Incidence of venous and arterial thromboembolic complications in COVID-19: A systematic review and meta-analysis

Abstract

Arterial thrombotic disease (atherosclerotic cardiovascular disease, CVD) and venous thromboembolism (VTE) (comprising of deep vein thrombosis (DVT) and pulmonary embolism (PE)), two distinct but closely related diseases, [[1]Delluc A. Lacut K. Rodger M.A. Arterial and venous thrombosis: what’s the link? A narrative review.Thromb. Res. 2020; 191: 97-102Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar] constitute major public health problems and are associated with substantial morbidity, premature mortality, and high economic costs. The coronavirus disease 2019 (COVID-19) pandemic which is one of the most significant modern-day public health challenges, predominantly affects the respiratory system, causing severe pneumonia and respiratory distress syndrome. Emerging data suggests COVID-19 adversely affects multiple organs; gastrointestinal, liver, kidney, neurological and cardiac complications have been reported [2Kunutsor S.K. Laukkanen J.A. Cardiovascular complications in COVID-19: a systematic review and meta-analysis.J. Infect. 2020; 81: e139-e141Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 3Kunutsor S.K. Laukkanen J.A. Hepatic manifestations and complications of COVID-19: a systematic review and meta-analysis.J. Infect. 2020; 81: e72-e74Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar, 4Behzad S. Aghaghazvini L. Radmard A.R. Gholamrezanezhad A. Extrapulmonary manifestations of COVID-19: radiologic and clinical overview.Clin. Imaging. 2020; 66: 35-41Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar]. Apart from pre-existing comorbidities such as CVD, hypertension, chronic kidney disease, chronic liver disease and diabetes being linked to increased risk of severe illness or death; [[5]Zheng Z. Peng F. Xu B. Zhao J. Liu H. Peng J. Li Q. Jiang C. Zhou Y. Liu S. Ye C. Zhang P. Xing Y. Guo H. Tang W. Risk factors of critical & mortal COVID-19 cases: a systematic literature review and meta-analysis.J. Infect. 2020; 81: e16-e25Abstract Full Text Full Text PDF PubMed Scopus (1264) Google Scholar] some extrapulmonary complications of COVID-19 such as acute myocardial injury have been shown to be associated with fatal outcomes [[6]Guo T. Fan Y. Chen M. Wu X. Zhang L. He T. Wang H. Wan J. Wang X. Lu Z. Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19).JAMA Cardiol. 2020; 5: 1-8Crossref Scopus (2369) Google Scholar]. Recently, COVID-19 has been linked to venous and arterial thromboembolic disease (henceforth referred to as thromboembolic complications). Three recent most downloaded and key studies published in the journal reported a high incidence of thromboembolic complications in COVID-19 patients, particularly in those admitted to the intensive care unit (ICU) [7Klok F.A. Kruip M. van der Meer N.J.M. Arbous M.S. Gommers D. Kant K.M. Kaptein F.H.J. van Paassen J. Stals M.A.M. Huisman M.V. Endeman H. Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: an updated analysis.Thromb. Res. 2020; 191: 148-150Abstract Full Text Full Text PDF PubMed Scopus (1173) Google Scholar, 8Thomas W. Varley J. Johnston A. Symington E. Robinson M. Sheares K. Lavinio A. Besser M. Thrombotic complications of patients admitted to intensive care with COVID-19 at a teaching hospital in the United Kingdom.Thromb. Res. 2020; 191: 76-77Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar, 9Lodigiani C. Iapichino G. Carenzo L. Cecconi M. Ferrazzi P. Sebastian T. Kucher N. Studt J.D. Sacco C. Alexia B. Sandri M.T. Barco S. Humanitas C.-T.F. Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy.Thromb. Res. 2020; 191: 9-14Abstract Full Text Full Text PDF PubMed Scopus (1258) Google Scholar]. Given the sparseness of the data and evolving nature of the disease, the thromboembolic complications of COVID-19 and their incidence estimates are not clearly defined. There is a need for robust aggregation of data on thromboembolic complications of COVID-19, which will be of great value for policy makers, healthcare providers and clinicians to aid decision making and implementing more efficacious preventative strategies. In this context, we conducted a systematic review and meta-analysis to attempt to address the following questions: (i) what are the thromboembolic complications associated with COVID-19 and (ii) what is the incidence of these complications overall and in those who develop severe disease? The review was conducted in accordance with PRISMA and MOOSE guidelines (Supplementary Materials 1–2). We searched MEDLINE and Embase from January 2020 to 6 August 2020 for published studies reporting on venous and arterial thromboembolic complications (e.g., VTE, PE, myocardial infarction (MI), acute coronary syndrome (ACS), ischemic stroke, disseminated intravascular coagulation (DIC)) in patients with COVID-19. Studies based on selected patients/populations (eg, cancer patients) were not included. Details of the search strategy are reported in Supplementary Material 3. The incidence of thromboembolic complications (estimated from the number of patients experiencing the specific complication within period of follow-up (hospital stay)/total number of patients with COVID-19) across studies with their 95% confidence intervals (CIs) were pooled using Freeman-Tukey variance stabilising double arcsine transformation and random-effects models. STATA release MP 16 (StataCorp LP, College Station, TX, USA) was used for all statistical analyses. Thirty-five observational cohort studies comprising of 9249 hospitalised patients with COVID-19 were eligible (Table 1; Supplementary Materials 4–5). Seven studies were based in China and France each, 6 each in Italy and USA, 4 in the UK, 2 in the Netherlands and one each in Germany, Spain, and Switzerland. The average age at baseline ranged from 53 to 71 years. Severe COVID-19 was defined as requiring Intensive Care Unit (ICU) care or admission and this was consistent across all studies.Table 1Baseline characteristics of 35 eligible studies.Author, year of publicationSource of patientsCountryDate of data collectionMean/median age (years)% malesNo. of patientsNOSKlok, 2020Dutch Univesity HospitalsNetherlandsMarch–April 202064.0761846Thomas, 2020Adenbrooke's HospitalUKUp to April 202020–89*69634Lodigiani, 2020University Hospital, MilanItalyFeb - April 202066.0683884Cui, 2020Union Hospital, WuhanChinaJan - March 202059.946814Chen, 2020Tongji Hospital in WuhanChinaJan - Feb 202062.0622744Du, 2020Hannan Hospital and Wuhan Union HospitalChinaJan - Feb 202065.872.9854Aggarwal, 2020UnityPoint ClinicUSAMarch–April 202067.075164Poissy, 2020Lille HospitalFranceFeb - March 2020NRNR1074Middeldorp, 2020Amsterdam Academic Medical CenterNetherlandsMarch–April 202061.0661986Mao, 2020Union Hospital of Huazhong University of Science and TechnologyChinaJan - Feb 202052.740.72144Llitjos, 20202 French ICUsFranceMarch–April 202068.077264Leonard-Lorant, 2020Strasbourg University HospitalFranceMarch 202064.0661064Helms, 2020French Tertiary HospitalFranceMarch 202063.081.31504Grillet, 2020Centre Hospitalier Universitaire de BesanconFranceMarch – April 202066.0701004Artifoni, 2020Nantes University Hospital and Châteaubriant HospitalFranceMarch–April 202064.060.6714Demelo-Rodríguez, 2020Third-level hospital in MadridSpainApril 202068.165.41565Faggiano, 2020NRItalyNR71.084254Longchamp, 2020Sion hospital ICUSwitzerlandMarch–April 202068.064254Mazzaccaro, 2020IRCCS Ospedale San RaaeleItalyMarch–April 202068.671.9324Bilaloglu, 2020NYU Langone HealthUSAMarch–April 202064.060.433346Merkler, 2020Academic Hospitals in New YorkUSAMarch–May 202064.057.519166Ren, 2020Zhongnan and Leishenshan HospitalsChinaFeb - March 202070.054.2484Rieder, 2020University Medical Center—University of FreiburgGermanyMarch–April 202060.061.2494Santoliquido, 2020Fondazione Policlinico Universitario A. Gemelli IRCCSItalyApril 202067.672.6844Tavazzi, 2020ICU of a Hub HospitalItalyUp to Feb 202068.083.0544Trigonis, 2020IU Health Methodist HospitalUSAMarch–April 202060.8NR454Moll, 2020Brigham and Women's HospitalUSAMarch–April 202062.248.12104Fang, 2020King's College Hospital NHS Foundation TrustUKMarch–April 202059.264.5934Mei, 2020Yichang Central People's HospitalChinaJan - March 202055.551.22564Li, 2020Union Hospital of Huazhong University of Science and TechnologyChinaJan - March 202053.340.62194Stoneham, 2020Brighton and Sussex University Hospitals NHS TrustUKMarch–April 2020NRNR2745Inciardi, 2020Civil Hospitals of BresciaItalyMarch 202067.081.0994Fraisse, 2020Centre Hospitalier Victor DupouyFranceMarch–April 202061.079.0924Desborough, 2020Guy's and St Thomas' NHS Foundation TrustUKMarch 202059.073.0664Maatman, 2020Indianapolis area academic hospitalsUSAMarch–May 202061.057.01094ICU, intensive care unit; NOS, Newcastle Ottawa Scale; NR, not reported; *, age range. Open table in a new tab ICU, intensive care unit; NOS, Newcastle Ottawa Scale; NR, not reported; *, age range. Fig. 1 portrays incidence of thromboembolic complications overall in COVID-19 patients over hospital stays/follow-up periods ranging from 2 to 30 days. The pooled incidence was 18.4% (12.0–25.7) for VTE (n = 19 studies), 13.5% (8.4–19.5) for PE (n = 22 studies) and 11.8% (7.1–17.4) for DVT (n = 18 studies) (Fig. 1A). The incidence of DVT subtypes are reported in Supplementary Material 6. The incidence of distal, bilateral, proximal, symptomatic and upper extremity DVT was 13.6% (2.6–31.0), 7.6% (4.9–10.9), 3.3% (1.2–6.2), 2.6% (0.5–5.9) and 1.7% (0.4–3.6) respectively. For PE subtypes, the incidence was 9.1% (5.0–14.3) for segmental PE, 7.5% (0.5–19.9) for central/lobar PE, 6.3% (2.3–11.8) for subsegmental PE, 4.1% (2.0–6.9) for main pulmonary artery PE and 1.9% (0.0–6.5) for multiple segmental PE (Supplementary Material 7). Other thromboembolic complications are reported in Fig. 1B. The incidence of the composite outcome of arterial and venous thromboembolic disease was 17.8% (9.9–27.4). The incidence of superficial vein thrombosis, DIC, ACS/MI, catheter-related thrombosis, ischemic stroke, overt DIC, systemic arterial embolism, mesenteric and limb ischemia was 7.7% (1.7–16.5), 5.6% (3.4–8.3), 3.3% (0.3–8.5), 2.4% (0.2–6.2), 1.8% (1.3–2.4), 1.7% (0.5–3.5), 1.6% (0.4–3.6), 1.4% (0.2–3.5) and 1.1% (0.1–3.0) respectively. Other outcomes reported were symptomatic VTE and portal vein thrombosis, but these were based on single reports (Fig. 1B). The incidence estimates of thromboembolic complications in patients with severe COVID-19 are reported in Supplementary Materials 8–11. The pooled incidence for VTE, PE and DVT was 21.6% (14.3–29.8), 11.8% (6.4–18.5) and 18.2% (9.6–28.6) respectively (Supplementary Material 8). The incidence of distal, proximal and upper extremity DVT was 21.5% (0.0–72.8), 7.8% (1.8–16.9) and 3.5% (1.2–6.9) respectively (Supplementary Material 9). For PE subtypes, the incidence was 7.7% (3.9–12.4) for segmental PE, 4.0% (0.7–9.3) for subsegmental PE, 2.8% (0.1–7.4) for central/lobar PE and 1.9% (0.0–6.5) for multiple segmental PE (Supplementary Material 10). The incidence of the composite outcome of arterial and venous thromboembolic disease, ACS/MI, ischemic stroke, catheter-related thrombosis, mesenteric and limb ischemia was 22.9% (14.5–32.4), 4.7% (0.0–14.6), 3.3% (2.5–4.2), 3.1% (0.8–6.5), 1.4% (0.2–3.5) and 1.1% (0.1–3.0) respectively (Supplementary Material 11). Based on the most up-to-date published evidence on patients with COVID-19, there is a high incidence of thromboembolic complications in these patients (ranging from 7.2 to 40.8%), which appears to be driven by venous thromboembolic disease. These thromboembolic complications are remarkably high in COVID-19 infection despite the use of thromboprophylaxis in patients. The most frequently diagnosed venous thromboembolic complication in the overall population is PE, with segmental and central/lobar PE being more common than other subtypes. Furthermore, it appears the incidence of thromboembolic complications is substantially higher in severe COVID-19 disease compared to the overall population, with a higher incidence of DVT than PE. Though arterial thrombosis and VTE have historically been viewed as two distinct diseases with different pathophysiology, they appear to be closely related via some shared risk factors (obesity and smoking) and mechanistic pathways (such as coagulation, platelet activation and dyslipidaemia) [[1]Delluc A. Lacut K. Rodger M.A. Arterial and venous thrombosis: what’s the link? A narrative review.Thromb. Res. 2020; 191: 97-102Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar]. Though the mechanistic pathways are still not very clear, the predisposition to venous and arterial thromboembolism by COVID-19 especially in severe infection has been attributed to the overwhelming inflammatory response, hypoxia, DIC and immobilisation [[2]Kunutsor S.K. Laukkanen J.A. Cardiovascular complications in COVID-19: a systematic review and meta-analysis.J. Infect. 2020; 81: e139-e141Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar]. There is an on-going discussion that pulmonary thrombotic events in COVID-19 may not be due to emboli but rather as a result of in-situ pulmonary thrombosis [[10]Al-Ani F. Chehade S. Lazo-Langner A. Thrombosis risk associated with COVID-19 infection. A scoping review.Thromb. Res. 2020; 192: 152-160Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar]. The high incidence of thromboembolic complications in COVID-19 patients is a big source of concern, especially given the fact that systemic thromboprophylactic agents were administered to patients. Furthermore, it has been acknowledged by some studies that the thromboembolic incidence estimates reported are actually underestimates [[7]Klok F.A. Kruip M. van der Meer N.J.M. Arbous M.S. Gommers D. Kant K.M. Kaptein F.H.J. van Paassen J. Stals M.A.M. Huisman M.V. Endeman H. Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: an updated analysis.Thromb. Res. 2020; 191: 148-150Abstract Full Text Full Text PDF PubMed Scopus (1173) Google Scholar,[8]Thomas W. Varley J. Johnston A. Symington E. Robinson M. Sheares K. Lavinio A. Besser M. Thrombotic complications of patients admitted to intensive care with COVID-19 at a teaching hospital in the United Kingdom.Thromb. Res. 2020; 191: 76-77Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar]. Aggressive monitoring of markers of thromboembolic complications such as D-dimer during admission, use of sensitive and specific VTE diagnostic tools and effective pharmacological thromboprophylaxis may be required in the management of patients with COVID-19. Given the bleeding risks associated with anticoagulants, clinical decisions to initiate thromboprophylaxis should also be individualised and tailored to each patient. There were some limitations in this study, but these were all inherent. These included the low methodological quality of some of the studies and small sample sizes; however, this was not unexpected given the urgency to understand the clinical course of COVID-19. Other limitations included some findings being based on single reports and the fact that some of the incidence estimates were under-reported due to inability to perform diagnostic imaging tests in all patients as a result of strict isolation procedures. Aggregate analysis of the available literature suggests a high incidence of thromboembolic complications in patients hospitalised with COVID-19, particularly in those with severe disease. The incidence is higher for venous thromboembolic events compared to arterial thromboembolic complications. There is an urgent need for improved diagnostic strategies as well as determining the most effective thromboprophylactic agents and their optimal dosages to be used in these patients.