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

Abstract

Importance: Thrombotic events are commonly reported in critically ill patients with COVID-19. Limited data exist to guide the intensity of antithrombotic prophylaxis.

Objective: To evaluate the effects of intermediate-dose vs standard-dose prophylactic anticoagulation among patients with COVID-19 admitted to the intensive care unit (ICU).

Design, setting, and participants: Multicenter randomized trial with a 2 × 2 factorial design performed in 10 academic centers in Iran comparing intermediate-dose vs standard-dose prophylactic anticoagulation (first hypothesis) and statin therapy vs matching placebo (second hypothesis; not reported in this article) among adult patients admitted to the ICU with COVID-19. Patients were recruited between July 29, 2020, and November 19, 2020. The final follow-up date for the 30-day primary outcome was December 19, 2020.

Interventions: Intermediate-dose (enoxaparin, 1 mg/kg daily) (n = 276) vs standard prophylactic anticoagulation (enoxaparin, 40 mg daily) (n = 286), with modification according to body weight and creatinine clearance. The assigned treatments were planned to be continued until completion of 30-day follow-up.

Main outcomes and measures: The primary efficacy outcome was a composite of venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days, assessed in randomized patients who met the eligibility criteria and received at least 1 dose of the assigned treatment. Prespecified safety outcomes included major bleeding according to the Bleeding Academic Research Consortium (type 3 or 5 definition), powered for noninferiority (a noninferiority margin of 1.8 based on odds ratio), and severe thrombocytopenia (platelet count <20 ×103/µL). All outcomes were blindly adjudicated.

Results: Among 600 randomized patients, 562 (93.7%) were included in the primary analysis (median [interquartile range] age, 62 [50-71] years; 237 [42.2%] women). The primary efficacy outcome occurred in 126 patients (45.7%) in the intermediate-dose group and 126 patients (44.1%) in the standard-dose prophylaxis group (absolute risk difference, 1.5% [95% CI, -6.6% to 9.8%]; odds ratio, 1.06 [95% CI, 0.76-1.48]; P = .70). Major bleeding occurred in 7 patients (2.5%) in the intermediate-dose group and 4 patients (1.4%) in the standard-dose prophylaxis group (risk difference, 1.1% [1-sided 97.5% CI, -∞ to 3.4%]; odds ratio, 1.83 [1-sided 97.5% CI, 0.00-5.93]), not meeting the noninferiority criteria (P for noninferiority >.99). Severe thrombocytopenia occurred only in patients assigned to the intermediate-dose group (6 vs 0 patients; risk difference, 2.2% [95% CI, 0.4%-3.8%]; P = .01).

Conclusions and relevance: Among patients admitted to the ICU with COVID-19, intermediate-dose prophylactic anticoagulation, compared with standard-dose prophylactic anticoagulation, did not result in a significant difference in the primary outcome of a composite of adjudicated venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days. These results do not support the routine empirical use of intermediate-dose prophylactic anticoagulation in unselected patients admitted to the ICU with COVID-19.

Trial registration: ClinicalTrials.gov Identifier: NCT04486508.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Jimenez reported receiving personal fees from Bristol Myers Squibb, Daiichi-Sankyo, Bayer, Pfizer, Rovi, and Leo-Pharma and grants from Sanofi outside the submitted work. Dr Gupta reported receiving consulting fees from Edwards Lifesciences, Arnold Porter Law Firm, and Ben C. Martin Law Firm and equity from Heartbeat Health Inc outside the submitted work. Dr Madhavan reported receiving an institutional research grant to Columbia University Irving Medical Center (T32 HL007854) from the National Institutes of Health/National Heart, Lung, and Blood Institute during the conduct of the study. Dr Sethi reported receiving personal fees from Janssen and Chiesi and grants from the American Heart Association outside the submitted work. Dr Parikh reported receiving grants from Abbott Vascular, Boston Scientific, Surmodics, and TriReme Medical; nonfinancial support from Cordis, Medtronic, Philips, and Cardiovascular Systems Inc; and personal fees from Terumo, Abiomed, Inari, and Penumbra outside the submitted work. Dr Monreal reported receiving grants from Sanofi outside the submitted work. Dr Piazza reported receiving grants from Bristol Myers Squibb/Pfizer, Janssen, Portola, Boston Scientific, and Bayer and serving on a data and safety monitoring board for Prairie Education and Research Cooperative outside the submitted work. Dr Kirtane reported receiving institutional funding to Columbia University and/or the Cardiovascular Research Foundation from Medtronic, Boston Scientific, Abbott Vascular, Abiomed, Cardiovascular Systems Inc, CathWorks, Siemens, Philips, and ReCor Medical, including fees paid to Columbia University and/or the Cardiovascular Research Foundation for speaking engagements and/or consulting; consulting fees from Neurotronic; and travel expenses/meals from Medtronic, Boston Scientific, Abbott Vascular, Abiomed, Cardiovascular Systems Inc, CathWorks, Siemens, Philips, ReCor Medical, Chiesi, OpSens, Zoll, and Regeneron. Dr Dobesh reported receiving personal fees from the Pfizer/Bristol Myers Squibb Alliance and Janssen Pharmaceuticals outside the submitted work. Dr Stone reported receiving personal fees from Terumo, Cook, TherOx, Reva, Vascular Dynamics, Robocath, HeartFlow, Gore, Ablative Solutions, Matrizyme, Miracor Neovasc, V-wave, Abiomed, MAIA Pharmaceuticals, Shockwave, Vectorious, Cardiomech , and Elucid Bio; equity/equity options from Applied Therapeutics, MedFocus, Biostar, Aria, Cagent, Cardiac Success; personal fees and equity/equity options from Spectrawave, Valfix, Ancora; and personal fees, equity/equity options, and honorarium from Orchestra Biomed, and outside the submitted work. Dr Lip reported being a consultant and speaker for Bristol Myers Squibb/Pfizer, Boehringer Ingelheim, and Daiichi-Sankyo outside the submitted work. Dr Krumholz reported receiving personal fees from UnitedHealth, IBM Watson Health, Element Science, Aetna, Facebook, Siegfried & Jensen Law Firm, Arnold & Porter Law Firm, Martin/Baughman Law Firm, F-Prime, and the National Center for Cardiovascular Diseases, Beijing; being the cofounder of HugoHealth, a personal health information platform, and Refactor Health, an enterprise health care artificial intelligence–augmented data management company; receiving contracts from the Centers for Medicare & Medicaid Services, through Yale New Haven Hospital, to develop and maintain measures of hospital performance; and receiving grants from Medtronic, the US Food and Drug Administration, Johnson & Johnson, and the Shenzhen Center for Health Information outside the submitted work. Dr Goldhaber reported receiving grants from Bayer, Boehringer-Ingelheim, Bristol Myers Squibb, Boston Scientific, Janssen, the National Heart, Lung, and Blood Institute, and Pfizer and personal fees from Agile, Bayer, Boehringer-Ingelheim, and Pfizer outside the submitted work. Dr Bikdeli reported being a consulting expert, on behalf of the plaintiff, for litigation related to 2 specific brand models of inferior vena cava filters. No other disclosures were reported.

Figures

Figure 1.. Flow of Participants in a Study of the Effect of Intermediate-Dose vs Standard-Dose Prophylactic Anticoagulation Among Patients With COVID-19 Admitted to the Intensive Care Unit

aSome patients had more than 1 reason for exclusion from the primary analysis cohort. bReasons for discontinuation of the trial regimen are summarized in eTable 4 in Supplement 3. cPatients who were randomized and were not excluded due to violation of the eligibility criteria or withdrawal of informed consent and continued their assigned anticoagulation regimen until 30-day follow-up or the occurrence of the prespecified efficacy outcome. See eTable 13 in Supplement 3 for the per-protocol safety cohort.

Figure 2.. Primary Outcome in the Prespecified Primary Cohort in a Study of the Effect of Intermediate-Dose vs Standard-Dose Prophylactic Among Patients With COVID-19 Admitted to the Intensive Care Unit

The primary outcome was a composite of adjudicated acute arterial thrombosis, venous thromboembolism, extracorporeal membrane oxygenation, or all-cause mortality during 30 days from enrollment. The prespecified primary cohort consisted of patients who received at least 1 dose of the study drug, were not excluded, and did not withdraw consent. The median (interquartile range) follow-up time was 30 (9-30) days in the intermediate-dose group and 30 (10-30) days in the standard-dose prophylactic anticoagulation group. aAll-cause mortality events were censored by precedent venous thromboembolism (VTE) events. In some cases, the thrombotic events occurred in the prior window (ie, in the first 5 days). bOne of the 2 VTE events was censored by a precedent ischemic stroke event.

Figure 3.. Subgroup Analysis for the Primary Outcome in a Study of the Effect of Intermediate-Dose vs Standard-Dose Prophylactic Anticoagulation Among Patients With COVID-19 Admitted to the Intensive Care Unit

P values indicate tests of interaction between the treatment group and each of the assessed variables for the primary composite outcome.