Keith D. Aaronson

Risk of Worsening Renal Function With Nesiritide in Patients With Acutely Decompensated Heart Failure

Background—Renal function is an important prognostic factor for patients with acutely decompensated heart failure (ADHF). We investigated the renal effects of nesiritide as treatment for ADHF. Methods and Results—Randomized clinical trials comparing nesiritide with either placebo or active control for ADHF were identified by electronic and manual searches and thorough review of US Food and Drug Administration files available via the website. Worsening renal function was defined as an increase in serum creatinine >0.5 mg/dL. Relative risk across all studies was determined by meta-analysis with Mantel-Haenszel fixed-effects models (RRMH). Risk of dialysis and medical intervention for worsening renal function were compared between therapies. Frequency of worsening renal function was determined from 5 randomized studies that included 1269 patients. Use of Food and Drug Administration–approved doses of nesiritide (≤0.03 μg · kg−1 · min−1) significantly increased the risk of worsening renal function compared with non–inotrope-based control (RRMH, 1.52; 95% CI, 1.16 to 2.00; P=0.003) or any control therapy, including non–inotrope- and inotrope-based therapies (RRMH, 1.54; 95% CI, 1.19 to 1.98; P=0.001). Even low-dose nesiritide (≤0.015 μg · kg−1 · min−1) significantly increased risk (P=0.012 and P=0.006 compared with non–inotrope- and inotrope-based controls, respectively), as did nesiritide administered at any dose up to 0.06 μg · kg−1 · min−1 (P=0.002 and P=0.001, respectively). There was no difference in the need for dialysis between therapies. Conclusions—Nesiritide significantly increases the risk of worsening renal function in patients with ADHF. Whether worsening renal function reflects hemodynamic effect or renal injury is unknown, but the prognostic importance of worsening renal function suggests the need for further investigation in appropriately powered clinical trials.

Extended Mechanical Circulatory Support With a Continuous-Flow Rotary Left Ventricular Assist Device

OBJECTIVES This study sought to evaluate the use of a continuous-flow rotary left ventricular assist device (LVAD) as a bridge to heart transplantation. BACKGROUND LVAD therapy is an established treatment modality for patients with advanced heart failure. Pulsatile LVADs have limitations in design precluding their use for extended support. Continuous-flow rotary LVADs represent an innovative design with potential for small size and greater reliability by simplification of the pumping mechanism. METHODS In a prospective, multicenter study, 281 patients urgently listed (United Network of Organ Sharing status 1A or 1B) for heart transplantation underwent implantation of a continuous-flow LVAD. Survival and transplantation rates were assessed at 18 months. Patients were assessed for adverse events throughout the study and for quality of life, functional status, and organ function for 6 months. RESULTS Of 281 patients, 222 (79%) underwent transplantation, LVAD removal for cardiac recovery, or had ongoing LVAD support at 18-month follow-up. Actuarial survival on support was 72% (95% confidence interval: 65% to 79%) at 18 months. At 6 months, there were significant improvements in functional status and 6-min walk test (from 0% to 83% of patients in New York Heart Association functional class I or II and from 13% to 89% of patients completing a 6-min walk test) and in quality of life (mean values improved 41% with Minnesota Living With Heart Failure and 75% with Kansas City Cardiomyopathy questionnaires). Major adverse events included bleeding, stroke, right heart failure, and percutaneous lead infection. Pump thrombosis occurred in 4 patients. CONCLUSIONS A continuous-flow LVAD provides effective hemodynamic support for at least 18 months in patients awaiting transplantation, with improved functional status and quality of life. (Thoratec HeartMate II Left Ventricular Assist System [LVAS] for Bridge to Cardiac Transplantation; NCT00121472).

The Right Ventricular Failure Risk Score: A Pre-Operative Tool for Assessing the Risk of Right Ventricular Failure in Left Ventricular Assist Device Candidates

OBJECTIVES This study sought to develop a model that estimates the post-operative risk of right ventricular (RV) failure in left ventricular assist device (LVAD) candidates. BACKGROUND Right ventricular failure after LVAD surgery is associated with increased morbidity and mortality, but identifying LVAD candidates at risk for RV failure remains difficult. METHODS A prospectively collected LVAD database was evaluated for pre-operative clinical, laboratory, echocardiographic, and hemodynamic predictors of RV failure. Right ventricular failure was defined as the need for post-operative intravenous inotrope support for >14 days, inhaled nitric oxide for > or =48 h, right-sided circulatory support, or hospital discharge on an inotrope. An RV failure risk score (RVFRS) was created from multivariable logistic regression model coefficients, and a receiver-operating characteristic curve of the score was generated. RESULTS Of 197 LVADs implanted, 68 (35%) were complicated by post-operative RV failure. A vasopressor requirement (4 points), aspartate aminotransferase > or =80 IU/l (2 points), bilirubin > or =2.0 mg/dl (2.5 points), and creatinine > or =2.3 mg/dl (3 points) were independent predictors of RV failure. The odds ratio for RV failure for patients with an RVFRS < or =3.0, 4.0 to 5.0, and > or =5.5 were 0.49 (95% confidence interval [CI] 0.37 to 0.64), 2.8 (95% CI 1.4 to 5.9), and 7.6 (95% CI 3.4 to 17.1), respectively, and 180-day survivals were 90 +/- 3%, 80 +/- 8%, and 66 +/- 9%, respectively (log rank for linear trend p = 0.0045). The area under the receiver-operating characteristic curve for the RVFRS (0.73 +/- 0.04) was superior to that of other commonly used predictors of RV failure (all p < 0.05). CONCLUSIONS The RVFRS, composed of routinely collected, noninvasive pre-operative clinical data, effectively stratifies the risk of RV failure and death after LVAD implantation.

Autologous Skeletal Myoblasts Transplanted to Ischemia-Damaged Myocardium in Humans Histological Analysis of Cell Survival and Differentiation

OBJECTIVES We report histological analysis of hearts from patients with end-stage heart disease who were transplanted with autologous skeletal myoblasts concurrent with left ventricular assist device (LVAD) implantation. BACKGROUND Autologous skeletal myoblast transplantation is under investigation as a means to repair infarcted myocardium. To date, there is only indirect evidence to suggest survival of skeletal muscle in humans. METHODS Five patients (all male; median age 60 years) with ischemic cardiomyopathy, refractory heart failure, and listed for heart transplantation underwent muscle biopsy from the quadriceps muscle. The muscle specimen was shipped to a cell isolation facility where myoblasts were isolated and grown. Patients received a transplant of 300 million cells concomitant with LVAD implantation. Four patients underwent LVAD explant after 68, 91, 141, and 191 days of LVAD support (three transplant, one LVAD death), respectively. One patient remains alive on LVAD support awaiting heart transplantation. RESULTS Skeletal muscle cell survival and differentiation into mature myofibers were directly demonstrated in scarred myocardium from three of the four explanted hearts using an antibody against skeletal muscle-specific myosin heavy chain. An increase in small vessel formation was observed in one of three patients at the site of surviving myotubes, but not in adjacent tissue devoid of engrafted cells. CONCLUSIONS These findings represent demonstration of autologous myoblast cell survival in human heart. The implanted skeletal myoblasts formed viable grafts in heavily scarred human myocardial tissue. These results establish the feasibility of myoblast transplants for myocardial repair in humans.

Discharge Education Improves Clinical Outcomes in Patients With Chronic Heart Failure

Background—Although interventions combining patient education and postdischarge management have demonstrated benefits in patients with chronic heart failure, the benefit attributable to patient education alone is not known. We hypothesized that a patient discharge education program would improve clinical outcomes in patients with chronic heart failure. Methods and Results—We conducted a randomized, controlled trial of 223 systolic heart failure patients and compared the effects of a 1-hour, one-on-one teaching session with a nurse educator to the standard discharge process. Subjects were contacted by telephone at 30, 90, and 180 days to collect information about clinical events, symptoms, and self-care practices. The primary end point of the study was the total number of days hospitalized or dead in the 180-day follow-up period. Subjects randomized to receive the teaching session (n=107) had fewer days hospitalized or dead in the follow-up period (0 and 10 days, median and 75th percentiles) than did controls (n=116, 4 and 19 days; P=0.009). Patients receiving the education intervention had a lower risk of rehospitalization or death (relative risk, 0.65; 95% confidence interval, 0.45 to 0.93; P=0.018). Costs of care, including the cost of the intervention, were lower in patients receiving the education intervention than in control subjects by

Continuous Flow Left Ventricular Assist Device Improves Functional Capacity and Quality of Life of Advanced Heart Failure Patients

2823 per patient (P=0.035). Conclusions—The addition of a 1-hour, nurse educator–delivered teaching session at the time of hospital discharge resulted in improved clinical outcomes, increased self-care measure adherence, and reduced cost of care in patients with systolic heart failure.

Use of an Intrapericardial, Continuous-Flow, Centrifugal Pump in Patients Awaiting Heart Transplantation

OBJECTIVES This study sought to assess the impact of continuous flow left ventricular assist devices (LVADs) on functional capacity and heart failure-related quality of life. BACKGROUND Newer continuous-flow LVAD are smaller and quieter than pulsatile-flow LVADs. METHODS Data from advanced heart failure patients enrolled in the HeartMate II LVAD (Thoratec Corporation, Pleasanton, California) bridge to transplantation (BTT) (n = 281) and destination therapy (DT) (n = 374) trials were analyzed. Functional status (New York Heart Association [NYHA] functional class, 6-min walk distance, patient activity scores), and quality of life (Minnesota Living With Heart Failure [MLWHF] and Kansas City Cardiomyopathy Questionnaires [KCCQ]) were collected before and after LVAD implantation. RESULTS Compared with baseline, LVAD patients demonstrated early and sustained improvements in functional status and quality of life. Most patients had NYHA functional class IV symptoms at baseline. Following implant, 82% (BTT) and 80% (DT) of patients at 6 months and 79% (DT) at 24 months improved to NYHA functional class I or II. Mean 6-min walk distance in DT patients was 204 m in patients able to ambulate at baseline, which improved to 350 and 360 m at 6 and 24 months. There were also significant and sustained improvements from baseline in both BTT and DT patients in median MLWHF scores (by 40 and 42 U in DT patients, or 52% and 55%, at 6 and 24 months, respectively), and KCCQ overall summary scores (by 39 and 41 U, or 170% and 178%). CONCLUSIONS Use of a continuous flow LVAD in advanced heart failure patients results in clinically relevant improvements in functional capacity and heart failure-related quality of life.

Results of the Post-U.S. Food and Drug Administration-Approval Study With a Continuous Flow Left Ventricular Assist Device as a Bridge to Heart Transplantation: A Prospective Study Using the INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support)

Background— Contemporary ventricular assist device therapy results in a high rate of successful heart transplantation but is associated with bleeding, infections, and other complications. Further reductions in pump size, centrifugal design, and intrapericardial positioning may reduce complications and improve outcomes. Methods and Results— We studied a small, intrapericardially positioned, continuous-flow centrifugal pump in patients requiring an implanted ventricular assist device as a bridge to heart transplantation. The course of investigational pump recipients was compared with that of patients implanted contemporaneously with commercially available devices. The primary outcome, success, was defined as survival on the originally implanted device, transplantation, or explantation for ventricular recovery at 180 days and was evaluated for both noninferiority and superiority. Secondary outcomes included a comparison of survival between groups and functional and quality-of-life outcomes and adverse events in the investigational device group. A total of 140 patients received the investigational pump, and 499 patients received a commercially available pump implanted contemporaneously. Success occurred in 90.7% of investigational pump patients and 90.1% of controls, establishing the noninferiority of the investigational pump (P<0.001; 15% noninferiority margin). At 6 months, median 6-minute walk distance improved by 128.5 m, and both disease-specific and global quality-of-life scores improved significantly. Conclusions— A small, intrapericardially positioned, continuous-flow, centrifugal pump was noninferior to contemporaneously implanted, commercially available ventricular assist devices. Functional capacity and quality of life improved markedly, and the adverse event profile was favorable. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00751972.

Cardiac Improvement During Mechanical Circulatory Support A Prospective Multicenter Study of the LVAD Working Group

OBJECTIVES The aim of this study was to determine whether results with the HeartMate (HM) II left ventricular assist device (LVAD) (Thoratec Corporation, Pleasanton, California) in a commercial setting are comparable to other available devices for the same indication. BACKGROUND After a multicenter pivotal clinical trial conducted from 2005 to 2008, the U.S. Food and Drug Administration approved the HM II LVAD for bridge to transplantation (BTT). A post-approval study was required by the U.S. Food and Drug Administration to determine whether results with the device in a commercial setting are comparable to other available devices for the same indication. METHODS The study was a prospective evaluation of the first 169 consecutive HM II patients enrolled in the national INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) who were listed for transplant or likely to be listed. Patients were enrolled from April through August 2008 at 77 U.S. centers and followed for at least 1 year after implant. A comparison group (COMP) included all patients (n = 169 at 27 centers) enrolled in the INTERMACS registry with other types of LVADs (79% HeartMate XVE, 21% Implantable Ventricular Assist Device [Thoratec Corporation]) for the same BTT indication in the same time period. Survival rates, adverse events, and quality of life with the EuroQol EQ-5D visual analog scale were obtained in the INTERMACS registry. RESULTS Baseline characteristics were similar, but creatinine and blood urea nitrogen were lower in the HM II versus COMP groups, and there were fewer patients in the highest-risk INTERMACS patient profile Number 1 (24% for HM II vs. 39% for COMP). Adverse event rates were similar or lower for HM II versus COMP for all events. Bleeding was the most frequent adverse event for both groups (1.44 vs. 1.79 events/patient-year). Operative 30-day mortality for HM II was 4% versus 11% for COMP. The percentage of patients reaching transplant, cardiac recovery, or ongoing LVAD support by 6 months was 91% for HM II and 80% for COMP, and the Kaplan-Meier survival for patients remaining on support at 1 year was 85% for HM II versus 70% for COMP. Quality of life was significantly improved at 3 months of support and sustained through 12 months in both groups compared with baseline. CONCLUSIONS The results in a post-market approval, actual patient care setting BTT population support the original findings from the pivotal clinical trial regarding the efficacy and risk profile of the HM II LVAD. These data suggest that dissemination of this technology after approval has been associated with continued excellent results.

Bone mass, vitamin D deficiency, and hyperparathyroidism in congestive heart failure.

Background— Myocardial recovery after left ventricular assist device (LVAD) support has been reported. The LVAD Working Group Recovery Study was a prospective multicenter trial to assess the incidence of myocardial recovery in patients bridged to cardiac transplantation. Methods and Results— After LVAD implantation, patients were evaluated with the use of rest echocardiograms with partial LVAD support and cardiopulmonary exercise testing. Dobutamine echocardiography with hemodynamic measurements was performed in those patients with left ventricular ejection fraction >40% during resting studies. Histological analysis was performed on myocardial samples taken at LVAD implantation and explantation. Sixty-seven LVAD patients with heart failure participated in the study. After 30 days, significant improvement occurred in left ventricular ejection fraction (17±7% versus 34±12%; P<0.001) and reductions in left ventricular end-diastolic diameter (7.1±1.2 versus 5.1±1.1 cm; P<0.001) and left ventricular mass (320±113 versus 194±79 g; P<0.001) compared with before LVAD. Thirty-four percent of patients had left ventricular ejection fraction >40% with partial device support. Left ventricular ejection fraction decreased over time to pre-LVAD measurement by 120 days. Peak &OV0312;o2 improved with mechanical support (13.7±4.2 versus 18.9±5.5 mL/kg per minute, 30 versus 120 days; P<0.001). Tissue analysis revealed significant reductions in myocyte size, collagen content, and cardiac tumor necrosis factor-&agr;. Six subjects (9%) underwent LVAD explantation for recovery. Conclusions— Cardiac function improves significantly after device implantation. Although cellular recovery and improvement in ventricular function are observed, the degree of clinical recovery is insufficient for device explantation in most patients with chronic heart failure.