A framework for the definition and interpretation of the use of surrogate endpoints in interventional trials.

Background: Interventional trials that evaluate treatment effects using surrogate endpoints have become increasingly common. This paper describes four linked empirical studies and the development of a framework for defining, interpreting and reporting surrogate endpoints in trials. Methods: As part of developing the CONSORT (Consolidated Standards of Reporting Trials) and SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) extensions for randomised trials reporting surrogate endpoints, we undertook a scoping review, e-Delphi study, consensus meeting, and a web survey to examine current definitions and stakeholder (including clinicians, trial investigators, patients and public partners, journal editors, and health technology experts) interpretations of surrogate endpoints as primary outcome measures in trials. Findings: Current surrogate endpoint definitional frameworks are inconsistent and unclear. Surrogate endpoints are used in trials as a substitute of the treatment effects of an intervention on the target outcome(s) of ultimate interest, events measuring how patients feel, function, or survive. Traditionally the consideration of surrogate endpoints in trials has focused on biomarkers (e.g., HDL cholesterol, blood pressure, tumour response), especially in the medical product regulatory setting. Nevertheless, the concept of surrogacy in trials is potentially broader. Intermediate outcomes that include a measure of function or symptoms (e.g., angina frequency, exercise tolerance) can also be used as substitute for target outcomes (e.g., all-cause mortality)-thereby acting as surrogate endpoints. However, we found a lack of consensus among stakeholders on accepting and interpreting intermediate outcomes in trials as surrogate endpoints or target outcomes. In our assessment, patients and health technology assessment experts appeared more likely to consider intermediate outcomes to be surrogate endpoints than clinicians and regulators. Interpretation: There is an urgent need for better understanding and reporting on the use of surrogate endpoints, especially in the setting of interventional trials. We provide a framework for the definition of surrogate endpoints (biomarkers and intermediate outcomes) and target outcomes in trials to improve future reporting and aid stakeholders' interpretation and use of trial surrogate endpoint evidence. Funding: SPIRIT-SURROGATE/CONSORT-SURROGATE project is Medical Research Council Better Research Better Health (MR/V038400/1) funded.

Detachable Aortic Clamp for Minimally Invasive Cardiac Surgery.

Since its first implementation, minimally invasive cardiac surgery has become more and more popular among surgeons. By avoiding a complete opening of the sternum, this surgery is traditionally associated with a faster recovery, less surgical pain and less postoperative bleeding and transfusions. With its growing popularity, the need for specifically designed surgical instrumentation is evident. Since 2008, the detachable-branch Glauber clamp (Cardiovision-Trytech, Tokyo, Japan) has been used to facilitate aortic cross-clamp during minimally invasive cardiac surgery, to optimize the intraoperative visualization field without the need for adjunctive incisions of the thorax. It has been specifically developed for limited single-access minimally invasive valve surgery. The clamp is introduced through the main access incision (mini-sternotomy or mini thoracotomy) by means of a specifically designed delivery system, which is subsequently removed, leaving inside the thorax only the detachable closed branches on the aorta. Since its first implementation, the clamp has been used in numerous patients at several cardiac surgery centers worldwide. Over the years, attempts have been made to improve its ergonomics and enhance its performance. The G2 detachable-branch Glauber clamp (USB Medical, Hatboro, PA, USA) occupies a smaller space inside the thorax, has a simplified gripping mechanism and comes with detachable arms that enhance versatility with up to 10 possible clamp configurations. This article describes the characteristics of detachable-branch aortic clamps and compares them to other aortic cross-clamps that are currently available for minimally invasive cardiac surgery.

Validation of the German Registry for Acute Aortic Dissection Type A Score in predicting 30-day mortality after type A aortic dissection surgery.

OBJECTIVES: No reliable scores are available to predict mortality following surgery for type A acute aortic dissection (TAAAD). Recently, the German Registry of Acute Aortic Dissection Type A (GERAADA) score has been developed. We aim to compare how the GERAADA score performs in predicting operative mortality for TAAAD to the European System for Cardiac Operative Risk Evaluation (EuroSCORE) II. METHODS: We calculated the GERAADA score and EuroSCORE II in patients who underwent TAAAD repair at the Bristol Heart Institute. As there are no precise criteria to calculate the GERAADA score, we used 2 methods: a Clinical-GERAADA score, which evaluated malperfusion with clinical and radiological evidence, and a Radiological-GERAADA score, where malperfusion was assessed by computed tomography scan alone. RESULTS: 207 consecutive patients had surgery for TAAAD, and the observed 30-day mortality was 15%. The Clinical-GERAADA score showed the strongest discriminative power with an area under the curve (AUC) of 0.80 [95% confidence interval (CI) 0.71-0.89], while the Radiological-GERAADA score had an AUC of 0.77 (95% CI 0.67-0.87). EuroSCORE II showed acceptable discriminative power with an AUC of 0.77 (95% CI 0.67-0.87). CONCLUSIONS: Clinical GERAADA score performed better than the other scores and it is specific and easy to use in the context of a TAAAD. Further validation of the new criteria for malperfusion is needed.

Systematic total arch replacement with thoraflex hybrid graft in acute type A aortic dissection: A single centre experience.

Introduction: In the last two decades, a more aggressive approach has been encouraged to treat patients with acute type A aortic dissection (ATAAD), extending the repair to the aortic arch and proximal descending thoracic aorta with the frozen elephant trunk (FET) implantation. Here, we report our single-centre experience with the FET technique for the systematic treatment of emergency type A aortic dissection. Materials and methods: Between December 2017 and January 2022, 69 consecutive patients were admitted with ATAAD; of those, 66 patients (62.9 ± 10.2 years of age, 81.8% men) underwent emergency hybrid aortic arch and FET repair with the multibranched Thoraflex hybrid graft and were enrolled in the study. Primary endpoints were 30 days- and in-hospital mortality. Secondary endpoints were postoperative morbidity and follow-up survival. To better clarify the impact of age on surgical outcomes, we have divided the study population into two groups: group A for patients <70 years of age (47 patients), and group B for patients ≥70 years (19 patients). Time-to-event analysis has been conducted using the Log-rank test and is displayed with Kaplan-Meier curves. A multiple Cox proportional Hazard model was developed to identify predictors of long-term survival with a stepwise backward/forward selection process. Results: 30-days- and in-hospital mortality were 10.6 and 13.6%, respectively. Stroke occurred in three (4.5%) patients. Two (3.0%) patients experienced spinal cord ischemia. We did not find any statistically significant difference between the two groups in terms of main post-operative outcomes. The multivariable Cox proportional hazard model showed left ventricular ejection fraction (HR: 0.83, 95% CI: 0.79-0.92, p < 0.01), peripheral vascular disease (HR: 15.8, 95% CI: 3.9-62.9, p < 0.01), coronary malperfusion (HR: 0.10, 95% CI: 0.01-0.77, p =0.03), lower limbs malperfusion (HR: 5.1, 95% CI: 1.10-23.4, p = 0.04), and cardiopulmonary bypass time (HR: 1.02, 95% CI: 1-1.04, p = 0.01) as independent predictors of long term mortality. Conclusions: Frozen elephant trunk repair to treat emergency type A aortic dissection appears to be associated with good early and mid-term clinical outcomes even in the elderly.

The need for custom made frozen elephant trunk: when and where.

The frozen elephant trunk (FET) technique is an increasingly common procedure to treat complex extensive aortic disease both in elective and emergency setting. In a contemporary era, several prostheses are available to be used by surgeons performing such procedures, merging the advantages of endovascular and conventional surgery and preparing a more useful landing zone for second-stage downstream endovascular or open repair. Thoraflex hybrid (Terumo Aortic, Scotland) is a largely used hybrid vascular device merging a conventional surgical vascular graft made of gelatin-sealed woven polyester graft with a nitinol self-expanding stent graft. Since its release in 2012, this prosthesis has gained a large consensus, mainly for the plexus version, which allows for single reimplantation of the epiaortic vessels. In the last few years, new devices have come out to offer new specific weapons to be used by the surgical team in different clinical scenarios. In this context, the need of making the supra-aortic vessel debranching easier and more functional to our surgical technique has pushed our demand for a customization of a conventional Thoraflex hybrid. Here we report a modification to its standard design, the concept beyond the "Custom device" and its potential advantages with regards to our peculiar implantation technique and intraoperative cerebral perfusion during circulatory arrest time.

Development and Preliminary Testing of Porcine Blood-Derived Endothelial-like Cells for Vascular Tissue Engineering Applications: Protocol Optimisation and Seeding of Decellularised Human Saphenous Veins.

Functional endothelial cells (EC) are a critical interface between blood vessels and the thrombogenic flowing blood. Disruption of this layer can lead to early thrombosis, inflammation, vessel restenosis, and, following coronary (CABG) or peripheral (PABG) artery bypass graft surgery, vein graft failure. Blood-derived ECs have shown potential for vascular tissue engineering applications. Here, we show the development and preliminary testing of a method for deriving porcine endothelial-like cells from blood obtained under clinical conditions for use in translational research. The derived cells show cobblestone morphology and expression of EC markers, similar to those seen in isolated porcine aortic ECs (PAEC), and when exposed to increasing shear stress, they remain viable and show mRNA expression of EC markers similar to PAEC. In addition, we confirm the feasibility of seeding endothelial-like cells onto a decellularised human vein scaffold with approximately 90% lumen coverage at lower passages, and show that increasing cell passage results in reduced endothelial coverage.

Hybrid coronary revascularization versus coronary artery bypass grafting for multivessel coronary artery disease: A systematic review and meta-analysis.

BACKGROUND: Hybrid coronary revascularization (HCR) combines the benefits of a left internal mammary artery to left anterior descending artery anastomosis, via a mini thoracotomy, with percutaneous coronary intervention (PCI) for other diseased coronaries. AIMS: The aim of this meta-analysis is to compare the short- and long-term outcomes of HCR with those of coronary artery bypass grafting (CABG) for multi-vessel coronary artery disease (MCAD). METHODS: We performed a meta-analysis with a primary outcome of short-term mortality and secondary outcomes of mid-term survival, length of hospital stay, stroke, renal failure and mid-term MACE rate. RESULTS: 3399 patients (HCR = 1164, CABG = 2235) were included, with no significant difference in short-term mortality between groups (OR = 1.50, 95% CI = [0.90,2.49], p = 0.11), although a higher mortality rate was seen in the HCR group (0.73% vs 0.64%). The average length of stay in intensive care unit was significantly shorter following HCR than CABG (mean difference = -15.52 h, CI = [-22.47,-8.59], p˂0.001) and overall hospital stay was also shorter in this group, although not statistically significant (mean difference = -3.15 days, 95% CI = [-6.55, 0.25], p = 0.07). HCR was associated with a reduced odds of blood transfusion (OR = 0.34, 95% CI = [0.22,0.54], p < 0.001). There was not a significant difference in mid-term survival (OR = 0.86, 95% CI = [0.62,1.21], p = 0.39) or MACE rate (OR = 0.82, 95% CI = [0.55,1.23], p = 0.34). No differences were found between HCR and CABG for post-operative stroke (OR = 1.36, 95% CI = [0.87, 2.13], p = 0.16) or renal failure (OR = 0.71, 95% CI = [0.43,1.16], p = 0.14). CONCLUSIONS: HCR has a higher incidence of short-term mortality compared to CABG in patients with MCAD, although this difference is not statistically significant. Similar rates of mid-term survival and other short term post-operative complications were found between the two groups. HCR has a shorter ICU stays and reduced requirement for blood transfusion.

Blood lactate predicts mortality after surgical repair of type A acute aortic dissection.

BACKGROUND: Ischemia and malperfusion are strong predictors of poor postoperative outcomes in type A acute aortic dissection (TAAAD). Serum lactate is an accurate surrogate point-of-care marker of malperfusion. The aim of this study is to investigate the correlation between lactate, in-hospital outcomes, and 1-year survival following TAAAD repair. METHODS: One hundred and thirty-two patients underwent operative repair of TAAAD over a 4-year period at our institution 128 patients had serum lactate measurements at three stages peri-operatively-preoperatively, at the end of cardiopulmonary bypass (post-CPB) and 6 h postintensive care unit (ICU) admission. The primary outcomes were in-hospital mortality and 1-year survival. The secondary outcomes were the incidences of in-hospital morbidities. RESULTS: Patients were divided into two groups: 88 (68.8%) with normal lactate and 40 (31.2%) with elevated lactate (>2.2 mmol/L). Lactate measured preoperatively (odds ratio 1.52, 95% confidence interval 1.17-2.07, p < .01), post-CPB (1.34, 1.14-1.64, p < .01) and 6 h post-ICU admission (1.29, 1.08-1.55, p < .01) was an independent predictor of in-hospital mortality. Following adjustment for the Penn Classification, lactate continued to have a significant correlation with in-hospital mortality at all three timepoints. There was a higher incidence of complications in the elevated lactate group and especially hemofiltration (20% vs. 9.1%, p = .08). 1-year survival was similar in both groups (p = .23). CONCLUSIONS: There is a direct correlation between elevated serum lactate and postoperative mortality after TAAAD repair, which is independent of the Penn Classification status on admission.

Surgical transcatheter valve implantation: The more pathways, the better.

Transcatheter aortic valve implantation (TAVI) is rapidly spreading across the world with the endorsement of the cardiological community and the supporting results of randomized controlled trials. However, TAVI-related complications like aortic dissection, aortic valvular rupture, or left ventricle perforation are still potentially catastrophic.

A novel small diameter nanotextile arterial graft is associated with surgical feasibility and safety and increased transmural endothelial ingrowth in pig.

Globally, millions of patients are affected by myocardial infarction or lower limb gangrene/amputation due to atherosclerosis. Available surgical treatment based on vein and synthetic grafts provides sub-optimal benefits. We engineered a highly flexible and mechanically robust nanotextile-based vascular graft (NanoGraft) by interweaving nanofibrous threads of poly-L-lactic acid to address the unmet need. The NanoGrafts were rendered impervious with selective fibrin deposition in the micropores by pre-clotting. The pre-clotted NanoGrafts (4 mm diameter) and ePTFE were implanted in a porcine carotid artery replacement model. The fibrin-laden porous milieu facilitated rapid endothelization by the transmural angiogenesis in the NanoGraft. In-vivo patency of NanoGrafts was 100% at 2- and 4-weeks, with no changes over time in lumen size, flow velocities, and minimal foreign-body inflammatory reaction. However, the patency of ePTFE at 2-week was 66% and showed marked infiltration, neointimal thickening, and poor host tissue integration. The study demonstrates the in-vivo feasibility and safety of a thin-layered vascular prosthesis, viz., NanoGraft, and its potential superiority over the commercial ePTFE.

Surgical treatment of a giant right coronary aneurysm following coronary stent fracture.

BACKGROUND: Coronary artery aneurysm represents a challenging and potentially fatal disease. AIM AND MATERIAL METHODS: We present the case of a giant right coronary artery aneurysm treated surgically after percutaneous intervention and fracture of the stent. RESULTS AND DISCUSSION: The aneurism was opened and the coronary ligated proximally and distally. It was not possible to re-established continuity of the coronary artery or perform a bypass graft. An early surgical strategy would have re-established blood flow in the involved coronary artery and avoided chronic ischemia of the supplied myocardial territory.

Frozen elephant trunk procedure for complex aortic arch surgery: The Salerno experience with Thoraflex hybrid.

BACKGROUND AND AIM OF THE STUDY: To report early clinical outcomes of the frozen elephant trunk (FET) technique for the treatment of complex aortic diseases after transition from conventional elephant trunk. METHODS: A single-center, retrospective study of patients who underwent hybrid aortic arch and FET repair for aortic arch and/or proximal descending aortic aneurysms, acute and chronic Stanford type A aortic dissection with arch and/or proximal descending involvement, Stanford type B acute and chronic aortic dissections with retrograde aortic arch involvement. RESULTS: Between December 2017 and May 2020, 70 consecutive patients (62.7 ± 10.6 years, 59 male) were treated: 41 (58.6%) for emergent conditions and 29 (41.4%) for elective. Technical success was 100%. In-hospital mortality was 14.2% (n = 12, 17.1% emergent vs. 10.3% elective, P = NS); 2 (2.9%) major strokes; 1 (1.4%) spinal cord injury. Mean follow-up was 12.5 months (interquartile range, 3.7-22.3). Overall survival at 3, 6, 12, and 24 months was 90% (95% confidence interval [CI], 83.2-97.3), 85.6% (95% CI, 77.7-94.3), 79.1% (95% CI, 69.9-89.5), 75.6% (95% CI, 65.8-86.9) and 73.5% (95% CI, 63.3-85.3). There were no aortic re-interventions and no distal stent graft-induced new entry (dSINE); 5 patients with residual type B dissection underwent TEVAR completion. CONCLUSIONS: In a real-world setting, FET with Thoraflex Hybrid demonstrated feasibility and good clinical outcomes, even in emergent setting. Our implant technique optimize cerebral perfusion reporting good results in terms of neurological complications. Techniques to perfect the procedure and to reduce remaining risks, and consensus on considerations such as standardized cerebral protection need to be reported.

Frozen Elephant Trunk Technique in Acute Type A Aortic Dissection: Is It for All?

Acute type A aortic dissection (ATAAD) is an indisputable emergency with very poor outcomes without surgical treatment. Although the aortic arch is often involved in the aortic dissection, its optimal management during surgical therapy remains uncertain. A conservative tear-oriented approach has traditionally been adopted, limiting the procedure to the ascending aorta (or hemiarch) replacement. However, dilation of the residual dissected aorta and subsequent rupture may occur, requiring further intervention in the future. In the last two decades, the frozen elephant trunk (FET) technique has become a valid and attractive option to treat aortic disease when the arch and the thoracic aorta are involved, both in elective and in emergency settings. Here, we report a review of the contemporary literature regarding the short- and long-term outcomes of the FET technique in ATAAD repair.