Abstract
Introduction: Coronavirus disease 2019 is a global health threat often accompanied with coagulopathy. Despite use of thromboprophylaxis in this population, thrombotic event rates are high. Materials and methods: This was a multicenter, retrospective cohort study comparing the safety and effectiveness of thromboprophylaxis strategies at 2 institutions in hospitalized patients with coronavirus disease 2019. Regimen A utilized a higher-than-standard thromboprophylaxis dosage and Regimen B received full-dose anticoagulation for any D-dimer 3 mcg/mL or greater and prophylactic for less than 3 mcg/mL. The primary outcome compared the rate of thrombotic events between treatment groups. Secondary endpoints compared rates of major or clinically relevant non-major bleeding as well as the proportion of patients in each group experiencing thrombotic events within 30 days of discharge. Results: One-hundred fifty-three patients were included in the analysis, 64 receiving Regimen A and 89 receiving Regimen B. Seven (4.6%) thrombotic events occurred, 3 (4.7%) in patients receiving Regimen A, and 4 (4.5%) in Regimen B (P = 1.0). Twelve patients (13.5%) receiving Regimen B had a bleeding event versus 2 (3.1%) in Regimen A (P = .04), half of which were major in each group. All patients who bled in either treatment group were receiving mechanical ventilation, and 12 of 14 were receiving full-dose anticoagulation. One patient receiving Regimen A was readmitted with a pulmonary embolism. Conclusions: In this study, the thromboprophylactic regimen impacted bleeding, but no significant difference was seen with thrombotic outcomes. Almost all patients who experienced a bleed were mechanically ventilated and receiving full-dose anticoagulation. The use of full-dose anticoagulation should be cautioned in this population without an additional indication.
Keywords: COVID-19, anticoagulation, thrombosis, thromboprophylaxis, hemorrhage
Introduction
Coronavirus disease 2019 (COVID-19) is a global health threat that has resulted in 221 million cases and over 4 and a half million fatalities as of September 2021. 1 COVID-19 is often accompanied with coagulopathy which has been identified through laboratory abnormalities including elevated D-dimer, fibrinogen, prothrombin time (PT), and activated partial thromboplastin time (aPTT), which have been linked with increased mortality in this population. 2 Venous thromboembolism (VTE) rates of 17% (95% CI, 13.4%-20.9%) have been reported in a systematic review and meta-analysis looking at 49 studies of patients hospitalized with COVID-19. 3
The use of anticoagulants, including full-dose anticoagulation, has been associated with improved morbidity and mortality in patients with COVID-19, particularly those with elevated D-dimer or sepsis-induced coagulopathy.4-6 Various thromboprophylaxis dosing strategies have been proposed including increased dosage (escalated or higher-than-standard dose and full-dose anticoagulation) based on severity of illness and coagulopathy laboratory markers; though, a consensus has not been determined on the optimal strategy.5,7 A meta-analysis examining various VTE prophylactic strategies in critically ill patients with COVID-19 determined that patients receiving prophylactic or full-dose anticoagulation were still at a high risk of developing a VTE at 31% (95% CI 20%-43%; I2: 92%); and those on prophylactic dosing alone had even higher rates of VTE at 38% (95% CI 10%-70%; I2: 96%). 8 Conversely, 30- and 90-day outcomes from a recent study suggest little benefit of higher-than-standard thromboprophylaxis in patients in the intensive care unit (ICU).9,10 Another set of recent studies investigated mortality and organ-free support at 21 days using an initial strategy of full-dose anticoagulation versus usual care. Outcomes were no different in critically ill patients, but improved in non-critically ill patients with more apparent treatment benefits in those with higher D-dimer levels.11,12 Current guidelines recommend the use of pharmacologic thromboprophylaxis in hospitalized patients with COVID-19 to prevent thrombotic events, but the exact recommendations vary.13-16 Therefore, the objective of this study was to compare the effectiveness and safety of a higher-than-standard and D-dimer driven VTE prophylaxis protocols in hospitalized patients with COVID-19.
Materials and Methods
This was a retrospective cohort study comparing VTE prophylaxis strategies at 2 institutions in patients with COVID-19. Both institutions are academic medical centers in Western New York with medical intensive care units. This protocol was approved by the Institutional Review Board at the University at Buffalo.
Each institution’s thromboprophylaxis protocol includes higher-than-standard dosing as an attempt to prevent the high rates of thrombotic events occurring in patients with COVID-19. Briefly, Regimen A was implemented at institution A and was a higher-than-standard dosing approach targeting patients to receive weight-based VTE prophylaxis with enoxaparin if possible, based on renal function (Table 1). Anti-factor Xa levels were targeted at 0.2 to 0.4 units/mL for patients receiving enoxaparin, and aPTT levels were targeted at 35 to 45 seconds for patients receiving heparin. Patients receiving Regimen B were admitted to institution B and received full-dose anticoagulation for any D-dimer greater than or equal to 3 mcg/mL. Patients whose D-dimer values were less than 3 mcg/mL, or decreased to less than 3 mcg/mL, received either standard (non-ICU patients) or higher-than-standard VTE prophylaxis (ICU patients) as described in Table 2. As patients’ clinical status changed, their regimens were adjusted to coincide with the protocols.
Table 1.
COVID-19 VTE Prophylaxis Regimen A.
| Creatinine clearance > 30 mL/min | Creatinine clearance ≤ 30 mL/min | End stage renal disease | |||
|---|---|---|---|---|---|
| BMI (kg/m2) | Dose | BMI (kg/m2) | Dose | BMI (kg/m2) | Dose |
| <20 | Heparin 5000 units sq every 8-12 h | <20 | Heparin 5000 units sq every 8-12 h | <20 | Heparin 5000 units sq every 8-12 h |
| 20-25.9 | Enoxaparin 40 mg sq daily | 20-34.9 | Enoxaparin 30 mg sq daily | 20-34.9 | Heparin 5000 units sq every 8 h |
| 26-39.9 | Enoxaparin 30 mg sq every 12 h | 35-50 | Enoxaparin 40 mg sq daily | 35-50 | Heparin 7500 units sq every 8 h |
| 40-50 | Enoxaparin 40 mg sq every 12 h | — | — | — | — |
| >50 | Enoxaparin 60 mg sq every 12 h | > 50 | Enoxaparin 60 mg sq daily | >50 | Heparin 10,000 units sq every 8 h |
BMI = body mass index; sq = subcutaneously.
Table 2.
COVID-19 VTE Prophylaxis Regimen B.
| D-dimer | Regimen |
|---|---|
| <3 mcg/mL | |
| Non-ICU patients | Standard VTE prophylaxis options: |
| Enoxaparin 40 mg sq daily | |
| Enoxaparin 30 mg sq daily for renal impairment | |
| Heparin 5000 units sq every 8 hours | |
| ICU patients | Higher-than-standard VTE prophylaxis options: |
| Enoxaparin 40 mg sq every 12 hours | |
| Heparin 7500 units sq every 8 hours | |
| Apixaban 2.5 mg enterally every 12 hours | |
| ≥3 mcg/mL | |
| Non-ICU patients | Full-dose anticoagulation options: |
| Heparin infusion | |
| Enoxaparin 1 mg/kg sq every 12 hours | |
| When D-dimer is < 3 mcg/mL transition to standard VTE prophylaxis | |
| ICU patients | Full-dose anticoagulation options: |
| Heparin infusion (Argatroban if unable to use heparin) | |
| Enoxaparin 1 mg/kg sq every 12 hours | |
| Apixaban 5 mg enterally every 12 hours | |
| When D-dimer is <3 mcg/mL transition to standard or higher-than-standard VTE prophylaxis (provider’s discretion) | |
Note. VTE = venous thromboembolism; sq = subcutaneously; ICU = intensive care unit.
Patients were identified by an internal quality review database of patients with COVID-19 receiving VTE prophylaxis according to each institution’s protocol. Patients admitted between January 1st and July 31st, 2020 were evaluated for the following inclusion criteria: (1) greater than or equal to 18 years of age; (2) a positive COVID-19 test; (3) receiving the higher-than-standard VTE prophylaxis (Regimen A) or D-dimer driven (Regimen B) approach. Each patient was only included once in the data set, and if there were multiple admissions, the first chronological admission was utilized.
Data collected included baseline demographics, past medical history, and laboratory parameters of each patient. An International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) bleeding risk score was calculated for each patient on admission to assess baseline bleed risk. 17 A score greater than or equal to 7 indicates high risk of bleeding. Data pertaining to severity of illness and COVID-19 treatment were also collected including admission to the ICU, highest level of respiratory support required, COVID-19 medication treatment, and the VTE prophylaxis regimen initiated as well as any change made to the regimen. Detailed information of each bleeding and thrombotic event was also collected including the event, the anticoagulation regimen the patient was on at the time of event, and any changes to the regimen that occurred due to the event.
The primary outcome was to compare the rate of thrombotic events in patients receiving Regimen A versus B in hospitalized patients with COVID-19 during their hospital stay. This included pulmonary embolism, deep vein thrombosis, thrombosis of a major organ, myocardial infarction, stroke, acute arterial occlusion, catheter occlusion, and intracardiac thrombus. Secondary endpoints sought to determine the proportion of patients in each treatment group with major bleeding or clinically relevant non-major bleeding per the International Society of Thrombosis and Hemostasis (ISTH) definitions during their hospital stay, and the proportion of patients in each treatment group with 30-day post-discharge thrombotic events determined via chart review if the patient was readmitted to the institution. 18 Major bleeding was defined as bleeding resulting in a 2-unit (g/dL) or greater drop in hemoglobin from the patient’s baseline prior to bleed or greater than or equal to 2 units of red blood cells transfused; bleeding into a critical organ (intracranial, intraspinal, intraocular, retroperitoneal, intra-articular, pericardial, or intramuscular with compartment syndrome); or a fatal bleed. Clinically relevant non-major bleeding was defined as any sign or symptom of bleeding not fitting the definition of major bleeding but requiring an emergency department visit or hospital admission, medical or surgical intervention for bleeding, or change in provider-directed antithrombotic therapy.
Patient demographics and clinical characteristics were presented using descriptive statistics. Chi-squared and Fisher’s exact tests were used to analyze categorical data and Mann-Whitney U and t-tests were used to analyze continuous data, as appropriate. A P-value of less than .05 was considered statistically significant. Data analyses were completed using SAS, version 9.4 (SAS Institute Inc., Cary, NC, USA).
Results
One-hundred fifty-three patients were included in the analysis, 64 receiving Regimen A and 89 receiving Regimen B (Table 3). Patients were a median of 58 years of age, and about half were female with more females receiving Regimen A (P = .0008). Baseline markers of coagulopathy such as PT, fibrinogen, and D-dimer were elevated in the cohort overall, but were not different between treatment groups. The median (Interquartile range [IQR]) IMPROVE bleeding risk score was similar between the groups, 6 (3.5-7) in Regimen A treated patients and 5 (2.5-7) in Regimen B treated patients (P = .51). Other baseline demographic information and laboratory values were similar between groups, except body mass index, a history of coronary artery disease or stroke, and baseline serum creatinine.
Table 3.
Baseline Demographics and Clinical Characteristics.
| Characteristic | Regimen A (n = 64) | Regimen B (n = 89) | P-value* |
|---|---|---|---|
| Age (years), med (IQR) | 58 (49-68) | 58 (50-66) | .85 |
| Sex (female), n (%) | 42 (65.5) | 34 (38.2) | .0008 |
| BMI (kg/m2), med (IQR) | 39.6 (30.1-45.2) | 30.8 (25.5-35.3) | <.0001 |
| History of renal disease, n (%) | 6 (9.4) | 18 (20.2) | .07 |
| History of hepatic disease, n (%) | 1 (1.6) | 2 (2.3) | 1.000 a |
| History of VTE, n (%) | 3 (4.7) | 3 (3.4) | .69 a |
| History of cancer, n (%) | 5 (7.8) | 8 (9.0) | .80 |
| History of GI bleed, n (%) | 0 (0) | 3 (3.4) | .27 a |
| History of stroke or TIA, n (%) | 9 (14.1) | 3 (3.4) | .02 |
| History of hypertension, n (%) | 39 (60.9) | 57 (64.0) | .69 |
| History of diabetes, n (%) | 21 (32.8) | 35 (39.3) | .41 |
| History of CAD, n (%) | 5 (7.8) | 17 (19.1) | .05 |
| History of PAD, n (%) | 2 (3.1) | 6 (6.7) | .47 a |
| Hemoglobin, med (IQR) | 12.6 (11.3-13.6) | 13.2 (11.5-14.6) | .08 |
| Platelets, med (IQR) | 214 (154-249) | 216 (163-271) | .40 |
| PT, med (IQR) | 13.8 (13.4-14.3) | 13.9 (13.0-15.0) | .96 |
| INR, med (IQR) | 1.1 (1.0-1.1) | 1.1 (1.0-1.2) | .96 |
| aPTT, med (IQR) | 32.8 (29.5-34.3) | 32.6 (30.0-35.3) | .88 |
| Fibrinogen, med (IQR) | 582 (471-630) | 630 (500-740) | .09 |
| D-dimer, med (IQR) | 1.1 (0.6-1.9) | 1.0 (0.6-1.9) | .92 |
| Serum creatinine, med (IQR) | 1.0 (0.8-1.3) | 1.2 (0.9-1.8) | .02 |
| ALT, med (IQR) | 25 (16-47) | 29 (17-44) | 1.0 |
| AST, med (IQR) | 47 (30-105) | 38 (26-59) | .45 |
| Ferritin, med (IQR) | 550 (268-950) | 561 (275-1713) | .37 |
| IMPROVE BRS, med (IQR) | 6 (3.5-7) | 5 (2.5-7) | .51 |
Note. IQR = interquartile range; BMI, body mass index; VTE = venous thromboembolism; GI = gastrointestinal; TIA = transient ischemic attack; CAD = coronary artery disease; PAD = peripheral artery disease; PT = prothrombin time; INR = international normalized ratio; aPTT, activated partial thromboplastin time; ALT = alanine aminotransferase; AST = aspartate aminotransferase; IMPROVE BRS = International Medical Prevention Registry on Venous Thromboembolism bleeding risk score.
Fisher’s Exact test.
All tests were Chi Squared and Mann–Whitney U unless otherwise noted.
In-hospital characteristics were similar between the 2 groups (Table 4). Approximately 40% of patients in each group required mechanical ventilation (MV). In patients receiving Regimen A, 49 were admitted to the ICU (55% requiring MV) and of those receiving Regimen B, 43 were admitted to the ICU (86% requiring MV). In patients admitted to the ICU, patients receiving Regimen A versus B had median (IQR) Sequential Organ Failure Assessment scores on the day of their worst partial pressure of oxygen (PaO2): fraction of inspired oxygen (FiO2) ratio of 7 (3-10) and 9 (5-11; P = .06), and duration of MV of 315 (172-497) hours and 421 (212-731; P = .12), respectively.
Table 4.
In-Hospital Characteristics and Treatment.
| Characteristic | Regimen A (n = 64) | Regimen B (n = 89) | P-value |
|---|---|---|---|
| Respiratory support (highest required), n (%) | |||
| Non-invasive respiratory support | 36 (56.3) | 40 (44.9) | .17 |
| Mechanical ventilation | 27 (42.2) | 38 (42.7) | .95 |
| Peak PaO2:FiO2 ratio, med (IQR) | 80 (54-143) | 90 (66-149) | .32 |
| Remdesivir, n (%) | 8 (12.5) | 18 (20.2) | .21 |
| Steroid, n (%) | 34 (53.1) | 42 (47.2) | 0.47 |
| Total exposure (mg prednisone equivalent), med (IQR) | 833.3 (400.0-1156.7) | 1093.8 (309.4-2871.9) | .12 |
| Steroid per day (mg prednisone equivalent), med (IQR) | 105 (84.4-133.3) | 112.6 (54.7-158.1) | .31 |
| Convalescent plasma, n (%) | 15 (23.4) | 32 (36.0) | .10 |
| Initial VTE Prophylaxis Regimen, n (%) | <.001 | ||
| Enoxaparin 30 u daily | 0 (0) | 1 (1.1) | |
| Enoxaparin 30 u twice daily | 10 (15.6) | 1 (1.1) | |
| Enoxaparin 40 u daily | 19 (29.7) | 31 (34.8) | |
| Enoxaparin 40 u twice daily | 15 (23.4) | 1 (1.1) | |
| Heparin 5000 u twice daily | 1 (1.6) | 0 (0) | |
| Heparin 5000 u every 8 hours | 15 (23.4) | 43 (48.3) | |
| Heparin 7500 u every 8 hours | 0 (0) | 2 (2.3) | |
| Full-Dose Anticoagulation | 4 (6.3) | 10 (11.2) | |
| Intensity Changes in VTE Proph, n (%) | .25 | ||
| None | 27 (42.2) | 51 (57.3) | |
| Increase only | 15 (40.5) | 18 (47.4) | |
| Decrease only | 2 (5.4) | 3 (7.9) | |
| Increase and Decrease | 20 (54.1) | 17 (44.7) | |
| VTE prophylaxis duration, days, med (IQR) | 12 (8-22.5) | 11 (5-20) | .33 |
| Discharged on anticoagulant, n (%) | 13 (20.3) | 27 (37.5) | .06 |
| Gastrointestinal prophylaxis, n (%) | |||
| PPI | 28 (43.8) | 43 (48.3) | .58 |
| H2RA | 17 (26.6) | 23 (25.8) | .92 |
Note. PaO2 = partial pressure of oxygen; FiO2 = fraction of inspired oxygen; IQR = interquartile range; VTE = venous thromboembolism; PPI = proton pump inhibitor; H2RA = histamine-2 receptor antagonist; u = units.
Anticoagulation dosing varied based on regimen and throughout the patients stay. Full-dose anticoagulation was started initially in more patients in Regimen B than Regimen A (11.2% (n = 10) and 6.3% (n = 4), respectively). Throughout hospitalization about half of patients experienced at least one change to their thromboprophylaxis regimen (57.8% [n = 37] in Regimen A and 42.7% [n = 38] in Regimen B). Almost all changes resulted in an increase in intensity (94.6% [n = 35] in Regimen A and 92.1% [n = 35] in Regimen B). In patients receiving Regimen A, 16 (32.7%) were escalated to full dose anticoagulation following escalation to ICU care, and 30 (70.0%) in Regimen B were escalated to full-dose anticoagulation. In patients not admitted to the ICU, all patients receiving Regimen A received higher-than-standard VTE prophylaxis dosing at some point during their stay (100%, n = 15), while in Regimen B, almost all patients were maintained on standard dosing VTE prophylaxis (95.7%, n = 44).
In the entire cohort, there were 7 (4.6%) thrombotic events, 6 (4.7%) occurring in patients receiving Regimen A, and 4 (4.5%) in Regimen B (P = 1.0), and all but 1 event occurred in ICU admitted patients (Tables 5 and 6). More patients receiving Regimen B had a bleeding event, 12 (13.5%) versus 2 (3.1%) in Regimen A (P = .04) of which are described in detail in Table 7. In each treatment group, half of the bleeding events were major bleeds, and half were clinically relevant non-major. In the patients who experienced a bleeding event in either treatment group, all patients were receiving MV, and 12 of the 14 were receiving full-dose anticoagulation at the time of the event. Patient disposition and 30-day readmissions for thrombotic events were similar between treatment groups.
Table 5.
Results.
| Outcome | Regimen A (n = 64) | Regimen B (n = 89) | P-value |
|---|---|---|---|
| Thrombotic event, n (%) | 3 (4.7) | 4 (4.5) | 1.00 a |
| Bleeding event, n (%) | 2 (3.1) | 12 (13.5) | .04 a |
| Clinically relevant non-major | 1 (50.0) | 6 (50.0) | 1.00 a |
| Major | 1 (50.0) | 6 (50.0) | 1.00 a |
| Hospital length of stay, med (SD) | 14.0 (10.0-26.0) | 12.0 (6.0-22.0) | .22 |
| Disposition, (%) | .12 | ||
| Expired | 5 (7.8) | 16 (10.5) | |
| Home | 33 (51.6) | 43 (48.3) | |
| Rehabilitation/Nursing home | 25 (39.1) | 27 (30.3) | |
| Left against medical advice | 0 (0) | 3 (3.4) | |
| Transferred | 1 (1.6) | 0 (0) | |
| 30-day readmission, (%) | 1 (1.7) | 1 (0.8) | 1.0 a |
| Bleed | 0 (0) | 0 (0) | - |
| Thrombosis | 1 (1.7) | 0 (0) | - |
| Other | 0 (0) | 1 (0.8) | 1.0 a |
Note. aFisher’s Exact Test.
Table 6.
Thrombotic Events.
| Regimen | Age | Sex | BMI (kg/m2) | Description of Event | Prophylaxis Regimen At Time of Event | Change in Prophylaxis Due to Event | aPTT at Time of Event | Anti-Xa at Time of Event |
|---|---|---|---|---|---|---|---|---|
| A | 60 | F | 34.7 | DVT | Enoxaparin 40 mg sq daily | Enoxaparin 100 mg sq every 12 hours | None | None |
| A | 65 | M | 24.9 | DVT | Enoxaparin 40 mg sq daily | Enoxaparin 80 mg sq every 12 hours | None | 0.1 |
| A | 58 | F | 39.6 | STEMI | Enoxaparin 40 mg sq every 12 hours | Heparin infusion | None | None |
| B | 65 | M | 24.0 | DVT | Enoxaparin 40 mg sq daily | Heparin infusion | 28.9 | None |
| B | 33 | F | 35.4 | DVT | Heparin 500 units sq every 8 hours | Apixaban 2.5 mg enterally every 12 hours | None | None |
| B | 53 | M | 39.4 | Embolic CVA with atrial fibrillation | Heparin infusion | None | 78.8 | None |
| B | 51 | M | 36.3 | DVT | Heparin 7500 units sq every 8 h | Enoxaparin 120 mg sq every 12 hours | None | None |
aPTT = activated prothrombin time; anti-Xa = anti-factor Xa; F = female; DVT = deep vein thrombosis; sq = subcutaneously; M = male; STEMI = ST-elevation myocardial infarction; CVA = cerebrovascular accident.
Table 7.
Bleeding Events.
| Regimen | Age | Sex | BMI (kg/m2) | Description of bleeding event | Bleed type | Prophylaxis regimen at time of event | Change in prophylaxis due to event | aPTT at time of event | Anti-Xa at time of event |
|---|---|---|---|---|---|---|---|---|---|
| A | 59 | F | 27.2 | GI bleed | Major | Enoxaparin 30 mg sq daily | None | None | None |
| A | 51 | F | 52.9 | Hematuria | CRNM | Enoxaparin 60 mg sq every 12 h | Enoxaparin 40 mg sq every 12 hours | None | 0.36 |
| B | 81 | M | 23.0 | Retroperitoneal hematoma | Major | Heparin infusion | Discontinued | 65.7 | None |
| B | 66 | M | 36.4 | Lower GI bleed with hypotension requiring pressor | Major | Heparin infusion | Discontinued | 100.2 | None |
| B | 58 | M | 25.7 | Lower GI bleed | CRNM | Heparin infusion | Discontinued | 63.7 | None |
| B | 51 | M | 36.3 | Upper GI bleed | CRNM | Heparin infusion | Discontinued | 74.5 | None |
| B | 66 | M | 20.2 | Upper and lower GI bleed | CRNM | Heparin infusion | Discontinued | 73.8 | None |
| B | 77 | M | 21.9 | Bleeding from femoral central venous catheter | Major | Heparin infusion | Discontinued | 86.4 | None |
| B | 78 | M | 33.9 | Lower GI bleed | Major | Apixaban 2.5 mg every 12 h | Discontinued | None | None |
| B | 53 | M | 39.4 | Bleeding from dialysis line site, GI bleed | Major | Heparin infusion | None | 75.7 | None |
| B | 71 | F | 26.7 | Upper GI bleed | CRNM | Apixaban 2.5 mg every 12 h | Discontinued | 41.6 | None |
| B | 61 | M | 30.8 | Hypovolemic shock | Major | Heparin infusion | Heparin 7500 units sq every 8 hours | 107.1 | None |
| B | 56 | M | 31.4 | Hemoptysis and arterial lip erosion requiring sutures | CRNM | Heparin infusion | Enoxaparin 40 units sq daily | 99 | None |
| B | 42 | M | 22.7 | Bleeding from tracheostomy site | CRNM | Apixaban 5 mg every 12 h | Discontinued | 27.9 | None |
Note. aPTT = activated prothrombin time; anti-Xa = anti-factor Xa; F = female; GI = gastrointestinal; sq = subcutaneously; CRNM = clinically-relevant non-major; M = male.
Discussion
The rate of thrombotic events was similar between patients receiving 2 different institutional regimens of VTE prophylaxis in COVID-19 positive patients. Bleeding event rates were statistically significantly higher in patients receiving Regimen B, though all bleeding events in the entire cohort occurred in patients receiving MV, and most patients were receiving full-dose anticoagulation. All bleeding, and all but 1 thrombotic event, occurred in patients admitted to the ICU. These findings suggest that patients with an increased severity of COVID-19 are at an increased risk of both bleeding and thrombotic events, and full-dose anticoagulation for VTE prophylaxis may increase the risk of bleeding in this population.
A wide variety of practice exists when it comes to approaching thromboprophylaxis in hospitalized patients with COVID-19, and there is little data to suggest improved outcomes using one strategy versus another. An analysis of 21 hospitals in the United States was conducted to characterize methods of VTE prophylaxis in patients with COVID-19. 19 Four (19%) of these institutions used standard prophylactic dosing, 2 (10%) used higher-than-standard dosing, and the remaining 12 (57%) used a tiered approach with those considered average risk of VTE development receiving standard dose, and high risk receiving higher-than-standard dose thromboprophylaxis. A global survey of 515 physicians found similar results. 20 Almost all (78%) respondents recommended pharmacologic thromboprophylaxis in hospitalized patients with COVID-19, and 72% of those recommended an escalated dose in certain scenarios including laboratory abnormalities (eg, elevated D-dimer), hospital protocols, and increased severity of illness. One meta-analysis utilized the current data available to create a guidance statement suggesting a tiered approach based on ICU admission and D-dimer level. 21
Our results align with reports that VTE events occur in this population despite a variety of prophylactic regimens. 7 Rates of VTE in our study were on the lower end of reported at about 5%. This is likely due to the absence of asymptomatic scanning for events that occurred in studies reporting higher rates of VTE. Bleeding rates were similar to previously reported studies. A letter to the editor by Lynn et al 22 reported rates of bleeding of 9% in those receiving full-dose anticoagulation and 3% in those receiving prophylactic doses of anticoagulation. In HESACOVID study, 20% (n = 2) of those receiving full-dose enoxaparin experienced a minor bleeding event as defined by the Thrombolysis in Myocardial Infarction (TIMI) bleeding definition, as opposed to none in the prophylactic anticoagulation group. 6 In a trial of patients with COVID-19 who had an autopsy performed, 1 of 26 patients experienced a major bleed who was receiving full-dose warfarin for pre-existing conditions, though no INR was reported at the time. 5 These results all align with our study that showed higher rates of bleeding in patients receiving higher dosing of thromboprophylaxis.
The Intermediate versus Standard-Dose Prophylactic Anticoagulation in Critically-ill Patients With COVID-19: An Open Label Randomized Controlled Trial (INSPIRATION) was conducted in 562 patients in Iran.8,9 The primary outcome of VTE, arterial thrombosis, use of extracorporeal membrane oxygenation (ECMO), and mortality at 30-days was not different between treatment groups (126 [45.7%] in the intermediate dose and 126 [44.1%] in the standard dose; P = .7). The rate of VTE alone and major or non-major Bleeding Academic Research Consortium (BARC) bleeding were similar between the intermediate and standard dosing groups (VTE: 3.3% vs 3.5%; P = .94, bleed: 6.2% vs 3.1; P = .08), respectively. These results differ slightly from our study, both the patient population (critically ill vs hospitalized) and definitions of outcomes reported differ as well. Rate of thrombosis in both studies was consistent, and lower than previously reported, possibly due to the lack of surveillance scanning. The INSPIRATION trial reported higher bleeding rates with the intermediate versus standard prophylaxis dosing, though not statistically significant. Our data support that higher doses of thromboprophylaxis may increase the bleed risk in these patients, as a majority of bleeds occurred in patients on full-dose anticoagulation.
Two open-label randomized controlled trials assessed therapeutic anticoagulation in patients with COVID-19.11,12 In noncritically ill patients those receiving therapeutic anticoagulation (n = 1171) experienced more organ support-free days (adjusted OR 1.27, 95% credible interval 1.03-1.57) compared to those receiving usual care thromboprophylaxis (n = 1048). 12 The rate of thrombosis was lower in those receiving therapeutic anticoagulation compared to usual-care (8.0% vs 9.9%; adjusted OR 0.72 (95% credible interval 0.53-0.98) and major bleeding wasn’t different between treatment groups (1.9% vs 0.9%; adjusted OR 1.80 (95% credible interval 0.90-3.74). In critically ill patients (n = 1098), the trial was stopped early due to futility, though patients in the therapeutic anticoagulation group had a similar risk of bleeding compared to usual care (3.8% vs 2.3%; adjusted OR 1.48 (95% credible interval 0.75-3.04)). 11 These results reflect our data, except the risk of bleeding in critically ill patients. Though patients receiving therapeutic anticoagulation had a numerically increased bleed risk, this didn’t reach significance, and differences with our study results may be due to the definition of critically ill in each study and would be more prudent to compare patients in each study receiving mechanical ventilation.
All bleeding occurred in patients receiving MV in our study, and 8 of these bleeding events were gastrointestinal bleeds despite use of gastrointestinal prophylaxis with a proton pump inhibitor or a histamine-2 receptor antagonist. Previous reports describe an increased incidence of gastrointestinal bleeds in this population. 23 Based on this data, it is possible that the higher bleeding rates in regimen B were due to a higher number of patients being mechanically ventilated, which should be considered when comparing the safety of the regimens. Additionally, almost all events occurred in patients receiving full-dose anticoagulation. Thus, caution should be used in mechanically ventilated patients with COVID-19 when selecting the thromboprophylaxis regimen, and the decision to use full-dose anticoagulation should be based on a compelling indication rather than laboratory markers alone.
Multiple randomized controlled trials are being conducted to determine the ideal antithrombotic regimen to be used as VTE prophylaxis in patients with COVID-19. These are investigating other nuances of prophylaxis in patients with COVID-19, including varying levels of severity of illness, different patient populations (eg, immunocompromised), and multiple different anticoagulant agents and dosing strategies. The results of these trials will help guide selection of antithrombotic regimens in patients with COVID-19.24-30
A barrier to determining the ideal VTE prophylactic regimen is changing clinical events which may lead to changes in the thromboprophylactic regimen used. In this study, about half of the patients had a change to their prophylaxis regimen during their hospital stay, of which about half had an increase in intensity only, and half experienced an increase and decrease in intensity, and very few experienced a decrease in intensity only. This can make it difficult to determine which regimen is impacting clinical outcomes. Previous reports do not address this issue, and this requires further investigation.
This study has limitations including the retrospective nature and small sample size of the investigation. Some baseline characteristics were different between groups, including a history of stroke and baseline serum creatinine. This is likely due to the local treatment centers for stroke and renal transplant at each institution, as we would anticipate these patients to be affiliated with each medical center. Additionally, BMI and sex varied between institutions which may have impacted the results. To combat this, details of each event are included for review. The authors were unable to account for these differences in a regression model, as there were not enough events to appropriately include multiple variables. A power calculation was not performed as this was based on a convenience sample with all patients receiving each regimen at each institution. Additionally, due to the continuously changing VTE prophylactic regimens, patients were grouped into treatment categories based on institutional regimen. To attempt to account for this, all bleeding and thrombotic events were reported in more detail including the regimen the patient was receiving at the time of the event as well as any monitoring parameters (eg, aPTT, anti-Xa levels) that would help to determine the safety and effectiveness of the regimen at that point in time. Lastly, this study included patients in any level of care (ward and ICU), and therefore, the results may not be able to be generalized to all patient populations.
Conclusion
After comparison of thromboprophylactic regimens at 2 institutions for patients with COVID-19, it appears that the regimen selected may impact bleeding, but not thrombotic outcomes. Almost all patients in this report who experienced a bleeding event were critically ill mechanically ventilated patients receiving full-dose anticoagulation. These results suggest that full-dose anticoagulation appeared to increase the risk of bleeding compared to intermediate dosing, particularly in this population. Further investigation and the anticipated results from ongoing clinical trials should be used to further elucidate the optimal VTE prophylactic regimen in hospitalized patients with COVID-19.
Research Data
This article is distributed under the terms of the Creative Commons Attribution 4.0 License (https://creativecommons.org/licenses/by/4.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).
sj-csv-1-hpx-10.1177_00185787211066456 for Comparison of Higher-Than-Standard to D-Dimer Driven Thromboprophylaxis in Hospitalized Patients With COVID-19 by Maya R. Chilbert, Collin M. Clark, Ashley E. Woodruff, Kimberly Zammit, Cynthia Lackie, Kristen Kusmierski, Patrick McGrath, Gregory Fuhrer, Anna Augostini, Olivia Denny, Nicole Ross, Marissa Saber and Natalie DelGuidice in Hospital Pharmacy
Footnotes
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
ORCID iDs: Maya R. Chilbert 
https://orcid.org/0000-0003-3183-5214
Marissa Saber
https://orcid.org/0000-0002-4335-8614
Data Availability Statement: All data generated or analyzed during this study are included in article submission for upload to the repository.
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Associated Data
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Supplementary Materials
This article is distributed under the terms of the Creative Commons Attribution 4.0 License (https://creativecommons.org/licenses/by/4.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).
sj-csv-1-hpx-10.1177_00185787211066456 for Comparison of Higher-Than-Standard to D-Dimer Driven Thromboprophylaxis in Hospitalized Patients With COVID-19 by Maya R. Chilbert, Collin M. Clark, Ashley E. Woodruff, Kimberly Zammit, Cynthia Lackie, Kristen Kusmierski, Patrick McGrath, Gregory Fuhrer, Anna Augostini, Olivia Denny, Nicole Ross, Marissa Saber and Natalie DelGuidice in Hospital Pharmacy