James M. Meza

Levosimendan in Patients with Left Ventricular Dysfunction Undergoing Cardiac Surgery

BACKGROUND Levosimendan is an inotropic agent that has been shown in small studies to prevent or treat the low cardiac output syndrome after cardiac surgery. METHODS In a multicenter, randomized, placebo‐controlled, phase 3 trial, we evaluated the efficacy and safety of levosimendan in patients with a left ventricular ejection fraction of 35% or less who were undergoing cardiac surgery with the use of cardiopulmonary bypass. Patients were randomly assigned to receive either intravenous levosimendan (at a dose of 0.2 μg per kilogram of body weight per minute for 1 hour, followed by a dose of 0.1 μg per kilogram per minute for 23 hours) or placebo, with the infusion started before surgery. The two primary end points were a four‐component composite of death through day 30, renal‐replacement therapy through day 30, perioperative myocardial infarction through day 5, or use of a mechanical cardiac assist device through day 5; and a two‐component composite of death through day 30 or use of a mechanical cardiac assist device through day 5. RESULTS A total of 882 patients underwent randomization, 849 of whom received levosimendan or placebo and were included in the modified intention‐to‐treat population. The four‐component primary end point occurred in 105 of 428 patients (24.5%) assigned to receive levosimendan and in 103 of 421 (24.5%) assigned to receive placebo (adjusted odds ratio, 1.00; 99% confidence interval [CI], 0.66 to 1.54; P=0.98). The two‐component primary end point occurred in 56 patients (13.1%) assigned to receive levosimendan and in 48 (11.4%) assigned to receive placebo (adjusted odds ratio, 1.18; 96% CI, 0.76 to 1.82; P=0.45). The rate of adverse events did not differ significantly between the two groups. CONCLUSIONS Prophylactic levosimendan did not result in a rate of the short‐term composite end point of death, renal‐replacement therapy, perioperative myocardial infarction, or use of a mechanical cardiac assist device that was lower than the rate with placebo among patients with a reduced left ventricular ejection fraction who were undergoing cardiac surgery with the use of cardiopulmonary bypass. (Funded by Tenax Therapeutics; LEVO‐CTS ClinicalTrials.gov number, NCT02025621.)

Evolving practice pattern changes and outcomes in the era of hybrid aortic arch repair

OBJECTIVE The role of hybrid repair in the management of aortic arch pathology, and long-term outcomes with these techniques, remains uncertain. We report a decade of experience with hybrid arch repair (HAR) and assess institutional practice patterns with regard to the use of hybrid and open techniques. METHODS Hybrid and open total and distal arch procedures performed between July 2005 and January 2015 were identified from a prospectively maintained, institutional aortic surgery database. Perioperative morbidity and mortality, freedom from reintervention, and long-term survival were calculated. Hybrid and open procedural volumes over the study period were assessed to evaluate for potential practice pattern changes. RESULTS During the study period 148 consecutive procedures were performed for repair of transverse and distal aortic arch pathology, including 101 hybrid repairs and 47 open total or distal arch repairs. Patients in the hybrid repair group were significantly older with a greater incidence of chronic kidney disease, peripheral vascular disease, and chronic lung disease. Perioperative mortality and outcomes were not significantly different between the hybrid and open groups, aside from decreased median length of stay after hybrid repair. Need for subsequent reintervention was significantly greater after hybrid repair. Unadjusted long-term survival was superior after open repair (70% 5-year survival open vs 47% hybrid; P = .03), although aorta-specific survival was similar (98% 5-year aorta-specific survival open vs 93% hybrid; P = .59). Institutional use of HAR decreased over the final 3 years of the study, with an associated increased use of open total or distal arch repairs. This was primarily the result of decreased use of native zone 0 hybrid procedures. Concurrent with this apparent increased stringency around patient selection for HAR, perioperative morbidity and mortality was reduced, including avoidance of retrograde type A dissection. CONCLUSIONS HAR remains a viable option for higher-risk patients with transverse arch pathology with perioperative outcomes and long-term aorta-specific survival similar to open repair, albeit at a cost of increased reintervention. This observational single-institution study would suggest decreased use in more recent years in favor of open repair due to avoidance of native zone 0 hybrid procedures. This decline in the institutional use of native zone 0 hybrid repairs was associated with improved perioperative outcomes.

What Is the Optimal Transplant for Older Patients With Idiopathic Pulmonary Fibrosis

BACKGROUND There is controversy regarding the optimal type of lung transplant--single orthotopic lung transplantation (SOLT) versus bilateral orthotopic lung transplantation (BOLT)--for patients with idiopathic pulmonary fibrosis. We performed this study to determine which type of transplant is more appropriate for older patients with this condition. METHODS We conducted a review of the United Network for Organ Sharing database from 2005 to 2013 for patients aged 65 years or more with idiopathic pulmonary fibrosis. A 1:1 nearest-neighbor propensity match was utilized to determine differences in survival by transplant procedure type (SOLT versus BOLT). Logistic regression modeling taking into account interaction terms between prespecified variables and the type of transplant was utilized to determine variables that altered the survival outcomes associated with SOLT versus BOLT. RESULTS Of 1,564 patients who met study criteria, 521 (33.3%) received BOLT. After propensity matching 498 BOLT recipients to 498 SOLT recipients, BOLT was associated with a significantly improved 5-year survival (48.7% versus 35.2%, p < 0.01). However, the mortality hazard associated with BOLT varied from a nonsignificant reduction in survival within 3 months after transplant (hazard ratio 1.24, 95% confidence interval: 0.80 to 1.93) to a significant survival benefit for patients who survived beyond 1 year (hazard ratio 0.64, 95% confidence interval: 0.47 to 0.86). Functional status was also found to be a significant predictor of the survival benefit associated with BOLT. CONCLUSIONS Bilateral orthotopic lung transplantation is associated with significantly improved survival over SOLT for older patients with idiopathic pulmonary fibrosis, driven by a late survival benefit from bilateral transplantation. However, patients with a reduced preoperative functional status do not appear to derive a similar benefit from bilateral transplantation.

The impact of tumor size on the association of the extent of lymph node resection and survival in clinical stage I non-small cell lung cancer.

INTRODUCTION Lymph node evaluation for node-negative non-small cell lung cancer (NSCLC) is associated with long-term survival but it is not clear if smaller tumors require as extensive a pathologic nodal assessment as larger tumors. This study evaluated the relationship of tumor size and optimal extent of lymph node resection using the National Cancer Data Base (NCDB). MATERIALS AND METHODS The incremental survival benefit of each additional lymph node that was evaluated for patients in the NCDB who underwent lobectomy for clinical Stage I NSCLC from 2003 to 2006 was evaluated using Cox multivariable proportional hazards regression modeling. The impact of tumor size was assessed by repeating the Cox analysis with patients stratified by tumor size ≥2 cm vs <2 cm. RESULTS A median of 7 [interquartile range: 4,11] lymph nodes were examined in 13,827 patients who met study criteria. Following adjustment, the evaluation of each additional lymph node demonstrated a significant survival benefit through 11 lymph nodes. After grouping patients by tumor size, patients with tumors <2 cm demonstrated a significant survival benefit for the incremental resection of each additional lymph node through 4 lymph nodes while patients with tumors ≥2 cm had a significant survival benefit through 14 lymph nodes. CONCLUSION Pathologic lymph node evaluation is associated with improved survival for clinically node-negative NSCLC, but the extent of the necessary evaluation varies by tumor size. These results have implications for guidelines for lymph node assessment as well as the choice of surgery vs other ablative techniques for clinical stage I NSCLC.

Levosimendan in patients with left ventricular systolic dysfunction undergoing cardiac surgery on cardiopulmonary bypass: Rationale and study design of the Levosimendan in Patients with Left Ventricular Systolic Dysfunction Undergoing Cardiac Surgery Requiring Cardiopulmonary Bypass (LEVO-CTS) trial

BACKGROUND Low cardiac output syndrome is associated with increased mortality and occurs in 3% to 14% of patients undergoing cardiac surgery on cardiopulmonary bypass (CPB). Levosimendan, a novel calcium sensitizer and KATP channel activator with inotropic, vasodilatory, and cardioprotective properties, has shown significant promise in reducing the incidence of low cardiac output syndrome and related adverse outcomes in patients undergoing cardiac surgery on CPB. METHODS LEVO-CTS is a phase 3 randomized, controlled, multicenter study evaluating the efficacy, safety, and cost-effectiveness of levosimendan in reducing morbidity and mortality in high-risk patients with reduced left ventricular ejection fraction (≤35%) undergoing cardiac surgery on CPB. Patients will be randomly assigned to receive either intravenous levosimendan (0.2 μg kg-1 min-1 for the first hour followed by 0.1 μg/kg for 23hours) or matching placebo initiated within 8hours of surgery. The co-primary end points are (1) the composite of death or renal replacement therapy through day 30 or perioperative myocardial infarction, or mechanical assist device use through day 5 (quad end point tested at α<.01), and (2) the composite of death through postoperative day 30 or mechanical assist device use through day 5 (dual end point tested at α<.04). Safety end points include new atrial fibrillation and death through 90days. In addition, an economic analysis will address the cost-effectiveness of levosimendan compared with placebo in high-risk patients undergoing cardiac surgery on CPB. Approximately 880 patients will be enrolled at approximately 60 sites in the United States and Canada between July 2014 and September 2016, with results anticipated in January 2017. CONCLUSION LEVO-CTS, a large randomized multicenter clinical trial, will evaluate the efficacy, safety, and cost-effectiveness of levosimendan in reducing adverse outcomes in high-risk patients undergoing cardiac surgery on CPB. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov (NCT02025621).

Reflux and Allograft Dysfunction: Is There a Connection?

Despite improving outcomes following lung transplantation, chronic rejection continues to limit survival. The predominant form of chronic rejection, bronchiolitis obliterans syndrome, has been associated with multiple etiologies including aspiration from gastroduodenal reflux. This article reviews the current literature with regards to the incidence of reflux following lung transplantation, the association of reflux with allograft dysfunction and survival, and the success of prevention and treatment of reflux in this patient population. Although antireflux surgery has been demonstrated to be safe in this population and leads to a stabilization of lung function in patients with reflux, there have not been definitive data that it improves survival.

Assessing Consequences of Intraaortic Balloon Counterpulsation Versus Left Ventricular Assist Devices at the Time of Heart Transplantation.

The proportion of heart transplant recipients bridged with durable, intracorporeal left ventricular assist devices (dLVADs) has dramatically increased; however, concern exists regarding obligate repeat sternotomy, increased bleeding risk because of anticoagulation and acquired von Willebrand disease, and increased rates of allosensitization. Whether dLVAD patients have impaired posttransplant outcomes compared with equivalent patients with less invasive intraaortic balloon pump counterpulsation (IABP) at the time of transplant is unknown. Therefore, we analyzed adult, first time, heart-only transplant procedures with dLVAD (n = 2,636) compared with IABP (n = 571) at the time of transplant based on data from the United Network for Organ Sharing (UNOS) July 2004 to December 2011. There was clear geographic variation in IABP and dLVAD at transplant. Multivariable analysis demonstrated equivalent cumulative risk of death (adjusted Cox proportional hazard ratio, 1.08; 95% confidence interval, 0.87–1.33; p = 0.51). There was no significant difference in adjusted comparison of perioperative morality, length of stay, postoperative renal failure requiring dialysis, or early acute rejection (p ≥ 0.14 for all). Therefore, data from UNOS suggest that the presence of dLVAD at the time of heart transplantation does not have a detrimental effect on postoperative outcomes compared with IABP, which must be considered in the context of pretransplant mortality and locoregional organ availability.

Conversion From Off-Pump Coronary Artery Bypass Grafting to On-Pump Coronary Artery Bypass Grafting

BACKGROUND Off-pump coronary artery bypass grafting (OPCAB) has been shown to be an effective strategy for surgical revascularization. The purpose of this study was to define the incidence of intraoperative conversion from OPCAB to on-pump coronary artery bypass grafting (ONCAB) and report outcomes based on the reason for conversion. METHODS Starting in July 2007, the Society of Thoracic Surgeons database captured patients that were planned OPCAB but then were converted to ONCAB. A total of 196,576 patients undergoing planned OPCAB within the Society of Thoracic Surgeons National Database from July 2007 to June 2014 were evaluated. Patients were grouped according to their intraoperative conversion to cardiopulmonary bypass: (1) planned conversion, (2) unplanned conversion for visualization, (3) unplanned conversion for hemodynamic instability, and (4) no conversion (OPCAB). Multiple logistic regression analysis was used to determine risk factors for conversion. RESULTS The overall rate of conversion from OPCAB to ONCAB was 5.5%, with 49.6% of the conversions being planned. When compared with those not undergoing conversion (OPCAB, 30-day mortality observed to expected ratio [O/E], 0.8), those undergoing conversion to ONCAB experienced greater 30-day mortality regardless of etiology of conversion (planned conversion O/E, 1.4; unplanned conversion for visualization O/E, 1.6; and unplanned conversion for hemodynamic instability O/E, 2.7). Similar O/E ratios were observed for renal failure and prolonged ventilation following conversion. Logistic regression analysis showed advanced age, ejection fraction less than 35%, preoperative intraaortic balloon pump placement, increasing number of diseased coronary arteries, preoperative heart failure within 2 weeks, and urgent procedural status were all independent predictors for conversion to ONCAB (p ≤ 0.01). CONCLUSIONS Intraoperative conversion from OPCAB to ONCAB remains a morbid event with a risk of mortality much higher than expected. Surgeons should consider elective ONCAB in those with a high risk for conversion during OPCAB.

Current Practices in the Timing of Stage 2 Palliation: A Survey of the CHSS and ECHSA

Background: Mortality through single-ventricle palliation remains high and the effect of the timing of stage 2 palliation (S2P) is not well understood. We investigated current practice patterns in the timing of S2P across two professional societies and compared them to actual practice patterns from two databases of patients who underwent S2P. Methods: A ten-question survey was distributed to the members of the Congenital Heart Surgeons’ Society (CHSS) and the European Congenital Heart Surgeons’ Association (ECHSA). Results were summarized using descriptive statistics. Surgeon-reported preferences were compared to clinical data from the CHSS Critical Left Ventricular Outflow Tract Obstruction (LVOTO) Registry and the Pediatric Heart Network Single Ventricle Reconstruction (SVR) database. Results: Overall, 38% (88 of 232) of surgeons from 74 institutions responded, of which 70% (62 of 88) were CHSS members and 30% (26 of 88) were ECHSA members. Surgeons reported performing S2P at a median of five months after stage 1 (interquartile range [IQR]: 4.5-6), with no difference between CHSS and ECHSA surgeons. Surgeons reported performing nonelective S2P at a median of 4.5 months after stage 1 (IQR: 3.5-5.5), again with no difference by society. No difference existed between the surgeon-reported preferences and patient data in the Critical LVOTO and SVR databases for the timing of elective (5 vs 5.1 vs 5.3 months, P = .19) or nonelective S2P (4.5 vs 4.6 vs 4.2 months, P = .06). Conclusion: There was a remarkable lack of variation in surgeon preferences regarding the timing of S2P. This may represent a natural standardization of practice across congenital heart surgery, which is notable, given the current lack of guidelines regarding the timing of S2P.

Effects of Exercise Restriction on Patients With Anomalous Aortic Origin of a Coronary Artery.

Background: Management of young patients with anomalous aortic origin of a coronary artery (AAOCA) may involve exercise restriction. We sought to identify the association of exercise restriction with changes over time in body mass index (BMI) and exercise capacity in this cohort. Methods: We performed a retrospective review of patients with AAOCA seen at The Children’s Hospital of Philadelphia between January 1, 1998, and August 31, 2014. Linear mixed model repeated-measures analysis assessed changes in BMI and exercise capacity. Results: We included 72 patients with a median age at presentation of 12.6 years (interquartile range: 10.1-15.8) and mean follow-up of 3.6 ± 3.0 years. The majority had an anomalous right coronary artery (71%) and interarterial ± intramural coronary course (90%). Surgery was performed in 54%, more often in those with interarterial/intramural course (P < .001) and symptoms (P = .003). Most patients (82%) were exercise-restricted on presentation, and restricted patients were older than those who were not restricted (P = .01). There was no significant difference between restricted and nonrestricted patients in initial BMI z scores, percentage of patients with BMI over 85th percentile (26%) or exercise capacity variables. In univariable analysis, exercise restriction over time was not associated with change in BMI z score (P = .25) or change in exercise variables. Restriction was not associated with significant change in these variables in multivariable analysis. Conclusions: Although further investigation is warranted to determine the degree of adherence to exercise restriction, the recommendation of restriction alone is not associated with increasing BMI or decreasing exercise performance in the short-term.