Standard vs ultrasound-assisted thrombolysis for acute pulmonary embolism: Awaiting the verdict

We read with interest the two recent retrospective comparative studies on standard (sCDT) versus ultrasound-assisted catheter-directed thrombolysis (usCDT) along with a very relevant editorial indicating the lack of good quality data to guide practice in our cost-effectiveness-based health system.^1–3 All relevant comparative studies have been recently systematically reviewed by our group: while no difference was seen in the intermediate-risk subgroups, the high-risk (massive) pulmonary embolism (PE) groups had more favorable results with usCDT. For mortality, the observed rate for sCDT was three times as great as for usCDT (11.9% vs 3.6%), and we can be 95% confident that the mortality rate will be no greater than 9% for usCDT but possibly as high as 30% for sCDT. ⁴

The Standard vs Ultrasound-assisted Catheter Throm-bolysis for Submassive Pulmonary Embolism (SUNSET sPE) trial is an ongoing randomized, head-to-head, single-blinded clinical trial designed to address this controversy. ⁵ Participants are randomized 1:1 to a usCDT catheter or a sCDT catheter. Technical details of the procedure are left to the discretion of the treating physician with a general guidance for short < 12-hour periods of thrombolysis to match the favorable outcomes demonstrated by the Optimum Duration of Acoustic Pulse Thrombolysis Procedure in Acute Pulmonary Embolism (OPTALYSE PE) study. ⁶ Trying to simulate real life practice termination is recommended when there is objective improvement of vital or echocardiographic signs (pragmatic trial). The primary outcome is clearance of pulmonary thrombus burden, assessed by post-procedure computed tomography angiography. This was chosen as thrombus clearance is the distinct assumed advantage of usCDT, but most importantly the only outcome we can power our randomized controlled trial since use of clinical outcomes would require thousands of patients. Secondary outcomes include resolution of right ventricular strain by echocardiography; improvement in pulmonary artery pressures; and 3- and 12-month improvement in echocardiographic, functional capacity, and quality of life measures.

We agree with Drs Klein and Shishehbor ³ that we lack appropriate clinically relevant outcome definitions and that right ventricular to left ventricular (RV/LV) ratios and thrombus scores are soft endpoints, but hard clinical endpoints are fairly uncommon and a comparative study based on such endpoints will be difficult if not impossible to complete given the financial and time constraints of the required sample size. On the other hand, the SUNSET sPE trial is attempting to minimize bias, randomizing only intermediate high-risk (positive biomarkers and echocardiographic RV strain) patients and is specifically powered to prove (or disprove) the notion that ultrasound can increase thrombus clearance in human pulmonary arteries. SUNSET sPE started enrolling in May 2017 at the University of Pittsburgh Medical Center, and more recently two more centers (Emory University – Cardiology and Piedmont Heart Institute, both in Atlanta) are also actively adding patients to the study, which is anticipated to be completed in early 2020. The study is sponsored by the enrolling institutions and more recently received funding from the American Venous Forum to include a pilot study on biomarkers’ prediction of longer-term pulmonary sequelae (NCT02758574).

We and our collaborators, based on the thoughtful design and conduct of this study, are hopeful that the results will be relevant to clinical practice and inform our treatment algorithm for patients with PE.