Low-Molecular-Weight Heparin for Adult ICU Patients Who Require Thromboprophylaxis: Protocol for the INCEPT-Thromboprophylaxis Platform Trial Domain.
Low-molecular-weight heparin (LMWH) is recommended for thromboprophylaxis in adult intensive care unit (ICU) patients. Despite its widespread use, there is insufficient evidence on the optimal dose, and there appears to be practice variation. Determining the LMWH dosing strategy that most effectively balances the risks of venous thromboembolism (VTE) and bleeding may improve outcomes in ICU patients.
The INCEPT-thromboprophylaxis domain is an investigator-initiated, open-label domain with an integrated feasibility phase on the international, pragmatic, parallel-group, randomised, embedded, multifactorial, adaptive Intensive Care Platform Trial (INCEPT). Adult acutely admitted ICU patients with an indication for thromboprophylaxis will be randomised to a fixed low dose, a fixed intermediate dose or a weight-adjusted dose of LMWH while in the ICU for a maximum of 90 days. The primary outcome is days alive out of hospital at 30 days. Secondary outcomes include 30-, 90- and 180-day all-cause mortality; days alive without life support at 30 and 90 days; days alive out of hospital at 90 days; days free of delirium at 30 days; health-related quality of life and cognitive function at 180 days; VTE and major bleeding during hospital stay at 30 and 90 days; and serious adverse reactions at 30 and 90 days. Analyses will primarily be conducted in the intention-to-treat population using Bayesian statistical models with neutral, weakly informative priors. We will assess feasibility after 300 participants and conduct adaptive analyses after follow-up for the primary outcome of 1500 participants and every additional 500 participants to a maximum of 10,000, with adaptive stopping for superiority/inferiority and practical equivalence (mean difference in the primary outcome < 1 day), and adaptive arm-dropping for superiority/inferiority. Allocation will initially be equal, followed by response-adaptive randomisation with a minimum 25% allocation to each arm. Expected sample sizes across different scenarios range from 2265 to 4892 participants, with approximately 100% probabilities of conclusiveness across scenarios.
INCEPT-thromboprophylaxis will with high probability provide conclusive results and inform clinical practice regarding the dosing of LMWH for thromboprophylaxis in adult acutely admitted ICU patients.
The INCEPT-thromboprophylaxis domain is an investigator-initiated, open-label domain with an integrated feasibility phase on the international, pragmatic, parallel-group, randomised, embedded, multifactorial, adaptive Intensive Care Platform Trial (INCEPT). Adult acutely admitted ICU patients with an indication for thromboprophylaxis will be randomised to a fixed low dose, a fixed intermediate dose or a weight-adjusted dose of LMWH while in the ICU for a maximum of 90 days. The primary outcome is days alive out of hospital at 30 days. Secondary outcomes include 30-, 90- and 180-day all-cause mortality; days alive without life support at 30 and 90 days; days alive out of hospital at 90 days; days free of delirium at 30 days; health-related quality of life and cognitive function at 180 days; VTE and major bleeding during hospital stay at 30 and 90 days; and serious adverse reactions at 30 and 90 days. Analyses will primarily be conducted in the intention-to-treat population using Bayesian statistical models with neutral, weakly informative priors. We will assess feasibility after 300 participants and conduct adaptive analyses after follow-up for the primary outcome of 1500 participants and every additional 500 participants to a maximum of 10,000, with adaptive stopping for superiority/inferiority and practical equivalence (mean difference in the primary outcome < 1 day), and adaptive arm-dropping for superiority/inferiority. Allocation will initially be equal, followed by response-adaptive randomisation with a minimum 25% allocation to each arm. Expected sample sizes across different scenarios range from 2265 to 4892 participants, with approximately 100% probabilities of conclusiveness across scenarios.
INCEPT-thromboprophylaxis will with high probability provide conclusive results and inform clinical practice regarding the dosing of LMWH for thromboprophylaxis in adult acutely admitted ICU patients.
Authors
Eck Eck, Granholm Granholm, Tøgern Tøgern, Jensen Jensen, Jonmarker Jonmarker, Sjövall Sjövall, Meijer Meijer, Cronhjort Cronhjort, Møller Møller, Perner Perner, Keus Keus
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