Ventricular assist device implant in the elderly is associated with increased, but respectable risk: a multi-institutional study.

BACKGROUND: There are an increasing number of elderly patients with end-stage heart failure. Destination mechanical circulatory support is often the only therapy available for these patients who are not transplant candidates. The outcomes after continuous flow left ventricular assist device (CF LVAD) implant in older patients remains unclear. We undertook this multi-institutional study to quantify short-term and midterm outcomes after CF LVAD implant in the elderly. METHODS: We retrospectively analyzed all patients in the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) national registry that underwent implant of a CF LVAD (June 2006 to April 2012). Patients were divided into 2 cohorts based upon age (<70 years [n = 4,439] and ≥ 70 years (n = 590]). Preoperative, intraoperative, and postoperative variables were analyzed. The primary endpoint, survival, was compared between cohorts. RESULTS: Patients age 70 and older were more hemodynamically stable pre-VAD implant as evidenced by INTERMACS profile and inotrope dependence. Perioperative outcomes, including median bypass time (89 vs 89 minutes) and length of stay (0.657 vs 0.657 months) were similar between cohorts (p = not significant). Kaplan-Meier analysis revealed a significant difference in 2-year survival between patients aged 70 years or greater (63%) and less than 70 (71%, p < 0.001). Multivariable Cox proportional hazard analysis revealed age as an independent predictor of mortality during follow-up (p < 0.001). Nonetheless, midterm cumulative survival in the older cohort was still reasonable (63% at 2 years). CONCLUSIONS: Multi-institutional analysis revealed advanced age as a predictor of increased mortality after CF LVAD implantation. Careful patient selection is critical in the elderly to optimize long-term outcomes after CF LVAD implantation.

Use of an intrapericardial, continuous-flow, centrifugal pump in patients awaiting heart transplantation.

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.

Chronic ambulatory intracardiac pressures and future heart failure events.

BACKGROUND: Intracardiac pressures in heart failure (HF) have been measured in patients while supine in the hospital but change at home with posture and activity. The optimal level of chronic ambulatory pressure is unknown. This analysis compared chronic intracardiac pressures to later HF events and sought a threshold above which higher pressures conferred worse outcomes. METHODS AND RESULTS: Median pressures were measured every 24 hours from continuous 8-minute segments for 6 months after implantation of hemodynamic monitors in 261 patients with New York Heart Association class III-IV HF in the Chronicle Offers Management to Patients with Advanced Signs and Symptoms of Heart Failure Study. Baseline and chronic daily medians of estimated pulmonary artery diastolic, right ventricular systolic, and right ventricular end-diastolic pressures were compared with HF event rate. The group median for chronic 24-hour estimated pulmonary artery diastolic pressure was 28 mm Hg (excluding 7 days before and after events). Despite weight-guided management, events occurred in 100 of 261 (38%) patients. Event risk increased progressively with higher chronic 24-hour estimated pulmonary artery diastolic pressure, from 20% at 18 mm Hg to 34% at 25 mm Hg and 56% at 30 mm Hg, with similar relations for right ventricular pressures. Among patients with baseline day median estimated pulmonary artery diastolic pressures of ≥25 mm Hg, event risk was 1.10/6 mo when they remained chronically ≥25 mm Hg, but risk fell to 0.47 when 24-hour pressures declined to <25 mm Hg for more than half of the days. CONCLUSIONS: Despite current management, many patients with advanced HF live on a plateau of high filling pressures from which later events occur. This risk is progressively higher with higher chronic ambulatory pressures. It is not known whether more targeted intervention could maintain lower chronic ambulatory pressures and better outcomes.

Calcium upregulation by percutaneous administration of gene therapy in cardiac disease (CUPID Trial), a first-in-human phase 1/2 clinical trial.

BACKGROUND: SERCA2a deficiency is commonly seen in advanced heart failure (HF). This study is designed to investigate safety and biological effects of enzyme replacement using gene transfer in patients with advanced HF. METHODS AND RESULTS: A total of 9 patients with advanced HF (New York Heart Association [NYHA] Class III/IV, ejection fraction [EF] < or = 30%, maximal oxygen uptake [VO2 max] <16 mL.kg.min, with maximal pharmacological and device therapy) received a single intracoronary infusion of AAV1/SERCA2a in the open-label portion of this ongoing study. Doses administered ranged from 1.4 x 10(11) to 3 x 10(12) DNase resistant particles per patient. We present 6- to 12-month follow-up data for these patients. AAV1/SERCA2a demonstrated an acceptable safety profile in this advanced HF population. Of the 9 patients treated, several demonstrated improvements from baseline to month 6 across a number of parameters important in HF, including symptomatic (NYHA and Minnesota Living with Heart Failure Questionnaire, 5 patients), functional (6-minute walk test and VO2 max, 4 patients), biomarker (NT-ProBNP, 2 patients), and LV function/remodeling (EF and end-systolic volume, 5 patients). Of note, 2 patients who failed to improve had preexisting anti-AAV1 neutralizing antibodies. CONCLUSIONS: Quantitative evidence of biological activity across a number of parameters important for assessing HF status could be detected in several patients without preexisting neutralizing antibodies in this open-label study, although the number of patients in each cohort is too small to conduct statistical analyses. These findings support the initiation of the Phase 2 double-blind, placebo-controlled portion of this study.

Risk score derived from pre-operative data analysis predicts the need for biventricular mechanical circulatory support.

BACKGROUND: Right ventricular (RV) failure after left ventricular assist device (LVAD) placement is a serious complication and is difficult to predict. In the era of destination therapy and the total artificial heart, predicting post-LVAD RV failure requiring mechanical support is extremely important. METHODS: We reviewed patient characteristics, laboratory values and hemodynamic data from 266 patients who underwent LVAD placement at the University of Pennsylvania from April 1995 to June 2007. RESULTS: Of 266 LVAD recipients, 99 required RV assist device (BiVAD) placement (37%). We compared 36 parameters between LVAD (n = 167) and BiVAD patients (n = 99) to determine pre-operative risk factors for RV assist device (RVAD) need. By univariate analysis, 23 variables showed statistically significant differences between the two groups (p < or = 0.05). By multivariate logistic regression, cardiac index < or =2.2 liters/min/m(2) (odds ratio [OR] 5.7), RV stroke work index < or =0.25 mm Hg . liter/m(2) (OR 5.1), severe pre-operative RV dysfunction (OR 5.0), pre-operative creatinine > or =1.9 mg/dl (OR 4.8), previous cardiac surgery (OR 4.5) and systolic blood pressure < or =96 mm Hg (OR 2.9) were the best predictors of RVAD need. CONCLUSIONS: The most significant predictors for RVAD need were cardiac index, RV stroke work index, severe pre-operative RV dysfunction, creatinine, previous cardiac surgery and systolic blood pressure. Using these data, we constructed an algorithm that can predict which LVAD patients will require RVAD with >80% sensitivity and specificity.

Randomized controlled trial of an implantable continuous hemodynamic monitor in patients with advanced heart failure: the COMPASS-HF study.

OBJECTIVES: The purpose of this study was to determine whether a heart failure (HF) management strategy using continuous intracardiac pressure monitoring could decrease HF morbidity. BACKGROUND: Patients with HF may experience frequent decompensations that require hospitalization despite intensive treatment and follow-up. METHODS: The COMPASS-HF (Chronicle Offers Management to Patients with Advanced Signs and Symptoms of Heart Failure) study was a prospective, multicenter, randomized, single-blind, parallel-controlled trial of 274 New York Heart Association functional class III or IV HF patients who received an implantable continuous hemodynamic monitor. Patients were randomized to a Chronicle (Medtronic Inc., Minneapolis, Minnesota) (n = 134) or control (n = 140) group. All patients received optimal medical therapy, but the hemodynamic information from the monitor was used to guide patient management only in the Chronicle group. Primary end points included freedom from system-related complications, freedom from pressure-sensor failure, and reduction in the rate of HF-related events (hospitalizations and emergency or urgent care visits requiring intravenous therapy). RESULTS: The 2 safety end points were met with no pressure-sensor failures and system-related complications in only 8% of the 277 patients who underwent implantation (all but 4 complications were successfully resolved). The primary efficacy end point was not met because the Chronicle group had a nonsignificant 21% lower rate of all HF-related events compared with the control group (p = 0.33). A retrospective analysis of the time to first HF hospitalization showed a 36% reduction (p = 0.03) in the relative risk of a HF-related hospitalization in the Chronicle group. CONCLUSIONS: The implantable continuous hemodynamic monitor-guided care did not significantly reduce total HF-related events compared with optimal medical management. Additional trials will be necessary to establish the clinical benefit of implantable continuous hemodynamic monitor-guided care in patients with advanced HF.

Rationale, design, and methods for the Transplant-Eligible MAnagement of Congestive Heart Failure (TMAC) trial: a multicenter clinical outcomes trial using nesiritide for TMAC.

BACKGROUND: Urgent heart transplant candidates classified as United Network for Organ Sharing status 1B who require continuous infusions of inotropic agents for hemodynamic stability often have hemodynamic, electrical, or multisystem decompensation. This multicenter trial will study both traditional safety and efficacy parameters and the physiologic mechanisms of benefit of the addition to conventional therapy of nesiritide, a recombinant analog of brain-type natriuretic peptide, in this population. METHODS: TMAC is a prospective, randomized, parallel, multicenter, double-blind, placebo-controlled study in patients awaiting heart transplantation who meet United Network for Organ Sharing status 1B criteria (N = 120) and receive continuous dobutamine or milrinone through a double-lumen central catheter for at least 3 consecutive days before randomization. Patients will receive standard care and continuous intravenous inotrope therapy plus a 28-day continuous infusion of nesiritide or placebo. There will be up to 6 months of follow-up. Primary efficacy end point will be days alive after treatment without renal, hemodynamic, or electrical worsening at completion. Secondary analyses will evaluate effects on hemodynamics, echocardiographic parameters, endogenous brain-type natriuretic peptide levels, modification of diet in renal disease-calculated glomerular filtration rate, and all-cause and cardiovascular mortality. Two mechanistic substudies will evaluate the effect on iohexol-determined glomerular filtration rate and assess changes in lung mechanics. CONCLUSION: This investigation will provide key data for clinical profiles of heart transplant candidates bound to inotropic support. It will investigate the efficacy and safety (especially renal) of nesiritide and provide mechanistic insight into benefits of its use for the relief of breathlessness.

Ultrafiltration versus intravenous diuretics for patients hospitalized for acute decompensated heart failure.

OBJECTIVES: This study was designed to compare the safety and efficacy of veno-venous ultrafiltration and standard intravenous diuretic therapy for hypervolemic heart failure (HF) patients. BACKGROUND: Early ultrafiltration may be an alternative to intravenous diuretics in patients with decompensated HF and volume overload. METHODS: Patients hospitalized for HF with > or =2 signs of hypervolemia were randomized to ultrafiltration or intravenous diuretics. Primary end points were weight loss and dyspnea assessment at 48 h after randomization. Secondary end points included net fluid loss at 48 h, functional capacity, HF rehospitalizations, and unscheduled visits in 90 days. Safety end points included changes in renal function, electrolytes, and blood pressure. RESULTS: Two hundred patients (63 +/- 15 years, 69% men, 71% ejection fraction < or =40%) were randomized to ultrafiltration or intravenous diuretics. At 48 h, weight (5.0 +/- 3.1 kg vs. 3.1 +/- 3.5 kg; p = 0.001) and net fluid loss (4.6 vs. 3.3 l; p = 0.001) were greater in the ultrafiltration group. Dyspnea scores were similar. At 90 days, the ultrafiltration group had fewer patients rehospitalized for HF (16 of 89 [18%] vs. 28 of 87 [32%]; p = 0.037), HF rehospitalizations (0.22 +/- 0.54 vs. 0.46 +/- 0.76; p = 0.022), rehospitalization days (1.4 +/- 4.2 vs. 3.8 +/- 8.5; p = 0.022) per patient, and unscheduled visits (14 of 65 [21%] vs. 29 of 66 [44%]; p = 0.009). No serum creatinine differences occurred between groups. Nine deaths occurred in the ultrafiltration group and 11 in the diuretics group. CONCLUSIONS: In decompensated HF, ultrafiltration safely produces greater weight and fluid loss than intravenous diuretics, reduces 90-day resource utilization for HF, and is an effective alternative therapy. (The UNLOAD trial; http://clinicaltrials.gov/ct/show/NCT00124137?order=1; NCT00124137).

Detection of cardiac allograft rejection and response to immunosuppressive therapy with peripheral blood gene expression.

BACKGROUND: Assessment of gene expression in peripheral blood may provide a noninvasive screening test for allograft rejection. We hypothesized that changes in peripheral blood expression profiles would correlate with biopsy-proven rejection and would resolve after treatment of rejection episodes. METHODS AND RESULTS: We performed a case-control study nested within a cohort of 189 cardiac transplant patients who had blood samples obtained during endomyocardial biopsy (EMB). Using Affymetrix HU133A microarrays, we analyzed whole-blood expression profiles from 3 groups: (1) control samples with negative EMB (n=7); (2) samples obtained during rejection (at least International Society for Heart and Lung Transplantation grade 3A; n=7); and (3) samples obtained after rejection, after treatment and normalization of the EMB (n=7). We identified 91 transcripts differentially expressed in rejection compared with control (false discovery rate <0.10). In postrejection samples, 98% of transcripts returned toward control levels, displaying an intermediate expression profile for patients with treated rejection (P<0.0001). Cluster analysis of the 40 transcripts with >25% change in expression levels during rejection demonstrated good discrimination between control and rejection samples and verified the intermediate expression profile of postrejection samples. Quantitative real-time polymerase chain reaction confirmed significant differential expression for the predictive markers CFLAR and SOD2 (UniGene ID No. 355724 and No. 384944). CONCLUSIONS: These data demonstrate that peripheral blood expression profiles correlate with biopsy-proven allograft rejection. Intermediate expression profiles of treated rejection suggest persistent immune activation despite normalization of the EMB. If validated in larger studies, expression profiling may prove to be a more sensitive screening test for allograft rejection than EMB.

Debate: Do all patients with heart failure require implantable defibrillators to prevent sudden death?

Sudden death is a major cause of mortality in patients with ventricular dysfunction. The highest risk occurs among patients with less severe functional impairment. Current methods of risk stratification are inadequate, and a rational therapy for prevention of sudden death is not available. The implantable cardioverter-defibrillator (ICD) has proven to be more effective than drugs in reducing sudden-death risk in some subsets of patients. Empiric ICD therapy, targeting the general population with mild to moderate heart failure, will maximize the impact of such a strategy to prevent sudden death and improve long-term survival.