David DeNofrio

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)

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.

Prognostic significance of atrial fibrillation in patients at a tertiary medical center referred for heart transplantation because of severe heart failure.

Atrial fibrillation (AF) occurs frequently in advanced heart failure. The prognostic significance of AF remains controversial. To determine the relation of AF to survival in patients with advanced heart failure, 234 consecutive patients referred for heart transplantation evaluation from January 1993 to June 1996 were studied to determine the effect of AF on event-free survival (freedom from death, heart transplantation, or placement of a left ventricular assist device). Clinical characteristics of the study population included: age, 51 +/- 17 years; maximum exercise oxygen consumption, 14.2 +/- 5.3 ml/kg/min; left ventricular ejection fraction, 24 +/- 11%; pulmonary capillary wedge pressure, 23 +/- 9 mm Hg; and ischemic etiology, 52%. Medical therapy included: diuretics (86%), angiotensin-converting enzyme inhibitors (80%), digoxin (80%), and anticoagulation therapy (72%). Mean duration of follow-up was 1.1 +/- 1.0 years. Sixty-two patients (27.4%) had AF. One-year event-free survival of the study population was 48%. No difference in event-free survival between patients with and without AF was observed. Univariate predictors of decreased event-free survival included: (1) advanced New York Heart Association class; (2) higher pulmonary capillary wedge pressure; (3) lower cardiac index; (4) lower maximum exercise oxygen consumption; (5) use of inotropic therapy; and (6) greater pulmonary artery systolic pressure. By multivariate analysis, independent predictors of decreased event-free survival included advanced New York Heart Association class (p <0.002) and higher pulmonary capillary wedge pressure (p = 0.02). Thus, AF in patients with advanced heart failure is not associated with decreased event-free survival.

Common Variant in AMPD1 Gene Predicts Improved Clinical Outcome in Patients With Heart Failure

BACKGROUND This study was undertaken to identify gene(s) that may be associated with improved clinical outcome in patients with congestive heart failure (CHF). The adenosine monophosphate deaminase locus (AMPD1) was selected for study. We hypothesized that inheritance of the mutant AMPD1 allele is associated with increased probability of survival without cardiac transplantation in patients with CHF. METHODS AND RESULTS AMPD1 genotype was determined in 132 patients with advanced CHF and 91 control reference subjects by use of a polymerase chain reaction-based, allele-specific oligonucleotide detection assay. In patients with CHF, those heterozygous (n=20) or homozygous (n=1) for the mutant AMPD1 allele (AMPD1 +/- or -/-, respectively) experienced a significantly longer duration of heart failure symptoms before referral for transplantation evaluation than CHF patients homozygous for the wild-type allele (AMPD1 +/+; n=111; 7.6+/-6.5 versus 3.2+/-3.6 years; P<0.001). The OR of surviving without cardiac transplantation >/=5 years after initial hospitalization for CHF symptoms was 8.6 times greater (95% CI: 3.05, 23.87) in those patients carrying >/=1 mutant AMPD1 allele than in those carrying 2 wild-type AMPD1 +/+ alleles. CONCLUSIONS After the onset of CHF symptoms, the mutant AMPD1 allele is associated with prolonged probability of survival without cardiac transplantation. The mechanism by which the presence of the mutant AMPD1 allele may modify the clinical phenotype of heart failure remains to be determined.

Pharmacokinetic, pharmacodynamic, and outcome investigations as the basis for mycophenolic acid therapeutic drug monitoring in renal and heart transplant patients

Mycophenolate mofetil is widely used in combination with either cyclosporine or tacrolimus for rejection prophylaxis in renal and heart transplant patients. Although not monitored routinely nearly to the degree that other agents such as cyclosporine or tacrolimus, there is an expanding body of experimental evidence for the utility of monitoring mycophenolic acid, the primary active metabolite of mycophenolate mofetil, plasma concentration as an index of risk for the development of acute rejection. The following are important experimentally-based reasons for recommending the incorporation of target therapeutic concentration monitoring of mycophenolic acid: (1) the MPA dose-interval area-under-the-concentration-time curve, and less precisely, MPA predose concentrations predict the risk for development of acute rejection; (2) the strong correlation between mycophenolic acid plasma concentrations and expression of important cell surface activation antigens, whole blood pharmacodynamic assays of lymphocyte proliferation and median graft rejection scores in a heart transplant animal model; (3) the greater than 10-fold interindividual variation of MPA area under the concentration time curve values in heart and renal transplant patients receiving a fixed dose of the parent drug; (4) drug-drug interactions involving other immunosuppressives are such that when switching from one to another (eg, from cyclosporine to tacrolimus or vice-versa) substantial changes in MPA concentrations can occur in patients receiving a fixed dose of the parent drug; (5) significant effects of liver and kidney diseases on the steady-state total and free mycophenolic acid area under the concentration time curve values; (6) the need to closely monitor mycophenolic acid when a major change in immunosuppression is planned such as steroid withdrawal. Current investigations are focused on determination of the most optimal sampling time and for mycophenolic acid target therapeutic concentration monitoring. Further investigations are needed to evaluate the pharmacologic activity of the newly described acyl glucuronide metabolite of mycophenolic acid which has been shown to inhibit, in vitro, inosine monophosphate dehydrogenase.

The effect of ventricular assist devices on post-transplant mortality an analysis of the United network for organ sharing thoracic registry

OBJECTIVES This study sought to determine the relationship between pre-transplant ventricular assist device (VAD) support and mortality after heart transplantation. BACKGROUND Increasingly, VADs are being used to bridge patients to heart transplantation. The effect of these devices on post-transplant mortality is unclear. METHODS Patients 18 years or older who underwent first-time, single-organ heart transplantation in the U.S. between 1995 and 2004 were included in the analyses. This study compared 1,433 patients bridged with intracorporeal and 448 patients bridged with extracorporeal VADs with 9,455 United Network for Organ Sharing status 1 patients not bridged with a VAD with respect to post-transplant mortality. Because the proportional hazards assumption was not met, hazard ratios (HRs) for different time periods were estimated. RESULTS Intracorporeal VADs were associated with an HR of 1.20 (95% confidence interval [CI]: 1.02 to 1.43; p = 0.03) for mortality in the first 6 months after transplant and an HR of 1.99 (95% CI: 1.44 to 2.75; p < 0.0001) beyond 5 years. Between 6 months and 5 years, the HRs were not significantly different from 1. Extracorporeal VADs were associated with an HR of 1.91 (95% CI: 1.53 to 2.37; p < 0.0001) for mortality in the first 6 months and an HR of 2.93 (95% CI: 1.19 to 7.25; p = 0.02) beyond 5 years. The HRs were not significantly different from 1 between 6 months and 5 years, except for an HR of 0.23 (95% CI: 0.06 to 0.91; p = 0.04) between 24 and 36 months. CONCLUSIONS Extracorporeal VADs are associated with higher mortality within 6 months and again beyond 5 years after transplantation. Intracorporeal VADs are associated with a small increase in mortality in the first 6 months and a clinically significant increase in mortality beyond 5 years. These data do not provide evidence supporting VAD implantation in stable United Network for Organ Sharing status I patients awaiting heart transplantation.

Prevention of primary cytomegalovirus disease in organ transplant recipients with oral ganciclovir or oral acyclovir prophylaxis.

Background: Optimal prophylaxis against cytomegalovirus (CMV) disease for organ transplant patients at risk for primary infection (donor seropositive, recipient seronegative, D+R−) remains to be determined. We hypothesized that prolonged oral ganciclovir therapy following intravenous therapy would provide increased protection.

Mycophenolic acid concentrations are associated with cardiac allograft rejection

BACKGROUND Mycophenolate mofetil (MMF) therapy decreases the incidence of allograft rejection following solid-organ transplantation. Current dosing strategies of MMF are not routinely adjusted based on mycophenolic acid (MPA) area under the concentration-time curve (AUC), MPA trough, or free MPA (fMPA) AUC values. METHODS To determine the clinical significance of MPA concentrations following orthotopic heart transplantation (OHT), we measured pre-dose MPA trough, MPA free fraction, an estimated MPA AUC using an abbreviated sampling schedule, and fMPA AUC in 38 consecutive patients. We measured MPA concentrations using a validated high-performance liquid chromatography method and graded endomyocardial biopsies based on the International Society for Heart and Lung Transplantation (ISHLT) grading system. RESULTS The MPA values for the study group were as follows: MPA trough of 1.2 +/- 0.6 microg/ml; MPA free fraction of 1.9 +/- 0.4%; MPA AUC of 44.5 +/- 16. 1 microg/hour/ml; and fMPA AUC of 0.83 +/- 0.30 microg/hour/ml. We compared patients with Grade 0 (n = 22), Grade 1 (n = 13), or Grade 2/3 (n = 3). The MPA AUC values were lower in patients with Grade 2/3 than in patients with Grade 0 (26.1 +/- 6.6 vs 42.8 +/- 14.0 microg/hour/ml, p < 0.08) or Grade 1 rejection (26.1 +/- 6.6 vs 51.7 +/- 17.5 microg/hour/ml, p < 0.05). The fMPA AUC values were lower in patients with Grade 2/3 than with patients with Grade 0 (0.49 +/- 0.11 vs 0.81 +/- 0.25 microg/hour/ml, p < 0.05) or Grade 1 (0.49 +/- 0.25 vs 0.95 +/- 0.34 microg/hour/ml, p < 0.05) rejection. We noted a trend in MPA trough concentrations between patients with Grade 2/3 vs 0 (0.65 +/- 0.15 vs 1.20 +/- 0.58 microg/ml, p = 0.15) and Grade 1 (0.65 +/- 0.15 vs 1.24 +/- 0.72 microg/ml, p = 0.14) rejection. CONCLUSION These preliminary results suggest that lower MPA AUC and fMPA AUC values are associated with cardiac allograft rejection in heart transplant recipients. Individualizing MMF dosing based on MPA determinations may minimize the risk of rejection following OHT.

Survival After Cardiac Transplantation in Patients With Hypertrophic Cardiomyopathy

Background—Heart transplant is a treatment option for selected patients with hypertrophic cardiomyopathy (HCM). However, the prevalence, clinical profile, and outcome of this subgroup of HCM patients are uncertain. Therefore, we sought to determine the occurrence, clinical characteristics, and prognosis of HCM patients who underwent cardiac transplantation in the United States during a 15-year period. Methods and Results—Demographic, clinical, and survival outcomes of 26 706 adult (age ≥18 years), heart-only transplant recipients between January 1990 and December 2004 were acquired from the United Network of Organ Sharing Registry. Pretransplant diagnoses were classified as follows: HCM (n=303, 1%) and non-HCM (26 403, 99%), comprising 3 patient subgroups: (1) ischemic cardiomyopathy (n=14 308, 54%), (2) dilated cardiomyopathy (n=11 760, 44%), and (3) restrictive cardiomyopathy (n=335, 1%). Study follow-up began at the time of heart transplant and was 76±44 months (mean±SD) among survivors. The 1-, 5-, and 10-year overall transplant survival for HCM patients was 85%, 75%, and 61%, respectively, with a trend toward greater survival compared with that of non-HCM transplant patients (82%, 70%, and 49%, respectively; log-rank test, P=0.05). However, propensity-matched, covariate-adjusted, Cox regression model analysis showed better survival over time (P<0.01) among the HCM patients. When HCM posttransplant survival was compared with that in each of the non-HCM patient subgroups, HCM patients had more favorable survival than did those transplanted for ischemic cardiomyopathy (P=0.02). In contrast, HCM posttransplant survival did not differ from that of patients transplanted for restrictive (P=0.08) or dilated (P=0.25) cardiomyopathy. Conclusions—HCM patients compose a small subset (1%) of the overall population of patients who undergo heart transplantation in the United States. Nonetheless, survival after transplant among HCM patients is comparable to that of patients transplanted for non-HCM cardiovascular diseases, with possible enhanced survival over time.

Effects of a percutaneous mechanical circulatory support device for medically refractory right ventricular failure

BACKGROUND Medically refractory right ventricular failure (MR-RVF) is associated with high in-hospital mortality and is managed with surgical assist devices, atrial septostomy, or extracorporeal membrane oxygenation. This study explored the hemodynamic effect associated with a percutaneous RV support device (pRVSD) for MR-RVF. METHODS Between 2008 and 2010, 9 patients with MR-RVF, defined as cardiogenic shock despite maximal medical therapy, were treated with a pRVSD. Medical records were reviewed for demographics, hemodynamic and laboratory data, and details of pRVSD implantation. RESULTS MR-RVF was due to severe sepsis in 1 patient (11.1%), post-cardiotomy syndrome in 2 (22.2%), and acute inferior wall myocardial infarction (IWMI) in 6 (66.7%). Five patients underwent right internal jugular-to-femoral cannulation, and 4 required bifemoral cannulation. No intra-procedural deaths or major vascular complications requiring surgical or peripheral intervention occurred. Time from admission to pRVSD implantation was 2.9 ± 3.3 days, with an average of 6516 ± 698 rotations/min, providing flow at 3.3 ± 0.4 liters/min. Mean duration of pRVSD activation was 3.1 ± 1.8 days. Compared with pre-procedural values, mean arterial pressure (57 ± 7 vs 75 ± 19 mm Hg, p < 0.05), right atrial pressure (22 ± 3 vs 15 ± 6 mm Hg, p < 0.05), cardiac index (1.5 ± 0.4 vs 2.3 ± 0.5 liters/min/m(2), p < 0.05), mixed venous oxygen saturation (40 ± 14 vs 58 ± 4 percent, p < 0.05), and RV stroke work (3.4 ± 3.9 vs 9.7 ± 6.8 g · m/beat, p < 0.05) improved significantly within 24 hours of pRVSD implantation. In-hospital mortality was 44% (n = 4). Time from admission to pRVSD placement was lower in patients who survived to hospital discharge (0.9 ± 0.8 days) vs non-survivors (4.8 ± 3.5 days; p = 0.04). All survivors presented with IWMI. CONCLUSION Use of a pRVSD for MR-RVF is feasible and associated with improved hemodynamics. Algorithms promoting earlier pRVSD use in MR-RVF warrant further investigation.

Survival Following Cardiac Transplantation in Patients with Hypertrophic Cardiomyopathy

Background—Heart transplant is a treatment option for selected patients with hypertrophic cardiomyopathy (HCM). However, the prevalence, clinical profile, and outcome of this subgroup of HCM patients are uncertain. Therefore, we sought to determine the occurrence, clinical characteristics, and prognosis of HCM patients who underwent cardiac transplantation in the United States during a 15-year period. Methods and Results—Demographic, clinical, and survival outcomes of 26 706 adult (age ≥18 years), heart-only transplant recipients between January 1990 and December 2004 were acquired from the United Network of Organ Sharing Registry. Pretransplant diagnoses were classified as follows: HCM (n=303, 1%) and non-HCM (26 403, 99%), comprising 3 patient subgroups: (1) ischemic cardiomyopathy (n=14 308, 54%), (2) dilated cardiomyopathy (n=11 760, 44%), and (3) restrictive cardiomyopathy (n=335, 1%). Study follow-up began at the time of heart transplant and was 76±44 months (mean±SD) among survivors. The 1-, 5-, and 10-year overall transplant survival for HCM patients was 85%, 75%, and 61%, respectively, with a trend toward greater survival compared with that of non-HCM transplant patients (82%, 70%, and 49%, respectively; log-rank test, P=0.05). However, propensity-matched, covariate-adjusted, Cox regression model analysis showed better survival over time (P<0.01) among the HCM patients. When HCM posttransplant survival was compared with that in each of the non-HCM patient subgroups, HCM patients had more favorable survival than did those transplanted for ischemic cardiomyopathy (P=0.02). In contrast, HCM posttransplant survival did not differ from that of patients transplanted for restrictive (P=0.08) or dilated (P=0.25) cardiomyopathy. Conclusions—HCM patients compose a small subset (1%) of the overall population of patients who undergo heart transplantation in the United States. Nonetheless, survival after transplant among HCM patients is comparable to that of patients transplanted for non-HCM cardiovascular diseases, with possible enhanced survival over time.