1/2 improving outcomes in vascular disease - aortic dissection (IMPROVE-ad) - this submission comprises two applications (clinical and statistical data coordinating centers)

We propose to conduct a large (N=1,100), simple, pragmatic, superiority trial in the US - IMPROVE-ad - comparing a strategy of medical therapy (MT) plus upfront thoracic endovascular aortic repair (TEVAR) to MT plus surveillance for deterioration in patients with uncomplicated type B aortic dissection (UTBAD). Surveillance will include clinically indicated TEVAR and/or open repair performed for deterioration during index hospitalization or follow up. This is the first trial of this size designed to establish guidance on UTBAD management. The trial leadership is comprised of an experienced group of investigators in a clinical coordination center (CCC; duke clinical research institute, durham, NC, baylor college of medicine, houston, TX, and university of washington, seattle, WA) a statistical and data coordination center (sdcc; duke clinical research institute, durham, NC) and a diverse, executive and steering committee of experts in the field representing clinicians, trialists, and patient advocates. Aortic dissection (ad) is the most common fatal event involving the aorta occurring in 5 to 30 cases per million of population resulting in 12,000 deaths in the US annually. Type B aortic dissections involve the entire descending aorta. Based on evidence from the 1960S, the main strategy for UTBAD is medical therapy with lifelong surveillance. This strategy has been shown to have poor long-term outcome in 25-50% of patients (aortic related events). The emergence of TEVAR as a less invasive alternative to open repair, however, has resulted in debate over the use of upfront TEVAR to treat UTBAD. A pilot european trial (INSTEAD) compared the outcomes of upfront TEVAR to optimal medical therapy in 140 patients with UTBAD. Despite being significantly underpowered for all-cause mortality, the findings, along with observational data suggest that medical therapy plus upfront TEVAR may be associated with decreased all- cause and aortic-related mortality. We have also demonstrated from our completed surveys that there is equipoise among practitioners with respect to the most appropriate treatment strategy in UTBAD. We propose a pragmatic trial with centralized, telephone follow-up, remote blood pressure monitoring, a clinically relevant hierarchical primary endpoint (mortality / aortic-related hospitalization), and multi-disciplinary teams of investigators and patient advocates. The trial duration is 84 months with 5-month start-up. Average follow-up is 4 year with a minimum of 2.5 years and maximum of 6 years for individuals enrolled early. IMPROVE-ad will have 88% power to detect a 25% relative reduction in the incidence of the primary endpoint for patients randomized to upfront MT plus TEVAR compared to MT plus surveillance for deterioration, assuming a 5 year cumulative incidence of 20% death and 20% aortic-related hospitalization in the MT plus surveillance for deterioration arm.