A feasible strategy for preventing blood clots in critically ill patients with acute kidney injury (FBI): study protocol for a randomized controlled trial

Abstract

Background: Previous pharmacokinetic trials suggested that 40 mg subcutaneous enoxaparin once daily provided inadequate thromboprophylaxis for intensive care unit patients. Critically ill patients with acute kidney injury are at increased risk of venous thromboembolism and yet are often excluded from these trials. We hypothesized that for critically ill patients with acute kidney injury receiving continuous renal replacement therapy, a dose of 1 mg/kg enoxaparin subcutaneously once daily would improve thromboprophylaxis without increasing the risk of bleeding. In addition, we seek to utilize urine output prior to discontinuing dialysis, and low neutrophil gelatinase-associated lipocalin in dialysis-free intervals, as markers of renal recovery.

Methods/design: In a multicenter, double-blind randomized controlled trial in progress at three intensive care units across Denmark, we randomly assign eligible critically ill adults with acute kidney injury into a treatment (1 mg/kg enoxaparin subcutaneously once daily) or control arm (40 mg enoxaparin subcutaneously once daily) upon commencement of continuous renal replacement therapy.We calculated that with 133 patients in each group, the study would have 80% power to show a 40% reduction in the relative risk of venous thromboembolism with 1 mg/kg enoxaparin, at a two-sided alpha level of 0.05. An interim analysis will be conducted after the first 67 patients have been included in each group.Enrolment began in March 2013, and will continue for two years. The primary outcome is the occurrence of venous thromboembolism. Secondary outcomes include anti-factor Xa activity, bleeding, heparin-induced thrombocytopenia, filter lifespan, length of stay, ventilator free days, and mortality. We will also monitor neutrophil gelatinase-associated lipocalin and urine volume to determine whether they can be used as prognostic factors for renal recovery.

Discussion: Critically ill unit patients with acute kidney injury present a particular challenge in the provision of thromboprophylaxis. This study hopes to add to the growing evidence that the existing recommendation of 40 mg enoxaparin is inadequate and that 1 mg/kg is both safe and effective for thromboprophylaxis.In addition, the study seeks to identify predictors of renal recovery allowing for the proper utilization of resources.

Trial registration: EU Clinical Trials Register: EudraCT number: 2012-004368-23, 25 September 2012.

Figure 1

Time schedule of enrolment, interventions, and assessments for participants. Routine tests (APTT, platelets, D-dimer, AT, leukocytes, CRP, PCT, hematocrit), anti-Xa, and urine and plasma NGAL and Cr are measured at baseline. Following randomization, the patient will receive sc enoxaparin according to group allocation. Bedside clinical assessment for VTE and bleeding using validated scoring systems (Well's scores, HEME tool) will be conducted, and samples for hematocrit and platelet count will be taken daily. Bilateral lower extremity CUS will be conducted on the 1st, 3rd and 7th day of inclusion. Once weekly CUS (more frequent if DVT is suspected), as well as samples for peak anti-X_a (measured at 4 hours after enoxaparin dose) and trough anti-X_a (measured at 20 hours after enoxaparin dose) will be taken. Spiral pulmonary CT angiography and echocardiography will be performed on clinical suspicion of PE. During CRRT-free intervals with CrCl <30 ml/min/1.73 m², group allocation will be discontinued and participants will receive 40 mg enoxaparin QD until the CrCl is >30 ml/min/1.73 m² when enoxaparin dose according to group allocation will be resumed. Samples of urine and plasma will be taken for NGAL and Cr during CRRT-free intervals. APTT, Activated partial thromboplastin time; anti-Xa, Antifactor Xa; AT, Antithrombin; CRP, C-reactive protein; PCT, Procalcitonin; NGAL, Neutrophil gelatinase-associated lipocalin; Cr, Creatinine; sc, subcutaneous; VTE, Venous thromboembolism; CUS, Compression ultrasound; DVT, Deep venous thrombosis; CT, Computed tomography; PE, Pulmonary emboli; CRRT, Continuous renal replacement therapy; CrCl, Creatinine Clearance; QD, Once daily; HIT, Heparin-induced thrombocytopenia; ICU, Intensive care unit.