Rationale and design of a randomized trial evaluating an external support device for saphenous vein coronary grafts.

BACKGROUND: Coronary artery bypass grafting (CABG) is the most common revascularization approach for the treatment of multi-vessel coronary artery disease. While the internal mammary artery is nearly universally used to bypass the left anterior descending coronary artery, autologous saphenous vein grafts (SVGs) are still the most frequently used conduits to grafts the remaining coronary artery targets. Long-term failure of these grafts, however, continues to limit the benefits of surgery. METHODS: The Cardiothoracic Surgical Trials Network trial of the safety and effectiveness of a Venous External Support (VEST) device is a randomized, multicenter, within-patient trial comparing VEST-supported versus unsupported saphenous vein grafts in patients undergoing CABG. Key inclusion criteria are the need for CABG with a planned internal mammary artery to the left anterior descending and two or more saphenous vein grafts to other coronary arteries. The primary efficacy endpoint of the trial is SVG intimal hyperplasia (plaque + media) area assessed by intravascular ultrasound at 12 months post randomization. Occluded grafts are accounted for in the analysis of the primary endpoint. Secondary confirmatory endpoints are lumen diameter uniformity and graft failure (>50% stenosis) assessed by coronary angiography at 12 months. The safety endpoints are the occurrence of major adverse cardiac and cerebrovascular events and hospitalization within 5 years from randomization. CONCLUSIONS: The results of the VEST trial will determine whether the VEST device can safely limit SVG intimal hyperplasia in patients undergoing CABG as treatment for coronary atherosclerotic disease.

A randomized trial of vonapanitase (PATENCY-1) to promote radiocephalic fistula patency and use for hemodialysis.

OBJECTIVE: Arteriovenous fistulas created in patients with chronic kidney disease often lose patency and fail to become usable. This prospective trial evaluated the efficacy of vonapanitase, a recombinant human elastase, in promoting radiocephalic fistula patency and use for hemodialysis. METHODS: PATENCY-1 was a double-blind, placebo-controlled trial that enrolled 349 patients on or approaching hemodialysis and being evaluated for radiocephalic arteriovenous fistula creation. Of these, 313 were randomized and 311 treated. Patients were assigned to vonapanitase (n = 210) or placebo (n = 103). The study drug solution was applied topically to the artery and vein for 10 minutes immediately after fistula creation. The primary and secondary end points were primary patency (time to first thrombosis or corrective procedure) and secondary patency (time to abandonment). Tertiary end points included use of the fistula for hemodialysis, fistula maturation by ultrasound, and procedure rates. RESULTS: The Kaplan-Meier estimates of 12-month primary patency were 42% (95% confidence interval [CI], 35-49) and 31% (95% CI, 21-42) for vonapanitase and placebo (P = .25). The Kaplan-Meier estimates of 12-month secondary patency were 74% (95% CI, 68-80) and 61% (95% CI, 51-71) for vonapanitase and placebo (P = .048). The proportions of vonapanitase and placebo patients were 39% and 25% (P = .035) with unassisted use for hemodialysis and 64% and 44% (P = .006) with unassisted plus assisted use. CONCLUSIONS: Vonapanitase treatment did not significantly improve primary patency but was associated with increased secondary patency and use for hemodialysis. Further research is needed to evaluate these end points.

Effects of red-cell storage duration on patients undergoing cardiac surgery.

BACKGROUND: Some observational studies have reported that transfusion of red-cell units that have been stored for more than 2 to 3 weeks is associated with serious, even fatal, adverse events. Patients undergoing cardiac surgery may be especially vulnerable to the adverse effects of transfusion. METHODS: We conducted a randomized trial at multiple sites from 2010 to 2014. Participants 12 years of age or older who were undergoing complex cardiac surgery and were likely to undergo transfusion of red cells were randomly assigned to receive leukocyte-reduced red cells stored for 10 days or less (shorter-term storage group) or for 21 days or more (longer-term storage group) for all intraoperative and postoperative transfusions. The primary outcome was the change in Multiple Organ Dysfunction Score (MODS; range, 0 to 24, with higher scores indicating more severe organ dysfunction) from the preoperative score to the highest composite score through day 7 or the time of death or discharge. RESULTS: The median storage time of red-cell units provided to the 1098 participants who received red-cell transfusion was 7 days in the shorter-term storage group and 28 days in the longer-term storage group. The mean change in MODS was an increase of 8.5 and 8.7 points, respectively (95% confidence interval for the difference, -0.6 to 0.3; P=0.44). The 7-day mortality was 2.8% in the shorter-term storage group and 2.0% in the longer-term storage group (P=0.43); 28-day mortality was 4.4% and 5.3%, respectively (P=0.57). Adverse events did not differ significantly between groups except that hyperbilirubinemia was more common in the longer-term storage group. CONCLUSIONS: The duration of red-cell storage was not associated with significant differences in the change in MODS. We did not find that the transfusion of red cells stored for 10 days or less was superior to the transfusion of red cells stored for 21 days or more among patients 12 years of age or older who were undergoing complex cardiac surgery. (Funded by the National Heart, Lung, and Blood Institute; RECESS ClinicalTrials.gov number, NCT00991341.).

Effects of RBT-1 on preconditioning response biomarkers in patients undergoing coronary artery bypass graft or heart valve surgery: a multicentre, double-blind, randomised, placebo-controlled phase 2 trial.

Background: RBT-1 is a combination drug of stannic protoporfin (SnPP) and iron sucrose (FeS) that elicits a preconditioning response through activation of antioxidant, anti-inflammatory, and iron-scavenging pathways, as measured by heme oxygenase-1 (HO-1), interleukin-10 (IL-10), and ferritin, respectively. Our primary aim was to determine whether RBT-1 administered before surgery would safely and effectively elicit a preconditioning response in patients undergoing cardiac surgery. Methods: This phase 2, double-blind, randomised, placebo-controlled, parallel-group, adaptive trial, conducted in 19 centres across the USA, Canada, and Australia, enrolled patients scheduled to undergo non-emergent coronary artery bypass graft (CABG) and/or heart valve surgery with cardiopulmonary bypass. Patients were randomised (1:1:1) to receive either a single intravenous infusion of high-dose RBT-1 (90 mg SnPP/240 mg FeS), low-dose RBT-1 (45 mg SnPP/240 mg FeS), or placebo within 24-48 h before surgery. The primary outcome was a preoperative preconditioning response, measured by a composite of plasma HO-1, IL-10, and ferritin. Safety was assessed by adverse events and laboratory parameters. Prespecified adaptive criteria permitted early stopping and enrichment. This trial is registered with ClinicalTrials.gov, NCT04564833. Findings: Between Aug 4, 2021, and Nov 9, 2022, of 135 patients who were enrolled and randomly allocated to a study group (46 high-dose, 45 low-dose, 44 placebo), 132 (98%) were included in the primary analysis (46 high-dose, 42 low-dose, 44 placebo). At interim, the trial proceeded to full enrollment without enrichment. RBT-1 led to a greater preconditioning response than did placebo at high-dose (geometric least squares mean [GLSM] ratio, 3.58; 95% CI, 2.91-4.41; p < 0.0001) and low-dose (GLSM ratio, 2.62; 95% CI, 2.11-3.24; p < 0.0001). RBT-1 was generally well tolerated by patients. The primary drug-related adverse event was dose-dependent photosensitivity, observed in 12 (26%) of 46 patients treated with high-dose RBT-1 and in six (13%) of 45 patients treated with low-dose RBT-1 (safety population). Interpretation: RBT-1 demonstrated a statistically significant cytoprotective preconditioning response and a manageable safety profile. Further research is needed. A phase 3 trial is planned. Funding: Renibus Therapeutics, Inc.

PATENCY-2 trial of vonapanitase to promote radiocephalic fistula use for hemodialysis and secondary patency.

OBJECTIVE: Arteriovenous fistulas created for hemodialysis often fail to become usable and are frequently abandoned. This prospective trial evaluated the efficacy of vonapanitase, a recombinant human elastase, in increasing radiocephalic fistula use for hemodialysis and secondary patency. METHODS: PATENCY-2 was a randomized, double-blind, placebo-controlled trial in patients on or approaching the need for hemodialysis undergoing radiocephalic arteriovenous fistula creation. Of 696 screened, 613 were randomized, and 603 were treated (vonapanitase n = 405, placebo n = 208). The study drug solution was applied topically to the artery and vein for 10 min immediately after fistula creation. The primary endpoints were fistula use for hemodialysis and secondary patency (fistula survival without abandonment). Other efficacy endpoints included unassisted fistula use for hemodialysis, primary unassisted patency, fistula maturation and unassisted maturation by ultrasound criteria, and fistula procedure rates. RESULTS: The proportions of patients with fistula use for hemodialysis was similar between groups, 70% vonapanitase and 65% placebo, (p = 0.33). The Kaplan-Meier estimates of 12-month secondary patency were 78% (95% confidence interval [CI], 73-82) for vonapanitase and 76% (95% CI, 70-82) for placebo (p = 0.93). The proportions with unassisted fistula use for hemodialysis were 46% vonapanitase and 37% placebo (p = 0.054). The Kaplan-Meier estimates of 12-month primary unassisted patency were 50% (95% CI, 44-55) for vonapanitase and 43% (95% CI, 35-50) for placebo (p = 0.18). There were no differences in the proportion of patients with fistula maturation or in fistula procedure rates. Adverse events were similar between groups. Vonapanitase was not immunogenic. CONCLUSIONS: Vonapanitase treatment did not achieve clinical or statistical significance to meaningfully improve radiocephalic fistula surgical outcomes. Outcome in the placebo group were better than in historical controls. Vonapanitase was well-tolerated and safe. TRIAL REGISTRATION: clinicaltrials.gov: NCT02414841 (https://clinicaltrials.gov/ct2/show/NCT02414841).

Intimal hyperplasia, saphenous vein graft disease, and clinical outcomes: Insights from the CTSN VEST randomized trial.

BACKGROUND: Diffuse intimal hyperplasia and graft irregularity adversely affect the long-term patency of saphenous vein grafts (SVGs) and clinical outcomes of patients undergoing coronary artery bypass grafting (CABG). The VEST trial evaluated the efficacy of external graft support in limiting the development of intimal hyperplasia (IH) at 1 year postsurgery. In the present secondary analysis, we explored the associations between graft disease and IH and clinical events. We also examined risk factors for early graft occlusion. METHODS: VEST is a within-patient randomized, multicenter trial that enrolled 224 patients with multivessel coronary disease undergoing CABG surgery, of whom 203 were evaluated by 1 year postsurgery. Intimal hyperplasia, lumen uniformity, graft stenosis, and graft perfusion were measured by intravascular ultrasound and angiography. Major cardiac and cerebrovascular events (MACCE; including death, myocardial infarction, stroke, and revascularization) were recorded over a median follow-up of 3 years. RESULTS: Worse lumen uniformity, greater stenosis, and worse graft perfusion were associated with higher IH values and an increased incidence of clinical events. Consistent with previous findings, we identified endoscopic vein harvesting, female sex, and transit time flow measurement of pulsatility index and flow as risk factors for SVG occlusion during the first year postsurgery. CONCLUSIONS: In this secondary analysis of the VEST trial, we observed an association between intimal hyperplasia area and clinical measures of SVG disease at 1 year postsurgery. More severe SVG disease and larger areas of IH were associated with a higher incidence of 3-year MACCE. Ongoing follow-up to 5 years will further elucidate the impact of SVG disease on long-term clinical outcomes of CABG.

External Support for Saphenous Vein Grafts in Coronary Artery Bypass Surgery: A Randomized Clinical Trial.

Importance: Intimal hyperplasia and subsequent saphenous vein graft failure may have significant adverse clinical effects in patients undergoing coronary artery bypass surgery. External support of saphenous vein grafts has the potential to prevent vein graft dilation and hence slow the rate of intimal hyperplasia and increase long-term vein patency. Objective: To determine efficacy, as measured by intimal hyperplasia, and safety of an external saphenous vein graft support device in patients undergoing a coronary bypass graft procedure. Design, Setting, and Participants: This within-patient randomized, open-label, multicenter study was conducted at 17 Cardiothoracic Surgical Trials Network centers in North America. Between January 2018 and February 2019, 224 patients with multivessel coronary artery disease undergoing isolated bypass surgery were enrolled. For each patient, 1 of 2 vein grafts was randomized to receive external support or no support. Interventions: External vein graft support or no support. Main Outcomes and Measures: The primary efficacy end point was intimal hyperplasia area assessed by intravascular ultrasound at 12 months postrandomization for each study graft. Secondary confirmatory end points were lumen diameter uniformity assessed by angiography and graft failure (≥50% stenosis) by quantitative coronary angiography. Major cardiac and cerebrovascular events were collected through month 12. Results: Among 224 patients (mean [SD] age, 65.8 [8.3] years; 178 [79.5%] male), 203 (90.6%) were eligible for intravascular ultrasound, of which 85 (41.9%) had at least 1 study graft occluded or severely diseased at 12 months (55 supported, 56 unsupported). After imputation of data missing because of graft occlusion or severe disease, the estimated mean (SE) intimal hyperplasia area was 5.11 (0.16) mm2 in supported grafts and 5.79 (0.20) mm2 in unsupported grafts (P = .07). In a sensitivity analysis of 113 patients with both grafts imaged, the mean intimal hyperplasia area was 4.58 (0.18) mm2 and 5.12 (0.23) mm2 in supported and unsupported grafts, respectively (P = .04). By 12 months, 5 patients (2.2%) died and 16 patients (7.1%) experienced a major cardiac or cerebrovascular event. Conclusions and Relevance: The 12-month difference in intimal hyperplasia area between supported and unsupported grafts did not achieve statistical significance. Cumulative mortality and major cardiac or cerebrovascular events rates were similar to those in other randomized coronary artery bypass trials. Further investigation to assess the effect of external graft support devices on long-term graft patency and clinical outcomes is warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT03209609.

Effect of an implantable gentamicin-collagen sponge on sternal wound infections following cardiac surgery: a randomized trial.

CONTEXT: Despite the routine use of prophylactic systemic antibiotics, sternal wound infection still occurs in 5% or more of cardiac surgical patients and is associated with significant excess morbidity, mortality, and cost. The gentamicin-collagen sponge, a surgically implantable topical antibiotic, is currently approved in 54 countries. A large, 2-center, randomized trial in Sweden reported in 2005 that the sponge reduced surgical site infection by 50% in cardiac patients. OBJECTIVE: To test the hypothesis that the sponge prevents infection in cardiac surgical patients at increased risk for sternal wound infection. DESIGN, SETTING, AND PARTICIPANTS: Phase 3 single-blind, prospective randomized controlled trial, 1502 cardiac surgical patients at high risk for sternal wound infection (diabetes, body mass index >30, or both) were enrolled at 48 US sites between December 21, 2007, and March 11, 2009. INTERVENTION: Single-blind randomization to insertion of 2 gentamicin-collagen sponges (total gentamicin of 260 mg) between the sternal halves at surgical closure (n = 753) vs no intervention (control group: n = 749). All patients received standardized care including prophylactic systemic antibiotics and rigid sternal fixation. MAIN OUTCOME MEASURES: The primary end point was sternal wound infection occurring through 90 days postoperatively as adjudicated by a clinical events classification committee blinded to study treatment group. The primary study comparison was done in the intent-to-treat population. Secondary outcomes included (1) superficial wound infection (involving subcutaneous tissue but not extending down to sternal fixation wires), (2) deep wound infection (involving the sternal wires, sternal bone, and/or mediastinum), and (3) score for additional treatment, presence of serous discharge, erythema, purulent exudate, separation of the deep tissues, isolation of bacteria, and duration of inpatient stay (ASEPSIS; minimum score of 0 with no theoretical maximum). RESULTS: Of 1502 patients, 1006 had diabetes (67%) and 1137 were obese (body mass index >30) (76%). In the primary analysis, there was no significant difference in sternal wound infection in 63 of 753 patients randomized to the gentamicin-collagen sponge group (8.4%) compared with 65 of 749 patients randomized to the control group (8.7%) (P = .83). No significant differences were observed between the gentamicin-collagen sponge group and the control group, respectively, in superficial sternal wound infection (49/753 [6.5%] vs 46/749 [6.1%]; P = .77), deep sternal wound infection (14/753 [1.9%] vs 19/749 [2.5%]; P = .37), ASEPSIS score (mean [SD], 1.9 [6.4] vs 2.0 [7.2]; P = .67), or rehospitalization for sternal wound infection (23/753 [3.1%] vs 24/749 [3.2%]; P = .87). CONCLUSION: Among US patients with diabetes, high body mass index, or both undergoing cardiac surgery, the use of 2 gentamicin-collagen sponges compared with no intervention did not reduce the 90-day sternal wound infection rate. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00600483.

POST-CONCUSSIVE CHANGES IN BALANCE AND POSTURAL STABILITY MEASURED WITH CANESENSE™ AND THE BALANCE ERROR SCORING SYSTEM (BESS) IN DIVISION I COLLEGIATE FOOTBALL PLAYERS: A CASE SERIES.

INTRODUCTION: Impairments in postural stability have been identified following sports-related concussion. CaneSense™ is a recently developed mobile lower limb motion capture system and mobile application for movement assessment which provides an objective measure of postural stability. One of the components within CaneSense™ is the Post-Concussive Excursion Index (PCEI), a measure of postural stability expressed as a percentage of symmetry between lower limbs. PURPOSE: The purpose of this case series is to examine pre- and post-concussion differences using two separate measures, CaneSense™, and a known test, the Balance Error Scoring System (BESS), in Division I collegiate football players. METHODS: A convenience sample of eight football players diagnosed with a concussion, were the subjects in this case series. All subjects underwent baseline testing prior to the start of pre-season camp consisting of the single limb stance (SLS) test with CaneSense™ and the BESS test. Twenty-four to 72 hours following their concussion, SLS with CaneSense™ test and the BESS test, were administered. Segmental excursions for the thigh and shank segments for each lower limb were combined into the Post-Concussion Excursion Profile (PCEP), which represents each segment's maximum excursion in the medial-lateral and anterior-posterior direction. The PCEI is a single metric generated to quantify differences within subjects by comparing the PCEP value between lower limbs during SLS where 100% suggests absolute symmetry. RESULTS: The PCEI value decreased significantly post-concussion (41.43 ± 15.53% vs. 87.41 ± 6.05%, p < 0.001) demonstrating a 52.6% decrease in inter-limb symmetry when compared to baseline values. There was an unanticipated 36.36% improvement in composite BESS performance post-concussion (10.5 ± 4.87 errors vs. 16.5 ± 8.49 errors, p = 0.10). CONCLUSIONS: Differences in inter-limb postural stability were found in subjects post-concussion. By assessing postural stability in both lower limbs individually, using the PCEI, impairments were detected that otherwise would have likely gone undiagnosed using the BESS test alone. LEVELS OF EVIDENCE: Therapy, Level 4.

A MULTIDISCIPLINARY APPROACH TO THE REHABILITATION OF A COLLEGIATE FOOTBALL PLAYER FOLLOWING ANKLE FRACTURE: A CASE REPORT.

BACKGROUND AND PURPOSE: Multiple rehabilitation factors including overall wellness need to be considered when an athlete returns to sport after an injury. The purpose of this case report is to describe a multidisciplinary approach for return to sport of a Division I collegiate football player following a traumatic ankle fracture requiring surgical repair. The assessment and treatment approach included the use of a performance-based physical therapy outcome measure, self-reported functional abilities, body composition assessments, and nutritional counseling. CASE DESCRIPTION: A 21 year-old running back fractured his lateral malleolus due to a mechanism of injury of excessive eversion with external rotation of the ankle. Surgical intervention included an open reduction internal fixation (ORIF) of the fibula and syndesmosis. In addition to six months of rehabilitation, the patient received consultations from the team sports nutritionist specialist to provide dietary counseling and body composition testing. The Comprehensive High-level Activity Mobility Predictor-Sport (CHAMP-S), a performance-based outcome measure, self-report on the Foot and Ankle Disability Index (FADI-ADL, FADI-S), and body composition testing using whole body densitometry (BOD POD®), were administered throughout rehabilitation. OUTCOMES: The subject was successfully rehabilitated, returned to his starting role, and subsequently was drafted by a National Football League (NFL) franchise. High-level mobility returned to above pre-injury values, achieving 105% of his preseason CHAMP-S score at discharge. Self-reported function on the FADI-ADL and FADI-Sport improved to 100% at discharge. Body fat percentages decreased (13.3% to 11.9%) and fat mass decreased (12.0 kg to 11.0kg). Lean body mass (78.1 kg to 81.5 kg) and lbm/in increased (1.14 kg/in to 1.19 kg/in). His BMI changed from 29.8 kg/m(2) to 30.6 kg/m(2). DISCUSSION: This case report illustrates the positive effects of a multidisciplinary approach where combining physical therapy and nutritional counseling demonstrated value with return to sport preparation and success following ankle fracture. A targeted physical therapy program combined with a personalized nutrition intervention based on body composition assessment assisted this athlete in avoiding deconditioning (atrophy, decreased aerobic capacities, and increases in body fat) often observed during postoperative care. LEVEL OF EVIDENCE: 5.

Return to Sport Following Surgery for a Complicated Tibia and Fibula Fracture in a Collegiate Women's Soccer Player with a Low Level of Kinesiophobia.

BACKGROUND & PURPOSE: Much attention has been solely paid to physical outcome measures for return to sport after injury in the past. However, current research shows that the psychological component of these injuries can be more predictive of return to sport than physical outcome measures. The purpose of this case report is to describe the successful return to sport following surgery of a complicated tibia and fibula fracture of a Division I collegiate women's soccer player with a low level of kinesiophobia. CASE DESCRIPTION: A 22-year-old female sustained a closed traumatic mid-shaft fracture of her tibia and fibula. During a high velocity play she sustained a direct blow while colliding with an opposing player's cleats. As a result of the play, her distal tibia was displaced 908 to the rest of her leg. She underwent a closed reduction and tibial internal fixation with an intramedullary rod. Outcome scores were tracked using the IKDC and TSK-11. The IKDC measures symptoms, function, and sport activity related to knee injuries. The TSK-11 measures fear of movement and re-injury, which was important to assess during this case due to the gruesome nature of the injury. OUTCOMES: At 4 months, the subject became symptomatic over the fibula and was diagnosed with a fibular nonunion fracture. This was unexpected due to the low incidence of and usual asymptomatic nature of fibular nonunion fractures, which required an additional surgery. TSK-11 scores ranged from 19-20 throughout, signifying low levels of kinesiophobia. IKDC scores improved from 8.05 to 60.92. The subject ultimately signed a professional soccer contract. DISCUSSION: The rehabilitation of this subject was complex due to her low levels of kinesiophobia, self-guided overtraining, and the potential role they may have had in her fibular nonunion fracture. This case study demonstrates a successful outcome despite a unique injury presentation, multiple surgeries, and low levels of kinesiophobia. While a low level of kinesiophobia can be detrimental to rehabilitation compliance, it may have benefited her in the long-term. LEVEL OF EVIDENCE: 5.

Application of human type I pancreatic elastase (PRT-201) to the venous anastomosis of arteriovenous grafts in patients with chronic kidney disease.

PURPOSE: To explore the safety and efficacy of PRT-201 applied to the outflow vein of a newly created arteriovenous graft (AVG). METHODS: Randomized, double-blind, placebo-controlled, single-dose escalation study of PRT-201 (0.01 to 9 mg) applied to the graft-vein anastomosis and adjacent outflow vein immediately after AVG placement. The primary outcome measure was safety. The efficacy measures were intraoperative increases in outflow vein diameter and blood flow rate, primary unassisted patency, and secondary patency by dose groups (placebo, low, medium, high and All PRT-201). RESULTS: A total of 89 patients were treated (28 placebo and 61 PRT-201). There were no significant differences in the proportion of placebo and PRT-201 patients reporting adverse events. Intraoperative outflow vein diameter increased 5% (p=0.14) in the placebo group compared with 13% (p=0.01), 15% (p=0.07) and 12% (p<0.001), in the low, medium and high groups, respectively. The comparison between the high and placebo groups was marginally statistically significant (p=0.06). The intraoperative blood flow did not change in the placebo group, and increased in the low, medium and high groups by 19% (p=0.34), 36% (p=0.09) and 46% (p=0.02), respectively. The low group had the longest primary unassisted and secondary patency and the fewest procedures to restore or maintain patency; however, the differences between groups were not statistically significant. CONCLUSIONS: PRT-201 was well tolerated and increased AVG intraoperative outflow vein diameter and blood flow. Low dose tended to increase secondary patency and decrease the rate of procedures to restore or maintain patency. Larger studies with these doses will be necessary to confirm these results.