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What does the literature say about intermediate-dose versus standard-dose prophylactic anticoagulation among patients with COVID-19 admitted to the intensive care unit?

Comment by InpharmD Researcher

Guidelines do not recommend an intermediate or therapeutic dose of anticoagulation over prophylactic doses for hospitalized COVID-19 patients. A randomized controlled trial did not find any difference between intermediate-dose and standard-dose prophylactic anticoagulation in ICU patients with COVID-19. Some studies have observed positive impacts on patient prognosis with intermediate and therapeutic anticoagulation dosing; however, these studies are limited by small sample sizes or retrospective designs.
Background

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

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

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

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

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

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

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

References:

[1] U.S. National Institute of Health (NIH). Antithrombotic Therapy in Patients With COVID-19. https://www.covid19treatmentguidelines.nih.gov/antithrombotic-therapy/. Updated March 5, 2021. Accessed April 10, 2021.
[2] Cuker A, Tseng EK, Nieuwlaat R, et al. American Society of Hematology 2021 guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19. Blood Adv. 2021;5(3):872-888. doi:10.1182/bloodadvances.2020003763
[3] American Society of Hematology. Should DOACs, LMWH, UFH, Fondaparinux, Argatroban, or Bivalirudin at intermediate-intensity or therapeutic-intensity vs. prophylactic intensity be used for patients with COVID-19 related critical illness who do not have suspected or confirmed VTE? 2020. https://guidelines.ash.gradepro.org/profile/3CQ7J0SWt58. Accessed April 5, 2021.
[4] Barnes GD, Burnett A, Allen A, et al. Thromboembolism and anticoagulant therapy during the COVID-19 pandemic: interim clinical guidance from the anticoagulation forum. J Thromb Thrombolysis. 2020;50(1):72-81.
[5] Spyropoulos AC, Levy JH, Ageno W, et al. Scientific and standardization committee communication: clinical guidance on the diagnosis, prevention, and treatment of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost. 2020 ;18(8):1859-1865. doi: 10.1111/jth.14929.
[6] Moores LK, Tritschler T, Brosnahan S, et al. Prevention, diagnosis, and treatment of VTE in patients with coronavirus disease 2019: CHEST guideline and expert panel report. Chest. 2020;158(3):1143-1163. doi:10.1016/j.chest.2020.05.559.
[7] Quek E, Tahir H, Kumar P, Hastings R, Jha R. Treatment of COVID-19: a review of current and prospective pharmacotherapies. Br J Hosp Med (Lond). 2021;82(3):1-9. doi:10.12968/hmed.2021.0112

Literature Review

A search of the published medical literature revealed 4 studies investigating the researchable question:

What does the literature say about intermediate-dose versus standard-dose prophylactic anticoagulation among patients with COVID-19 admitted to the intensive care unit?

Please see Tables 1-4 for your response.


 

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

Design

Randomized, open-label, multicenter, 2x2 factorial trial

N=562

Objective

To evaluate the effects of intermediate-dose vs standard-dose prophylactic anticoagulation among patients with COVID-19 admitted to the intensive care unit (ICU)

Study Groups

Intermediate-dose (n=276)

Standard-dose (n=286)

Inclusion Criteria

Aged ≥18 years; PCR-confirmed COVID-19; admitted to ICU within 7 days of initial hospitalization; did not have another indication for anticoagulation (such as mechanical valve, high-risk AF, VTE, or left ventricular thrombus)

Exclusion Criteria

Weight <40 kg; use of systemic anticoagulation for another indication; overt bleeding during screening; known major bleeding within 30 days of enrollment; platelet count <50,000/µL; history of heparin-induced thrombocytopenia or immune thrombocytopenia; ischemic stroke within past 2 weeks; major head or spinal trauma within the past 30 days; craniotomy/major neurosurgery within the past 3 months; obesity (BMI >35 kg/m2 or >120 kg) plus renal insufficiency (CrCl <30 mL/min)

Methods

Eligible patients were randomized 1:1 to receive either intermediate-dose or standard-dose prophylactic anticoagulation. All anticoagulation was given subcutaneously. The assigned treatments were planned to be continued until the 30-day follow-up, irrespective of hospital discharge status.

Intermediate-dose anticoagulation was enoxaparin 1 mg/kg daily in patients with adequate renal function. If patients were obese, they received enoxaparin 0.6 mg/kg BID. Patients with a CrCl between 15-30 mL/min received enoxaparin 0.5 mg/kg daily, and if their CrCl ≤15 mL/min, they received unfractionated heparin (UFH) 10,000 U BID.

Standard-dose anticoagulation was enoxaparin 40 mg daily. If patients were obese, they received enoxaparin 40 mg BID. Patients with a CrCl between 15-30 mL/min received enoxaparin 30 mg daily, and if their CrCl ≤15 mL/min, they received unfractionated heparin (UFH) 5,000 U BID.

Duration

Study period: July 29 to November 19, 2020

Follow-up: up to 30 days

Outcome Measures

Primary: composite of adjudicated acute arterial thrombosis, venous thromboembolism (VTE), undergoing extracorporeal membrane oxygenation (ECMO), or all-cause death at 30 days

Secondary: all-cause mortality, objectively confirmed VTE, ventilator-free days

Baseline Characteristics

 

Intermediate-dose (n=276)

Standard-dose (n=286)

 

Age, years (IQR)

62 (51-70.7) 61 (47-71)  

Male

58.7% 57.0%  

Body mass index, kg/m2 (IQR)

26.7 (24.4-29.1) 27.2 (24.3-29.1)  

Duration of symptoms, days (IQR)

7 (4-8) 7 (5-10)  

Oxygen support

Nasal cannula

Face mask

Reservoir mask

High-flow nasal cannula

Noninvasive ventilation

Mechanical ventilation

 

3.6%

12%

27.5%

3.3%

33.7%

19.9%

 

4.9%

9.4%

33.6%

2.1%

29.7%

20.3%

 

Baseline aspirin use

33% 28.3%  

Corticosteroid use

94.9% 91.6%  

Results

 

Intermediate-dose (n=276)

Standard-dose (n=286)

P-value

Composite primary outcome

126 (45.7%) 126 (44.1%) 0.70

All-cause mortality

119 (43.1%) 117 (40.9%) 0.50

Confirmed VTE

9 (3.3%) 10 (3.5%) 0.87

Ventilator-free days (IQR)

30 (3-30) 30 (1-30) 0.50

In addition to the lack of significance found in the primary and secondary endpoints, there was no significance in ant exploratory outcomes of myocardial infarction, stroke, periphery arterial thrombosis, ICU length of stay, atrial fibrillation, and new renal replacement therapy.

Adverse Events

Major bleeding (2.5% vs 1.4%); clinically relevant nonmajor bleeding (4.3% vs 1.7%; P=0.07); severe thrombocytopenia (<20,000/µL; 2.2% vs 0%, P=0.01); mild thrombocytopenia (<100,000/µL; 18.2% vs 19.9%)

There was 1 case of intracranial hemorrhage and 2 cases of fatal bleeding events in the intermediate-dose group compared to none in the standard-dose group.

Study Author Conclusions

Among patients admitted to the ICU with COVID-19, intermediate-dose prophylactic anticoagulation, compared with standard-dose prophylactic anticoagulation, did not result in a significant difference in the primary outcome of a composite of adjudicated venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days. These results do not support the routine empirical use of intermediate-dose prophylactic anticoagulation in unselected patients admitted to the ICU with COVID-19.

InpharmD Researcher Critique

This study, although multicenter, was conducted entirely in Iran. Patients on ECMO (who would be the most severely ill) were excluded from this study. Another limitation is the open-label design, but it is arguably unfeasible to mask using a double-dummy during a pandemic.

The incidence of VTE seen in this study was lower than expected, but this likely did not affect the results due to the composite primary endpoint. 



References:

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. Published online March 18, 2021. doi:10.1001/jama.2021.4152

 

Beneficial Effects of Intermediate Dosage of Anticoagulation Treatment on the Prognosis of Hospitalized COVID-19 Patients: The ETHRA Study

Design

Retrospective analysis

N=95

Objective

To study the potential beneficial effects of different dosages of anticoagulation treatment on the prognosis of COVID-19 inpatients and on coagulation and inflammatory biomarkers as well as to evaluate the safety profile of this therapeutic strategy

Study Groups

No prophylaxis (n=15)

Prophylaxis (n=26)

Intermediate (n=42)

Therapeutic (n=12)

Inclusion Criteria

Hospitalized in general COVID-19 wards, anticoagulation within first 5 days post-admission

Exclusion Criteria

Contraindication to anticoagulation therapy (e.g. active bleeding), venous thromboembolism (VTE) or intubation or death within the first 24 hours post-admission

Methods

Medical records of patients were obtained and analyzed. On March 11, 2020, the hospital adopted the Enhanced dose THRomboprophylaxis (intermediate dose) in all COVID-19 Admissions (ETHRA). This protocol was revised on March 25, 2020. The intermediate and therapeutic doses were not described but consisted of LMWH or fondaparinux. Patients received intermediate doses by default and therapeutic doses if there is radiological deterioration, clinical deterioration with hypoxemia and/or unexplained fever, clinical suspicion for DVT/PE, or increasing D-dimers. They were compared with patients who received prophylaxis and no prophylaxis treatment (possibly denoting a group of patients deviating from the ETHRA hospital protocol. But, once again, this was unspecified).

Duration

Not specified

Outcome Measures

Primary outcome: Incidence of intubations or VTE, pulmonary embolism (PE), and deep vein thrombosis (DVT) confirmed with imaging

Secondary outcome: Inflammatory biomarkers in patients treated with intermediate dosages, safety

Baseline Characteristics

 

No prophylaxis (n=15)

Prophylaxis (n=26)

Intermediate (n=42) Therapeutic (n=12)

Age, years

53.7 56.8 58.5 76

Males

8 (53.3%) 14 (53.8%) 30 (71.4%) 6 (50%)

Smoking

Hypertension

Diabetes

20%

13.3%

0

26.9%

19.2%

11.5%

21.4%

35.7%

7.1%

8.3%

33.3%

16.7%

Charlson Comorbidity Index*

1 (0 to 3)

2 (0 to 3.3)

2 (0 to 3)

5 (5 to 7.5)

Hydroxychloroquine

Axithromycin

Other antibiotics

Lopniavir/Ritonavir

Remdesivir

60%

80%

73%

20%

0

81%

88%

88%

8%

0

79%

90%

83%

14%

2%

58%

67%

83%

17%

0

*p-value for Charlson Comorbidity index was <0.001 indicating a significant difference between groups (due to the high score in the therapeutic group).

Results

Endpoint

No prophylaxis (n=15)

Prophylaxis (n=26)

Intermediate (n=42)

Therapeutic (n=12)

Incidence of primary outcome

Death

6 (40%)

1

5 (19%)

1

6 (14%)

0

4 (33%)

2

Regression analysis of reduction of events compared to the no prophylaxis and prophylaxis group, hazard ratio (95% confidence interval [CI]; p-value)

-

-

0.16 (0.05 to 0.52; p=0.002)

0.17 (0.04 to 0.71; p=0.015)

Intermediate group (n=15) ferritin increased before initiation of LMWH and decreased to similar levels of untreated controls > 3 days after. No other biomarkers were significantly different between treatment group

Adverse Events

Hemorrhagic complications: n=2 in the intermediate group and n=1 in the prophylactic group. None required discontinuation.

Study Author Conclusions

Anticoagulation treatment (particularly intermediate dosage) appears to have positive impact on COVID-19 inpatients’ prognosis by inhibiting both coagulation and inflammatory cascades.

InpharmD Researcher Critique

Retrospective studies are exploratory and need to be verified in subsequent studies. There were a lack of frequent measurements of clinical markers. The therapeutic group also had a higher Charlson Comorbidity Index which may be the cause of higher incidences or morbidity and mortality.



References:

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

 

Therapeutic versus prophylactic anticoagulation for severe COVID-19: a randomized phase II clinical trial (HESACOVID)

Design

Randomized, open-label, phase II trial

N=20

Objective

To evaluate whether therapeutic anticoagulation could improve gas exchange compared to the standard anticoagulant thromboprophylaxis, reducing the need to maintain mechanical ventilation in severe COVID-19 patients

Study Groups

Prophylactic anticoagulation (n=10)

Therapeutic anticoagulation (n=10)

Inclusion Criteria

Aged >18 years, SARS-CoV-2 infection confirmed by reverse transcriptase-polymerase chain reaction (RT-PCR), acute respiratory distress syndrome (ARDS) per the Berlin definition, severe respiratory failure requiring mechanical ventilation, D-dimer >1,000 μg/L; prothrombin time (PT)/INR <1.5; activated partial thromboplastin time (aPTT)/ratio < 1.5, platelets >100,000/mm3

Exclusion Criteria

Age >85 years, creatinine clearance (CrCl) <10 mL/min, severe circulatory shock with a dose of norepinephrine >1.0 μg/kg/min, chronic renal failure in renal replacement therapy, liver disease (Child-Pugh B or C), other advanced disease (e.g., active cancer, heart failure NYHA class III or IV, COPD), cardiorespiratory arrest, pregnant women, recent major surgery or severe trauma in the last 3 weeks, recent stroke in the last 3 months, active bleeding, blood dyscrasia (e.g., hemophilia, von Willebrand factor deficiency), indication for therapeutic anticoagulation

Methods

Patients were randomized 1:1 to receive prophylactic or therapeutic anticoagulation. The prophylactic anticoagulation group received subcutaneous unfractionated heparin (UFH) at a dose of 5000 IU TID (if weight < 120 kg) and 7500 IU TID (if weight > 120 kg) or enoxaparin at a dose of 40 mg daily (if weight < 120 kg) and 40 mg BID (if weight > 120 Kg) according to the doctor's judgment.

Therapeutic anticoagulation consisted of subcutaneous (SC) enoxaparin dosed according to age and CrCl (1 mg/kg BID if aged <75 years with CrCl >50 mL/min). If the patient's CrCl worsened to <10 mL/min during the study period, then UFH was given adjusted to an activated partial thromboplastin time (aPTT) between 1.5 and 2.0. Therapeutic enoxaparin was given for at least 96 hours, but was ideally given for 14 days.

Anticoagulation could be suspended at any time if there was evidence of clinical bleeding.

Duration

Recruitment: April to July 2020

Follow-up: up to 28 days

Outcome Measures

Primary: PaO2/FiO2 ratio at days 7 and 14

Secondary: time until removed from ventilation; ventilator-free days (of the 28-day study period); D-Dimer levels; mortality

Baseline Characteristics

 

Prophylactic anticoagulation (n=10)

Therapeutic anticoagulation (n=10)

P-value

Age, years

58 ± 16 55 ± 10 0.529

Male

70% 90% 0.264

Time from symptom onset to hospitalization, days

Time in ICU before enrollment, days (IQR)

6 ± 3

1 (0-2)

7 ± 2

0 (0-2)

0.464

0.496

Body mass index, kg/m2

34 ± 8 33 ± 8 0.828

Previous anticoagulation use

Prophylactic

Therapeutic

 

70%

0

 

40%

0

 

0.137

1.000

Concomitant medications*

Norepinephrine

Corticosteroids

Hydroxychloroquine

Macrolide antibiotic

 

60%

70%

10%

90%

 

60%

70%

40%

90%

 

1.00

1.00

0.121

1.00

SOFA score (IQR)

10 (8-11) 10 (7-11) 0.877

Baseline PaO2/FiO2 ratio

184 ± 53 163 ± 41 0.336

*No patients received remdesivir, any interleukin-6 inhibitors, or antiplatelet agents; all patients received neuromuscular blocking agents.

Therapeutic anticoagulation was prescribed for a median of 14 days, which may be considered excessive for these patients. 

IQR=interquartile range; SOFA=sequential organ failure assessment

Results

 

Prophylactic anticoagulation (n=10)

Therapeutic anticoagulation (n=10)

P-value

PaO2/FiO2 ratio (95% confidence interval)

Day 0

Day 7

Day 14

 

184 (146–222)

168 (142–195)

195 (128–262)**

 

163 (133–193)

209 (171–247)

261 (230–293)**

 

0.336

0.060

0.057

Ventilator-free days (IQR)

ICU-free days (IQR)

0 (0−11)

0 (0−10)

15 (6-16)

12 (2-12)

0.028

0.067

All-cause 28-day mortality

In-hospital mortality

30%

50%

10%

20%

0.264

0.160

D-dimer, µg/L (95% CI)

Baseline

After anticoagulation

Days between measurements

 

3408 (1283–5532)

4878 (2291–7465)

4.3 ± 1.2

 

4176 (1986–6365]

1469 (1034–1904)

3.9 ± 1.2

 
Length of hospital stay, days (IQR)

30 (23-38)

31 (22-35) 0.838

Thrombotic events

20% 20% 1.000

**An intergroup analysis showed a significant increase from baseline to 14 days in PaO2/FiO2 ratio with the therapeutic group (P=0.0004), but not with the prophylactic group (P=0.487).

Adverse Events    

Prophylactic anticoagulation (n=10)

Therapeutic anticoagulation (n=10)   
Major bleeding  0 0  
Minor bleeding  0 20%  
Bleeding requiring medical attention 20% 40%  
Drop in hemoglobin >5.0 g/dL 20% 40%  

Study Author Conclusions

This open-label, controlled, randomized clinical trial demonstrated that therapeutic enoxaparin improved gas exchange over time and increased the ratio of successful liberation from mechanical ventilation. After these results, a larger clinical trial is urgently needed to evaluate the anticoagulant therapy in severe COVID-19 patients.

InpharmD Researcher Critique

This study is limited by its single-center design and small sample size, which was not large enough to power for mortality. Instead, the primary endpoint (PaO2/FiO2 [P/F] ratio) is limited in quantifying pulmonary dysfunction improvement. Additionally, this study was conducted relatively early in the pandemic (April to July 2020), which may represent different practices for patients with COVID-19. 



References:

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

 

Intermediate-dose anticoagulation, aspirin, and in-hospital mortality in COVID-19: a propensity score-matched analysis

Design

Retrospective, propensity score-matched, observational study

N=2785

Objective

To examine the impact of intermediate-dose anticoagulation and aspirin on in-hospital mortality in COVID-19

Study Groups

Alive (n=2402)

Dead (n=383)

Inclusion Criteria

Diagnosis of COVID-19 via PCR test

Exclusion Criteria

Age < 18 years, multiple inpatient hospital encounters, missing data

Methods

Patient medical records were extracted from the analytics team and analyzed. Patients were categorized into one of six anticoagulation intensity groups based on the criteria.

1. Prophylaxis dose: received a maximum enoxaparin dose of 30–40 mg at a weight-adjusted concentration of < 0.7 mg/kg every 24 hours, enoxaparin 30–40 mg at a weight-adjusted concentration of < 0.4 mg/kg every 12 hours, subcutaneous unfractionated heparin (UFH) 5000 units up to three times per day, or subcutaneous UFH 5000 or 7500 units up to three times per day with a BMI ≥ 40 kg/m2, and who did not receive any other type of documented anticoagulant during their hospitalization

2. Intermediate dose: received a maximum enoxaparin dose of ≥ 0.4 and < 0.7 mg/kg every 12 hours or subcutaneous UFH 7500 U at any frequency with a BMI < 40 kg/m2, and who did not receive any other type of anticoagulant during their hospitalization.

3. Therapeutic dose: received a maximum enoxaparin dose ≥ 0.7 mg/kg every 12 hours, enoxaparin ≥ 0.7 mg/kg every 24 hours with creatinine clearance < 30 mL/min, enoxaparin ≥ 1.4 mg/kg every 24 hours, intravenous UFH, or intravenous bivalirudin.

4. Alternative dose: received any other dose of enoxaparin and who did not receive a direct oral anticoagulant (DOAC) or any other therapeutic-dose anticoagulant.

5. DOAC: received a DOAC and no other type of therapeutic-dose anticoagulation

6. No documented anticoagulation: All other patients.

Propensity score-matching calculated using multivariable regression analysis was performed to adjust for disease severity and other clinical covariates. These were individually reported as hazard ratio (HR) for death based on the individual covariates.

Duration

March 2020 to June 2020

Outcome Measures

Primary outcome: In-hospital death

Secondary outcome: Multivariable analysis of in-hospital death in the propensity-score matched anticoagulation cohort for the intermediate dose anticoagulation versus prophylactic dose.

Baseline Characteristics

 

Total

Alive (n=2402)

Dead (n=383)

p-value

Age, years

18 to 40

>40 to 50

>50 to 60

>60 to 70

>70 to 80

>80 to 90

>90 to 110

 

359

298

501

553

492

421

161

 

356 (99.2%)

285 (95.6%)

467 (93.2%)

499 (90.2%)

389 (79.1%)

301 (71.5%)

105 (65.2%)

 

3 (0.8%)

13 (4.4%)

34 (6.8%)

54 (9.8%)

103 (20.9%)

120 (28.5%)

56 (34.8%)

<0.001

Female

1389 1212 (87.3%) 177 (12.7%) 0.12

Race

Caucasian

African-american

Asian-merican

Others

 

1300

746

62

677

 

1074 (82.6%)

650 (87.1%)

51 (82.3%)

627 (92.6%)

 

226 (17.4%)

96 (12.9%)

11 (17.7%)

50 (7.4%)

<0.001

Cardiovascular disease

1683

1406 (83.5%)

277 (16.5%)

<0.001

Home antiplatelet prior to hospitalization

804

650 (80.8%)

154 (19.2%)

<0.001

In-hospital aspirin use

964

811 (84.1%)

153 (15.9%)

 

Results

Endpoint

Total

Alive (n=2402)

Dead (n=383)

p-Value

Anticoagulation during hospitalization

Prophylactic

Intermediate

Therapeutic

Alternative enoxaparin dose

DOAC

No documented anticoagulation

 

1395

229

531

162

233

235

 

1291 (92.5%)

189 (82.5%)

386 (72.7%)

141 (87.0%)

206 (88.4%)

189 (80.4%)

 

104 (7.5%)

40 (17.5%)

145 (27.3%)

21 (13.0%)

27 (11.6%)

46 (19.6%)

<0.001

  Hazard ratio for death

95% confidence interval

p-value

Multivariable analysis of in-hospital death for anticoagulation when comparing intermediate dose anticoagulation with prophylactic dose

0.518

0.308 to 0.872

0.013

Study Author Conclusions

In this propensity score-matched, observational study of COVID-19, intermediate-dose anticoagulation and aspirin were each associated with a lower cumulative incidence of in-hospital death.

InpharmD Researcher Critique

This article is a preprint and must be interpreted with caution. Nevertheless, this is one of newer studies that attempted to control for baseline characteristics. Observational studies are investigational by nature but the propensity score-matching strengthens the applicability of the results.



References:

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