitely yes

Reason:

Only 1 person in the intervention group withdrew consent and was therefore excluded from primary analysis. Out of 304 persons in the control group, 1 did not receive the allocation intervention but was nevertheless still analysed in this group. This gives no indication of bias.

Definitely yes

Reason:

Publication in line with protocol

Definitely yes

Reason:

1. The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.
2. It seems that there was made use of an ITT protocol.

LOW (mortality, length of hospital stay, ICU-admission, organ support free days)

Reasons:

- open-label trial, could possibly have influenced the ‘soft’ outcome measures