Impact of Financial Conflicts on Study Outcomes and Patient Mortality Rates

Reference: Jansen et al. Emergency Department Resuscitative Endovascular Balloon Occlusion of the Aorta in Trauma Patients With Exsanguinating Hemorrhage: The UK-REBOA Randomized Clinical Trial. JAMA. 2023 Date: June 10, 2024 Guest Skeptic: Dr. Rob Leeper is an intensivist, trauma surgeon, and general surgeon at Western University where he also serves as the director of the Royal College Surgical Foundations program. He is particularly enthusiastic about medical education and the use of high-fidelity simulation to identify latent threats to patient safety and improve team-based crisis resource management. Case: A 24-year-old patient is involved in a high-speed motor vehicle collision.  The patient was the intoxicated driver of a sport utility vehicle that left the road and collided head-on with a traffic light.  The driver was ejected from the vehicle.  On scene, he has a Glasgow Coma Scale (GCS) score of 14, is tachycardic at 130 beats per minute and hypotensive at 85/50 mmHg.  He complains of severe pain in his abdomen and left upper extremity.  He has an obvious angulated deformity of his left wrist. Pre-hospital personnel placed the patient in a cervical spine collar, obtained peripheral intravenous (IV) access, administered 250cc of 0.9% saline and provided rapid transport to the local trauma center which is less than 15 minutes away.  On arrival at the trauma center, the patient’s vital signs and symptoms remain essentially unchanged from those on scene. You initiate standard, simultaneous assessment and resuscitation following the Advanced Trauma Life Support (ATLS) principles.  You are debating the addition of resuscitative endovascular balloon occlusion of the aorta (REBOA) as an adjunct to your standard care.  You wonder what the evidence is for this additional approach. Background: We covered REBOA on the SGEM 5 years ago with Dr. Robert Edmonds (SGEM#258). That was a review of a retrospective observational study of 593,818 trauma patients of which 140 received REBOA compared to 240 matched controls who did not receive this treatment. The overall mortality was worse with REBOA (35.7% vs. 18.9%, p=0.01). The SGEM bottom line in 2019 was that REBOA is currently an intervention of uncertain benefit. Although it has shown promise in some studies, this investigation leaves its therapeutic potential in question and arguably demonstrates harm. There may be substantial benefits in select groups of trauma patients, but these groups are not yet known. Trauma surgeons are hemorrhage control surgeons.  Bleeding is the enemy and patient survival turns tenuously on our ability to identify and staunch hemorrhage in as expedient a fashion as possible.  Time is our currency and, for patients with massive hemorrhage, minutes matter.  Every strategy that enhances time to hemorrhage control is deserving of examination: Trauma Systems - Enhancing the training and tools for our pre-hospital teams, faster helicopters, more trauma centers, etc. Hemostatic Resuscitation - Permissive hypotension, whole blood and factor ratio resuscitation, warmed products, dynamic coagulation monitoring, etc. Enhanced Operative Strategies - Damage control surgery with truncated interventions, energy devices, hemostatic foams/gels/packs, etc. These approaches hold the possibility of enhancing our ability to save patient’s lives. One approach, which has seen a revival in its interest and utilization, is proximal balloon occlusion of the aorta.  The rationale is simple, occluding the aorta above the level of bleeding will de facto reduce blood loss at the site of injury and lead to immediately increased blood pressure and, presumably, perfusion to the zone above the occlusion, typically the upper body, the heart, and the brain.  A great variety of medical devices designed for this purpose have come to market over the last 15 years and a relatively heterogeneous collection of retrospective clinical data has been published with conflicting results. There are signals of improvement but also signals of harm with this technique. Given this equipoise, a robust prospective clinical trial was undertaken by a group of international trauma providers and researchers.  The UK-REBOA was designed and conducted across 16 English trauma centers from 2017 to 2022 to provide the most evidence-based answer to the question of whether the addition of REBOA to standard care improves survival in massively bleeding trauma patients. Clinical Question: Does the addition of REBOA to standard trauma resuscitation practice improve survival for injured patients presenting to lead trauma centres with massive hemorrhage? Reference: Jansen et al. Emergency Department Resuscitative Endovascular Balloon Occlusion of the Aorta in Trauma Patients With Exsanguinating Hemorrhage: The UK-REBOA Randomized Clinical Trial. JAMA. 2023 Population: Adults aged 16 years or older presenting to 16 major trauma centers in the UK (2017-2022) with confirmed or suspected life-threatening torso hemorrhage amenable to adjunctive treatment with REBOA. Exclusions: Key exclusion criteria were known or suspected pregnancy or injuries that were clearly not survivable. Intervention: REBOA in addition to standard care. This entailed the percutaneous insertion of a balloon catheter into the aorta, which was then inflated to control hemorrhage while maintaining cerebral and myocardial perfusion. Comparison: Standard care alone, which could include intubation, balanced blood product transfusion, tourniquet application, and early operative or endovascular hemorrhage control. Outcomes: Primary Outcome: All-cause mortality at 90 days. Secondary Outcomes: Mortality at various timeframes, the need for definitive hemorrhage control procedures, time to commencement of such procedures, complications, length of stay, blood product use, and cause of death. Trial: This was a pragmatic, Bayesian, multi-centred randomized clinical trial Authors’ Conclusions: “In trauma patients with exsanguinating hemorrhage, a strategy of REBOA and standard care in the emergency department does not reduce, and may increase, mortality compared with standard care alone.” Quality Checklist for Randomized Clinical Trials: The study population included or focused on those in the emergency department. Yes The patients were adequately randomized. Yes The randomization process was concealed. Yes The patients were analyzed in the groups to which they were randomized. Yes The study patients were recruited consecutively (i.e. no selection bias). No The patients in both groups were similar with respect to prognostic factors. No All participants (patients, clinicians, and outcome assessors) were unaware of group allocation. No All groups were treated equally except for the intervention. No Follow-up was complete (i.e. at least 80% for both groups). Yes All patient-important outcomes were considered. Yes The treatment effect was large enough and precise enough to be clinically significant. Yes Financial conflicts of interest. Several of the biggest names in REBOA technology are investors and shareholders in companies that sell these balloons.  Jansen’s disclosure slide had plenty of industry sponsorships and grants. Results: The study population (n=90) predominantly comprised males (69%) with a median age of 41 years. Most injuries (97%) were due to blunt trauma, and the median Injury Severity Score was 41, indicating severe injuries. Key Result: Mortality was higher in those trauma patients allocated to receive REBOA. Primary Outcome: Mortality at 90 days 54% REBOA care group vs 42% in the standard care alone group Odds Ratio (OR)1.58 [95% Credible Interval, 0.72 to 3.52] The posterior probability of an OR >1 (indicating increased odds of death with REBOA) was 86.9%. This means the probability of increased odds of death with REBOA was 86.9%. Secondary Outcomes: All secondary outcomes numerically favoured standard care without REBOA. They are listed in Table 2 of the manuscript 1. Small Sample Size: 90 patients represent a small sample size. It demonstrates how difficult this type of research can be. We should congratulate the authors and all those involved in conducting such a high-quality trial. They asked a good question, used appropriate methods to try to answer the question and in 16 trauma centres over five years found less than 50 patients to allocate to each group. Remember the earlier observational study we mentioned in the background material, those authors had to search ~600,000 trauma patients to identify 140 patients who received REBOA. This treatment is not common and is incredibly hard to conduct an RCT investigating its impact. Again, well done Dr. Jensen and their team. 2. What can we learn from the mortality curve (Kaplan-Meier plot)? The key thing that jumps out at you visually from the Kaplan-Meier plot is that the separation in the two survival curves happens early with about half of the difference jumping out in the first day and nearly all of it being complete by ten days. After that the curves are very much flat and follow each other out to 90 days in parallel.  To me, this looks like a signal for hemorrhagic death (the first half) and complications of delay in hemorrhage control and protracted resuscitation (in the second half). 3. Can we get any more granular than that on mortality at different time points? Showing a breakdown of the risks of death at 3 hours, 6 hours, 24 hours, and in hospital you can see that there is an increased hazard of death at every timepoint with REBOA.  Odds Ratios (OR) are higher but the posterior probability of the ORs being > 1 are between 99% and 87% at each time point, once again suggesting that REBOA is associated with more harm in the most critical period of hemorrhage care. the earliest phase.