key: cord-0852590-wlq3a0zr authors: Fares, Yara; Eyoum, Yeyinou Calliste Sinzogan; Billoir, Paul; Bogaert, Aymeric; Armengol, Guillaume; Alexandre, Kevin; Lammens, Justine; Grall, Maximillien; Levesque, Hervé; Benhamou, Ygal; Miranda, Sebastien title: Systematic screening for a proximal DVT in COVID-19 hospitalized patients: results of a comparative study date: 2021-05-14 journal: J Med Vasc DOI: 10.1016/j.jdmv.2021.05.003 sha: c5e1b29f60f5d72c5a5698539af221000678f036 doc_id: 852590 cord_uid: wlq3a0zr INTRODUCTION: The COVID-19 pandemic is associated with a high incidence of venous thromboembolism questioning the utility of a systematic screening for deep venous thrombosis (DVT) in hospitalised patients. METHODS: In this prospective bicentric controlled study, 4-point ultrasound using a pocket device was used to screen for DVT, in patients with SARS-CoV-2 infection and controls admitted for acute medical illness not related to COVID-19 hospitalised in general ward, in order to assess the utility of a routine screening and to estimate the prevalence of VTE among those patients. RESULTS: Between April and May 2020, 135 patients were screened, 69 in the COVID+ group and 66 in the control one. There was no significant difference in the rate of proximal DVT between the two groups (2.2% vs 1.5%; p=0.52), despite the high rate of PE diagnosed among COVID-19 infected patients (10.1% vs 1.5%, p=0.063). No isolated DVT was detected, 37.5% of PE was associated with DVT. Mortality (7.2% vs 1.5%) was not different (p=0.21) between COVID-19 patients and controls. CONCLUSION: The systematic screening for proximal DVT was not found to be relevant among COVID-19 patients hospitalized in general ward despite the increase of VTE among this population. Further studies are needed to confirm the hypothesis of a local pulmonary thrombosis which may lead to new therapeutic targets. The world is witnessing since December 2019 a global health crisis related to Coronavirus disease 2019 (COVID- 19) , which main clinical manifestation is severe acute respiratory syndrome. Mortality related to hospitalized COVID-19 infection is high, ranging from 5 to 20% [1] [2] [3] [4] . In France, the estimated mortality rate is 6% mainly due to cardiac and respiratory complications of the virus. This poor prognosis has been shown to be associated with a high prevalence of venous thromboembolic events (VTE), estimated between 20 and 30 % among infected patients [5, 6] . In a post-mortem study, autopsies performed on COVID-19 patients found that pulmonary embolism (PE) was the direct cause of death in 33% of the cases [7] . This association can be explained by Associated Coagulopathy (CAC), a distinct form of coagulopathy that includes inflammation storm, endothelial dysfunction and immunothrombosis [8] [9] [10] . The prevalence of VTE in COVID-19 patients hospitalized in general ward is estimated around 10% according to recent meta-analyses [11, 12] , but ranges vary between 0 and 94%, with large index of heterogeneity ranges. This can be explained by the variable thromboprophylaxis strategies explained by the empiric use of intermediate or therapeutic doses for some patients [13] and most importantly by discrepancies in the screening strategy for VTE between centres. Some study groups have advocated a systematic screening for Deep Venous Thrombosis (DVT) [6, 14, 15] for ICU-patients suffering from Acute Respiratory Distress Syndrome (ARDS). However, little is known about the utility of such strategies in general ward patients. Nopp et al. reported that systematic ultrasound screening in general ward showed a remarkably high rate of DVT 23% ([95%CI: 3.2-52.5]) [12] . This finding questions about the screening in this population. Therefore, given a significant increased mortality in patient with VTE [16, 17] , we can assume that early detection of DVT complication could reduce the embolic risk and therefore the mortality associated with the COVID-19.. However, because no study had a control group, the real over risk of DVT in this population and the benefit of its screening remains unknown. Thus, we conducted a prospective open-label controlled study, in which all new COVID-19 patients (COVID+) admitted in general ward of two hospital centres in the region of Normandy in the west of France were screened for DVT and compared to a group of non-COVID-19 (COVID-) patients with similar baseline, clinical and biological characteristics. The main purpose of this study was to assess the utility of a routine screening for proximal DVT among COVID-19 patients hospitalised in general ward. Moreover, we aimed to estimate the prevalence of VTE among those patients compared to COVID-and identify clinical or biological risk factors of developing DVT, in order to adjust the screening strategy among infected patients. J o u r n a l P r e -p r o o f This was a prospective open-label controlled bicentric trial. The study was approved by the Institutional Ethical Committee (20.04.03.44507) and patients or their legal representative gave standard oral consent. Consecutive adult patients with COVID-19 who have been admitted to the University Hospital Centre of Rouen and the Hospital Centre of Dieppe, in general ward, between the 6 th of April and the 10th of May were enrolled in the COVID+ group. In parallel, patients admitted for an acute medical inflammatory affection unrelated to COVID-19 disease in general ward (in internal medicine and infectious diseases departments) at the same period were enrolled in the control group. COVID-19 infection was diagnosed with either a positive real-time-transcriptase polymerase chain reaction (RT-PCR) for COVID-19 using nasopharyngeal swab or a high likelihood of COVID-19 on thin-section computed tomographic CT of the chest [18] . Patients were excluded if they were on therapeutic dose of anticoagulant. The primary outcome was the incidence of symptomatic and asymptomatic proximal DVT found on pocket-sized ultrasound device. DVT was defined by the lack of a vein compression in a systematic 4-point compression ultrasonography (CUS) with pocket-sized ultrasound devices (CUS-PUD) screening. The secondary outcome was the incidence of either PE or DVT (regardless symptoms) All patients underwent systematic bilateral 4-point CUS-PUD (V-Scan Dualprobe © , GE Healthcare, Milwaukee, Wisconsin, USA) for proximal lower limb DVT at day 0(+ 1), 7(± 1) from the hospital admission and at discharge. CUS-PUD was performed according the previously described protocols [19] by 4 trained physicians (YF, CES, AB, JL). If PE was suspected diagnosis was based on CTPA. We collected for all patients their clinical risk factors for VTE which implies their age, personal or familial VTE background, and BMI. We also checked at each visit their laboratory findings (platelet count, D-dimer, prothrombin time, fibrinogen level and Creactive protein), and the occurrence of a poor outcome, defined by death or the need of a transfer to an ICU unit. DOQBOARD software (Mont Saint Aignan, FRANCE) was used to collect data. SPSS Statistics Software (SPSS Inc., Chicago, IL, U.S.A.) were used to conduct the statistical analyses. Continuous variables are presents as the means and standard deviations, and categorical variables are presented as numbers and percentages. The differences between groups in relation to the continuous variables were analysed using the Student's t-test for parametric values and a Mann-Whitney U test for non-parametric ones. Pearson's chi-squared test and Kruskall Wallis's test were used to analyse the difference between groups in relation to the categorical variables respectively for the parametric and non-parametric values. Between April and May 2020 69 patients with COVID19 disease were recruited and matched with 66 controls. In the control group, 3 patients were excluded from analysis because they were admitted for scheduled hospitalization, 69% of the remaining patients had an infectious disease of which 68% were respiratory. In the infected group, the mean age was 63 years old (±17.6), a BMI at 28±5.7 and 39.4% were men, with no difference compared to the COVID-patients. Medical history and VTE risk factors were similar in both groups. Baseline characteristics of the study population are summarized in Table 1 . Among the 135 patients enrolled 3 (2.2%) were diagnosed having a DVT on CUS-PUD. In the COVID+ group, 2 patients experienced DVT (2.9%) and 1 (1.5%) patient had a DVT in the control group (p=0.52). All the positive CUS-PUD were found at the first assessment between day 0 and day 1. No DVT was diagnosed during follow up at day 7 or at discharge. Only one out of the three patients with DVT were symptomatic. PE was diagnosed in 8 patients, 7 (10.1%) in the COVID+ group and 1 (1.5%) in the control group (p=0.63). In all cases but 1 the diagnosis of PE was performed the day of admission. The mean time between the onset of COVID symptoms and the PE was 13.28 (±8.08) days. All cases of acute lower limb DVT on CUS-PUD were associated with a PE. On the other hand, despite the similar screening strategy in both groups, a higher rate of isolated PE was found among COVID-19 patients (71.42%) compared to the control ones (0%). In fact, there was no significant difference between the numbers of computed tomography pulmonary angiogram (CTPA) performed between both groups (46.37% vs 40.90%, p=0.60). In the COVID+ group, 25% of the patients who underwent CTPA were diagnosed with PE. Death occurred in 7.2% of COVID+ patients but there was no significant increase in the mortality rate compared to 1.51% in the COVID-group (p=0.209) ( A pocket-sized device was selected as a screening tool because of its portable technology, which makes it easier to use and allow physicians to perform the exam at bedside, avoiding patients transport. 4 points CUS-PUD has already proven its good sensitivity and specificity for the diagnosis of DVT, compared to whole leg ultrasound [21] . In order to describe the specific risk associated to COVID 19 infection we performed a similar real-time screening strategy in a control group of patients admitted in Internal Medicine or Infectious Disease units, with an acute medical illness. This group of patients had a similar inflammatory state to those who were infected with COVID-19 and thus a similar procoagulant state regarding thrombosis risk factors other than COVID-19 disease. Our strategy of performing a proximal 4-point CUS repeated CUS at 1 week has already shown its relevance with a similar 3-month rate of VTE as the complete single CUS (0,9% vs 1,2%) and a comparable safety, while being less costly and time consuming [22] , which already lead to question the relevance of treating calf DVT with therapeutic anticoagulation. Moreover, we found no new DVT in the repeated exams at day 7 and before discharge confirming the absence of extension of a distal DVT to the proximal veins. Our study is representative of COVID-19 patients requiring general ward hospitalization. Except for the higher rate of women that was not found in other studies, the patient included in our cohort had similar clinical and biological characteristics than other published cohorts table 3. Moreover, the mortality rate (7.2%) is consistent with the national rate at that time. In our study, incidence rate of DVT in the COVID+ patients were 2.9% which is lower than previously reported in prospective cohorts. This apparent discrepancy is probably explained by the fact that we focused DVT screening on the proximal area while other study found up to 30% of below knee DVT. To detect hypothetic extension of undiagnosed distal DVT in our cohort we have prospectively followed the patients at day 7 and at discharge. We failed to demonstrate new DVT on this ultrasound confirming the absence of extension of an hypothetic distal DVT to the proximal veins. Similar results were found in prospective cohorts conducted in general ward of confirmed COVID-19 patients. Authors showed a rate of proximal DVT between 0.6 to 4.5% among a rate of DVT between 11.9 to 14.7%. Given the absence of new proximal event during our follow up our results suggesting that asymptomatic distal DVT in hospitalized is not clinically relevant in COVID-19 patients. In our study, comparatively to previously published cohort studies performed in the same population, we have found a higher prevalence of PE in COVID-19 patients (10.1%) ( Table 3) . This difference is probably related to the fact that we have systematically excluded patients treated with therapeutic dose of anticoagulation at admission. The other reason is that while the study was performed the medical world was particularly concerned about the VTE risk. In fact, almost half of our patients underwent a CTPA to screen for PE at admission particularly if they required oxygen therapy. In previous study, PE screening test was less exhaustive with only 8.7% and 11.3% of CTPA performed respectively in the studies of Middledorp et al. and Lodigiani et al [23, 24] . The results of a recent systematic review support the screening given increased rate of DVT diagnosed from 1.4% (95%CI:0.7-2.3) to 12.7% (95%CI:3.7-25.5%) when ultrasound screening was performed [12] . However, studies included in this review were J o u r n a l P r e -p r o o f heterogeneous, most of them were retrospective studies with patients recruited in an intensive care unit and in general ward indistinctly [25] [26] [27] . Importantly prophylaxis coverage was sometimes very low and most of the patients should have received a prophylaxis [28] . Finally, high DVT rate seem to be largely accounted by asymptomatic distal DVT, as the prevalence of proximal DVT ranged between 0 to 3% which is consistent with our findings. In our prospective controlled study, we found a similar rate of proximal rate of DVT than in the control group suggesting that in this population systemic DVT screening is useless. Another important finding of our study is that PE is overrepresented compared to DVT and isolated PE represents almost two-thirds of PE while no DVT diagnosed were isolated. Similar finding has previously been described [6, 29, 30] and raise the question of a localized thrombotic microangiopathy that would be responsible of in situ pulmonary thrombosis rather than venous thromboembolism as it usually occurs in VTE. In fact, it is unknown whether thromboprophylaxis can prevent this kind of thrombotic disorder. Moreover, guidelines and several teams suggest increasing the dose of anticoagulant while the benefit risk ratio is largely unknown. Our study has some limitations and strength. First our sample size is relatively small. Secondly, we did not confirm the results of our pocket size 4-point ultrasound with a whole leg ultrasound. One of the strength of our study is the prospective and bicentric design. Moreover, to our knowledge, our study in the only one comparing in real-time a group of COVID-19 patients to a similar population of patients hospitalized for an acute inflammatory medical affection with a follow up of both groups until discharge. Both groups had a similar screening strategy for DVT and for PE and thromboprophylaxis recommendations were applied in both groups. This allows us to overcome the heterogeneity issue that make us questions the reliability of the conclusions in previous studies. Page 13 of 20 J o u r n a l P r e -p r o o f In conclusion, our study confirms the absence of relevance for a systematic DVT screening in COVID-19 patients hospitalized in general ward. In fact, our results confirmed the low prevalence of proximal DVT with no significant increase in proximal DVT among COVID-19 infected patients compared to patients hospitalized in general ward for another acute medical. Our results therefore comfort the hypothesis of a local pulmonary thrombosis rather than the classical venous thromboembolism. Whether this hypothesis should lead to change the current "high dose" anticoagulation strategy remains to be clarified by further studies. Table 3 Comparison between our population characteristics and outcomes and other general ward cohorts Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China Real estimates of mortality following COVID-19 infection épidémie Covid19 aux hôpitaux universitaires de Strasbourg (HUS), focus sur la maladie veineuse thromboembolique Circulation Pulmonaire et Interactions Coeur-Poumons group of the SPLF. Venous thromboembolism and COVID-19 Autopsy Findings and Venous Thromboembolism in Patients With COVID-19: A Prospective Cohort Study COVID-19 and its implications for thrombosis and anticoagulation Coagulopathy in COVID-19 ISTH interim guidance on recognition and management of coagulopathy in COVID-19 Venous thromboembolism in patients with COVID-19: Systematic review and meta-analysis Risk of venous thromboembolism in patients with COVID-19: A systematic review and meta-analysis A Comparison of Enoxaparin with Placebo for the Prevention of Venous Thromboembolism in Acutely Ill Medical Patients Venous Thromboembolism in COVID-19: Towards an Ideal Approach to Thromboprophylaxis, Screening, and Treatment Thromboembolic Events and Role of Point of Care Ultrasound in Hospitalized Covid-19 Patients Needing Intensive Care Unit Admission Prevalence and characteristics of pulmonary embolism in 1042 COVID-19 patients with respiratory symptoms: A nested case-control study Pulmonary embolism in COVID-19 patients: a French multicentre cohort study Diagnosis of the Coronavirus disease (COVID-19): rRT-PCR or CT? How to screen and diagnose deep venous thrombosis (DVT) in patients hospitalized for or suspected of COVID-19 infection, outside the intensive care units Prevention, Diagnosis, and Treatment of VTE in Patients With Coronavirus Disease Detection of Deep Venous Thrombosis Using a Pocket-Size Ultrasound Examination Device Should we diagnose and treat distal deep vein thrombosis? Incidence of venous thromboembolism in hospitalized patients with COVID-19 Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Early detection of deep vein thrombosis in patients with coronavirus disease 2019: who to screen and who not to with Doppler ultrasound? Systematic Screening for Venous Thromboembolic Events in COVID-19 Pneumonia Deep vein thrombosis in SARS-CoV-2 pneumonia-affected patients within standard care units: Exploring a submerged portion of the iceberg Deep Vein Thrombosis in Hospitalized Patients With COVID-19 in Wuhan, China: Prevalence, Risk Factors, and Outcome Incidence of thrombotic complications in critically ill ICU patients with COVID-19 Pulmonary Embolism or Pulmonary Thrombosis in COVID-19? Is the Recommendation to Use High-Dose Heparin for Thromboprophylaxis Justified? Incidence of deep vein thrombosis among non-ICU patients hospitalized for COVID-19 despite pharmacological thromboprophylaxis Incidence of asymptomatic deep vein thrombosis in patients with COVID-19 pneumonia and elevated D-dimer levels COVID-19 and venous thromboembolism in intensive care or medical ward Deep Vein Thrombosis in Hospitalized Patients With COVID-19 in Wuhan, China: Prevalence, Risk Factors, and Outcome High prevalence of early asymptomatic venous thromboembolism in anticoagulated COVID-19 patients hospitalized in general wards Non-Overt Coagulopathy in Non-ICU Patients with Mild to Moderate COVID-19 Pneumonia Prevalence of proximal deep vein thrombosis in hospitalized COVID-19 patients Type of study