Intermediate-Dose versus Standard-Dose Prophylactic Anticoagulation in Patients with COVID-19 Admitted to the Intensive Care Unit: 90-Day Results from the INSPIRATION Randomized Trial

Abstract

Background Thrombotic complications are considered among the main extrapulmonary manifestations of coronavirus disease 2019 (COVID-19). The optimal type and duration of prophylactic antithrombotic therapy in these patients remain unknown.

Methods This article reports the final (90-day) results of the Intermediate versus Standard-dose Prophylactic anticoagulation In cRitically-ill pATIents with COVID-19: An opeN label randomized controlled trial (INSPIRATION) study. Patients with COVID-19 admitted to intensive care were randomized to intermediate-dose versus standard-dose prophylactic anticoagulation for 30 days, irrespective of hospital discharge status. The primary efficacy outcome was a composite of adjudicated venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation (ECMO), or all-cause death. The main safety outcome was major bleeding.

Results Of 600 randomized patients, 562 entered the modified intention-to-treat analysis (median age [Q1, Q3]: 62 [50, 71] years; 237 [42.2%] women), of whom 336 (59.8%) survived to hospital discharge. The primary outcome occurred in 132 (47.8%) of patients assigned to intermediate dose and 130 (45.4%) patients assigned to standard-dose prophylactic anticoagulation (hazard ratio [HR]: 1.21, 95% confidence interval [CI]: 0.95–1.55, p = 0.11). Findings were similar for other efficacy outcomes, and in the landmark analysis from days 31 to 90 (HR: 1.59, 95% CI: 0.45–5.06). There were 7 (2.5%) major bleeding events in the intermediate-dose group (including 3 fatal events) and 4 (1.4%) major bleeding events in the standard-dose group (none fatal) (HR: 1.82, 95% CI: 0.53–6.24).

Conclusion Intermediate-dose compared with standard-dose prophylactic anticoagulation did not reduce a composite of death, treatment with ECMO, or venous or arterial thrombosis at 90-day follow-up.

Keywords

anticoagulation - heparin - enoxaparin - COVID-19 - trial

• References

• 1 Gupta A, Madhavan MV, Sehgal K. et al. Extrapulmonary manifestations of COVID-19. Nat Med 2020; 26 (07) 1017-1032
• 2 Driggin E, Madhavan MV, Bikdeli B. et al. Cardiovascular considerations for patients, health care workers, and health systems during the COVID-19 pandemic. J Am Coll Cardiol 2020; 75 (18) 2352-2371
• 3 Nalbandian A, Sehgal K, Gupta A. et al. Post-acute COVID-19 syndrome. Nat Med 2021; 27 (04) 601-615
• 4 Bikdeli B, Madhavan MV, Jimenez D. et al; Global COVID-19 Thrombosis Collaborative Group, Endorsed by the ISTH, NATF, ESVM, and the IUA, Supported by the ESC Working Group on Pulmonary Circulation and Right Ventricular Function. COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up: JACC state-of-the-art review. J Am Coll Cardiol 2020; 75 (23) 2950-2973
• 5 Fauvel C, Weizman O, Trimaille A. et al; Critical Covid-19 France Investigators. Pulmonary embolism in COVID-19 patients: a French multicentre cohort study. Eur Heart J 2020; 41 (32) 3058-3068
• 6 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
• 7 Torbicki A. COVID-19 and pulmonary embolism: an unwanted alliance. Eur Heart J 2020; 41 (32) 3069-3071
• 8 Libby P, Lüscher T. COVID-19 is, in the end, an endothelial disease. Eur Heart J 2020; 41 (32) 3038-3044
• 9 Bikdeli B, Madhavan MV, Gupta A. et al; Global COVID-19 Thrombosis Collaborative Group. Pharmacological agents targeting thromboinflammation in COVID-19: review and implications for future research. Thromb Haemost 2020; 120 (07) 1004-1024
• 10 Middeldorp S, Coppens M, van Haaps TF. et al. Incidence of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost 2020; 18 (08) 1995-2002
• 11 Al-Samkari H, Karp Leaf RS, Dzik WH. et al. COVID-19 and coagulation: bleeding and thrombotic manifestations of SARS-CoV-2 infection. Blood 2020; 136 (04) 489-500
• 12 Hendren NS, de Lemos JA, Ayers C. et al. Association of body mass index and age with morbidity and mortality in patients hospitalized with COVID-19: results from the American Heart Association COVID-19 Cardiovascular Disease Registry. Circulation 2021; 143 (02) 135-144
• 13 Jiménez D, García-Sanchez A, Rali P. et al. Incidence of VTE and bleeding among hospitalized patients with coronavirus disease 2019: a systematic review and meta-analysis. Chest 2021; 159 (03) 1182-1196
• 14 Spyropoulos AC, Levy JH, Ageno W. et al; Subcommittee on Perioperative, Critical Care Thrombosis, Haemostasis of the Scientific, Standardization Committee of the International Society on Thrombosis and Haemostasis. Scientific and Standardization Committee communication: clinical guidance on the diagnosis, prevention, and treatment of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost 2020; 18 (08) 1859-1865
• 15 Gerotziafas GT, Catalano M, Colgan MP. et al; Scientific Reviewer Committee. Guidance for the management of patients with vascular disease or cardiovascular risk factors and COVID-19: position paper from VAS-European Independent Foundation in Angiology/Vascular Medicine. Thromb Haemost 2020; 120 (12) 1597-1628
• 16 The European Society for Cardiology. ESC guidance for the diagnosis and management of CV disease during the COVID-19 pandemic. Last update: June 10, 2020. Accessed March 12, 2021 at: https://www.escardio.org/Education/COVID-19-and-Cardiology/ESC-COVID-19-Guidance
• 17 Bikdeli B. Anticoagulation in COVID-19: randomized trials should set the balance between excitement and evidence. Thromb Res 2020; 196: 638-640
• 18 Bikdeli B, Talasaz AH, Rashidi F. et al. Intermediate versus standard-dose prophylactic anticoagulation and statin therapy versus placebo in critically-ill patients with COVID-19: rationale and design of the INSPIRATION/INSPIRATION-S studies. Thromb Res 2020; 196: 382-394
• 19 Tritschler T, Mathieu ME, Skeith L. et al; International Network of VENous Thromboembolism Clinical Research Networks INVENT-VTE. Anticoagulant interventions in hospitalized patients with COVID-19: a scoping review of randomized controlled trials and call for international collaboration. J Thromb Haemost 2020; 18 (11) 2958-2967
• 20 Talasaz AH, Sadeghipour P, Kakavand H. et al. Recent randomized trials of antithrombotic therapy for patients with COVID-19: JACC state-of-the-art review. J Am Coll Cardiol 2021; 77 (15) 1903-1921
• 21 Sadeghipour P, Talasaz AH, Rashidi F. et al. Effect of intermediate-dose vs standard-dose prophylactic anticoagulation on thrombotic events, extracorporeal membrane oxygenation treatment, or mortality among patients with COVID-19 admitted to the intensive care unit: the INSPIRATION randomized clinical trial. JAMA 2021; 325 (16) 1620-1630
• 22 Nalbandian A, Sehgal K, Gupta A. et al. Post-acute COVID-19: multiorgan sequelae and management considerations. Nat Med 2021
• 23 Mehran R, Rao SV, Bhatt DL. et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation 2011; 123 (23) 2736-2747
• 24 Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 1999; 94 (446) 496-509
• 25 Moores LK, Tritschler T, Brosnahan S. et al. Prevention, diagnosis, and treatment of VTE in patients with coronavirus disease 2019: CHEST guideline and expert panel report. Chest 2020; 158 (03) 1143-1163
• 26 Cuker A, Tseng EK, Nieuwlaat R. et al. American Society of Hematology 2021 guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19. Blood Adv 2021; 5 (03) 872-888
• 27 Zarychanski R. Therapeutic anticoagulation in critically ill patients with Covid-19–preliminary report. medRxiv 2021;
• 28 Picariello C, Caravita S, Vatrano M. et al; a nome dell'Area Malattie del Circolo Polmonare ANMCO. ANMCO position paper: pulmonary circulation diseases and COVID-19 [in Italian]. G Ital Cardiol (Rome) 2020; 21 (08) 575-583
• 29 Hill JB, Garcia D, Crowther M. et al. Frequency of venous thromboembolism in 6513 patients with COVID-19: a retrospective study. Blood Adv 2020; 4 (21) 5373-5377
• 30 Rashidi F, Barco S, Kamangar F. et al. Incidence of symptomatic venous thromboembolism following hospitalization for coronavirus disease 2019: prospective results from a multi-center study. Thromb Res 2021; 198: 135-138
• 31 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
• 32 Venturelli S, Benatti SV, Casati M. et al. Surviving COVID-19 in Bergamo province: a post-acute outpatient re-evaluation. Epidemiol Infect 2021; 149: e32
• 33 Roubinian NH, Dusendang JR, Mark DG. et al. Incidence of 30-day venous thromboembolism in adults tested for SARS-CoV-2 infection in an integrated health care system in Northern California. JAMA Intern Med 2021;
• 34 Piazza G, Campia U, Hurwitz S. et al. Registry of arterial and venous thromboembolic complications in patients with COVID-19. J Am Coll Cardiol 2020; 76 (18) 2060-2072
• 35 Regitz-Zagrosek V, Kararigas G. Mechanistic pathways of sex differences in cardiovascular disease. Physiol Rev 2017; 97 (01) 1-37
• 36 Gallastegui N, Zhou JY, Drygalski AV, Barnes RFW, Fernandes TM, Morris TA. Pulmonary embolism does not have an unusually high incidence among hospitalized COVID19 patients. Clin Appl Thromb Hemost 2021; 27: 1076029621996471
• 37 Al-Samkari H, Gupta S, Leaf RK. et al; STOP-COVID-19 Investigators. Thrombosis, bleeding, and the observational effect of early therapeutic anticoagulation on survival in critically ill patients with COVID-19. Ann Intern Med 2021;