Surgical or Transcatheter Aortic-Valve Replacement in Intermediate-Risk Patients.

BACKGROUND: Although transcatheter aortic-valve replacement (TAVR) is an accepted alternative to surgery in patients with severe aortic stenosis who are at high surgical risk, less is known about comparative outcomes among patients with aortic stenosis who are at intermediate surgical risk. METHODS: We evaluated the clinical outcomes in intermediate-risk patients with severe, symptomatic aortic stenosis in a randomized trial comparing TAVR (performed with the use of a self-expanding prosthesis) with surgical aortic-valve replacement. The primary end point was a composite of death from any cause or disabling stroke at 24 months in patients undergoing attempted aortic-valve replacement. We used Bayesian analytical methods (with a margin of 0.07) to evaluate the noninferiority of TAVR as compared with surgical valve replacement. RESULTS: A total of 1746 patients underwent randomization at 87 centers. Of these patients, 1660 underwent an attempted TAVR or surgical procedure. The mean (±SD) age of the patients was 79.8±6.2 years, and all were at intermediate risk for surgery (Society of Thoracic Surgeons Predicted Risk of Mortality, 4.5±1.6%). At 24 months, the estimated incidence of the primary end point was 12.6% in the TAVR group and 14.0% in the surgery group (95% credible interval [Bayesian analysis] for difference, -5.2 to 2.3%; posterior probability of noninferiority, >0.999). Surgery was associated with higher rates of acute kidney injury, atrial fibrillation, and transfusion requirements, whereas TAVR had higher rates of residual aortic regurgitation and need for pacemaker implantation. TAVR resulted in lower mean gradients and larger aortic-valve areas than surgery. Structural valve deterioration at 24 months did not occur in either group. CONCLUSIONS: TAVR was a noninferior alternative to surgery in patients with severe aortic stenosis at intermediate surgical risk, with a different pattern of adverse events associated with each procedure. (Funded by Medtronic; SURTAVI ClinicalTrials.gov number, NCT01586910 .).

Clinical impact of baseline chronic kidney disease in patients undergoing transcatheter or surgical aortic valve replacement.

OBJECTIVES: To assess the treatment effect of TAVR versus SAVR on clinical outcomes to 3 years in patients stratified by chronic kidney disease (CKD) by retrospectively studying patients randomized to TAVR or SAVR. BACKGROUND: The impact of CKD on mid-term outcomes of patients undergoing TAVR versus SAVR is unclear. METHODS: Patients randomized to TAVR or SAVR in the CoreValve US Pivotal High Risk Trial were retrospectively stratified by eGFR: none/mild or moderate/severe CKD. To evaluate the impact of baseline CKD in TAVR patients only, all patients undergoing an attempted TAVR implant in the US Pivotal Trial and CAS were stratified by baseline eGFR into none/mild, moderate, and severe CKD. The primary endpoint was major adverse cardiovascular and renal events (MACRE), a composite of all-cause mortality, myocardial infarction, stroke/TIA, and new requirement of dialysis. RESULTS: Moderate/severe CKD was present in 62.7% and 60.7% of high-risk patients randomized to TAVR or SAVR, respectively. Baseline characteristics were similar between TAVR and SAVR patients in both CKD subgroups, except for higher rates of diabetes and higher serum creatinine in SAVR patients. Among high-risk patients with moderate/severe CKD, TAVR provided a lower 3-year MACRE rate compared with SAVR: 42.1% vs. 51.0, P = .04. Of 3,733 extreme- and high-risk TAVR patients, 39.9% had none/mild, 53.8% moderate, and 6.4% severe CKD. Worsening baseline CKD was associated with increased 3-year MACRE rates [none/mild 51.5%, moderate 54.5%, severe 63.1%, P = .001]. CONCLUSIONS: TAVR results in lower 3-year MACRE versus SAVR in high-risk patients with moderate/severe CKD. In patients undergoing TAVR, worsening CKD increases mid-term mortality and MACRE. Randomized trials of TAVR vs. SAVR in patients with moderate-severe CKD would help elucidate the best treatment for these complex patients. TRIAL REGISTRATION: CoreValve US Pivotal Trial: NCT01240902. CoreValve Continued Access Study: NCT01531374.

Transcatheter aortic-valve replacement with a self-expanding prosthesis.

BACKGROUND: We compared transcatheter aortic-valve replacement (TAVR), using a self-expanding transcatheter aortic-valve bioprosthesis, with surgical aortic-valve replacement in patients with severe aortic stenosis and an increased risk of death during surgery. METHODS: We recruited patients with severe aortic stenosis who were at increased surgical risk as determined by the heart team at each study center. Risk assessment included the Society of Thoracic Surgeons Predictor Risk of Mortality estimate and consideration of other key risk factors. Eligible patients were randomly assigned in a 1:1 ratio to TAVR with the self-expanding transcatheter valve (TAVR group) or to surgical aortic-valve replacement (surgical group). The primary end point was the rate of death from any cause at 1 year, evaluated with the use of both noninferiority and superiority testing. RESULTS: A total of 795 patients underwent randomization at 45 centers in the United States. In the as-treated analysis, the rate of death from any cause at 1 year was significantly lower in the TAVR group than in the surgical group (14.2% vs. 19.1%), with an absolute reduction in risk of 4.9 percentage points (upper boundary of the 95% confidence interval, -0.4; P<0.001 for noninferiority; P = 0.04 for superiority). The results were similar in the intention-to-treat analysis. In a hierarchical testing procedure, TAVR was noninferior with respect to echocardiographic indexes of valve stenosis, functional status, and quality of life. Exploratory analyses suggested a reduction in the rate of major adverse cardiovascular and cerebrovascular events and no increase in the risk of stroke. CONCLUSIONS: In patients with severe aortic stenosis who are at increased surgical risk, TAVR with a self-expanding transcatheter aortic-valve bioprosthesis was associated with a significantly higher rate of survival at 1 year than surgical aortic-valve replacement. (Funded by Medtronic; U.S. CoreValve High Risk Study ClinicalTrials.gov number, NCT01240902.).

Autologous mesenchymal stem cells produce concordant improvements in regional function, tissue perfusion, and fibrotic burden when administered to patients undergoing coronary artery bypass grafting: The Prospective Randomized Study of Mesenchymal Stem Cell Therapy in Patients Undergoing Cardiac Surgery (PROMETHEUS) trial.

RATIONALE: Although accumulating data support the efficacy of intramyocardial cell-based therapy to improve left ventricular (LV) function in patients with chronic ischemic cardiomyopathy undergoing CABG, the underlying mechanism and impact of cell injection site remain controversial. Mesenchymal stem cells (MSCs) improve LV structure and function through several effects including reducing fibrosis, neoangiogenesis, and neomyogenesis. OBJECTIVE: To test the hypothesis that the impact on cardiac structure and function after intramyocardial injections of autologous MSCs results from a concordance of prorecovery phenotypic effects. METHODS AND RESULTS: Six patients were injected with autologous MSCs into akinetic/hypokinetic myocardial territories not receiving bypass graft for clinical reasons. MRI was used to measure scar, perfusion, wall thickness, and contractility at baseline, at 3, 6, and 18 months and to compare structural and functional recovery in regions that received MSC injections alone, revascularization alone, or neither. A composite score of MRI variables was used to assess concordance of antifibrotic effects, perfusion, and contraction at different regions. After 18 months, subjects receiving MSCs exhibited increased LV ejection fraction (+9.4 ± 1.7%, P=0.0002) and decreased scar mass (-47.5 ± 8.1%; P<0.0001) compared with baseline. MSC-injected segments had concordant reduction in scar size, perfusion, and contractile improvement (concordant score: 2.93 ± 0.07), whereas revascularized (0.5 ± 0.21) and nontreated segments (-0.07 ± 0.34) demonstrated nonconcordant changes (P<0.0001 versus injected segments). CONCLUSIONS: Intramyocardial injection of autologous MSCs into akinetic yet nonrevascularized segments produces comprehensive regional functional restitution, which in turn drives improvement in global LV function. These findings, although inconclusive because of lack of placebo group, have important therapeutic and mechanistic hypothesis-generating implications. CLINICAL TRIAL REGISTRATION URL: http://clinicaltrials.gov/show/NCT00587990. Unique identifier: NCT00587990.

Association of Selective Serotonin Reuptake Inhibitors with Transfusion in Surgical Patients.

BACKGROUND: The clinical relevance of chronic exposure to selective serotonin reuptake inhibitors (SSRIs) to transfusion in surgical patients is unclear. METHODS: We conducted a prospective cohort study involving patients undergoing cardiac, vascular, spinal, and intracranial surgery at 2 academic medical centers. Medication use, demographics, comorbidities, and laboratory values were determined at baseline by patient interview and review of medical records. The primary outcome was transfusion of any hemostatic allogeneic blood product (i.e., fresh frozen plasma, platelets, and/or cryoprecipitate) through postoperative day 2. RESULTS: The study sample consisted of 767 patients; 364 patients (47.5%) underwent cardiac surgery and the remainder underwent noncardiac surgery. Eighty-eight patients (11.5%) used SSRIs preoperatively. Among cardiac patients, the absolute number of allogeneic transfusions was higher for SSRI users than nonusers (2 [0-6] vs 0 [0-2], median [25%-75%], respectively, P = 0.008), and a similar trend was observed for noncardiac surgery. After adjusting for covariates using ordinal logistic regression, preoperative SSRI use was associated with an approximately 2-fold (odds ratio, 2.2; 95% confidence interval, 1.2-3.98) increase in odds of exposure to allogeneic hemostatic blood products; similar results were observed using propensity score adjustment (odds ratio, 1.85; 95% confidence interval, 1.11-3.07). A significant interaction between SSRI use and surgery type, age, sex, or concurrent antiplatelet therapy was not found; however, heterogeneity in magnitude of effect could not be excluded. CONCLUSIONS: Preoperative use of SSRIs is associated with increased exposure to allogeneic hemostatic blood products in surgical patients at high risk for perioperative bleeding. Determining whether perioperative continuation or withdrawal of SSRIs produces a net clinical benefit requires randomized controlled trials.

Blood Pressure Deviations From Optimal Mean Arterial Pressure During Cardiac Surgery Measured With a Novel Monitor of Cerebral Blood Flow and Risk for Perioperative Delirium: A Pilot Study.

OBJECTIVE: The aim of this study was to evaluate whether excursions of blood pressure from the optimal mean arterial pressure during and after cardiac surgery are associated with postoperative delirium identified using a structured examination. DESIGN: Prospective, observational study. SETTING: University hospital. PARTICIPANTS: The study included 110 patients undergoing cardiac surgery. INTERVENTIONS: Patients were monitored using ultrasound-tagged near-infrared spectroscopy to assess optimal mean arterial pressure by cerebral blood flow autoregulation monitoring during cardiopulmonary bypass and the first 3 hours in the intensive care unit. MEASUREMENTS AND MAIN RESULTS: The patients were tested preoperatively and on postoperative days 1 to 3 with the Confusion Assessment Method or Confusion Assessment Method for the Intensive Care Unit, the Delirium Rating Scale-Revised-98, and the Mini Mental State Examination. Summative presence of delirium on postoperative days 1 through 3, as defined by the consensus panel following Diagnostic and Statistical Manual of Mental Disorders-IV-TR criteria, was the primary outcome. Delirium occurred in 47 (42.7%) patients. There were no differences in blood pressure excursions above and below optimal mean arterial pressure between patients with and without summative presence of delirium. Secondary analysis showed blood pressure excursions above the optimal mean arterial pressure to be higher in patients with delirium (mean±SD, 33.2±26.51 mmHgxh v 23.4±16.13 mmHgxh; p = 0.031) and positively correlated with the Delirium Rating Scale score on postoperative day 2 (r = 0.27, p = 0.011). CONCLUSIONS: Summative presence of delirium was not associated with perioperative blood pressure excursions; but on secondary exploratory analysis, excursions above the optimal mean arterial pressure were associated with the incidence and severity of delirium on postoperative day 2.

A pharmacometric pulmonary model predicting the extent and rate of distribution from plasma to epithelial lining fluid and alveolar cells--using rifampicin as an example.

PURPOSE: The purpose of the study was to develop a drug-unspecific approach to pharmacometric modeling for predicting the rate and extent of distribution from plasma to epithelial lining fluid (ELF) and alveolar cells (AC) for data emanating from studies involving bronchoalveolar lavage (BAL) sampling, using rifampicin (RIF) as an example. METHODS: Data consisting of RIF plasma concentrations sampled at approximately 2 and 4 h postdose and ELF and AC concentrations quantified from one BAL sample, taken at approximately 4 h postdose, in 40 adult subjects without tuberculosis was used as an example for model development. RESULTS: This study emphasized the usage of drug-specific plasma pharmacokinetics (PK) for a correct characterization of plasma to pulmonary distribution. As such, RIF PK was described using absorption transit compartments and a one compartment distribution model coupled with an enzyme turn-over model. The ELF and AC distribution model consisted of characterization of the rate of distribution of drug from plasma to ELF and AC by two distribution rate constant, k ELF and k AC, respectively. The extent of distribution to ELF and AC was described by unbound ELF/plasma concentration ratio (R ELF/unbound-plasma) and unbound AC/plasma concentration ratio (R AC/unbound-plasma) which typical values were predicted to be 1.28 and 5.5, respectively. CONCLUSIONS: The model together with a drug-specific plasma PK description provides a tool for handling data from both single and multiple BAL sampling designs and directly predicts the rate and extent of distribution from plasma to ELF and AC. The model can be further used to investigate design aspects of optimized BAL studies.

Cerebral Autoregulation Monitoring with Ultrasound-Tagged Near-Infrared Spectroscopy in Cardiac Surgery Patients.

BACKGROUND: Individualizing mean arterial blood pressure (MAP) based on cerebral blood flow (CBF) autoregulation monitoring during cardiopulmonary bypass (CPB) holds promise as a strategy to optimize organ perfusion. The purpose of this study was to evaluate the accuracy of cerebral autoregulation monitoring using microcirculatory flow measured with innovative ultrasound-tagged near-infrared spectroscopy (UT-NIRS) noninvasive technology compared with transcranial Doppler (TCD). METHODS: Sixty-four patients undergoing CPB were monitored with TCD and UT-NIRS (CerOx™). The mean velocity index (Mx) was calculated as a moving, linear correlation coefficient between slow waves of TCD-measured CBF velocity and MAP. The cerebral flow velocity index (CFVx) was calculated as a similar coefficient between slow waves of cerebral flow index measured using UT-NIRS and MAP. When MAP is outside the autoregulation range, Mx is progressively more positive. Optimal blood pressure was defined as the MAP with the lowest Mx and CFVx. The right- and left-sided optimal MAP values were averaged to define the individual optimal MAP and were the variables used for analysis. RESULTS: The Mx for the left side was 0.31 ± 0.17 and for the right side was 0.32 ± 0.17. The mean CFVx for the left side was 0.33 ± 0.19 and for the right side was 0.35 ± 0.19. Time-averaged Mx and CFVx during CPB had a statistically significant "among-subject" correlation (r = 0.39; 95% confidence interval [CI], 0.22-0.53; P < 0.001) but had only a modest agreement within subjects (bias 0.03 ± 0.20; 95% prediction interval for the difference between Mx and CFVx, -0.37 to 0.42). The MAP with the lowest Mx and CFVx ("optimal blood pressure") was correlated (r = 0.71; 95% CI, 0.56-0.81; P < 0.0001) and was in modest within-subject agreement (bias -2.85 ± 8.54; 95% limits of agreement for MAP predicted by Mx and CFVx, -19.60 to 13.89). Coherence between ipsilateral middle CBF velocity and cerebral flow index values averaged 0.61 ± 0.07 (95% CI, 0.59-0.63). CONCLUSIONS: There was a statistically significant correlation and agreement between CBF autoregulation monitored by CerOx compared with TCD-based Mx.

General and acute care surgical procedures in patients with left ventricular assist devices.

BACKGROUND: Left ventricular assist devices (LVADs) have become common as a bridge to heart transplant as well as destination therapy. Acute care surgical (ACS) problems in this population are prevalent but remain ill-defined. Therefore, we reviewed our experience with ACS interventions in LVAD patients. METHODS: A total of 173 patients who received HeartMate(®) XVE or HeartMate(®) II (HMII) LVADs between December 2001 and March 2010 were studied. Patient demographics, presentation of ACS problem, operative intervention, co-morbidities, transplantation, complications, and survival were analyzed. RESULTS: A total of 47 (27 %) patients underwent 67 ACS procedures at a median of 38 days after device implant (interquartile range 15-110), with a peri-operative mortality rate of 5 % (N = 3). Demographics, device type, and acuity were comparable between the ACS and non-ACS groups. A total of 21 ACS procedures were performed emergently, eight were urgent, and 38 were elective. Of 29 urgent and emergent procedures, 28 were for abdominal pathology. In eight patients, the cause of the ACS problem was related to LVADs or anticoagulation. Cumulative survival estimates revealed no survival differences if patients underwent ACS procedures (p = 0.17). Among HMII patients, transplantation rates were unaffected by an ACS intervention (p = 0.2). CONCLUSIONS: ACS problems occur frequently in LVAD patients and are not associated with adverse outcomes in HMII patients. The acute care surgeon is an integral member of a comprehensive approach to effective LVAD management.

Simple score to assess the risk of rejection after orthotopic heart transplantation.

BACKGROUND: The aim of this study was to derive and validate a risk score for rejection after orthotopic heart transplantation. METHODS AND RESULTS: The United Network for Organ Sharing registry was used to identify patients undergoing orthotopic heart transplantation between 1998 and 2008. A total of 14 265 eligible patients were randomly divided into derivation (80%; n=11 412) and validation (20%; n=2853) cohorts. The primary outcome was drug-treated rejection within 1 year of orthotopic heart transplantation. Covariates found to be associated (exploratory univariate P<0.2) with rejection were entered into a multivariable logistic regression model. Inclusion of each variable in the model was assessed by improvement in the McFadden pseudo-R(2), likelihood ratio test, and c index. A risk score was then generated through the use of relative magnitudes of the odds ratios from the derivation cohort, and its ability to predict rejection was tested independently in the validation cohort. A 13-point risk score incorporating 4 variables (age, race, sex, HLA matching) was created. The mean scores in the derivation and validation cohorts were 8.3±2.2 and 8.4±2.1, respectively. Predicted 1-year rejection rates based on the derivation cohort ranged from 16.2% (score=0) to 50.7% (score=13; P<0.001). In weighted regression analysis, there was a strong correlation between these predicted rates of rejection and actual, observed rejection rates in the validation cohort (r(2)=0.96, P<0.001). Logistic regression analysis also demonstrated a significant association (odds ratio, 1.13; P<0.001). The c index of the composite score was equivalent in both the derivation and validation cohorts (c=0.67). CONCLUSIONS: This novel 13-point risk score is highly predictive of clinically significant rejection episodes within 1 year of orthotopic heart transplantation. It has potential utility in tailoring immunosuppressive regimens and in research stratification in orthotopic heart transplantation.