Predictors of premature termination of cardiac surgery trials: insights from the Clinicaltrial.gov database.

OBJECTIVES: Clinical trials that are terminated prematurely may generate incomplete and potentially biased data and the reasons for premature trials termination are poorly understood. Our objective was to describe the incidence of premature trial termination and identify factors associated with it. METHODS: We performed a systematic search on ClinicalTrials.gov to identify all cardiac surgery trials from 1991 to 2023. Trials that were terminated prematurely were identified. Factors independently associated with premature termination were identified using multivariable logistic regression analysis. RESULTS: A total of 746 clinical trials were included; of them 577 were completed and 169 (22.6%) were terminated prematurely. Most of the trials originated from North America [294 (39.4%)], Europe [264 (35.4%)] or Asia [141 (18.9%)]. Fourteen of the trials terminated prematurely (8.3%) were phase 1, 75 (44.4%) phase 2, 49 (29.0%) phase 3 and 31 (18.3%) phase 4. Fifty (29.6%) trials were terminated because of slow recruitment, 20 (11.8%) because of sponsor decision and 12 (7.1%) because of lack of funding. Left ventricular assist device trials [odds ratio (OR) 3.65, 95% confidence interval (CI) (1.65-8.00) P = 0.001], valve surgery trials [OR 4.30, 95% CI (2.33-8.00) P < 0.001], aortic surgery trials [OR 2.86 95% CI (1.22-6.43) P = 0.012], phase 2 [OR 3.02, 95% CI (1.31-7.93) P = 0.015] and phase 4 trials [OR 3.62, 95% CI (1.43-10.23) P = 0.010] were at higher risk of premature termination while trials performed in Asia [OR 0.18, 95% CI (0.07-0.39) P ≤ 0.001] and Europe [OR 0.49, 95% CI (0.30-0.80) P = 0.004] were less likely to be terminated prematurely. CONCLUSIONS: Slow recruitment is the most common reason for premature termination of cardiac surgery trials. Trials on left ventricular assist device, valve surgery, aortic surgery, phase 2 trials and phase 4 trials are more likely to be terminated, while trials conducted in Asia and Europe are less likely to be terminated prematurely.

Association between overweight and obesity with coronary artery bypass graft failure: an individual patient data analysis of clinical trials.

OBJECTIVES: The association between obesity and graft failure after coronary artery bypass grafting has not been previously investigated. METHODS: We pooled individual patient data from randomized clinical trials with systematic postoperative coronary imaging to evaluate the association between obesity and graft failure at the individual graft and patient levels. Penalized cubic regression splines and mixed-effects multivariable logistic regression models were performed. RESULTS: Six trials comprising 3928 patients and 12 048 grafts were included. The median time to imaging was 1.03 (interquartile range 1.00-1.09) years. By body mass index (BMI) category, 800 (20.4%) patients were normal weight (BMI 18.5-24.9), 1668 (42.5%) were overweight (BMI 25-29.9), 983 (25.0%) were obesity class 1 (BMI 30-34.9), 344 (8.8%) were obesity class 2 (BMI 35-39.9) and 116 (2.9%) were obesity class 3 (BMI 40+). As a continuous variable, BMI was associated with reduced graft failure [adjusted odds ratio (aOR) 0.98 (95% confidence interval (CI) 0.97-0.99)] at the individual graft level. Compared to normal weight patients, graft failure at the individual graft level was reduced in overweight [aOR 0.79 (95% CI 0.64-0.96)], obesity class 1 [aOR 0.81 (95% CI 0.64-1.01)] and obesity class 2 [aOR 0.61 (95% CI 0.45-0.83)] patients, but not different compared to obesity class 3 [aOR 0.94 (95% CI 0.62-1.42)] patients. Findings were similar, but did not reach significance, at the patient level. CONCLUSIONS: In a pooled individual patient data analysis of randomized clinical trials, BMI and obesity appear to be associated with reduced graft failure at 1 year after coronary artery bypass grafting.

Does prehabilitation before esophagectomy improve postoperative outcomes? A systematic review and meta-analysis.

Esophagectomy for esophageal cancer is associated with high morbidity. It remains unclear whether prehabilitation, a strategy aimed at optimizing patients' physical and mental functioning prior to surgery, improves postoperative outcomes. A systematic review and meta-analysis was conducted to evaluate the effect of prehabilitation on post-operative outcomes after esophagectomy. Data sources included Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CINAHL, and PEDro, with information from 1 January 2000 to 5 August 2023. The analysis included randomized controlled trials and observational studies that compared prehabilitation interventions to standard care prior to esophagectomy. A random effects model was used to generate a pooled estimate for pairwise meta-analysis, meta-analysis of proportions, and meta-analysis of means. A total of 1803 patients were included with 584 in randomized controlled trials (RCTs) and 1219 in observational studies. In the randomized evidence, there were no significant differences between prehabilitation and control in the odds of postoperative pneumonia (15.0 vs. 18.9%, odds ratio (OR) 1.06 [95% confidence interval (CI): 0.66;1.72]) or pulmonary complications (14 vs. 25.6%, OR 0.68 [95% CI: 0.32;1.45]). In the observational data, there was a reduction in both postoperative pneumonia (22.5 vs. 32.9%, OR 0.48 [95% CI: 0.28;0.83]) and pulmonary complications (26.1 vs. 52.3%, OR 0.35 [95% CI: 0.17;0.75]) with prehabilitation. Hospital and intensive care unit length of stay (days), operative mortality, and severe complications (Clavien-Dindo ≥ 3) did not differ between groups in both the randomized data and observational data. Prehabilitation demonstrated reductions in postoperative pneumonia and pulmonary complications in observational studies, but not RCTs. The overall certainty of these findings is limited by the low quality of the available evidence.

Outcomes According to Coronary Revascularization Modality in the ISCHEMIA Trial.

BACKGROUND: In the ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trial, the risk of ischemic events was similar in patients with stable coronary artery disease treated with an invasive (INV) strategy of angiography and percutaneous coronary intervention (PCI) or surgical (coronary artery bypass grafting [CABG]) coronary revascularization and a conservative (CON) strategy of initial medical therapy. OBJECTIVES: The authors analyzed separately the outcomes of INV patients treated with PCI or CABG. METHODS: Patients without preceding primary outcome events were categorized as INV-PCI or INV-CABG from the time of revascularization. The ISCHEMIA primary outcome (composite of cardiovascular death, protocol-defined myocardial infarction or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest) was used. RESULTS: Among INV-CABG patients, primary outcome events occurred in 84 of 512 (16.4%) at a median follow-up of 2.85 years; 48 events (57.1%) occurred within 30 days after CABG, including 40 procedural MIs. Among INV-PCI patients, primary outcome events occurred in 147 of 1,500 (9.8%) at median follow-up of 2.94 years; 31 of which (21.1%) occurred within 30 days after PCI, including 24 procedural MIs. In comparison, 352 of 2,591 CON patients (13.6%) had primary outcome events at a median follow-up of 3.2 years, 22 of which (6.3%) occurred within 30 days of randomization. The adjusted primary outcome risks were higher after both CABG and PCI within 30 days (HR: 16.25 [95% CI: 11.44-23.07] and HR: 2.99 [95% CI: 1.97-4.53]) and lower thereafter (0.63 [95% CI: 0.44-0.89] and 0.66 [95% CI: 0.53-0.82]). CONCLUSIONS: In ISCHEMIA, early revascularization by PCI and CABG was associated with higher early risks and lower long-term risks of cardiovascular events compared with CON. The early risk was greatest after CABG, owing to protocol-defined procedural MIs.

Cancer and the Risk of Perioperative Arterial Ischemic Events.

BACKGROUND AND AIMS: Most cancer patients require surgery for diagnosis and treatment. This study evaluated whether cancer is a risk factor for perioperative arterial ischemic events. METHODS: The primary cohort included patients registered in the National Surgical Quality Improvement Program (NSQIP) between 2006-2016. The secondary cohort included Healthcare Cost and Utilization Project (HCUP) claims data from 11 U.S. states between 2016-2018. Study populations comprised patients who underwent inpatient (NSQIP, HCUP) or outpatient (NSQIP) surgery. Study exposures were disseminated cancer (NSQIP) and all cancers (HCUP). The primary outcome was a perioperative arterial ischemic event, defined as myocardial infarction or stroke diagnosed within 30 days after surgery. RESULTS: Among 5,609,675 NSQIP surgeries, 2.2% involved patients with disseminated cancer. The perioperative arterial ischemic event rate was 0.96% among patients with disseminated cancer versus 0.48% among patients without (HR, 2.01; 95% CI, 1.90-2.13). In Cox analyses adjusting for demographics, functional status, comorbidities, surgical specialty, anesthesia type, and clinical factors, disseminated cancer remained associated with higher risk of perioperative arterial ischemic events (HR, 1.37; 95% CI, 1.28-1.46). Among 1,341,658 surgical patients in the HCUP cohort, 11.8% had a diagnosis of cancer. A perioperative arterial ischemic event was diagnosed in 0.74% of patients with cancer versus 0.54% of patients without cancer (HR, 1.35; 95% CI, 1.27-1.43). In Cox analyses adjusted for demographics, insurance, comorbidities, and surgery type, cancer remained associated with higher risk of perioperative arterial ischemic events (HR, 1.31; 95% CI, 1.21-1.42). CONCLUSIONS: Cancer is an independent risk factor for perioperative arterial ischemic events.

STICH3C: Rationale and Study Protocol.

BACKGROUND: Coronary artery bypass grafting (CABG) is the recommended mode of revascularization in patients with ischemic left ventricular dysfunction (iLVSD) and multivessel disease. However, contemporary percutaneous coronary intervention (PCI) outcomes have improved with the integration of novel technologies and refinement of revascularization strategies, and PCI is often used in clinical practice in this population. There is a lack of evidence from randomized trials comparing contemporary state-of-the-art PCI versus CABG for the treatment of iLVSD and multivessel disease. This was the impetus for the STICH3C trial (Canadian CABG or PCI in Patients With Ischemic Cardiomyopathy), described here. METHODS: The STICH3C trial is a prospective, unblinded, international, multicenter trial with an expected sample size of 754 participants from ≈45 centers. Patients with multivessel/left main coronary artery disease and iLVSD with left ventricular ejection fraction ≤40% considered by the local Heart Team appropriate for and amenable to revascularization by both modes of revascularization will be randomized in a 1:1 ratio to state-of-the-art PCI or CABG. RESULTS: The primary end point is the composite of death from any cause, stroke, spontaneous myocardial infarction, urgent repeat revascularization, or heart failure readmission, summarized as a time-to-event outcome. The key hierarchical end point is time to death and frequency of hospitalizations for heart failure. The key safety outcome is a composite of major adverse events. Disease-specific quality-of-life and health economics measures will be compared between groups. Participants will be followed for a median of 5 years, with a minimum follow-up of 4 years. CONCLUSIONS: STICH3C will directly inform patients, clinicians, and international practice guidelines about the efficacy and safety of CABG versus PCI in patients with iLVSD. The results will provide novel and broad evidence, including clinical events, health status, and economic assessments, to guide care for patients with iLVSD and severe coronary artery disease. REGISTRATION: URL: https://clinicaltrials.gov/; Unique identifier: NCT05427370.

ESC/EACTS vs. ACC/AHA guidelines for the management of severe aortic stenosis.

Aortic stenosis (AS) is a serious and complex condition, for which optimal management continues to evolve rapidly. An understanding of current clinical practice guidelines is critical to effective patient care and shared decision-making. This state of the art review of the 2021 European Society of Cardiology/European Association for Cardio-Thoracic Surgery Guidelines and 2020 American College of Cardiology/American Heart Association Guidelines compares their recommendations for AS based on the evidence to date. The European and American guidelines were generally congruent with the exception of three key distinctions. First, the European guidelines recommend intervening at a left ventricular ejection fraction of 55%, compared with 60% over serial imaging by the American guidelines for asymptomatic patients. Second, the European guidelines recommend a threshold of ≥65 years for surgical bioprosthesis, whereas the American guidelines employ multiple age categories, providing latitude for patient factors and preferences. Third, the guidelines endorse different age cut-offs for transcatheter vs. surgical aortic valve replacement, despite limited evidence. This review also discusses trends indicating a decreasing proportion of mechanical valve replacements. Finally, the review identifies gaps in the literature for areas including transcatheter aortic valve implantation in asymptomatic patients, the appropriateness of Ross procedures, concomitant coronary revascularization with aortic valve replacement, and bicuspid AS. To summarize, this state of the art review compares the latest European and American guidelines on the management of AS to highlight three areas of divergence: timing of intervention, valve selection, and surgical vs. transcatheter aortic valve replacement criteria.

Incidence and Impact of a Single-Unit Red Blood Cell Transfusion: Analysis of The Society of Thoracic Surgeons Database 2010-2019.

BACKGROUND: As the adverse effects of blood transfusions are better understood, recommendations support single-unit red blood cell (RBC) transfusions (SRBCT). However, an isolated SRBCT across the entire index admission suggests even the single unit may be avoidable. We sought to identify the characteristics of cardiac surgery patients receiving an isolated SRBCT and analyze the impact on outcomes. METHODS: The Society of Thoracic Surgeons Adult Cardiac Surgery Database was queried for the period between January 1, 2010, and December 31, 2019. Patients aged >18 years undergoing isolated coronary artery bypass grafting or isolated aortic valve replacement were included. A total of 2,151,430 encounters were analyzed. RESULTS: Of the 847,442 patients (39.3%) receiving any RBC transfusion during their index admission, 206,555 (24.4%) received only 1 unit. Propensity-matching analysis determined SRBCT patients were significantly older (67.26 vs 64.02 years; odds ratio [OR], 1.02; P < .001), female (39.1% vs 17.8%; OR, 1.57; P < .001), non-White (18.2% vs 13.1%; OR, 0.81; P < .001), and had a smaller body surface area (1.94 vs 2.07 m2; OR, 0.20; P < .001). They also had higher mortality (1.4% vs 1.0%, P < .001), stroke (1.7% vs 1.2%, P < .001), prolonged ventilation (6.4% vs 3.4%, P < .001), renal failure (1.8% vs 0.9%, P < .001), and reoperations (1.3% vs. 0.5%, P < .001) than patients who received 0 RBCs. CONCLUSIONS: SRBCT is a common occurrence in adult cardiac surgery. This low-volume transfusion is strongly associated with higher morbidity, even after controlling for preoperative risk factors.

Differences Among Clinical Trials and Registries on Surgical and Percutaneous Coronary Interventions.

BACKGROUND: A need exists for systematic evaluation of the differences in baseline characteristics and early outcomes between patients enrolled in randomized controlled trials (RCTs) and clinical practice for coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI). METHODS: Systematic searches were conducted to identify RCTs comparing CABG vs PCI and CABG or PCI registries. Sixteen predefined baseline characteristics and 30-day mortality were extracted from the included studies. Pooled proportion and mean with 95% CI were calculated for binary and continuous outcomes, respectively, by using the random effects model. RESULTS: Fourteen RCTs and 10 registries including more than 2 million patients were included. Registry patients who underwent CABG had a higher prevalence of hypertension, smoking, reduced left ventricular ejection fraction, and prior myocardial infarction, but a lower prevalence of single-vessel disease when compared with CABG-treated patients included in RCTs. Regarding PCI, hypertension, hyperlipidemia, left main coronary artery disease, triple-vessel coronary disease, and NYHA functional class

Multiple arterial coronary bypass grafting is associated with better survival compared with second-generation drug-eluting stents in patients with stable multivessel coronary artery disease.

OBJECTIVE: We sought to compare the long-term outcomes of multiarterial graft (MAG) coronary artery bypass grafting (CABG) versus percutaneous coronary intervention (PCI) with second-generation drug-eluting stents (DES) to treat stable multivessel coronary artery disease. METHODS: This study was a multicenter population-based retrospective analysis of all residents of Ontario, Canada, from January 1, 2011, to December 31, 2019. We identified 3600 cases of elective primary isolated CABG with MAG and 2187 cases of PCI with second-generation DES. RESULTS: After the application of propensity score-weighting using overlap weights, MAG was associated with better survival over 5 years compared with DES (96.8% vs 94.5%; hazard ratio [HR], 0.56; 95% CI, 0.37-0.85). MAG was also associated with better secondary outcomes including a composite of death, myocardial infarction, and stroke (94.3% vs 88.5%; HR, 0.49; 95% CI, 0.36-0.65). The rate of death, stroke, myocardial infarction, and repeat revascularization (91.2% vs 70.7%; HR, 0.24; 95% CI, 0.20-0.30), and the individual end points of myocardial infarction (1.4% vs 6.9%; HR, 0.22; 95% CI, 0.13-0.35), and repeat revascularization (4.1% vs 24.2%; HR, 0.14; 95% CI, 0.10-0.18) were lower with MAG. PCI with second-generation DES was associated with a lower rate of stroke up to 5 years (0.6% vs 1.8%; HR, 3.97; 95% CI, 1.45-10.88). CONCLUSIONS: CABG with MAG was associated with better survival and fewer major cardiac adverse events compared with second-generation DES and might be considered the treatment of choice for patients with stable multivessel coronary artery disease. Further randomized controlled trials are needed to confirm this hypothesis.

Impact of advanced imaging techniques on cardiac surgery-New insights provided by cardiac magnetic resonance.

This dialog between a cardiac surgeon (C.L.) and cardiac imager (J.W.W.) provides an overview of cardiac MRI (CMR) methods relevant to cardiac surgery. Major areas of focus include logistics of performing a CMR exam, as well as established and emerging methods for assessment of cardiac structure, function, valvular performance, and tissue characterization. Regarding tissue characterization, a major area of focus concerns CMR assessment of viability, for which this modality has been shown to provide incremental utility to conventional techniques for detection of presence and transmural extent of infarction, as well as powerful predictive utility of recovery of left ventricular systolic function as well as long term clinical prognosis in patients with an array of clinical conditions, including coronary artery disease and valvular heart disease both before and following cardiac surgery.

The impact of concomitant mitral valve intervention on outcomes of aortic root replacement.

OBJECTIVE: To investigate the impact of concomitant mitral valve repair (MVr) or replacement (MVR) at the time of aortic root replacement (ARR). METHODS: We queried our aortic database for consecutive patients undergoing ARR in combination with MVr or MVR from 1997 to 2021. Patients undergoing valve sparing root replacement (VSRR) were excluded. We compared operative mortality (OM) and a composite of major adverse events (MAE) in those undergoing CVG both with (Group 2) and without a concomitant MV procedure (Group 1). We also analyzed outcomes between patients undergoing MV repair versus MV replacement. RESULTS: Sixty-one patients underwent ARR with concomitant MVr (29/47.5%) or MVR (32/52.5%). Compared to patients in Group 2 (n = 955), those in Group 1 presented with worse NYHA class, lower ejection fraction, higher rate of connective tissue disease, and underwent more frequently urgent/emergent procedures. Group 1 had higher incidence of postoperative MAE (8/61(13%) vs 51/955(5%), p = .03). There was no difference in operative mortality between the two groups (0/61(0%) vs. 3/955(0.3%), p = 1). Compared to the ARR + MVR subgroup, the ARR + MVr subgroup had higher incidence of postoperative MAE (5/29(17.2%) vs. 3/32(9.4%), p = 0.02). Multivariate analysis identified MVr (OR 2.78, 95% confidence interval [CI] [1.03;7.48], p = 0.04) as an independent predictor of MAE. CONCLUSIONS: Operative mortality remained low in both groups. The addition of MVR/MVr to composite valve-graft replacement of the aortic root does not increase OM in experienced hands. The incidence of MAEs was higher in those undergoing MVr but may be a reflection of greater preoperative comorbidity rather than issues related to a more complex operation.

Treatment and outcomes of mechanical complications of acute myocardial infarction during the Covid-19 era: A comparison with the pre-Covid-19 period. A systematic review and meta-analysis.

This study aims to compare treatments and outcomes of mechanical complications of acute myocardial infarction (MI) during the Covid-19 and in the pre-Covid-19 era. Electronic databases have been searched for MI mechanical complications during the Covid-19 era and in the previous period from January 1998 to January 2020 (pre-Covid-19 era), until October 2021. To perform a quantitative analysis of non-comparative series, a meta-analysis of proportion has been conducted. Early mortality after surgical treatment was 15.0% while it was significantly higher after conservative treatment (62.4%) (P = 0.026). Early mortality after surgical treatment was seemingly higher in the pre-Covid-19 era but the difference did not reach statistical significance (15.0% vs 38.9%; P = 0.13). Mortality in patients treated conservatively, or turned down for surgery, was lower during the Covid-19 pandemic (62.4% vs 97.7%; P = 0.001). The crude mean prevalence of the use rate of conservative or surgical treatment across the studies during Covid-19 and in the pre-Covid-19 era was comparable. The current increased incidence of MI mechanical complications might be a consequence of delayed presentation or restricted access to hospital facilities. Despite the general negative impact of Covid-19 on cardiac surgery volumes and outcomes and the apparent increase of the incidence of MI complications, the outcomes of their surgical and clinical treatment seem not to have been affected during the pandemic.

Impact of ascending aortic prosthetic grafts on early postoperative descending aortic biomechanics on cardiac magnetic resonance imaging.

OBJECTIVES: Among patients with ascending thoracic aortic aneurysms, prosthetic graft replacement yields major benefits but risk for recurrent aortic events persists for which mechanism is poorly understood. This pilot study employed cardiac magnetic resonance to test the impact of proximal prosthetic grafts on downstream aortic flow and vascular biomechanics. METHODS: Cardiac magnetic resonance imaging was prospectively performed in patients with thoracic aortic aneurysms undergoing surgical (Dacron) prosthetic graft implantation. Imaging included time resolved (4-dimensional) phase velocity encoded cardiac magnetic resonance for flow quantification and cine-cardiac magnetic resonance for aortic wall distensibility/strain. RESULTS: Twenty-nine patients with thoracic aortic aneurysms undergoing proximal aortic graft replacement were studied; cardiac magnetic resonance was performed pre- [12 (4, 21) days] and postoperatively [6.4 (6.2, 7.2) months]. Postoperatively, flow velocity and wall shear stress increased in the arch and descending aorta (P < 0.05); increases were greatest in hereditary aneurysm patients. Global circumferential strain correlated with wall shear stress (r = 0.60-0.72, P < 0.001); strain increased postoperatively in the native descending and thoraco-abdominal aorta (P < 0.001). Graft-induced changes in biomechanical properties of the distal native ascending aorta were associated with post-surgical changes in descending aortic wall shear stress, as evidenced by correlations (r = -0.39-0.52; P ≤ 0.05) between graft-induced reduction of ascending aortic distensibility and increased distal native aortic wall shear stress following grafting. CONCLUSIONS: Prosthetic graft replacement of the ascending aorta increases downstream aortic wall shear stress and strain. Postoperative increments in descending aortic wall shear stress correlate with reduced ascending aortic distensibility, suggesting that grafts provide a nidus for high energy flow and adverse distal aortic remodelling.

Contemporary coronary artery bypass graft surgery and subsequent percutaneous revascularization.

Patients who have undergone coronary artery bypass graft (CABG) surgery are susceptible to bypass graft failure and progression of native coronary artery disease. Although the saphenous vein graft (SVG) was traditionally the most-used conduit, arterial grafts (including the left and right internal thoracic arteries and the radial artery) have improved patency rates. However, the need for secondary revascularization remains common, and percutaneous coronary intervention (PCI) has become the most common modality of secondary revascularization after CABG surgery. Procedural characteristics and clinical outcomes differ considerably from those associated with PCI in patients without previous CABG surgery, owing to altered coronary anatomy and differences in conduit pathophysiology. In particular, SVG PCI carries an increased risk of complications, and operators are shifting their focus towards embolic protection strategies and complex native-vessel interventions, increasingly using SVGs as conduits to facilitate native-vessel PCI rather than pursuing SVG PCI. In this Review, we discuss the differences in conduit pathophysiology, changes in CABG surgery techniques, and the latest evidence in terms of PCI in patients with previous CABG surgery, with a particular emphasis on safety and long-term efficacy. We explore the subject of contemporary CABG surgery and subsequent percutaneous revascularization in this complex patient population.