Statistical primer: Composite endpoints and competing risks analysis.

Composite end-points are common primary outcomes in clinical trials. Their main benefit of utilizing a composite outcome is increasing the number of primary outcome events meaning fewer participants are required to deliver an adequately powered trial. By combining multiple important end-points in the primary outcome rather than having to select only one, composite end-points potentially make clinically meaningful benefits easier to detect and avoid ranking outcomes hierarchically. However there are a number of important considerations when designing and interpreting clinical trials that utilize composite end-points. In this Statistical Primer, issues with composite end-points such as competing events, halo effect, risk of bias, time to event limitations and the win ratio are discussed in the context of real world clinical trials.

[Total artificial heart: past, present, and future]. / Cuore artificiale totale: passato, presente e futuro.

Every year, approximately 5 out of 1000 patients receive a diagnosis of advanced heart failure, with a prevalence of 1-2% in the adult population. This figure is likely underestimated, considering undiagnosed cases. Despite significant progress in medical therapy for heart failure, mortality rates persist around 20% within the first year, reaching 50-60% at 5 years from the initial diagnosis. For patients with severe end-stage heart failure, the 1-year mortality rate can reach up to 70%. Heart transplantation remains the preferred treatment for terminal stages of the disease; however, the significant challenge lies in the mismatch between available donors and recipients. Given this dilemma, both short-term solutions including extracorporeal membrane oxygenation and long-term options such as left ventricular assist devices have gained prominence. These mechanical circulatory support systems become crucial for patients in critical conditions, temporarily ineligible for heart transplantation, such as those with severe irreversible pulmonary hypertension or acute organ failure. Despite these advancements, a growing number of patients on the waiting list develops severe biventricular dysfunction, precluding the use of a left ventricular assist device as a bridge to transplant. In such cases, a total artificial heart emerges as a viable therapeutic option.

Comparison of 4 mortality scores for surgical repair of type A aortic dissection: a multicentre external validation.

OBJECTIVES: In the last decades, 4 different scores for the prediction of mortality following surgery for type A acute aortic dissection (TAAD) were proposed. We aimed to validate these scores in a large external multicentre cohort. METHODS: We retrospectively analysed patients who underwent surgery for TAAD between 2000 and 2020. Patients were enrolled from 10 centres from 2 European countries. Outcomes were the early (30-day and/or in-hospital) and 1-year mortality. Discrimination, calibration and observed/expected (O/E) ratio were evaluated. RESULTS: A total of 1895 patients (31.7% females, mean age 63.72 ± 12.8 years) were included in the study. Thirty-day mortality and in-hospital mortality were 21.7% (n = 412) and 22.5% (n = 427) respectively. The German Registry of Acute Aortic Dissection Type A (GERAADA) score shows to have the best discrimination [area under the curve (AUC) 0.671 and 0.672] in predicting as well the early and the 1-year mortality, followed by the International Registry of Acute Aortic Dissection (IRAD) model 1 (AUC 0.658 and 0.672), the Centofanti (AUC 0.645 and 0.66) and the UK aortic score (AUC 0.549 and 0.563). According to Hosmer-Lemeshow and Brier tests, the IRAD model I and GERAADA, respectively, were well calibrated for the early mortality, while the GERAADA and Centofanti for the 1-year mortality. The O/E analysis showed a marked underestimation for patients labelled as low-risk for UK aortic score and IRAD model I for both outcomes. CONCLUSIONS: The GERAADA score showed the best performance in comparison with other scores. However, none of them achieved together a fair discrimination and a good calibration for predicting either the early or the 1-year mortality.

Mechanical heart valves and oral anticoagulation: a survey of the Italian Society of Cardiac Surgery.

In the latest European guidelines for the management of valvular heart disease, mechanical valve prostheses maintain a strategic role, particularly for certain patient subsets and age groups. Despite the high number of devices implanted in clinical practice, particularly in non-European and North American regions, current scientific literature and debate seem to suggest a limited use of mechanical heart valves. The cardiac surgery community seems to be highly interested in biological and transcatheter valve prostheses but less interested in mechanical heart valves, including possible strategies for self-management of anticoagulation therapy. In this respect, the Italian Society of Cardiac Surgery (SICCH), in particular the Italian Group of Research for Outcome in Cardiac Surgery (GIROC), has promoted a survey among its members to stimulate the interest in this topic and express their opinion on this issue that, due to the prevalence of the affected population and the new treatment options for improving patients' quality of life, should be more appraised and debated in the cardiac surgery community. The recorded results, obtained on the answers to 111 questionnaires, seem to divide the specialists into 'pros' and 'contras' on a useful tool for the entire cardiac surgery community. For this reason, SICCH proposes in conclusion to declare its unified and institutional opinion on this topic.

[Choosing a tailored prosthetic valve in cardiac surgery: what is the current role of mechanical prostheses?] / Il ruolo delle protesi valvolari meccaniche oggi. Dalla letteratura alla situazione italiana.

The choice of the mechanical/biological heart valve prosthesis is a topic currently debated in the light of the transcatheter prosthetic models and the results obtained/expected with the new biological valve models. Consequently, it seems that increasingly younger patients would be indicated for an implantation of a biological prosthesis. This is also in order to improve the quality of life of patients who want to avoid oral anticoagulant therapy. On the other hand, the guidelines for the treatment of heart valve disease assign a central role to the use of mechanical valve prostheses, particularly for certain patient subsets and age groups. This means that mechanical prostheses are still widely used worldwide, especially in non-European or North American regions. The cardiac surgery community therefore seems to be very interested in biological prostheses and transcatheter implants and scarcely interested in mechanical prostheses, including possible strategies for self-management of anticoagulant therapy. Recently, the Italian Society of Cardiac Surgery promoted a survey among its members to stimulate interest in the cardiac surgery community. This review article aims to summarize the most current results recorded with the use of mechanical prostheses and possible strategies, especially for the management of oral anticoagulant therapy, which can improve the patient's quality of life.

Bilateral Internal Thoracic Arteries Improve 10-Year Outcomes of Coronary Artery Bypass Grafting.

BACKGROUND: This observational cohort study was designed by the PRIORITY (PRedictIng long-term Outcomes afteR Isolated coronary arTery bypass surgery) steering committee to evaluate the 10-year follow-up outcome of bilateral internal thoracic arteries (BITA) versus single internal thoracic artery. METHODS: The PRIORITY project was designed to evaluate long-term outcome of 2 large prospective multicenter cohort studies of coronary artery bypass grafting. Clinical data on isolated coronary artery bypass grafting were merged with administrative data to collect follow-up information. The primary endpoint was the composite outcome of major adverse cardiac and cerebrovascular events at 10-year follow-up. Secondary endpoints were individual components of major adverse cardiac and cerebrovascular events at 10 years and surgical site complications or infections. A propensity score-based inverse probability treatment weighting (IPTW) was used to overcome the selection bias related to the observational nature of the study. RESULTS: The study population consisted of 10,988 patients who underwent isolated coronary artery bypass grafting. BITA was used in 23.5%. The use of BITA is related to lower incidence of major adverse cardiac and cerebrovascular events at 10 years (adjusted hazard ratio [HR] 0.88, 95% CI 0.79-0.98, P < .001). BITA correlated with better 10-year survival (IPTW adjusted HR 0.87, 95% CI 0.78-1.00, P = .05), re-revascularization (IPTW adjusted HR 0.83, 95% CI 0.74-0.92, P < .001), and myocardial infarction (IPTW adjusted HR 0.86, 95% CI 0.77-0.95, P = .005) but to increased incidence of surgical site complications or infections (HR 2.12, 95% CI 1.39-3.24, P < .001). CONCLUSIONS: In propensity-matched patients, use of BITA was associated with improved 10-year survival, freedom from repeat revascularization, and myocardial infarction but also higher incidence of surgical site complications.

Risk of Bias in Randomized Clinical Trials Comparing Transcatheter and Surgical Aortic Valve Replacement: A Systematic Review and Meta-analysis.

Importance: Recent European Society of Cardiology/European Association for Cardio-Thoracic Surgery (ESC/EACTS) guidelines highlighted some concerns about the randomized clinical trials (RCTs) comparing transcatheter aortic valve implantation (TAVI) and surgical aortic valve replacement (SAVR) for aortic stenosis. Quantification of these biases has not been previously performed. Objective: To assess whether randomization protects RCTs comparing TAVI and SAVR from biases other than nonrandom allocation. Data Sources: A systematic review of the literature between January 1, 2007, and June 6, 2022, on MEDLINE, Embase, and Cochrane Central Register of Controlled Trials was performed. Specialist websites were also checked for unpublished data. Study Selection: The study included RCTs with random allocation to TAVI or SAVR with a maximum 5-year follow-up. Data Extraction and Synthesis: Data extraction was performed by 2 independent investigators following the PRISMA guidelines. A random-effects meta-analysis was used for quantifying pooled rates and differential rates between treatments of deviation from random assigned treatment (DAT), loss to follow-up, and receipt of additional treatments. Main Outcomes and Measures: The primary outcomes were the proportion of DAT, loss to follow-up, and patients who were provided additional treatments and myocardial revascularization, together with their ratio between treatments. The measures were the pooled overall proportion of the primary outcomes and the risk ratio (RR) in the TAVI vs SAVR groups. Results: The search identified 8 eligible trials including 8849 participants randomly assigned to undergo TAVI (n = 4458) or SAVR (n = 4391). The pooled proportion of DAT among the sample was 4.2% (95% CI, 3.0%-5.6%), favoring TAVI (pooled RR vs SAVR, 0.16; 95% CI, 0.08-0.36; P < .001). The pooled proportion of loss to follow-up was 4.8% (95% CI, 2.7%-7.3%). Meta-regression showed a significant association between the proportion of participants lost to follow-up and follow-up time (slope, 0.042; 95% CI, 0.017-0.066; P < .001). There was an imbalance of loss to follow-up favoring TAVI (RR, 0.39; 95% CI, 0.28-0.55; P < .001). The pooled proportion of patients who had additional procedures was 10.4% (95% CI, 4.4%-18.5%): 4.6% (95% CI, 1.5%-9.3%) in the TAVI group and 16.5% (95% CI, 7.5%-28.1%) in the SAVR group (RR, 0.27; 95% CI, 0.15-0.50; P < .001). The imbalance between groups also favored TAVI for additional myocardial revascularization (RR, 0.40; 95% CI, 0.24-0.68; P < .001). Conclusions and Relevance: This study suggests that, in RCTs comparing TAVI vs SAVR, there are substantial proportions of DAT, loss to follow-up, and additional procedures together with systematic selective imbalance in the same direction characterized by significantly lower proportions of patients undergoing TAVI that might affect internal validity.

Survival and Recurrence of Endocarditis following Mechanical vs. Biological Aortic Valve Replacement for Endocarditis in Patients Aged 40 to 65 Years: Data from the INFECT-Registry.

BACKGROUND: Infective endocarditis (IE) is a serious disease, and in many cases, surgery is necessary. Whether the type of prosthesis implanted for aortic valve replacement (AVR) for IE impacts patient survival is a matter of debate. The aim of the present study is to quantify differences in long-term survival and recurrence of endocarditis AVR for IE according to prosthesis type among patients aged 40 to 65 years. METHODS: This was an analysis of the INFECT-REGISTRY. Trends in proportion to the use of mechanical prostheses versus biological ones over time were tested by applying the sieve bootstrapped t-test. Confounders were adjusted using the optimal full-matching propensity score. The difference in overall survival was compared using the Cox model, whereas the differences in recurrence of endocarditis were evaluated using the Gray test. RESULTS: Overall, 4365 patients were diagnosed and operated on for IE from 2000 to 2021. Of these, 549, aged between 40 and 65 years, underwent AVR. A total of 268 (48.8%) received mechanical prostheses, and 281 (51.2%) received biological ones. A significant trend in the reduction of implantation of mechanical vs. biological prostheses was observed during the study period (p < 0.0001). Long-term survival was significantly higher among patients receiving a mechanical prosthesis than those receiving a biological prosthesis (hazard ratio [HR] 0.546, 95% CI: 0.322-0.926, p = 0.025). Mechanical prostheses were associated with significantly less recurrent endocarditis after AVR than biological prostheses (HR 0.268, 95%CI: 0.077-0.933, p = 0.039). CONCLUSIONS: The present analysis of the INFECT-REGISTRY shows increased survival and reduced recurrence of endocarditis after a mechanical aortic valve prosthesis implant for IE in middle-aged patients.

Ten-year outcomes after off-pump and on-pump coronary artery bypass grafting: an inverse probability of treatment weighting comparative study.

AIMS: The debate on the advantages and limitations of off-pump myocardial revascularization (OPCAB) on long-term outcomes has not still arrived to a conclusion. This study was designed to compare the impact of OPCAB vs, on-pump coronary artery bypass grafting (CABG) on long-term mortality and major adverse cardiac and cerebrovascular events (MACCEs). METHODS: The PRIORITY project was designed to evaluate the long-term outcomes of two large prospective multicenter cohort studies on CABG. Data on isolated CABG were linked to two administrative datasets. The inverse probability of treatment weight was employed to balance the treatment groups. Time-to-event methods were employed to analyze endpoints. RESULTS: The cohort consisted of 10 988 patients who underwent isolated CABG (27.2% OPCAB). The median follow-up time was 7.9 years and was 100% complete. Unadjusted long-term survival was significantly worst for OPCAB, confirmed by weighted models (hazard ratio 1.08, 95% confidence interval (CI) 1.01-1.14, P = 0.01). OPCAB was associated to an increased risk of MACCE at 10 years (weighted hazard ratio 1.18, 95% CI 1.12-1.23, P < 0.001). Inside the MACCEs, OPCAB was significantly related to increased incidence of repeat revascularization (hazard ratio 2.27, 95% CI 1.39-3.85, P < 0.001, in the first 6 months, hazard ratio 1.19, 95% CI 1.09-1.32, P < 0.001 afterward) and stroke (hazard ratio 1.22, 95% CI 1.10-1.35, P < 0.001). CONCLUSION: The results of this study suggest that OPCAB was associated with an increased risk of mortality, repeat myocardial revascularization and stroke at 10 years compared with on-pump CABG.

Similar outcome of tricuspid valve repair and replacement for isolated tricuspid infective endocarditis.

AIMS: To compare early and late mortality of acute isolated tricuspid valve infective endocarditis (TVIE) treated with valve repair or replacement. METHODS: Patients who were surgically treated for TVIE from 1983 to 2018 were retrieved from the Italian Registry for Surgical Treatment of Valve and Prosthesis Infective Endocarditis. All the patients were followed up by means of phone interview or calling patient referral physicians or cardiologists. Kaplan-Meier method was used to assess late survival and survival free from TVIE recurrence with log-rank test for univariate comparison. The primary end points were early mortality (30 days after surgery) and long-term survival free from TVIE recurrence. RESULTS: A total of 4084 patients were included in the registry. Among them, 149 patients were included in the study. Overall, 77 (51.7%) underwent TV repair and 72 (48.3%) TV replacement. Early mortality was 9% (13 patients). Expected early mortality according to EndoSCORE was 12%. The TV repair showed lower mortality and major complication rate (7% and 16%), compared with TV replacement (11% and 25%), but statistical significance was not reached. Median follow-up was 19.1 years (14.3-23.8). Late deaths were 30 and IE recurrences were 5. No difference in cardiac survival free from IE was found between the two groups after 20 years (80 ±â€Š6% Repair Group vs 59 ±â€Š13% Replacement Group, P = 0.3). CONCLUSIONS: Overall results indicate that once surgically addressed, TVIE has a low recurrence rate and excellent survival, apparently regardless of the type of surgery used to treat it.

[ANMCO Position paper: Care pathway for advanced heart failure patients candidate for heart transplantation/ventricular assist device]. / Position paper ANMCO: Percorso assistenziale del paziente con insufficienza cardiaca avanzata candidabile a trapianto/assistenza ventricolare meccanica.

Heart failure is a complex clinical syndrome with a severe prognosis, despite therapeutic progress. The management of the advanced stages of the syndrome is particularly complex in patients who are referred to palliative care as well as in those who are candidates for cardiac replacement therapy. For the latter group, a prompt recognition of the transition to the advanced stage as well as an early referral to the centers for cardiac replacement therapy are essential elements to ensure that patients follow the most appropriate diagnostic-therapeutic pathway. The aim of this document is to focus on the main diagnostic and therapeutic aspects related to the advanced stages of heart failure and, in particular, on the management of patients who are candidates for cardiac replacement therapy.

The day after tomorrow: cardiac surgery and coronavirus disease-2019.

The impact of the coronavirus disease-2019 (COVID-19) pandemic forced the governments worldwide to deal with an unprecedented health crisis. The aim of this review is to summarize what happened to cardiac surgery worldwide during the first wave of this pandemic. A literature search was performed to extrapolate key concepts regarding guidelines and reorganization of cardiac surgery wards during COVID-19. Supporting literature was also included to discuss the hot topics related to COVID-19 and cardiac surgery. Hence, both official documents from national scientific societies and single- or multiple-center experiences during the pandemics are reviewed and discussed. In Italy, the first western country hit by the pandemic, two different models were proposed to cope with the need for ICU/ward beds and to reallocate cardiac surgical services: Hub-and-Spoke system ('Hubs', dedicated to perform urgent and nondeferrable surgery, and 'Spokes', turned into COVID centers) and/or a progressive reduction in surgical activity. Worldwide, several guidelines/consensus statements were published, suggesting how to deal with the outbreak. Two different approaches for stratifying surgical indications were proposed: dynamic, based on the number of hospitalized COVID-19 patients; static, based only on the severity of the cardiovascular disease. Moreover, the importance of personal protective equipment was stressed. Several measures should have been adopted to deal with an unprecedented need for healthcare resources allocation to care for COVID-19 patients, putting the healthcare systems under serious stress. Cardiac surgery has, as have most surgical activities, been asked to reduce its own activity, giving priority to emergency and nondeferrable cases.

Prognostic value of SARS-CoV-2 on patients undergoing cardiac surgery.

OBJECTIVE: To analyze Italian Cardiac Surgery experience during the pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) identifying risk factors for overall mortality according to coronavirus disease 2019 (COVID-19) status. METHODS: From February 20 to May 31, 2020, 1354 consecutive adult patients underwent cardiac surgery at 22 Italian Centers; 589 (43.5%), patients came from the red zone. Based on COVID-19 status, 1306 (96.5%) were negative to SARS-CoV-2 (COVID-N), and 48 (3.5%) were positive to SARS-CoV-2 (COVID-P); among the COVID-P 11 (22.9%) and 37 (77.1%) become positive, before and after surgery, respectively. Surgical procedures were as follows: 396 (29.2%) isolated coronary artery bypass grafting (CABG), 714 (52.7%) isolated non-CABG procedures, 207 (15.3%) two associate procedures, and three or more procedures in 37 (2.7%). Heart failure was significantly predominant in group COVID-N (10.4% vs. 2.5%, p = .01). RESULTS: Overall in-hospital mortality was 1.6% (22 cases), being significantly higher in COVID-P group (10 cases, 20.8% vs. 12, 0.9%, p < .001). Multivariable analysis identified COVID-P condition as a predictor of in-hospital mortality together with emergency status. In the COVID-P subgroup, the multivariable analysis identified increasing age and low oxygen saturation at admission as risk factors for in-hospital mortality. CONCLUSION: As expected, SARS-CoV-2 infection, either before or soon after cardiac surgery significantly increases in-hospital mortality. Moreover, among COVID-19-positive patients, older age and poor oxygenation upon admission seem to be associated with worse outcomes.

Impact of preoperative glycometabolic status on outcomes in cardiac surgery: Systematic review and meta-analysis.

BACKGROUND: Historically, impaired glucose metabolism has been associated with early and late complicated clinical outcomes after cardiac surgery; however, such a condition is not specific to subjects with diabetes mellitus and involves a larger patient population. METHODS: Databases were screened (January 2000 to December 2020) to identify eligible articles; studies that evaluated the association between preoperative metabolic status, as assessed by glycosylated hemoglobin levels and clinical outcomes, were considered. The studies were stratified in thresholds by baseline glycosylated hemoglobin level (lower vs higher). RESULTS: Thirty studies, involving 34,650 patients, were included in the review. In a meta-analysis stratified by glycosylated hemoglobin levels, early mortality was numerically reduced in each threshold comparison and yielded the highest reductions when less than 5.5% versus greater than 5.5% glycosylated hemoglobin levels were compared (risk ratio, 0.39; 95% confidence interval, 0.18-0.84; P = .02). Comparing higher glycosylated hemoglobin threshold values yielded comparable results. Late mortality was reduced with lower levels of glycosylated hemoglobin. Low preoperative glycosylated hemoglobin was associated with the lowest risk of sternal wound infections (risk ratio, 0.50; 95% confidence interval, 0.32-0.80; P = .003 and risk ratio, 0.53; 95% confidence interval, 0.39-0.70; P < .0001) for comparisons of less than 7.5% versus greater than 7.5% and less than 7.0% versus greater than 7.0% glycosylated hemoglobin thresholds, respectively. Additionally, levels of glycosylated hemoglobin lower than 7% were associated with reduced hospital stay, lower risk of stroke/transient ischemic attack (risk ratio 0.53; 95% confidence interval, 0.39-0.70; P < .0001), and acute kidney injury (risk ratio, 0.65; 95% confidence interval, 0.54-0.79; P < .0001). CONCLUSIONS: Lower levels of glycosylated hemoglobin in patients undergoing cardiac surgery are associated with a lower risk of early and late mortality, as well as in the incidence of postoperative acute kidney injury, neurologic complications, and wound infection, compared with higher levels.