J Kjaergaard, L E Bang, Emilie Sonne-Holm, Sebastian Wiberg, Lene Holmvang, Jens Flensted Lassen, R. Sörensen, D E Høfsten, P S Ulriksen, Samir Jawad, Pernille Palm, C Søe, M K Ersbøll, S Boesgaard, J E Møller, Jens Jakob Thune, C Hassager, H-H Tilsted, J Lønborg, Michael Egstrup, O P Kristiansen, Ekin Seven, M G Lindholm, Kristian Eskesen, Søren Fanø, J Carlsen
AIMS: Intermediate high-risk pulmonary embolism (PE) is associated with increased risk of haemodynamic deterioration and death, but balancing the 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 multicentre trial, we randomized 210 adult patients with acute, intermediate high-risk PE 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 h) 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 the intravenous route. The safety endpoint included the risk of bleeding.We included 210 patients with acute PE, 49% were female, the mean age was 70 (IQR 62-76), and the mean body mass index was 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 (USAT) vs. the 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 statistically significant. No differences in other outcomes were observed. CONCLUSION: Low-dose thrombolysis reduced thrombus burden more than heparin alone in patients with acute intermediate high-risk PE. However, USAT did not show greater thrombus reduction than intravenous thrombolysis. The rate of death and risk of bleeding complications were increased with low-dose thrombolysis. TRIAL REGISTRATION: clinicaltrials.gov, NCT04088292.