Randomized controlled trials in emergency settings: Taking a HEADSTART on acute type A aortic dissection trials

Emergency operations comprise up to 50% of the surgical practice across specialties, yet only 9.4% of surgical trials are related to emergency surgery settings.1Morley R.L. Edmondson M.J. Rowlands C. Blazeby J.M. Hinchliffe R.J. Registration and publication of emergency and elective randomised controlled trials in surgery: a cohort study from trial registries.BMJ Open. 2018; 8e021700Crossref Scopus (7) Google Scholar In vascular surgery, nascent experiences arose from the IMPROVE trial (Immediate Management of Patients with Rupture: Open Versus Endovascular Repair) for ruptured abdominal aortic aneurysms (AAA), randomizing patients to either open or endovascular surgical repair. In emergency thoracic aortic surgery, the Dissected Aorta Repair Through Stent Implantation (DARTS) and ARISE trials provided non-randomized insights, but no randomized trials have been conducted in the acute setting to date. Acute Type A aortic dissections (ATAAD), however, remain associated with considerable morbidity and mortality as up to 25% of patients die before reaching the hospital and operative mortality remains as high as 20-25%.2Hagan P.G. Nienaber C.A. Isselbacher E.M. et al.The International Registry of Acute Aortic Dissection (IRAD): new insights into an old disease.JAMA. 2000; 283: 897-903Crossref PubMed Google Scholar,3LeMaire S.A. Russell L. Epidemiology of thoracic aortic dissection.Nat Rev Cardiol. 2011; 8: 103-113Crossref PubMed Scopus (264) Google Scholar Although the burden of ATAAD is proportionally lower than AAAs and ruptured AAAs, (known) incidence and prevalence rates are growing across countries due to improved diagnostics and referral, ageing populations, and increasing rates of hypertension. Conversely, pre-hospital and pre-operative mortality rates have decreased due to faster referral and emergency care networks and reduced time-to-intervention, whereas operative mortality has decreased due to improved perioperative care practices and surgical techniques. Nevertheless, practice variation persists. For example, in the United States, center volumes for ATAAD repair range from a handful of procedures per year to high-volume referral centers.4Bowdish M.E. D’Agostino R.S. Thourani V.H. et al.STS Adult Cardiac Surgery Database: 2021 update on outcomes, quality, and research.Ann Thorac Surg. 2021; 111: 1770-1780Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar Surgery for ATAAD involves either the standard hemiarch repair or extended arch repair techniques. Hemiarch repair is in the skillset of every cardiac surgeon and involves a more conservative approach to quickly manage the dissection; extended arch repair techniques require specialized aortic expertise to perform more extensive distal repairs but are associated with improved false lumen thrombosis and lower rates of reinterventions. In patients without an intimal tear in the aortic arch or additional arch aneurysm, hemiarch repair is recommended, whereas in patients with malperfusion, societal guidelines encourage the consideration of extended arch repair techniques.5Isselbacher E.M. Preventza O. Hamilton Black J 3rd et al.2022 ACC/AHA guideline for the diagnosis and management of Aortic Disease: A report of the American heart association/American college of cardiology joint committee on clinical practice guidelines.Circulation. 2022; (Published online November 2)https://doi.org/10.1161/CIR.0000000000001106Crossref PubMed Scopus (286) Google Scholar However, in patients eligible for both procedures, clinical equipoise remains based on expert consensus and meta-analyses based on purely observational evidence. As a result, rates of extended arch repair vary substantially between countries (e.g., higher rates in Europe and Asia compared to North America) and within countries (e.g., across Canada).6Elbatarny M. Stevens L.M. Dagenais F. et al.Hemiarch versus Extended Arch Repair for Acute Type A Dissection: Results from a Multicenter National Registry.J Thorac Cardiovasc Surg. 2023; (Published online April 19)https://doi.org/10.1016/j.jtcvs.2023.04.012Abstract Full Text Full Text PDF Scopus (2) Google Scholar,7Ouzounian M. Hage A. Chung J. et al.Hybrid arch frozen elephant trunk repair: evidence from the Canadian Thoracic Aortic Collaborative.Ann Cardiothorac Surg. 2020; 9: 189-196Crossref Scopus (13) Google Scholar Randomized evidence is thus urgently needed to best inform patients and guide training and practice of future cardio-aortic surgeons. The Treatment in Thoracic Aortic Aneurysm: Hemiarch vs Extended Arch in Aortic Dissection - a SystemaTic Analysis by Randomized Trial (TITAN:HEADSTART, NCT03885635) will seek to randomize patients with ATAAD eligible for both hemiarch and extended arch repair procedures to either intervention with deferred consent. The trial will comprise of a pilot trial (n=50) to determine the feasibility of randomizing patients in an emergency surgery setting and, if successful, a full trial (n=296) to comparatively evaluate both procedures with three-year outcomes. Outcomes will include detailed neurological and imaging endpoints with a core computed tomography laboratory. The trial has surgeon and center expertise criteria that are manageable for most cardiac centers in order to minimize confounding in procedural outcomes. The trial will operate under the TITAN trial umbrella, alongside other successful (but non-emergency) trials in thoracic aortic surgery, such as the Treatment in Thoracic Aortic Aneurysm: Surgery versus Surveillance (TITAN:SvS, NCT03536312) trial8Guo M.H. Appoo J.J. Wells G.A. et al.Protocol for a randomised controlled trial for Treatment in Thoracic Aortic Aneurysm: Surgery versus Surveillance (TITAN: SvS).BMJ Open. 2021; 11e052070Crossref Scopus (9) Google Scholar and the Comparing Hypothermic Temperatures During Hemiarch Surgery (TITAN:COMMENCE, NCT02860364) trial. It has further obtained competitive grant funding and laid the foundation among participating pilot sites across Canada. Despite the initial successes of TITAN:HEADSTART, several challenges are anticipated. First, the heterogeneity in extended arch procedures (e.g., total arch replacement, frozen elephant trunk [FET], Ascyrus Medical Dissection Stent [AMDS]) requires a balance between matching variability in clinical practice and ensuring statistical power for trial analysis and subsequent generalizability of findings.9Smith H.N. Boodhwani M. Ouzounian M. et al.Classification and outcomes of extended arch repair for acute Type A aortic dissection: a systematic review and meta-analysis.Interact Cardiovasc Thorac Surg. 2017; 24: 450-459PubMed Google Scholar To overcome this, the pilot trial will compare hemiarch repair with total arch and FET, excluding other techniques, such as the AMDS. Depending on the success of the pilot trial and the experience of participating sites, the full trial may follow the same protocol or expand on the scope of extended arch procedures as an adaptive trial. Second, expertise plays an important role in the performance of extended arch repair, which raises the question whether regionalization and/or the establishment of centers of excellence for extended arch procedures is necessary.10Dobaria V. Kwon O.J. Hadaya J. et al.Impact of center volume on outcomes of surgical repair for type A acute aortic dissections.Surgery. 2020; 168: 185-192Abstract Full Text Full Text PDF Scopus (0) Google Scholar The expertise criterion for participation is introduced to standardize outcomes, as randomization among surgeons uncomfortable performing extended arch procedures would not be justifiable. Whether findings will be generalizable to smaller centers or all surgeons can thus be debated. Third, quality of life and patient preference must be evaluated, as ATAADs, rehabilitation after surgery, and potential reinterventions substantially impact patients’ and families’ lives. The trial incorporates a range of patient-reported outcome measures to accompany clinical outcomes. Encouragingly, we foresee several opportunities to take a head start on trials for ATAAD. The TITAN:HEADSTART trial will be the first randomized controlled trial for ATAADs, opening the door for other aortic and non-aortic cardiac trials in the emergency setting. In so doing, the trial will be a learning opportunity for the cardiovascular surgical community as it relates to setting up the “ideal” trial for ATAAD surgery, both for TITAN:HEADSTART and for future trials. Adaptive trial designs may become the norm, particularly in increasingly complex, personalized, and specialized domains such as thoracic aortic surgery, wherein flexibility and sustained methodological rigor will be paramount. Furthermore, deferred consent and neurological and imaging endpoints with a core lab will provide novel insights into their application for thoracic aortic surgical trials. In particular, deferred consent can enable recruitment for randomized controlled trials even in emergency settings, where the acuity, severity, and emotional load would otherwise not facilitate standard trial consent practices. Lastly, the trial actively incorporates room for qualitative and mixed-methods research to inform future center participation, patient recruitment, deferred consent, imaging, and funding.

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