Permanent Pacemaker Implantation and Long-Term Outcomes of Patients Undergoing Concomitant Mitral and Tricuspid Valve Surgery.

BACKGROUND: Tricuspid valve annuloplasty (TA) during mitral valve repair (MVr) is associated with increased risk of permanent pacemaker (PPM) implantation, but the magnitude of risk and long-term clinical consequences have not been firmly established. OBJECTIVES: This study assesses the incidence rates of PPM implantation after isolated MVr and following MVr with TA as well as the associated long-term clinical consequences of PPM implantation. METHODS: State-mandated hospital discharge databases of New York and California were queried for patients undergoing MVr (isolated or with concomitant TA) between 2004 and 2019. Patients were stratified by whether or not they received a PPM within 90 days of index surgery. After weighting by propensity score, survival, heart failure hospitalizations (HFHs), endocarditis, stroke, and reoperation were compared between patients with or without PPM. RESULTS: A total of 32,736 patients underwent isolated MVr (n = 28,003) or MVr + TA (n = 4,733). Annual MVr + TA volumes increased throughout the study period (P < 0.001, trend), and PPM rates decreased (P < 0.001, trend). The incidence of PPM implantation <90 days after surgery was 7.7% for MVr and 14.0% for MVr + TA. In 90-day conditional landmark-weighted analyses, PPMs were associated with reduced long-term survival among MVr (HR: 1.96; 95% CI: 1.75-2.19; P < 0.001) and MVr + TA recipients (HR: 1.65; 95% CI: 1.28-2.14; P < 0.001). In both surgical groups, PPMs were also associated with an increased risk of HFH (HR: 1.56; 95% CI: 1.27-1.90; P < 0.001) and endocarditis (HR: 1.95; 95% CI: 1.52-2.51; P < 0.001), but not with stroke or reoperation. CONCLUSIONS: Compared to isolated MVr, adding TA to MVr was associated with a higher risk of 90-day PPM implantation. In both surgical groups, PPM implantation was associated with an increase in mortality, HFH, and endocarditis.

Clinical Trial Diversity, Equity, and Inclusion: Roadmap of the Cardiothoracic Surgical Trials Network.

BACKGROUND: There is a recognized lack of diversity among patients enrolled in cardiovascular interventional and surgical trials. Diverse patient representation in clinical trials is necessary to enhance generalizability of findings, which may lead to better outcomes across broader populations. The Cardiothoracic Surgical Trials Network (CTSN) recently developed a plan of action to increase diversity among participating investigators and trial participants and is the focus of this review. METHODS: A review of literature and enrollment data from CTSN trials was conducted. RESULTS: CTSN completed more than a dozen major clinical trials (2008-2022), enrolling >4000 patients, of whom 30% were women, 11% were non-White, and 5.6% were Hispanic. CTSN also completed trials of hospitalized patients with coronavirus disease 2019, wherein enrollment was more diverse, with 42% women, and 58% were Asian, Black, Hispanic, or from another underrepresented racial group. The discrepancy in diversity of enrollment between cardiac surgery trials and coronavirus disease trials highlights the need for a more comprehensive understanding of (1) the prevalence of underlying disease requiring cardiac interventions across broad populations, (2) differences in access to care and referral for cardiac surgery, and (3) barriers to enrollment in cardiac surgery trials. CONCLUSIONS: Committed to diversity, CTSN's multifaceted action plan includes developing site-specific enrollment targets, collecting social determinants of health data, understanding reasons for nonparticipation, recruiting sites that serve diverse populations, emphasizing greater diversity among clinical trial teams, and implicit bias training. The CTSN will prospectively assess how these interventions influence enrollment as we work to ensure trial participants are more representative of the communities we serve.

Prospective Study of Risk Factors for Postoperative Atrial Fibrillation After Cardiac Surgery.

INTRODUCTION: To examine risk factors for new-onset postoperative atrial fibrillation (POAF) after cardiac surgery. METHODS: Patients enrolled in the Cardiothoracic Surgical Trials Network multicenter, randomized trial of rate control versus rhythm control for POAF were included. Predictors of POAF were determined using multivariable logistic regression. RESULTS: Among the 2104 patients who were enrolled preoperatively, 695 developed POAF (33.0%). Rates of POAF were 28.1% after isolated coronary artery bypass grafting (CABG), 33.7% after isolated valve repair or replacement, and 47.3% after CABG plus valve repair or replacement. Baseline characteristics associated with an increased risk of POAF identified on multivariable analysis included older age (odds ratio [OR] 1.57; 95% confidence interval [CI] 1.42-1.73, per 10 y), White race or non-Hispanic ethnicity (OR 1.52; CI: 1.11-2.07), history of heart failure (OR 1.55; CI: 1.16-2.08), and history of hypothyroidism (OR 1.42; CI 1.04-1.94). The type of cardiac procedure was associated with an increased risk of POAF with both isolated valve repair or replacement (OR 1.33, CI 1.08-1.64) and combined CABG plus valve repair or replacement (OR 1.64, CI 1.24-2.17) having increased risk of POAF compared to isolated CABG. No preoperative cardiac medication was associated with POAF. CONCLUSIONS: In this prospective cohort of patients, older age, a history of hypothyroidism, a history of heart failure, and valve repair or replacement, with or without CABG, and White non-Hispanic race were associated with an increased risk of POAF.

Infarct-related structural disconnection and delirium in surgical aortic valve replacement patients.

OBJECTIVE: Although acute brain infarcts are common after surgical aortic valve replacement (SAVR), they are often unassociated with clinical stroke symptoms. The relationship between clinically "silent" infarcts and in-hospital delirium remains uncertain; obscured, in part, by how infarcts have been traditionally summarized as global metrics, independent of location or structural consequence. We sought to determine if infarct location and related structural connectivity changes were associated with postoperative delirium after SAVR. METHODS: A secondary analysis of a randomized multicenter SAVR trial of embolic protection devices (NCT02389894) was conducted, excluding participants with clinical stroke or incomplete neuroimaging (N = 298; 39% female, 7% non-White, 74 ± 7 years). Delirium during in-hospital recovery was serially screened using the Confusion Assessment Method. Parcellation and tractography atlas-based neuroimaging methods were used to determine infarct locations and cortical connectivity effects. Mixed-effect, zero-inflated gaussian modeling analyses, accounting for brain region-specific infarct characteristics, were conducted to examine for differences within and between groups by delirium status and perioperative neuroprotection device strategy. RESULTS: 23.5% participants experienced postoperative delirium. Delirium was associated with significantly increased lesion volumes in the right cerebellum and temporal lobe white matter, while diffusion weighted imaging infarct-related structural disconnection (DWI-ISD) was observed in frontal and temporal lobe regions (p-FDR < 0.05). Fewer brain regions demonstrated DWI-ISD loss in the suction-based neuroprotection device group, relative to filtration-based device or standard aortic cannula. INTERPRETATION: Structural disconnection from acute infarcts was greater in patients who experienced postoperative delirium, suggesting that the impact from covert perioperative infarcts may not be as clinically "silent" as commonly assumed.

A Randomized Trial of Mesenchymal Stromal Cells for Moderate to Severe Acute Respiratory Distress Syndrome from COVID-19.

Rationale: There are limited therapeutic options for patients with coronavirus disease (COVID-19)-related acute respiratory distress syndrome with inflammation-mediated lung injury. Mesenchymal stromal cells offer promise as immunomodulatory agents. Objectives: Evaluation of efficacy and safety of allogeneic mesenchymal cells in mechanically-ventilated patients with moderate or severe COVID-19-induced respiratory failure. Methods: Patients were randomized to two infusions of 2 million cells/kg or sham infusions, in addition to the standard of care. We hypothesized that cell therapy would be superior to sham control for the primary endpoint of 30-day mortality. The key secondary endpoint was ventilator-free survival within 60 days, accounting for deaths and withdrawals in a ranked analysis. Measurements and Main Results: At the third interim analysis, the data and safety monitoring board recommended that the trial halt enrollment as the prespecified mortality reduction from 40% to 23% was unlikely to be achieved (n = 222 out of planned 300). Thirty-day mortality was 37.5% (42/112) in cell recipients versus 42.7% (47/110) in control patients (relative risk [RR], 0.88; 95% confidence interval, 0.64-1.21; P = 0.43). There were no significant differences in days alive off ventilation within 60 days (median rank, 117.3 [interquartile range, 60.0-169.5] in cell patients and 102.0 [interquartile range, 54.0-162.5] in control subjects; higher is better). Resolution or improvement of acute respiratory distress syndrome at 30 days was observed in 51/104 (49.0%) cell recipients and 46/106 (43.4%) control patients (odds ratio, 1.36; 95% confidence interval, 0.57-3.21). There were no infusion-related toxicities and overall serious adverse events over 30 days were similar. Conclusions: Mesenchymal cells, while safe, did not improve 30-day survival or 60-day ventilator-free days in patients with moderate and/or severe COVID-19-related acute respiratory distress syndrome.

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.

The impact of perioperative stroke and delirium on outcomes after surgical aortic valve replacement.

OBJECTIVE: The effects of stroke and delirium on postdischarge cognition and patient-centered health outcomes after surgical aortic valve replacement (SAVR) are not well characterized. Here, we assess the impact of postoperative stroke and delirium on these health outcomes in SAVR patients at 90 days. METHODS: Patients (N = 383) undergoing SAVR (41% received concomitant coronary artery bypass graft) enrolled in a randomized trial of embolic protection devices underwent serial neurologic and delirium evaluations at postoperative days 1, 3, and 7 and magnetic resonance imaging at day 7. Outcomes included 90-day functional status, neurocognitive decline from presurgical baseline, and quality of life. RESULTS: By postoperative day 7, 25 (6.6%) patients experienced clinical stroke and 103 (28.5%) manifested delirium. During index hospitalization, time to discharge was longer in patients experiencing stroke (hazard ratio, 0.62; 95% confidence interval [CI], 0.42-0.94; P = .02) and patients experiencing delirium (hazard ratio, 0.68; 95% CI, 0.54-0.86; P = .001). At day 90, patients experiencing stroke were more likely to have a modified Rankin score >2 (odds ratio [OR], 5.9; 95% CI, 1.7-20.1; P = .01), depression (OR, 5.3; 95% CI, 1.6-17.3; P = .006), a lower 12-Item Short Form Survey physical health score (adjusted mean difference -3.3 ± 1.9; P = .08), and neurocognitive decline (OR, 7.8; 95% CI, 2.3-26.4; P = .001). Delirium was associated with depression (OR, 2.2; 95% CI, 0.9-5.3; P = .08), lower 12-Item Short Form Survey physical health (adjusted mean difference -2.3 ± 1.1; P = .03), and neurocognitive decline (OR, 2.2; 95% CI, 1.2-4.0; P = .01). CONCLUSIONS: Stroke and delirium occur more frequently after SAVR than is commonly recognized, and these events are associated with disability, depression, cognitive decline, and poorer quality of life at 90 days postoperatively. These findings support the need for new interventions to reduce these events and improve patient-centered outcomes.

Concomitant Tricuspid Repair in Patients with Degenerative Mitral Regurgitation.

BACKGROUND: Tricuspid regurgitation is common in patients with severe degenerative mitral regurgitation. However, the evidence base is insufficient to inform a decision about whether to perform tricuspid-valve repair during mitral-valve surgery in patients who have moderate tricuspid regurgitation or less-than-moderate regurgitation with annular dilatation. METHODS: We randomly assigned 401 patients who were undergoing mitral-valve surgery for degenerative mitral regurgitation to receive a procedure with or without tricuspid annuloplasty (TA). The primary 2-year end point was a composite of reoperation for tricuspid regurgitation, progression of tricuspid regurgitation by two grades from baseline or the presence of severe tricuspid regurgitation, or death. RESULTS: Patients who underwent mitral-valve surgery plus TA had fewer primary-end-point events than those who underwent mitral-valve surgery alone (3.9% vs. 10.2%) (relative risk, 0.37; 95% confidence interval [CI], 0.16 to 0.86; P = 0.02). Two-year mortality was 3.2% in the surgery-plus-TA group and 4.5% in the surgery-alone group (relative risk, 0.69; 95% CI, 0.25 to 1.88). The 2-year prevalence of progression of tricuspid regurgitation was lower in the surgery-plus-TA group than in the surgery-alone group (0.6% vs. 6.1%; relative risk, 0.09; 95% CI, 0.01 to 0.69). The frequencies of major adverse cardiac and cerebrovascular events, functional status, and quality of life were similar in the two groups at 2 years, although the incidence of permanent pacemaker implantation was higher in the surgery-plus-TA group than in the surgery-alone group (14.1% vs. 2.5%; rate ratio, 5.75; 95% CI, 2.27 to 14.60). CONCLUSIONS: Among patients undergoing mitral-valve surgery, those who also received TA had a lower incidence of a primary-end-point event than those who underwent mitral-valve surgery alone at 2 years, a reduction that was driven by less frequent progression to severe tricuspid regurgitation. Tricuspid repair resulted in more frequent permanent pacemaker implantation. Whether reduced progression of tricuspid regurgitation results in long-term clinical benefit can be determined only with longer follow-up. (Funded by the National Heart, Lung, and Blood Institute and the German Center for Cardiovascular Research; ClinicalTrials.gov number, NCT02675244.).

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.

Pacemaker implantation associated with tricuspid repair in the setting of mitral valve surgery: Insights from a Cardiothoracic Surgical Trials Network randomized trial.

OBJECTIVES: In a recent trial, tricuspid annuloplasty (TA) during mitral valve surgery (MVS) for degenerative mitral regurgitation and moderate or less tricuspid regurgitation (TR) reduced the composite rate of death, reoperation for TR, or TR progression at 2 years. However, this benefit was counterbalanced by an increase in implantation of permanent pacemakers (PPMs). In this study, we analyzed the timing, indications, and risk factors for these implantations. METHODS: We randomized 401 patients (MVS alone = 203; MVS + TA = 198). Potential risk factors for PPMs were assessed using multivariable time-to-event models with death and PPM implantation for heart failure indications as competing risks. RESULTS: A PPM was implanted in 36 patients (9.6; 95% CI, 6.8-13.0) within 2 years of randomization, with 30/187 (16.0%) in the MVS + TA and 6/188 (3.2%) in the MVS groups (rate ratio, 5.08; 95% CI, 2.16-11.94; P < .001). Most (29/36; 80.6%) implantations occurred within 30 days postoperatively. Independent risk factors for PPM implantation within 2 years were TA (hazard ratio [HR], 5.94; 95% CI, 2.27-15.53; P < .001), increasing age (5 years, HR, 1.23; 95% CI, 1.01-1.52; P = .04), and left ventricular ejection fraction (LVEF; HR, 0.96; 95% CI, 0.92-0.99; P = .02). In the subset of TA recipients (n = 197), age (5 years, HR, 1.05; 95% CI, 1.00-1.10; P = .04) and LVEF (HR, 0.95; 95% CI, 0.91-0.99; P = .01) were associated with PPM within 2 years. CONCLUSIONS: Concomitant TA, age, and baseline LVEF were risk factors for PPM implantation in patients who underwent MVS for degenerative mitral regurgitation. Although TA was effective in preventing progression of TR, innovation is needed to identify ways to decrease PPM implantation rates.

Progression of Tricuspid Regurgitation After Surgery for Ischemic Mitral Regurgitation.

BACKGROUND: Whether to repair nonsevere tricuspid regurgitation (TR) during surgery for ischemic mitral valve regurgitation (IMR) remains uncertain. OBJECTIVES: The goal of this study was to investigate the incidence, predictors, and clinical significance of TR progression and presence of ≥moderate TR after IMR surgery. METHODS: Patients (n = 492) with untreated nonsevere TR within 2 prospectively randomized IMR trials were included. Key outcomes were TR progression (either progression by ≥2 grades, surgery for TR, or severe TR at 2 years) and presence of ≥moderate TR at 2 years. RESULTS: Patients' mean age was 66 ± 10 years (67% male), and TR distribution was 60% ≤trace, 31% mild, and 9% moderate. Among 2-year survivors, TR progression occurred in 20 (6%) of 325 patients. Baseline tricuspid annular diameter (TAD) was not predictive of TR progression. At 2 years, 37 (11%) of 323 patients had ≥moderate TR. Baseline TR grade, indexed TAD, and surgical ablation for atrial fibrillation were independent predictors of ≥moderate TR. However, TAD alone had poor discrimination (area under the curve, ≤0.65). Presence of ≥moderate TR at 2 years was higher in patients with MR recurrence (20% vs. 9%; p = 0.02) and a permanent pacemaker/defibrillator (19% vs. 9%; p = 0.01). Clinical event rates (composite of ≥1 New York Heart Association functional class increase, heart failure hospitalization, mitral valve surgery, and stroke) were higher in patients with TR progression (55% vs. 23%; p = 0.003) and ≥moderate TR at 2 years (38% vs. 22%; p = 0.04). CONCLUSIONS: After IMR surgery, progression of unrepaired nonsevere TR is uncommon. Baseline TAD is not predictive of TR progression and is poorly discriminative of ≥moderate TR at 2 years. TR progression and presence of ≥moderate TR are associated with clinical events. (Comparing the Effectiveness of a Mitral Valve Repair Procedure in Combination With Coronary Artery Bypass Grafting [CABG] Versus CABG Alone in People With Moderate Ischemic Mitral Regurgitation, NCT00806988; Comparing the Effectiveness of Repairing Versus Replacing the Heart's Mitral Valve in People With Severe Chronic Ischemic Mitral Regurgitation, NCT00807040).

Trends in MitraClip, mitral valve repair, and mitral valve replacement from 2000 to 2016.

OBJECTIVE: The dissemination of mitral valve repair as the first-line treatment and the introduction of MitraClip for patients who have a prohibitive risk for surgery have changed the landscape of mitral valve intervention. The aim of this study is to provide current and generalizable data regarding the trend of mitral valve interventions and outcomes from 2000 to 2016. METHODS: Patients ≥18 years of age who underwent mitral-valve interventions were identified using the National Inpatient Sample database. National estimates were generated by means of discharge weights; comorbid conditions were identified using Elixhauser methods. All trends were analyzed with JoinPoint software. RESULTS: A total of 656,030 mitral valve interventions (298,102 mitral valve replacement, 349,053 mitral valve repair, and 8875 MitraClip) were assessed. No changes in rate of procedures (per 100,000 people in the United States) were observed over this period (annual percent change, -0.4; 95% confidence limit, -1.1 to 0.3; P = .3). From 2000 to 2010, the number of replacements decreased by 5.6% per year (P < .001), whereas repair increased by 8.4% per year from 2000 to 2006 (P < .001). MitraClip procedures increased by 84.4% annually from 2013 to 2016 (P < .001). The burden of comorbidities increased throughout the study for all groups, with the greatest score for MitraClip recipients. Overall, length of stay has decreased for all interventions, most significantly for MitraClip. In-hospital mortality decreased from 8.5% to 3.7% for all interventions, with MitraClip having the most substantial decrease from 3.6% to 1.5%. CONCLUSIONS: Over a 17-year period, mitral-valve interventions were associated with improved outcomes despite being applied to an increasingly sicker population.

Risk for non-home discharge following surgery for ischemic mitral valve disease.

OBJECTIVES: To determine the frequency and risk factors for non-home discharge (NHD) and its association with clinical outcomes and quality of life (QOL) at 1 year following cardiac surgery in patients with ischemic mitral regurgitation (IMR). METHODS: Discharge disposition was evaluated in 552 patients enrolled in trials of severe or moderate IMR. Patient and in-hospital factors associated with NHD were identified using logistic regression. Subsequently, association of NHD with 1-year mortality, serious adverse events (SAEs), and QOL was assessed. RESULTS: NHD was observed in 30% (154/522) with 25% (n = 71/289) in moderate and 36% (n = 83/233) in patients with severe IMR (unadjusted P = .006), a difference not significant after including age (5-year change: adjusted odds ratio [adjOR], 1.52; 95% confidence interval [CI], 1.35-1.72; P < .001), diabetes (adjOR, 1.94; 95% CI, 1.27-2.94; P = .002), and previous heart failure (adjOR, 1.64; 95% CI, 1.06-2.52; P = .03). Odds of NHD were increased for patients with postoperative SAEs (adjOR, 1.85; 95% CI, 1.19-2.86; P = .01) but not based on type of cardiac surgery. Greater rates of death and SAEs were observed in NHD patients at 1 year: adjusted hazard ratio, 4.29 (95% CI, 2.14-8.59; P < .001) and adjusted rate ratio, 1.45 (95% CI, 1.03-2.02; P = .03), respectively. QOL did not differ significantly between groups. CONCLUSIONS: NHD is common following surgery for IMR, influenced by older age, diabetes, previous heart failure, and postoperative SAEs. These patients may be at greater risk of death and subsequent SAEs after discharge. Discussion of NHD with patients may have important implications for decision-making and guiding expectations following cardiac surgery.

Transcatheter mitral valve repair for functional mitral regurgitation: Evaluating the evidence.

OBJECTIVES: Two trials (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation Trial and Percutaneous Repair with the MitraClip Device for Severe Functional/Secondary Mitral Regurgitation Trial) were published in 2018 evaluating the effectiveness and safety of transcatheter repair for patients with heart failure with significant functional mitral regurgitation, which yielded different results. This article reviews the strength of the evidence, differences in trial designs, ethical and implementation implications, and delineates future research needs to help guide the appropriate dissemination of transcatheter repair for functional patients with mitral regurgitation. METHODS: The National Heart, Lung, and Blood Institute convened a workshop of interdisciplinary experts to address these objectives. RESULTS: Transcatheter repair of functional mitral regurgitation can provide significant benefits in terms of heart failure hospitalizations, survival, and quality of life when appropriate heart failure candidates with moderate to severe or severe mitral regurgitation while on optimal guideline-directed medical therapy can be identified. Key ingredients for success are preoperative evaluation and management and postoperative care by an interdisciplinary heart team. CONCLUSIONS: Given the discordance observed between trials, ongoing innovation in patient management, and potential expansion of indications for use, the evidence base must be expanded to optimize appropriate implementation of this complex therapy. This will require more complete capture of outcome data in real-world settings for all eligible candidates whether or not they receive this therapy. Inevitably, the indications for use of this therapy will expand, as will the devices and therapeutic approaches for this population, necessitating the study of comparative effectiveness through randomized trials or observational studies. Moreover, given the substantial variations in care delivery, conducting implementation research to delineate characteristics of the optimal care model would be of benefit.

Developing an Institute for Health Care Delivery Science: successes, challenges, and solutions in the first five years.

Medical knowledge is increasing at an exponential rate. At the same time, unexplained variations in practice and patient outcomes and unacceptable rates of medical errors and inefficiencies in health care delivery have emerged. Our Institute for Health Care Delivery Science (I-HDS) began in 2014 as a novel platform to conduct multidisciplinary healthcare delivery research. We followed ten strategies to develop a successful institute with excellence in methodology and strong understanding of the value of team science. Our work was organized around five hubs: 1) Quality/Process Improvement and Systematic Review, 2) Comparative Effectiveness Research, Pragmatic Clinical Trials, and Predictive Analytics, 3) Health Economics and Decision Modeling, 4) Qualitative, Survey, and Mixed Methods, and 5) Training and Mentoring. In the first 5 years of the I-HDS, we have identified opportunities for change in clinical practice through research using our health system's electronic health record (EHR) data, and designed programs to educate clinicians in the value of research to improve patient care and recognize efficiencies in processes. Testing the value of several model interventions has guided prioritization of evidence-based quality improvements. Some of the changes in practice have already been embedded in the EHR workflow successfully. Development and sustainability of the I-HDS has been fostered by a mix of internal and external funding, including philanthropic foundations. Challenges remain due to the highly competitive funding environment and changes needed to adapt the EHR to healthcare delivery research. Further stakeholder engagement and culture change working with hospital leadership and I-HDS core and affiliate members continues.

Medical management with interventional therapy versus medical management alone for unruptured brain arteriovenous malformations (ARUBA): final follow-up of a multicentre, non-blinded, randomised controlled trial.

BACKGROUND: In A Randomized trial of Unruptured Brain Arteriovenous malformations (ARUBA), randomisation was halted at a mean follow-up of 33·3 months after a prespecified interim analysis showed that medical management alone was superior to the combination of medical management and interventional therapy in preventing symptomatic stroke or death. We aimed to study whether these differences persisted through 5-years' follow-up. METHODS: ARUBA was a non-blinded, randomised trial done at 39 clinical centres in nine countries. Adults (age ≥18 years) diagnosed with an unruptured brain arteriovenous malformation, who had never undergone interventional therapy, and were considered by participating clinical centres to be suitable for intervention to eradicate the lesion, were eligible for inclusion. Patients were randomly assigned (1:1) by a web-based data collection system, stratified by clinical centre in a random permuted block design with block sizes of two, four, and six, to medical management alone or with interventional therapy (neurosurgery, embolisation, or stereotactic radiotherapy, alone or in any combination, sequence, or number). Although patients and investigators at a given centre were not masked to treatment assignment, investigators at other centres and those in the clinical coordinating centre were not informed of assignment or outcomes at any of the centres. The primary outcome was time to death or symptomatic stroke confirmed by imaging, assessed by a neurologist at each centre not involved in the management of participants' care, and monitored by an independent committee using an adaptive approach with interim analyses. Enrolment began on April 4, 2007, and was halted on April 15, 2013, after which follow-up continued until July 15, 2015. All analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, NCT00389181. FINDINGS: Of 1740 patients screened, 226 were randomly assigned to medical management alone (n=110) or medical management plus interventional therapy (n=116). During a mean follow-up of 50·4 months (SD 22·9), the incidence of death or symptomatic stroke was lower with medical management alone (15 of 110, 3·39 per 100 patient-years) than with medical management with interventional therapy (41 of 116, 12·32 per 100 patient-years; hazard ratio 0·31, 95% CI 0·17 to 0·56). Two patients in the medical management group and four in the interventional therapy group (two attributed to intervention) died during follow-up. Adverse events were observed less often in patients allocated to medical management compared with interventional therapy (283 vs 369; 58·97 vs 78·73 per 100 patient-years; risk difference -19·76, 95% CI -30·33 to -9·19). INTERPRETATION: After extended follow-up, ARUBA showed that medical management alone remained superior to interventional therapy for the prevention of death or symptomatic stroke in patients with an unruptured brain arteriovenous malformation. The data concerning the disparity in outcomes should affect standard specialist practice and the information presented to patients. The even longer-term risks and differences between the two therapeutic approaches remains uncertain. FUNDING: National Institute of Neurological Disorders and Stroke for the randomisation phase and Vital Projects Fund for the follow-up phase.

Strategies of Wait-listing for Heart Transplant vs Durable Mechanical Circulatory Support Alone for Patients With Advanced Heart Failure.

Importance: Given the shortage of donor hearts and improvement in outcomes with left ventricular assist device (LVAD) therapy, a relevant but, to date, unanswered question is whether select patients with advanced heart failure should receive LVAD destination therapy as an alternative to heart transplant. Objective: To determine whether a strategy of LVAD destination therapy is associated with similar survival benefit as wait-listing for heart transplant with or without LVAD therapy among patients with advanced heart failure. Design, Setting, and Participants: This retrospective propensity-matched cohort analysis used data on heart transplants from the United Network for Organ Sharing registry and LVAD implants from the Interagency Registry for Mechanically Assisted Circulatory Support from January 1, 2010, to December 31, 2014. The matched LVAD destination therapy cohort included 3411 patients. Data analysis for this study was conducted from December 22, 2017, to May 24, 2019. Main Outcomes and Measures: Survival at 5 years was analyzed using Cox proportional hazards models. Results: In total, 8281 patients had albumin level, creatinine level, and BMI data recorded and were included in the analysis. Despite propensity score matching, the 3411 patients receiving LVAD destination therapy still tended to be slightly older than the 3411 patients wait-listed for heart transplant (64.0 years [interquartile range, 55.0-70.0 years] vs 60.0 [interquartile range, 54.0-65.0 years]; P < .001), but there was no significant difference in sex (2701 men [79.2%] vs 2648 men [77.6%]; P = .13). After propensity score matching for age, sex, body mass index, renal function, and albumin level, 3411 patients were wait-listed for heart transplant. This included 1607 patients with bridge to transplant LVAD therapy and 1804 patients without LVAD. The strategy of wait-listing for heart transplant was associated with better 5-year survival than LVAD destination therapy (risk ratio, 0.42; 95% CI, 0.38-0.46) after matching and adjusting for key clinical factors. This survival advantage was associated with heart transplant (adjusted risk ratio for time-dependent transplant status, 0.27; 95% CI, 0.24-0.32). Conclusions and Relevance: The present analysis suggests that heart transplant with or without bridge to transplant LVAD therapy was associated with superior 5-year survival compared with LVAD destination therapy among patients matched on several relevant clinical factors. Continued improvement in LVAD technology, along with prospective comparative research, appears to be needed to amend this strategy.

Randomized Trials in Cardiac Surgery: JACC Review Topic of the Week.

Compared with randomized controlled trials (RCTs) in medical specialties, RCTs in cardiac surgery face specific issues. Individual and collective equipoise, rapid evolution of the surgical techniques, as well as difficulties in obtaining funding, and limited education in clinical epidemiology in the surgical community are among the most important challenges in the design phase of the trial. Use of complex interventions and learning curve effect, differences in individual operators' expertise, difficulties in blinding, and slow recruitment make the successful completion of cardiac surgery RCTs particularly challenging. In fact, over the course of the last 20 years, the number of cardiac surgery RCTs has declined significantly. In this review, a team of surgeons, trialists, and epidemiologists discusses the most important challenges faced by RCTs in cardiac surgery and provides a list of suggestions for the successful design and completion of cardiac surgery RCTs.

Impact of Aortic Atherosclerosis Burden on Outcomes of Surgical Aortic Valve Replacement.

BACKGROUND: Epiaortic ultrasound detects and localizes ascending aortic atherosclerosis. In this analysis we investigated the association between epiaortic ultrasound-based atheroma grade during surgical aortic valve replacement (SAVR) and perioperative adverse outcomes. METHODS: SAVR patients in a randomized trial of 2 embolic protection devices underwent a protocol-defined 5-view epiaortic ultrasound read at a core laboratory. Aortic atherosclerosis was quantified with the Katz atheroma grade, and patients were categorized as mild (grade I-II) or moderate/severe (grade III-V). Multivariable logistic regression was used to estimate associations between atheroma grade and adverse outcomes, including death, clinically apparent stroke, cerebral infarction on diffusion-weighted magnetic resonance imaging, delirium, and acute kidney injury (AKI) by 7 and 30 days. RESULTS: Precannulation epiaortic ultrasound data were available for 326 of 383 randomized patients (85.1%). Of these, 106 (32.5%) had moderate/severe Katz atheroma grade at any segment of the ascending aorta. Although differences in the composite of death, stroke, or cerebral infarction on diffusion-weighted magnetic resonance imaging by 7 days were not statistically significant, moderate/severe atheroma grade was associated with a greater risk of AKI by 7 days (adjusted odds ratio, 2.63; 95% confidence interval, 1.24-5.58; P = .01). At 30 days, patients with moderate/severe atheroma grade had a greater risk of death, stroke, or AKI (adjusted odds ratio, 1.97; 95% confidence interval, 1.04-3.71; P = .04). CONCLUSIONS: Moderate/severe aortic atherosclerosis was associated with an increased risk of adverse events after SAVR. Epiaortic ultrasound may serve as a useful adjunct for identifying patients who may benefit from strategies to reduce atheroembolic complications during SAVR.