Background: Patients with acute spinal cord injury (SCI) have a high risk of venous thromboembolism despite thromboprophylaxis. Low molecular weight heparin (LMWH), the current standard of care, is inconvenient for long term thromboprophylaxis, costly, and partially effective. Direct oral anticoagulants (DOACs) have been shown to be at least as effective and as safe as LMWH in other thromboprophylaxis settings but there is no randomized evaluation of DOACs in this population.
Aim: By conducting a feasibility randomized trial, we aimed to determine the likely recruitment rate of eligible patients into an RCT in which patients with acute SCI were randomized to a prophylactic dose of LMWH or apixaban.
Methods: A pilot study was performed at Hamilton General Hospital (HGH). Adult patients with an acute traumatic SCI presenting to the hospital within 1 week of SCI and at least 36 h after the injury were included. Exclusion criteria were the need for therapeutic oral anticoagulation prior to enrolment; active bleeding, intracranial or peri-spinal hematoma, or a bleeding disorder; pregnancy or breastfeeding; severe renal failure (creatinine clearance ≤30 ml/min); severe cirrhosis (Child-Pugh class C); severe thrombocytopenia (platelets <50), unsuitability as determined by the attending physician; geographic inaccessibility; failure to obtain written consent; previous hypersensitivity to study drugs; or expected short hospital admission (≤7 days) due to a minor injury.
Eligible patients were randomized to apixaban 2.5 mg twice daily or dalteparin 5000 units once daily for 90 days or until fully mobilized, whatever came first. The primary feasibility outcome was recruitment rate per year. We expected a recruitment rate of 20 patients per year based on an estimated admission rate in a retrospective study at HGH. The primary efficacy outcome was a composite of symptomatic, objectively verified, venous thromboembolism (upper or lower limb deep vein thrombosis (DVT) and/or pulmonary embolism (PE)) or sudden death where PE cannot be excluded. This outcome did not include a catheter-associated DVT. The primary safety end-point was major bleeding.
Results: A total of 26 eligible patients were screened and 8 patients were enrolled per year resulting in a recruitment yield of 30.8% (95% confidence interval: 16-50%). The reasons for exclusion included: presence of an epidural hemorrhage (n=8), failure to obtain consent (n=2), not suitable for the study (n=2), >1 week from SCI (n=2), indication for therapeutic anticoagulation (n=2), active bleeding (n=1), and minor injury with an expected short hospital admission (n=1). Four patients were randomized to each drug. Median age was 61 (range 51 to 70) and 7 (87.5%) were males. There were no symptomatic VTE or sudden deaths. One patient randomized to apixaban had major bleeding. There were no serious adverse events.
Conclusions: Our pilot study is the first randomized trial to examine the role of a DOAC compared with LMWH for thromboprophylaxis in this high-risk group. The primary feasibility outcome was not met, and therefore a multicenter RCT is unlikely to be feasible. The efficacy and safety of DOACs on this indication should be evaluated in registry- or health care database studies.
Eikelboom: Heart and Stroke Foundation: Research Funding; Sanofi Aventis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Glaxo Smith Kline: Honoraria, Research Funding; Eli Lilly: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Boehringer Ingelheim: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding.