Randomized trial of low-dose -, ultrasound assisted thrombolysis or heparin for pulmonary embolism

Abstract Aims Intermediate high-risk pulmonary embolism is associated with increased risk of hemodynamic deterioration and death, but balancing risk of thrombolytics or catheter-based treatment and efficacy has been challenging. This trial compared the additional efficacy of catheter-based ultrasound low-dose thrombolysis (USAT) over intravenous low-dose thrombolysis or heparin alone. Methods and results In an investigator-initiated randomized clinical multi-center trial we randomized 210 adult patients with acute, intermediate high-risk pulmonary embolism admitted to emergency departments in two regions of Denmark. Patients were allocated 1:1:1 to one of three treatment strata: low-dose thrombolysis (20 mg alteplase administered over 6 hours) by USAT, by intravenous administration or heparin alone. The efficacy of the interventions was assessed by comparing the refined Modified Miller Score, rmMS, (0-40 points, higher score indicating higher thrombus burden) from CT angiographies performed at baseline and 48-96 h post randomization. Two comparisons were investigated: the reduction of rmMS with low-dose thrombolysis (USAT or intravenously) compared to heparin alone, and the reduction of rmMS with low-dose thrombolysis administered by USAT compared to intravenous route. Safety endpoint included risk of bleeding. We included 210 patients with acute pulmonary embolism, 49% were female, mean age was 70 (IQR 62-76) and mean body mass index 30 (26-34). Compared to heparin alone, low-dose thrombolysis reduced the rmMS by 3.6 points, (95% CI 2.2-5.0, p 0.001), but the reduction in rmMS was not different in the ultrasound assisted thrombolysis vs. intravenous route, mean difference -0.1, (95% CI: -1.9–1.7), p = 0.88. Bleeding complications were numerically more frequent with low-dose thrombolysis, albeit not statically significant. No differences in other outcomes were observed. Conclusions Low-dose thrombolysis reduced thrombus burden more than heparin alone in patients with acute intermediate high-risk pulmonary embolism. However, ultrasound assisted thrombolysis did not show greater thrombus reduction than thrombolysis administrated intravenously. The rate of death and risk of bleeding complications was increased with low-dose thrombolysis. Trial Registration clinicaltrials.gov, NCT04088292