Incidence of deep venous thrombosis in COVID-19 critically ill patients treated with intermediate-dose of heparin for thromboprophylaxis: The COVIDOP-DVT observational study

Abstract

Introduction

The high prevalence of deep vein thrombosis (DVT) in patients admitted to intensive care unit (ICU) for COVID-19-related acute respiratory distress syndrome (ARDS) would justify systematic screening of these patients or higher therapeutic dose of heparin for thromboprophylaxis.

Material and method

We performed a systematic echo-Doppler of the lower limb proximal veins during the first 48 h (visit 1) and from 7 to 9 days after visit 1 (visit 2) in consecutive patients admitted to the ICU of a university-affiliated tertiary hospital for severe proven COVID-19 during the second wave. All patients received intermediate-dose heparin (IDH). The primary objective was to determine DVT incidence on venous Doppler ultrasound. Secondary objectives were to determine whether the presence of DVT modifies the anticoagulation regimen, the incidence of major bleeding according to International Society on Thrombosis and Haemostasis (ISTH) criteria, and the mortality rate of patients with and without DVT.

Results

We included 48 patients (30 [62.5%] men) with a median age of 63 years [IQR, 54–70]. The prevalence of proximal deep vein thrombosis was 4.2% (2/48). In these two patients, after DVT diagnosis, anticoagulation was changed from intermediate to curative dose. Two patients (4.2%) had a major bleeding complication according to ISTH criteria. Among the 48 patients, 9 (18.8%) died before hospital discharge. No DVT or pulmonary embolism was diagnosed in these deceased patients during their hospital stay.

Conclusion

In critically ill patients with COVID-19, management with IDH results in a low incidence of DVT. Although our study is not designed to demonstrate any difference in outcome, our results do not suggest any signal of harm when using intermediate-dose heparin (IDH) COVID-19 with a frequency of major bleeding complications less than 5%.

Highlights

• -With routine use of intermediate-dose heparin, the incidence of lower limb deep vein thrombosis in severe COVID-19 patients admitted to the ICU is less than 5%.

• -There is no benefit in repeating routine venous lower limb Doppler ultrasound 7 days after ICU admission for patients treated with intermediate-dose of heparin for thromboprophylaxis.

• -In this study, the incidence of major bleeding complications in ICU patients treated with intermediate-dose heparin is less than 5%.

Introduction

The deep vein thrombosis (DVT) prevalence in patients with severe SARS-CoV2 infection is estimated to be 25% during ICU stay (1–7). The DVT prevalence in ICU patients without SARS-CoV2 infection in routine testing during their hospitalization varies between studies, but is estimated to be 5–10% in patients with anticoagulant prophylaxis (4–6). The prevalence of deep vein thrombosis in ICU patients with SARS-CoV2 is therefore higher than in patients without SARS-CoV2, with a prevalence that would warrant routine screening of all patients. This increased VTE risk has been attributed to systemic coagulopathy (8,9).

However, this prevalence was only found in small populations (2,10) during the first wave in 2020, and before introduction of an intermediate-dose heparin (IDH) adapted to the higher risk of thromboembolic disease in these patients and according to guidelines initially established in the context of the pandemic emergency at this time (10).

The primary objective of this study was to determine the incidence of lower limb deep vein thrombosis on venous Doppler ultrasound in patients with SARS-CoV2 infection during the first 48 h after ICU admission (visit 1) and from 7 to 9 days after visit 1 (visit 2) treated by intermediate-dose heparin. Secondary objectives were to determine, whether the presence of DVT modifies the anticoagulation regimen, the incidence of major bleeding according to ISTH criteria in included patients, and to evaluate the mortality rate of patients with and without thrombosis.

Patients and methods

Methodology of the trial

This is a single-centre descriptive study. This study was approved by the EST-III committee for the protection of individuals (n° 20.04.14). Informed consent was sought from the next of kin, if available, and from the patients upon recovery of competency, in compliance with French law.

Study population

Consecutive patients admitted between 24 April 2020 and 21 December 2020 (second COVID-19 wave) to Versailles hospital ICU for severe proven SARS-CoV2 infection were eligible for study. The Versailles Hospital is a university-affiliated tertiary hospital in the Paris area with 800 medical and surgical beds. The 28-bed closed ICU has 20 ICU beds and eight intermediate-care beds for continuous monitoring. During COVID-19 surge, transient ICU beds for COVID-19 patients were set up in the intermediate-bed unit, the post-anaesthesia care units, and the cardiology ICU. Patients with proven COVID-19 were eligible for inclusion if they were over 18 years of age; if they had been hospitalized in the ICU for less than 48 h at the time of inclusion. Exclusion criteria were: current pregnancy; liberty deprivation or guardianship measures; refusal to participate; chronic curative anticoagulation or administration of curative anticoagulant for more than 48 h before inclusion; unavailable echo-Doppler due to organizational constraints during COVID-19 surge.

All patients on the basis of the haemostasis reference group (GIHP/GFHT) (11) received intermediate-dose heparin (IDH) with sub cutaneous enoxaparin 4000 IU/12h if they weighted <120 kg or 6000 IU/12h if they weighted >120 kg. In case of renal insufficiency (Cockcroft creatinine clearance less than 30 mL/min), patients were treated with unfractionated heparin (UFH) at a dose of 200 IU/kg/24h.

Data collection

Data for each patient were collected into an electronic file (Excel^®, Microsoft, Redmond, WA) whose access was restricted by a code known only by the data collectors [AF, AM, and SC] and statistician [JLG]). The data files were anonymized by assigning a number to each patient. We collected demographic characteristics and comorbidities, VTE risk factors according to international guidelines, confirmed thromboembolism events, anticoagulant medication (molecule and daily posology). Clinical and laboratory findings at ICU admission were recorded. The following data were also collected: severity and description of organ failures according to the Simplified Acute Physiology score II (SAPS-II) and the Sepsis-related Organ Failure Assessment (SOFA) score, the use of vasoactive drugs, renal replacement therapy, and ECMO. We recorded the total mechanical ventilation duration including non-invasive ventilation and/or high flow nasal oxygen duration. Finally, we collected ICU and hospital lengths of stay, ICU mortality, and in-hospital mortality.

For the definition of ‘VTE provoked by a transient risk factor’, ‘VTE provoked by a persistent risk factor’ and ‘unprovoked VTE’, we followed the ISTH SSC recommendations (12).

Specifics factors due to COVID-19 disease and therapeutic management were added as artificial ventilation, extracorporeal membrane oxygenation (ECMO), iterative catheter thrombosis, and renal haemodialysis filter thrombosis.

Study intervention

For each included patient, a vascular physician [AM, SC, GR, or ST] performed a lower limb venous Doppler ultrasound during the first 48 h after ICU admission (visit 1) and from 7 to 9 days after visit 1 (visit 2). During the venous Doppler ultrasound, the common femoral veins, superficial femoral veins, popliteal veins, and veins with a central catheter were examined. A complementary examination at the abdominal level was carried out only if there was a Doppler anomaly in the common femoral veins.

Judging criteria

The primary endpoint was the presence of DVT on venous Doppler ultrasound. Secondary endpoints included the incidence of major bleeding according to ISTH criteria (13) (death, symptomatic bleeding in a critical organ, haemoglobin decrease of more than 2 g/dl, transfusion of more than two red blood cells), mortality rate of patients at hospital discharge, and the percentage of patients in whom the presence of DVT changed the management of patients.

Statistical analysis

Continuous variables were expressed as medians and interquartile range in brackets, and categorical variables were presented as number and percentages. Comparisons between groups were made using χ² test or Fisher’s exact test for categorical variables, and Mann–Whitney U test for continuous variables, as appropriate. Analyses were performed using SPSS software©, version 23 (IBM Inc., Armonk, NY, USA). A p value <0.05 was considered significant.

Results

Study patients

During the study period, 72 patients with SARS-CoV2 were admitted to the ICU, of whom 48 patients were included (Figure 1).

Figure 1.

Patient flowchart.

SARS-CoV2: Severe acute respiratory syndrome-coronavirus type 2; ICU: Intensive care unit; US: Ultrasound; COVID-19: Coronavirus viral disease-19; v1: visit 1 for Doppler ultrasound; v2: visit 2 for Doppler ultrasound.

Table 1 reports the main patients characteristics. There were 30 (62.5%) men with a median age of 63 [IQR, 54–70] years. Median of patient’s body mass index (kg/m²) was 28.0 [IQR, 25.0–31.4], and a history of treated (CEI or ARA) arterial hypertension and diabetes mellitus was present in 7 (14.6%) and 17 (35.4%) patients, respectively. Median time from symptom onset to ICU admission was 9 [IQR, 5–12] days. Nine (18.8%) patients had VTE risk factors.

Table 1.

Baseline and ICU admission characteristics according to deep vein thrombosis events in patients with acute respiratory failure due to COVID-19.

Variables	All patients n = 48 (100)	Absence of venous thrombosis n = 46 (95.8)	Presence of venous thrombosis n = 2 (4.2)
Demographic characteristics	—	—
Age (years)	63 [54–70]	63 [53–70]	66 [62–70]
Male sex	30 (62.5)	28 (60.9)	2 (100)
Comorbidities	—	—	—
Chronic heart failure	2 (4.2)	2 (4.3)	0 (0.0)
CEI or ARA treated arterial hypertension	7 (14.6)	7 (15.2)	0 (0.0)
Antiplatelet therapy	9 (18.8)	9 (19.6)	0 (0.0)
Diabetes mellitus	17 (35.4)	15 (32.6)	2 (100)
Active cancer/homeopathy	4 (8.3)	4 (8.7)	0 (0.0)
Chronic renal failure (clearance <30 mL/min)	2 (4.2)	2 (4.3)	0 (0.0)
Body mass index (kg/m2)	28.0 [25.0–31.4]	28.0 [25.0–31.4]	29.8 [28.3–31.2]
Respiratory disease (asthma, COPD, bronchiectasis)	3 (6.4)	3 (6.7)	0 (0.0)
VTE risk factors	—	—	—
VTE history within past 2 years	0 (0.0)	0 (0.0)	0 (0.0)
Major transient risk factors	1 (2.1)	1 (2.2)	0 (0.0)
Minor transient risk factors	2 (4.2)	2 (4.3)	0 (0.0)
Permanent risk factors	6 (12.5)	6 (13.0)	0 (0.0)
Characteristics at ICU admission	—	—	—
SAPS II	37 [33–46]	36 [33–44]	77 [77–78]
Time from symptom onset to ICU admission (days)	9 [5–12]	9 [6–12]	2 [1–2]
Time from hospitalization to ICU admission (days)	1 [0–3]	1 [0.25–3]	0 [0–0]
Laboratory tests at ICU admission	—	—	—
Lymphocytes (G/L)	0.7 [0.5–1.0]	0.7 [0.5–1.0]	0.9 [0.9–1.0]
Platelets (G/L)	237 [189–331]	237 [187–319]	324 [273–374]
Fibrinogen (g/L)	6.7 [5.8–7.7]	6.7 [5.8–7.7]	5.5 [5.3–5.8]
D-dimers (ng/mL)	1530 [755–2550]	1510 [730–2480]	5660 [5515–5805]
C-reactive protein (mg/L)	127 [74–234]	127 [75–229]	190 [119–260]
Procalcitonin (ng/mL)	0.34 [0.14–1.05]	0.32 [0.13–0.92]	0.99 [0.92–1.05]

Data are presented as N (%) or Median (interquartile range); there is no missing information reported in the study.

CEI: Conversion enzyme inhibitor; ARA: Angiotensin receptor antagonist; COPD: chronic obstructive pulmonary disease; VTE: venous thromboembolism; ICU: intensive care unit; SAPS II: Simplified Acute Physiology Score II; CRP: C-reactive protein; PCT: Procalcitonin.

Among included patients, 22 angiography CT scans (45.8% of the patients) were performed for PE suspicion during ICU stay, which was confirmed in one patient 10 days after ICU admission (Table 2).

Table 2.

ICU management and outcomes according to deep vein thrombosis events in patients with acute respiratory failure due to COVID-19.

Variables	All patients n = 48	Absence of venous thrombosis n = 46 (95.8)	Presence of venous thrombosis n = 2 (4.2)
ICU Management	—	—	—
Initial injected CT scan	22 (45.8)	22 (47.8)	0 (0.0)
Pulmonary embolism on initial CT scan	1 (4.5)	1 (4.5)	-
Catheter-related thrombosis diagnosed on Doppler US	1 (2.1)	0 (0.0)	1 (50.0)
High-flow nasal oxygen success	20 (41.7)	20 (43.5)	0 (0.0)
Invasive mechanical ventilation	28 (58.3)	26 (56.5)	2 (100)
Time from ICU admission to intubation (days)	1 [0–3]	1 [0–3]	0 [0–0]
ECMO	0 (0.0)	0 (0.0)	0 (0.0)
Need for vasoactive drugs in the ICU	19 (39.6)	17 (36)	2 (100)
Need for renal replacement therapy in the ICU	2 (4.2)	2 (4.3)	0 (0.0)
Dexamethasone initiated at ICU admission	44 (91.7)	43 (93.5)	1 (50.0)
Outcomes	—	—	—
Major bleeding complication during ICU	2 (4.2)	1 (2.2)	1 (50.0)
ICU length of stay (days)	8 [5–15]	8 [5–15]	34 [22–47]
Hospital mortality	9 (18.8)	9 (19.6)	0 (0.0)

Data are presented as N (%) or Median (interquartile range); there is no missing information reported in the study.

ICU: intensive care unit; CT: computed tomography; US: ultrasound; ECMO: extracorporeal membrane oxygenation.

Judging criteria

The prevalence of DVT was 2/48 patients (4.2%). The two DVT were diagnosed within 48 h of admission, during visit 1. In these two patients, after the diagnosis of DVT, the anticoagulation was switched from IDH to a curative dose by LMWH or UFH. For the 44 who completed visit 2, none present DVT on Doppler ultrasound.

In two (4.2%) patients, a major bleeding complication occurred according to the ISTH criteria. One was on curative-dose anticoagulation at the time of bleeding complication and the other was on intermediate-dose anticoagulation (Table 2). Major bleeding events were not intracranial haemorrhage.

Nine patients (18.8%) died before hospital discharge. No deep vein thrombosis had been diagnosed in these patients.

Discussion

In our study, performed during the second wave of COVID-19 in France, the incidence of deep thrombosis during the first week of patients admitted in ICU for SARS-CoV2 infection and treated by intermediate-dose heparin (IDH) was 4.2%. Additionally, the incidence of major bleeding complications in IDH patients was 4.2%. We were unable to detect a significant difference in the incidence of major bleeding in patients with and without thrombosis or in mortality rates considering our limited sample and the low number of venous thromboses diagnosed. However, one of the two patients with DVT experienced bleeding during ICU stay. Performing a second Doppler ultrasound 7 days after the first exam did not increase the incidence of diagnosed deep vein thrombosis. The diagnosis of DVT led to a change in anticoagulation therapy (change from increased prophylaxis to curative anticoagulation) in both cases.

At the time of our study (April 2020 to December 2020), no etiological treatment had demonstrated efficacy against severe COVID-19. Consequently, the treatment relied on ventilatory assistance, other organ-supportive interventions, and symptomatic anti-inflammatory medications (14). We focused on patients admitted for COVID-19-related acute hypoxemic respiratory failure. Their baseline characteristics, with a median age of 63 years, almost three-fourths of males, and high prevalence of obesity, arterial hypertension, and diabetes are consistent with earlier data (15–18).

ICU mortality in patients with COVID-19-related acute respiratory failure has ranged across studies from 29% to 53% (15–18). As compared to previous studies of populations with similar baseline characteristics, we report a lower mortality rate in our study (18.8%) (19,20). This difference could be related to differences in selection criteria for ICU admission and/or in ICU surge during this period.

At this, the incidence of proximal DVT in patients with SARS-CoV2 hospitalized in the ICU was reported in the literature to be 25% (1–7). However, this incidence was established only on the basis of monocentric retrospective studies performed during the first wave and before anticoagulation prophylaxis was introduced at higher posology (intermediate or curative) to address the specific high risk of thromboembolic events in COVID-19 patients according to guidelines (11,14,21). The thrombotic events in critically ill COVID-19 population are described as a specific physiopathology phenomenon including lung microvascular thrombosis, confirmed by post-mortem cases-series (22–25). Using heparin for thromboprophylaxis at higher posology could prevent clinically relevant event or avoid asymptomatic event and microvascular thrombosis formation leading to better outcomes (11,14,21). In the studies that investigated the prevalence of proximal deep vein thrombosis after the introduction of IDH, this prevalence ranged from 5 to 12.5% (26,27), which is consistent with our results. Despite all, recent randomized controlled study did not show better outcomes with higher dose of heparin prophylaxis (28,29) and update NICE and ISTH guidelines do not recommend IDH (30). In our cohort, the incidence of major bleeding complications in our IDH patients was 4.2%. However, one of which occurred after a switch to curative anticoagulant treatment for late catheter related thrombosis and cannot be attributed to IDH This result, showing a little and acceptable risk of bleeding, is not consistent with these recent guidelines and studies which do not recommend IDH. Because of the low rate of DVT and bleeding event, the lack of statistical power of our study does not allow us to make strong conclusion.

To our knowledge, few studies were conducted during the second wave in patients who benefited from IDH (27,31). As previously described, distal DVT has a low risk of pulmonary embolism (32,33). Therefore, it was interesting to focus exclusively on proximal DVT in our study although screening for VTE disease by performing Doppler US without CT scan is still a matter of debate and questionable.

Strengths of this study are the prospective design and the low rate of missing data. Nevertheless, some limitations of our study must be acknowledged. First, although our cohort is prospective, the observational nature of the study implies that possible unmeasured confounders could affect the outcomes. Second, the limited sample size (48 patients) does not allow highlighting all potential risk factors. Third, our study was a single-centre cohort that may not reflect all ICUs in countries that have similar health resources. The limited sample size and the low number of event (DVT) did not allow us to detect differences between patients with DVT and patients without DVT. As we did not use different anticoagulation strategies, we are not able to determine the direct impact of intermediate-dose heparin (IDH). Our study, because of lack of power, cannot allow us to make therapeutic recommendations regarding IDH treatment.

Conclusion

In our centre, during the second wave of COVID-19 surge in ICU, the deep vein thrombosis incidence in patients under intermediate-dose heparin (IDH) is low (4.2%), as the frequency of major bleeding events. Multicenter studies of larger ICU populations managed based on the current knowledge of COVID-19 are needed to further compare associations between different anticoagulation regimens and patient outcomes.

Abbreviations

ICU, Intensive care unit; DVT, Deep venous thrombosis; ARDS, Acute respiratory distress syndrome; IDH, Intermediate-dose-heparin; ISTH, International Society on Thrombosis and Haemostasis; UFH, Unfractionated heparin; SOFA, Sepsis-related Organ Failure Assessment; SAPS-II, Simplified Acute Physiology score II; ECMO, extracorporeal membrane oxygenation; PE, Pulmonary embolism; COVID-19, Coronavirus disease-2019; CRP, C-reactive protein; SARS-CoV2, Severe acute respiratory syndrome-coronavirus two; CEI, Conversion enzyme inhibitor; ARA2, Angiotensin two receptor blocker; CT, Computerized tomography; LMWH, Low-molecular-weight heparin

ORCID iD

Aurélien Maurizot https://orcid.org/0000-0002-8742-1195