Risk Factors for Postdischarge Major Thromboembolism and Mortality in Hospitalized Patients with COVID-19 with Cardiovascular Comorbidities: Insights from the CORE-19 Registry

Abstract

Background Coronavirus disease 2019 (COVID-19) is associated with venous and arterial thromboembolism (VTE and ATE) and all-cause mortality (ACM) in hospitalized patients. High-quality data are needed on postdischarge outcomes in patients with cardiovascular disease.

Objectives To analyze outcomes and identify risk factors for ATE, VTE, and ACM in a high-risk subgroup of hospitalized COVID-19 patients with baseline cardiovascular disease.

Methods We investigated postdischarge rates and associated risk factors of ATE, VTE, and ACM in 608 hospitalized COVID-19 patients with coronary artery disease, carotid artery stenosis (CAS), peripheral arterial disease (PAD), or ischemic stroke.

Results Through 90 days postdischarge, outcome rates were: ATE 27.3% (10.2% myocardial infarction, 10.1% ischemic stroke, 13.2% systemic embolism, 12.7% major adverse limb event); VTE 6.9% (4.1% deep vein thrombosis, 3.6% pulmonary embolism); composite of ATE, VTE, or ACM 35.2% (214/608). Multivariate analysis showed significant association between this composite endpoint and age >75 years (odds ratio [OR]: 1.90, 95% confidence interval [CI]: 1.22–2.94, p = 0.004), PAD (OR: 3.23, 95% CI: 1.80–5.81, p ≤ 0.0001), CAS (OR: 1.74, 95% CI: 1.11–2.75, p = 0.017), congestive heart failure (CHF) (OR: 1.84, 95% CI: 1.02–3.35, p = 0.044), previous VTE (OR: 3.08, 95% CI: 1.75–5.42, p < 0.0001), and intensive care unit (ICU) admission (OR: 2.93, 95% CI: 1.81–4.75, p < 0.0001).

Conclusion COVID-19 inpatients with cardiovascular disease experience high rates of ATE, VTE, or ACM through 90 days postdischarge. Age >75 years, PAD, CAS, CHF, previous VTE, and ICU admission are independent risk factors.

Keywords

COVID-19 - arterial thromboembolism - venous thromboembolism - anticoagulation - postdischarge outcomes

• References

• 1 Klok FA, Kruip MJHA, van der Meer NJM. et al. Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: an updated analysis. Thromb Res 2020; 191: 148-150
• 2 Hanif A, Khan S, Mantri N. et al. Thrombotic complications and anticoagulation in COVID-19 pneumonia: a New York City hospital experience. Ann Hematol 2020; 99 (10) 2323-2328
• 3 Bilaloglu S, Aphinyanaphongs Y, Jones S, Iturrate E, Hochman J, Berger JS. Thrombosis in hospitalized patients with COVID-19 in a New York City health system. JAMA 2020; 324 (08) 799-801
• 4 Spyropoulos AC, Weitz JI. Hospitalized COVID-19 patients and venous thromboembolism. Circulation 2020; 142 (02) 129-132
• 5 Tiwari R, Mishra AR, Mikaeloff F. et al. In silico and in vitro studies reveal complement system drives coagulation cascade in SARS-CoV-2 pathogenesis. Comput Struct Biotechnol J 2020; 18: 3734-3744
• 6 Low RN, Low RJ, Akrami A. A review of cytokine-based pathophysiology of Long COVID symptoms. Front Med (Lausanne) 2023; 10: 1011936
• 7 Nab L, Groenwold RHH, Klok FA, Bhoelan S, Kruip MJHA, Cannegieter SC. Estimating incidence of venous thromboembolism in COVID-19: methodological considerations. Res Pract Thromb Haemost 2022; 6 (06) e12776
• 8 Tan BK, Mainbourg S, Friggeri A. et al. Arterial and venous thromboembolism in COVID-19: a study-level meta-analysis. Thorax 2021; 76 (10) 970-979
• 9 Nopp S, Moik F, Jilma B, Pabinger I, Ay C. Risk of venous thromboembolism in patients with COVID-19: a systematic review and meta-analysis. Res Pract Thromb Haemost 2020; 4 (07) 1178-1191
• 10 Suh YJ, Hong H, Ohana M. et al. Pulmonary embolism and deep vein thrombosis in COVID-19: a systematic review and meta-analysis. Radiology 2021; 298 (02) E70-E80
• 11 Fournier M, Faille D, Dossier A. et al. Arterial thrombotic events in adult inpatients with COVID-19. Mayo Clin Proc 2021; 96 (02) 295-303
• 12 Lax SF, Skok K, Zechner P. et al. Pulmonary arterial thrombosis in COVID-19 with fatal outcome: results from a prospective, single-center, clinicopathologic case series. Ann Intern Med 2020; 173 (05) 350-361
• 13 Wichmann D, Sperhake JP, Lütgehetmann M. et al. Autopsy findings and venous thromboembolism in patients with COVID-19: a prospective cohort study. Ann Intern Med 2020; 173 (04) 268-277
• 14 Martins-Gonçalves R, Hottz ED, Bozza PT. Acute to post-acute COVID-19 thromboinflammation persistence: mechanisms and potential consequences. Curr Res Immunol 2023; 4: 100058
• 15 Schulman S, Sholzberg M, Spyropoulos AC. et al; International Society on Thrombosis and Haemostasis. ISTH guidelines for antithrombotic treatment in COVID-19. J Thromb Haemost 2022; 20 (10) 2214-2225
• 16 Giannis D, Allen SL, Tsang J. et al. Postdischarge thromboembolic outcomes and mortality of hospitalized patients with COVID-19: the CORE-19 registry. Blood 2021; 137 (20) 2838-2847
• 17 Zuin M, Engelen MM, Barco S. et al. Incidence of venous thromboembolic events in COVID-19 patients after hospital discharge: a systematic review and meta-analysis. Thromb Res 2022; 209: 94-98
• 18 Knight R, Walker V, Ip S. et al; CVD-COVID-UK/COVID-IMPACT Consortium and the Longitudinal Health and Wellbeing COVID-19 National Core Study. Association of COVID-19 with major arterial and venous thrombotic diseases: a population-wide cohort study of 48 million adults in England and Wales. Circulation 2022; 146 (12) 892-906
• 19 Spyropoulos AC, Crawford JM, Chen YC. et al. Occurrence of thromboembolic events and mortality among hospitalized coronavirus 2019 patients: large observational cohort study of electronic health records. TH Open 2022; 6 (04) e408-e420
• 20 Mansory EM, Abu-Farhaneh M, Iansavitchene A, Lazo-Langner A. Venous and arterial thrombosis in ambulatory and discharged COVID-19 patients: a systematic review and meta-analysis. TH Open 2022; 6 (03) e276-e282
• 21 Gibson CM, Chi G, Halaby R. et al; APEX Investigators. Extended-duration betrixaban reduces the risk of stroke versus standard-dose enoxaparin among hospitalized medically ill patients: an APEX trial substudy (acute medically ill venous thromboembolism prevention with extended duration betrixaban). Circulation 2017; 135 (07) 648-655
• 22 Spyropoulos AC, Ageno W, Albers GW. et al. Post-discharge prophylaxis with rivaroxaban reduces fatal and major thromboembolic events in medically ill patients. J Am Coll Cardiol 2020; 75 (25) 3140-3147
• 23 Ramacciotti E, Barile Agati L, Calderaro D. et al; MICHELLE investigators. Rivaroxaban versus no anticoagulation for post-discharge thromboprophylaxis after hospitalisation for COVID-19 (MICHELLE): an open-label, multicentre, randomised, controlled trial. Lancet 2022; 399 (10319): 50-59
• 24 Schulman S, Kearon C. Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005; 3 (04) 692-694
• 25 Bourguignon A, Beaulieu C, Belkaid W, Desilets A, Blais N. Incidence of thrombotic outcomes for patients hospitalized and discharged after COVID-19 infection. Thromb Res 2020; 196: 491-493
• 26 Salisbury R, Iotchkova V, Jaafar S. et al. Incidence of symptomatic, image-confirmed venous thromboembolism following hospitalization for COVID-19 with 90-day follow-up. Blood Adv 2020; 4 (24) 6230-6239
• 27 Eswaran H, Jarmul JA, Shaheen AW. et al. Vascular thromboembolic events following COVID-19 hospital discharge: Incidence and risk factors. Res Pract Thromb Haemost 2021; 5 (02) 292-295
• 28 Rungjirajittranon T, Owattanapanich W, Leelakanok N. et al. Thrombotic and hemorrhagic incidences in patients after discharge from COVID-19 infection: a systematic review and meta-analysis. Clin Appl Thromb Hemost 2021; 27: 10 760296211069082
• 29 Li P, Zhao W, Kaatz S, Latack K, Schultz L, Poisson L. Factors associated with risk of postdischarge thrombosis in patients with COVID-19. JAMA Netw Open 2021; 4 (11) e2135397
• 30 Zuin M, Rigatelli G, Battisti V, Costola G, Roncon L, Bilato C. Increased risk of acute myocardial infarction after COVID-19 recovery: a systematic review and meta-analysis. Int J Cardiol 2023; 372: 138-143
• 31 Bradbury CA, Lawler PR, Stanworth SJ. et al; REMAP-CAP Writing Committee for the REMAP-CAP Investigators. Effect of antiplatelet therapy on survival and organ support-free days in critically ill patients with COVID-19: a randomized clinical trial. JAMA 2022; 327 (13) 1247-1259
• 32 Mozos I, Malainer C, Horbańczuk J. et al. Inflammatory markers for arterial stiffness in cardiovascular diseases. Front Immunol 2017; 8: 1058
• 33 Golia E, Limongelli G, Natale F. et al. Inflammation and cardiovascular disease: from pathogenesis to therapeutic target. Curr Atheroscler Rep 2014; 16 (09) 435
• 34 Park S, Lakatta EG. Role of inflammation in the pathogenesis of arterial stiffness. Yonsei Med J 2012; 53 (02) 258-261
• 35 Ortega-Paz L, Arévalos V, Fernández-Rodríguez D. et al; CV COVID-19 registry investigators. One-year cardiovascular outcomes after coronavirus disease 2019: The cardiovascular COVID-19 registry. PLoS One 2022; 17 (12) e0279333
• 36 Boukhris M, Hillani A, Moroni F. et al. Cardiovascular implications of the COVID-19 pandemic: a global perspective. Can J Cardiol 2020; 36 (07) 1068-1080
• 37 Zheng YY, Ma YT, Zhang JY, Xie X. COVID-19 and the cardiovascular system. Nat Rev Cardiol 2020; 17 (05) 259-260
• 38 Zong X, Wang X, Liu Y. et al. Antiplatelet therapy for patients with COVID-19: systematic review and meta-analysis of observational studies and randomized controlled trials. Front Med (Lausanne) 2022; 9: 965790
• 39 Martha JW, Pranata R, Lim MA, Wibowo A, Akbar MR. Active prescription of low-dose aspirin during or prior to hospitalization and mortality in COVID-19: a systematic review and meta-analysis of adjusted effect estimates. Int J Infect Dis 2021; 108: 6-12
• 40 Kow CS, Hasan SS. Use of antiplatelet drugs and the risk of mortality in patients with COVID-19: a meta-analysis. J Thromb Thrombolysis 2021; 52 (01) 124-129
• 41 Srivastava R, Kumar A. Use of aspirin in reduction of mortality of COVID-19 patients: a meta-analysis. Int J Clin Pract 2021; 75 (11) e14515
• 42 Berger JS, Kornblith LZ, Gong MN. et al; ACTIV-4a Investigators. Effect of P2Y12 inhibitors on survival free of organ support among non-critically ill hospitalized patients with COVID-19: a randomized clinical trial. JAMA 2022; 327 (03) 227-236
• 43 Abani O, Abbas A, Abbas F. et al; RECOVERY Collaborative Group. Aspirin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet 2022; 399 (10320): 143-151
• 44 Bohula EA, Berg DD, Lopes MS. et al; COVID-PACT Investigators. Anticoagulation and antiplatelet therapy for prevention of venous and arterial thrombotic events in critically ill patients with COVID-19: COVID-PACT. Circulation 2022; 146 (18) 1344-1356
• 45 Eikelboom JW, Jolly SS, Belley-Cote EP. et al. Colchicine and the combination of rivaroxaban and aspirin in patients hospitalised with COVID-19 (ACT): an open-label, factorial, randomised, controlled trial. Lancet Respir Med 2022; 10 (12) 1169-1177