key: cord-0743221-j5snuszr
authors: Tholin, Birgitte; Ghanima, Waleed; Einvik, Gunnar; Aarli, Bernt; Brønstad, Eivind; Skjønsberg, Ole H.; Stavem, Knut
title: Incidence of thrombotic complications in hospitalised and non‐hospitalised patients after COVID‐19 diagnosis
date: 2021-05-24
journal: Br J Haematol
DOI: 10.1111/bjh.17522
sha: 2e353d4cbf9feb22f978bbac6d0b75d3553ecb83
doc_id: 743221
cord_uid: j5snuszr

Infection with coronavirus disease‐2019 (COVID‐19) may predispose for venous thromboembolism (VTE). There is wide variation in reported incidence rates of VTE in COVID‐19, ranging from 3% to 85%. Therefore, the true incidence of thrombotic complications in COVID‐19 is uncertain. Here we present data on the incidence of VTE in both hospitalised and non‐hospitalised patients from two ongoing prospective cohort studies. The incidence of VTE after diagnosis of COVID‐19 was 3·9% [95% confidence interval (CI): 2·1–7·2] during hospitalisation, 0·9% (95% CI: 0·2–3·1) in the three months after discharge and 0·2% (95% CI: 0·00–1·25) in non‐hospitalised patients, suggesting an incidence rate at the lower end of that in previous reports.

During the past year, numerous studies have reported on the incidence and prevalence of venous thromboembolism (VTE) in coronavirus disease-2019 (COVID-19) patients, with incidence rates varying from 3% to 85%, depending on populations, settings and assessment methods. [1] [2] [3] [4] Variations may also be associated with a lack of a consensus on the indication, dosage and duration of prophylactic anticoagulation. The majority of reports are from studies of selected patients or hospital cohorts using intensive case findings. The information on the incidence of VTE after hospital discharge and among those not needing hospital admission is limited.

This study assessed the incidence of VTE in both hospitalised and non-hospitalised patients in two ongoing cohort studies in Norway. Furthermore, we assessed the variation in the use of prophylactic anticoagulation between five hospitals.

Participants and data collection PROLUN (patient-reported outcomes and lung function after hospitalisation for COVID-19) is an ongoing multicentre prospective cohort study in six Norwegian hospitals comprising 262 surviving patients hospitalised before June 1, 2020. Patients with a discharge diagnosis of U07.1 (confirmed COVID-19 diagnosis), U07.2 (COVID-19, diagnosis unconfirmed) or J12.x [viral pneumonia, in combination with positive Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) polymerase chain reaction (PCR)] were considered eligible. Consenting patients were invited to a threemonth follow-up visit. 5 At the follow-up, patients were asked if they had been diagnosed with a VTE during the last months, which was subsequently verified by medical record review. Through a re-review of medical records, we also checked if the patients had been prescribed anticoagulation for primary thromboprophylaxis at discharge. PROTROM (patient-reported outcomes and thromboembolism after COVID-19 without hospitalisation) is another ongoing prospective population-based cohort study assessing non-hospitalised individuals with COVID-19. 6 Patients from the geographical catchment area of two Norwegian hospitals [Akershus University Hospital (Ahus) and Østfold Hospital (ØH)] with a positive real-time PCR for SARS-CoV-2 before June 1, 2020 were invited. Patients admitted to hospital <22 days after a positive PCR test were excluded, because we considered the probability to be high that this hospital stay was COVID-19-related. In total, 458 of 938 eligible subjects (49%) responded to a survey on average four months after symptom onset; 451 (48%) responded to items on recent VTE. Self-reported VTE events were verified by medical record review in each local hospital.

The uncertainty of the incidence rates for VTE was estimated by calculating 95% confidence intervals using the Wilson method. For display of anticoagulation practice, we excluded one hospital, as we only included hospitals with ≥20 patients. Data were analysed using Stata software version 16.1 (Stata-Corp, College Station, TX, USA).

Among the 262 hospitalised patients (PROLUN), the median (25th to 75th percentile) length of stay was 6 (3-12) days, and 51 patients (19%) were admitted to the intensive-care unit (ICU). At admission, the median clinical frailty scale score was 2 (range: 1-7) and 26/262 (10%) were considered as at least pre-frail (>3). Only (17%) had severe disease according to the COVID-19 ordinal scale for clinical improvement (Table I) , i.e. requiring non-invasive ventilation, high-flow oxygen, intubation/mechanical ventilation, or extracorporeal membrane oxygenation (ECMO; only one patient had ECMO). A chest computed tomography (CT) was performed in 39/262 (15%) during the hospital stay. Fifteen of 262 patients (5Á7%) had a history of prior VTE.

At the three-month follow-up, 232 responded to items about VTE; 11/232 (5%) patients reported a VTE during or after being discharged from the hospital, and ten of these had the diagnosis confirmed by compression ultrasound or CT pulmonary angiography, as verified by review of medical records. Thus, the incidence rate of verified VTE during hospitalisation for COVID-19 was 3Á9% [95% confidence interval (CI): 2Á1-7Á2] and 0Á9% (95% CI: 0Á2-3Á1) in the three months after discharge from the hospital ( Table I) . The incidence rate among those admitted to the ICU was 7Á8% (95% CI: 3Á1-18Á5%).

In non-hospitalised patients (PROTROM), 11/458 patients (2Á4%) had a history of VTE, and 1/451 (0Á2%, 95% CI: 0Á0-1Á3%) reported a VTE after COVID-19 that was verified.

In the hospitalised patients, the incidence rate was at the low end of those previously reported. 1,2 All patients being hospitalised before June 1, 2020, with a positive SARS-CoV-2 PCR were included, although many of these patients were only moderately affected by COVID-19, as shown by the distribution of scores on the COVID-19 ordinal scale for clinical improvement. Norwegian hospitals have not been overwhelmed with COVID-19-related admissions compared to other countries, and so the population hospitalized may have milder disease than in countries with high demand for hospital beds. This might contribute to the low incidence of VTE for the hospitalised patients presented here. In addition, we only obtained data from patients who were discharged alive, which represents a limitation. Two recent meta-analyses reported overall incidence rates of 21% (95% CI: 17-26%) and 26% (95% CI: 6-66%), range 2Á6-85Á4%, for VTE in hospitalised COVID-19 patients, but it was emphasized that the quality of the evidence was low due to heterogeneity and risk of bias. 1,2 These variations in incidence rates in previous reports may largely be explained by the variations in sample selection and methods.

In the current study, the rate of chest CT during the hospital stay of 15% was lower than in some other studies. For example, a recent study reported rates of chest CT of 1 042/1 259 (83%). 7 Yet, the case fatality rate of hospitalised patients in Norway seems similar to that in other countries. In Norway, as of June 21, 2020, 1 142 patients had been hospitalised with COVID-19; 929 with the disease as a primary diagnosis, and 94 hospitalised patients were reported dead with COVID-19, i.e., a case fatality rate in hospitals of 8Á2% (95% CI: 6Á8-10Á0) or 10Á1% (95% CI: 8Á3-12Á2), depending on choice of denominator. 8 Liberal use of chest CT or compression ultrasonography of the lower extremities has been discouraged in Norway due to both capacity challenges and in the interest of infection control. This practice could possibly have led to underreporting in our setting, and physicians might instead have administered higher doses of low molecular weight heparin (LMWH). The incidence of symptomatic VTE following hospital discharge for COVID-19 has been reported to be 0Á2% within 45 days, 9 suggesting that most VTEs occur during the hospital stay.

The uncertainty associated with the true incidence of VTE in unselected COVID-19 patients might also have influenced the use of thromboprophylaxis. In this study, we observed a wide variation in the practice of prophylactic anticoagulation with LMWH between the participating hospitals (Table II) .

In Norway, the use of prophylactic anticoagulation was liberal in the early days of the pandemic due to several case reports and smaller studies reporting a high incidence of VTE in COVID-19 patients. 10, 11 The majority of patients in PROLUN received ≥ 5 000 iu dalteparin as thromboprophylaxis, and in total 66% received anticoagulation, initiated prior to or during the hospitalisation. Although 5 000 iu dalteparin once daily is the standard thromboprophylactic dosage for immobilisation because of acute illness in Norway, 17% of patients received higher doses, and only 1Á9% of those receiving prophylactic anticoagulation during hospitalization were diagnosed with a VTE. This might have influenced the incidence of VTE in this study, although the number of VTE events was considered too small to compare the results between hospitals. It is possible that the variation might be smaller now, after implementation of more recent guidelines on anticoagulation during COVID-19 like the American Society of Hematology suggesting using prophylactic-intensity anticoagulation in patients who do not have suspected or confirmed VTE. 12 In other studies, a fair proportion of patients have been diagnosed with VTE despite prophylactic anticoagulation. 7 This can be used as an argument for the use of higher doses of prophylactic anticoagulation than usual, which seems to be practiced at several hospitals.

There is little information available on the incidence of VTE among those not hospitalised for COVID-19, except for some case reports. 13 We found a low incidence rate of VTEs following COVID-19. This low rate may be explained by a healthier population with a lesser degree of inflammation, immobilization and possibly comorbidities, than in hospitalised patients. Moreover, the sample in this study was population-based with a 48% response to the item on VTE and should therefore be reasonably representative of non-hospitalised COVID-19 patients. It is possible that patients with an increased symptom burden (i.e. if they have a VTE) respond more often than patients without symptoms, although patients with considerable comorbidity or language problems may have a lower propensity to respond. Therefore, responder bias may influence the findings, although it is not evident in what direction this would work. It was not possible to assess the incidence rate of VTEs among non-participants in the survey. There is, however, a possibility that some patients diagnosed with a VTE within 21 days of having a positive COVID-19 test might have been hospitalised and thereby excluded. One may also speculate that some patients may have hesitated to seek medical attention due to the ongoing pandemic. This might contribute to the low incidence rate in our study.

If the incidence of VTE in non-hospitalised patients is as low as these results suggest, large-scale data from populationbased studies or studies with record linkage between registries may provide more accurate data, although verification of the events may be more difficult. 14 Reported incidence rates of VTE in COVID-19 may seem high; however, it is not clear if the incidence of VTE is higher in COVID-19 than in other viral or bacterial pneumonias, e.g. community-acquired pneumonia. 15 This may easily be forgotten during the current pandemic.

In conclusion, in this study, we found a low incidence rate of VTEs compared to previous reports in hospitalised patients. In a population-based study of non-hospitalised COVID-19 patients, the incidence rate was considerably lower (0Á2%). These incidence rates are at the low end of previous reports. The study also noticed a wide variation in the practice of prophylactic anticoagulation in the hospitalised patients.

Thromboembolism risk of COVID-19 is high and associated with a higher risk of mortality: a systematic review and meta-analysis

Venous thromboembolism in patients with COVID-19: systematic review and meta-analysis

Thromboembolic risk and anticoagulant therapy in COVID-19 patients: emerging evidence and call for action

Incidence of venous thromboembolism in hospitalized patients with COVID-19

lung function and CT findings three months after hospital admission for COVID-19

Persistent symptoms 1.5-6 months after COVID-19 in non-hospitalised subjects: a population-based cohort study

Prevalence and characteristics of pulmonary embolism in 1042 COVID-19 patients with respiratory symptoms: a nested case-control study

Incidence of symptomatic venous thromboembolism following hospitalization for coronavirus disease 2019: prospective results from a multi-center study

Incidence of thrombotic complications in critically ill ICU patients with COVID-19

Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia

ASH 2020 guidelines on the use of anticoagulation in patients with COVID-19: Draft recommendations

Venous thromboembolism and coronavirus disease 2019 in an ambulatory care setting -a report of 4 cases

COVID-19 Positive Outpatient Thrombosis Prevention in Adults Aged 40-80

Comparison of venous thromboembolism risks between COVID-19 pneumonia and community-acquired pneumonia patients

All authors have contributed to drafting, revision and approval of the manuscript. BT and KS are responsible for the final version. KS analysed the data.

Both studies have approval from the Norwegian Regional Ethics committee (REK).

BT, KS, BA, EB and OHS have no conflict of interest to disclose. GE has received unrestricted research grants from Boehringer Ingelheim and Novartis. WG has received honoraria from Amgen, MSD, Novartis and Pfizer, and research funding from Bayer, BMS/Pfizer and Novartis.