Cost-effectiveness of implantable ventricular assist devices in older children with stable, inotrope-dependent dilated cardiomyopathy.

BACKGROUND: In a stable, inotrope-dependent pediatric patient with dilated cardiomyopathy, we evaluated the cost-effectiveness of continuous-flow VAD implantation compared to a watchful waiting approach using chronic inotropic therapy. METHODS: We used a state-transition model to estimate the costs and outcomes of 14-year-old (INTERMACS profile 3) patients receiving either VAD or watchful waiting. We measured benefits in terms of lifetime QALYs gained. Model inputs were taken from the literature. We calculated the ICER, or the cost per additional QALY gained, of VADs and performed multiple sensitivity analyses to test how our assumptions influenced the results. RESULTS: Compared to watchful waiting, VADs produce 0.97 more QALYs for an additional $156 639, leading to an ICER of $162 123 per QALY gained from a healthcare perspective. VADs have 17% chance of being cost-effective given a cost-effectiveness threshold of $100 000 per QALY gained. Sensitivity analyses suggest that VADs can be cost-effective if the costs of implantation decrease or if hospitalization costs or mortality among watchful waiting patients is higher. CONCLUSIONS: As a bridge to transplant, VADs provide a health benefit to children who develop stable, inotrope-dependent heart failure, but immediate implantation is not yet a cost-effective strategy compared to watchful waiting based on commonly used cost-effectiveness thresholds. Early VAD support can be cost-effective in sicker patients and if device implantation is cheaper. In complex conditions such as pediatric heart failure, cost-effectiveness should be just one of many factors that inform clinical decision-making.

The impact of patient sex on the response to intramyocardial mesenchymal stem cell administration in patients with non-ischaemic dilated cardiomyopathy.

AIMS: Sex differences impact the occurrence, presentation, prognosis, and response to therapy in heart disease. Particularly, the phenotypic presentation of patients with non-ischaemic dilated cardiomyopathy (NIDCM) differs between men and women. However, whether the response to mesenchymal stem cell (MSC) therapy is influenced by sex remains unknown. We hypothesize that males and females with NIDCM respond similarly to MSC therapy. METHODS AND RESULTS: Male (n = 24) and female (n = 10) patients from the POSEIDON-DCM trial who received MSCs via transendocardial injections were evaluated over 12 months. Endothelial function was measured at baseline and 3 months post-transendocardial stem cell injection (TESI). At baseline, ejection fraction (EF) was lower (P = 0.004) and end-diastolic volume (EDV; P = 0.0002) and end-systolic volume (ESV; P = 0.0002) were higher in males vs. females. In contrast, baseline demographic characteristics, Minnesota Living with Heart Failure Questionnaire (MLHFQ), and 6-min walk test (6MWT) were similar between groups. EF improved in males by 6.2 units (P = 0.04) and in females by 8.6 units (P = 0.04; males vs. females, P = 0.57). EDV and ESV were unchanged over time. The MLHFQ score, New York Heart Association (NYHA) class, endothelial progenitor cell-colony forming units, and serum tumour necrosis factor alpha improved similarly in both groups. CONCLUSION: Despite major differences in phenotypic presentation of NIDCM in males and females, this study is the first of its kind to demonstrate that MSC therapy improves a variety of parameters in NIDCM irrespective of patient sex. These findings have important clinical and pathophysiologic implications regarding the impact of sex on responses to cell-based therapy for NIDCM.

Case Report: Early Transplant Rejection of a Methanol-Intoxicated Donor Heart in a Young Female Patient. A Diagnostic Approach With CMR, Cardiac Biopsy, and Genetic Risk Assessment.

This case report describes the contributions of multimodality imaging, cardiac biopsy, and genetic sequencing to the diagnosis and management of heart transplant rejection in a 23-year old patient with dilated cardiomyopathy.

Preliminary report on the cost effectiveness of ventricular assist devices.

The aim of the present study was to perform a cost-effectiveness analysis (CEA) of ventricular assist devices (VAD) implantation surgery in the Japanese medical reimbursement system. The study group consisted of thirty-seven patients who had undergone VAD implantation surgery for dilated cardiomyopathy (n = 25; 67.6 %) or hypertrophic cardiomyopathy (n = 4; 10.8 %), and others (n = 8; 21.6 %). Quality-adjusted life years (QALYs) were calculated using the utility score and years of life. Medical reimbursement bills were chosen as cost indices. The observation period was the 12-month period after surgery. Then, the incremental cost-effectiveness ratio was calculated according to the VAD type. In addition, the prognosis after 36 months was estimated on the basis of the results obtained using the Markov chain model. The mean preoperative INTERMACS profile score was 2.35 ± 0.77. Our results showed that the utility score, which indicates the effectiveness of VAD implantation surgery, improved by 0.279 ± 0.188 (ΔQALY, p < 0.05). The cost of VAD implantation surgery was 313,282 ± 25,275 (ΔUS$/year) on the basis of medical reimbursement bills associated with therapeutic interventions. The calculated result of CEA was 364,501 ± 190,599 (ΔUS$/QALY). The improvement in the utility score was greater for implantable versus extracorporeal VADs (0.233 ± 0.534 vs. 0.371 ± 0.238) and ICER was 303,104 (ΔUS$/ΔQALY). Furthermore, when we estimated CEA for 36 months, the expected baseline value was 102,712 (US$/QALY). Therefore, VAD implantation surgery was cost effective considering the disease specificities.

Clinical utility and prognostic value of left atrial volume assessment by cardiovascular magnetic resonance in non-ischaemic dilated cardiomyopathy.

AIMS: Echocardiographic studies have shown that left atrial volume (LAV) predicts adverse outcome in small heart failure (HF) cohorts of mixed aetiology. However, the prognostic value of LAV in non-ischaemic dilated cardiomyopathy (DCM) is unknown. Cardiovascular magnetic resonance (CMR) allows accurate and reproducible measurement of LAV. We sought to determine the long-term prognostic significance of LAV assessed by CMR in DCM. METHODS AND RESULTS: We measured LAV indexed to body surface area (LAVi) in 483 consecutive DCM patients referred for CMR. Patients were prospectively followed up for a primary endpoint of all-cause mortality or cardiac transplantation. During a median follow-up of 5.3 years, 75 patients died and 9 underwent cardiac transplantation. After adjustment for established risk factors, LAVi was an independent predictor of the primary endpoint [hazard ratio (HR) per 10 mL/m(2) 1.08; 95% confidence interval (CI) 1.01-1.15; P = 0.022]. LAVi was also independently associated with the secondary composite endpoints of cardiovascular mortality or cardiac transplantation (HR per 10 mL/m(2) 1.11; 95% CI 1.04-1.19; P = 0.003), and HF death, HF hospitalization, or cardiac transplantation (HR per 10 mL/m(2) 1.11; 95% CI 1.04-1.18; P = 0.001). The optimal LAVi cut-off value for predicting the primary endpoint was 72 mL/m(2). Patients with LAVi >72 mL/m(2) had a three-fold elevated risk of death or transplantation (HR 3.00; 95% CI 1.92-4.70; P < 0.001). LAVi provided incremental prognostic value for the prediction of transplant-free survival (net reclassification improvement 0.17; 95% CI 0.05-0.29; P = 0.002). CONCLUSIONS: LAVi is a powerful independent predictor of transplant-free survival and HF outcomes in DCM. Assessment of LAV improves risk stratification in DCM and should be incorporated into routine CMR examination.

Cardiac sarcoidosis diagnosed by histological assessment of a left ventricular apical core excised for insertion of a left ventricular assist device.

A 58-year-old male with no history of heart disease was admitted to hospital for congestive heart failure due to severe left ventricular dysfunction, and clinically diagnosed with dilated cardiomyopathy. He developed recurrent heart failure requiring several admissions to hospital and was finally referred to our institution with severe congestive heart failure. Despite medical treatment with inotropic agents, his symptoms gradually worsened. A left ventricular assist device (LVAD) was implanted together with mitral and tricuspid valve repair at 22 days after hospitalization. A histological assessment of a left ventricular apical core specimen revealed non-caseating granulomas consistent with cardiac sarcoidosis. The postoperative course was uneventful, and he remains under cardiac rehabilitation while waiting for cardiac transplantation.

Serial multidetector computed tomography assessment of left ventricular reverse remodeling, mass, and regional wall stress after restrictive mitral annuloplasty in dilated cardiomyopathy.

OBJECTIVE: To evaluate serial data on left ventricular and myocardial reverse remodeling after restrictive mitral annuloplasty. METHODS: Thirteen patients (age, 64 ± 6 years) with functional mitral regurgitation associated with dilated cardiomyopathy (ejection fraction, ≤ 35%) were examined before (baseline), soon (1.7 ± 1.5 months), and more than 1 year (16 ± 8 months) after restrictive mitral annuloplasty using multidetector computed tomography. The left ventricular end-diastolic and end-systolic volume indexes, left ventricular ejection fraction, left ventricular mass index, and end-systolic wall stress were estimated. RESULTS: In the period soon after restrictive mitral annuloplasty, significant reverse left ventricular remodeling was present, with decreases in the left ventricular end-diastolic volume index (149 ± 42 to 119 ± 41 mL/m(2), P = .04) and left ventricular end-systolic volume index (114 ± 44 to 78 ± 43 mL/m(2), P = .02), and an increase in left ventricular ejection fraction (25% ± 10% to 37% ± 14%, P = .01). Additional changes in these parameters were seen in the later period (103 ± 29 mL/m(2), 61 ± 23 mL/m(2), and 42% ± 9%, respectively; all P < .05 vs baseline). In the early postrestrictive mitral annuloplasty period, the left ventricular mass index did not change significantly (104 ± 22 to 104 ± 18 g/m(2), P = NS), but significant regression occurred in the later period (90 ± 17 g/m(2), P < .05 vs baseline). The end-systolic wall stress was significantly decreased in the early period (P < .05) and was sustained in the late period. Furthermore, the increase in left ventricular ejection fraction in the late period correlated significantly with the magnitude of the end-systolic wall stress reduction (r = -0.67, P = .01). CONCLUSIONS: Our findings indicate that ventricular reverse remodeling occurs soon after restrictive mitral annuloplasty. In contrast, myocardial reverse remodeling (ie, regression of myocardial hypertrophy) occurs over time between the early and late postoperative periods. Our data also suggest that the late improvement in left ventricular systolic performance might be attributable to a decrease in the left ventricular afterload.

Association of left ventricular dilation at listing for heart transplant with postlisting and early posttransplant mortality in children with dilated cardiomyopathy.

BACKGROUND: In patients with dilated cardiomyopathy, the magnitude of cardiac remodeling often correlates with the clinical severity of heart failure. We sought to determine whether measures of left ventricular (LV) dilation and systolic dysfunction in children with dilated cardiomyopathy at the time of listing for cardiac transplantation are associated with survival while waiting for and early after transplant. METHODS AND RESULTS: We analyzed echocardiographic data obtained within 6 months of listing for heart transplant and clinical data from 261 children with dilated cardiomyopathy who were included in both the Pediatric Cardiomyopathy Registry and the Pediatric Heart Transplant Study. Median time to listing after diagnosis was 1.9 months and to transplant after listing was 0.8 months. There were 42 deaths (29 waiting and 13 within 6 months after transplant). We found a significant age-dependent association of LV end-diastolic dimension z score (n=204, 31 deaths) with death controlling for race, transplant status, and medical insurance. The association was strongest for infants younger than 6 months at diagnosis (hazard ratio 1.47, P=0.008) and was not significant in children older than 5 years at diagnosis. A similar interaction was identified between age and LV end-systolic dimension z score (P=0.04). Neither LV function nor mass was associated with death, overall, or in subgroups. CONCLUSIONS: The severity of LV dilation at listing for heart transplant is associated with outcome in infants and young children with dilated cardiomyopathy, whereas the severity of LV systolic dysfunction is not. These findings should be considered in risk stratification of these children at listing.

Restarting the clock...again: ethical considerations in retransplantation.

Cardiac and pulmonary transplantation has revolutionized end-stage heart and lung therapy. With the advent of cyclosporine and other immunosuppressive therapies, many patients lead productive lives. Unfortunately, other patients who have undergone cardiac and/or pulmonary transplantation do not have favorable results. In fact, some require retransplantation to live. Because of organ scarcity, healthcare professionals and patients must examine not only retransplantation survival rates but also the ethical considerations when dealing with resource-limited organs. Given that retransplantation survival rates are not as favorable as those for primary transplantation and that no studies involving quality of life and morbidity could be located, considerable thought should be given to this controversial practice.

Cost utility evaluation of extracorporeal membrane oxygenation as a bridge to transplant for children with end-stage heart failure due to dilated cardiomyopathy.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) and cardiac transplantation are recognized to be expensive. METHODS: We performed a cost utility evaluation with a decision model approach, including 75 children with dilated cardiomyopathy. A cohort of patients with end stage heart failure who were offered ECMO bridging was compared with a similar cohort offered only conventional intensive care. Outcome was measured in cost per quality adjusted life year (QALY). RESULTS: Median follow-up was 4.39 years (interquartile range, 1.83-5.74 years), during which 50 children underwent transplantation, 16 had a period of recovery, and 25 died. ECMO bridging was highly effective (hazard ratio, 0.181; 95% confidence interval, 0.067-0.489; p = 0.001) but exceeded conventional criteria for cost-effectiveness. The reference incremental cost-effectiveness ratio (ICER) was pound65,645 per QALY and pound54,284 per life-year gained. Average life expectancy rose from 6.78 to 9.79 years and costs from pound146,398 to pound309,599 per patient with ECMO bridging. The ICER was sensitive to ECMO cost, the long-term transplant survival rate, and quality of life in transplant recipients. CONCLUSIONS: ECMO bridging is effective but expensive. The eligible target population is small, nationally, positively influencing affordability. We strongly support our national policy of mechanical bridge to transplant for suitable children in end stage heart failure. Cost effectiveness could be optimized by: 1) increased availability of organ donors, 2) reduction in mechanical support costs possibly by alternate devices and 3) inclusion of patients most likely to benefit.

Magnetic resonance imaging assessment of reverse left ventricular remodeling late after restrictive mitral annuloplasty in early stages of dilated cardiomyopathy.

OBJECTIVE: Magnetic resonance imaging was used to evaluate left ventricular reverse remodeling at long-term follow-up (3-4 years) after restrictive mitral annuloplasty in patients with early stages of nonischemic, dilated cardiomyopathy, and severe mitral regurgitation. METHODS: Twenty-two selected patients (eligible to undergo magnetic resonance imaging) with mild to moderate heart failure (mean New York Heart Association class 2.2 +/- 0.4), dilated cardiomyopathy (left ventricular ejection fraction 37% +/- 5%, left ventricular end-diastolic volume 215 +/- 34 mL), and severe mitral regurgitation (grade 3-4+) underwent restrictive mitral annuloplasty. Magnetic resonance imaging was performed 1 week before surgery and repeated after 3 to 4 years. RESULTS: There was no hospital mortality or major morbidity. Two patients died during follow-up (9%), and 2 patients could not undergo repeat magnetic resonance imaging because of comorbidity. New York Heart Association class improved from 2.2 +/- 0.4 to 1.2 +/- 0.4 (P < .05). Mitral regurgitation was minimal at late echocardiographic follow-up. There were significant decreases in indexed (to body surface area) left atrial end-systolic volume (from 84 +/- 20 mL/m(2) to 68 +/- 12 mL/m(2), P < .01), left ventricular end-systolic volume (from 42 +/- 14 mL/m(2) to 31 +/- 12 mL/m(2), P < .01), left ventricular end-diastolic volume (from 110 +/- 18 mL/m(2) to 80 +/- 17 mL/m(2), P < .01), and left ventricular mass (from 76 +/- 21 g/m(2) to 66 +/- 12 g/m(2), P = .03). Forward left ventricular ejection fraction improved from 37% +/- 5% to 55% +/- 10% (P < .01). Indexed left atrial end-diastolic volume did not show a significant decrease (from 48 +/- 16 mL/m(2) to 44 +/- 10 mL/m(2), P = .15). CONCLUSION: Magnetic resonance imaging confirms sustained significant reverse left atrial and ventricular remodeling at late (3-4 years) follow-up in patients with nonischemic, dilated cardiomyopathy, and mild to moderate heart failure after restrictive mitral annuloplasty.

Economic evaluation of everolimus and mycophenolate mofetil versus azathioprine in de novo heart transplantation.

UNLABELLED: Both the proliferation signal inhibitor everolimus (1.5 mg/day) and mycophenolate mofetil (MMF) (3 g/day) have shown superior efficacy versus azathioprine in de novo heart transplantation. The cost-effectiveness of everolimus and MMF versus azathioprine was assessed to 6 months posttransplantation. METHODS: The evaluation was performed from the German health insurance payer perspective. The composite efficacy endpoint in the everolimus trial was death, graft loss/retransplantation, biopsy-proven acute rejection (BPAR) grade>or=3A, rejection with hemodynamic compromise, and loss to follow-up. The composite endpoint in the MMF trial included only death, retransplantation, and BPAR with hemodynamic compromise. To mimic the everolimus endpoint, an estimated number of patients with BPAR>or=3A was added to the MMF trial results, using two mapping scenarios. RESULTS: The incremental 6-month cost versus azathioprine was euro2535 for everolimus and euro3007 for MMF. The absolute reduction in efficacy failure versus azathioprine was 10.4% for everolimus and 9.8% and 10.1% for MMF, respectively, using scenarios 1 and 2. The incremental cost per efficacy failure avoided (ie, the incremental cost versus azathioprine divided by the reduction in efficacy failure) was euro24,457 for everolimus, and euro30,628 and euro29,912 for MMF in scenarios 1 and 2. CONCLUSION: This analysis, based on findings from two clinical trials, suggested that everolimus was more cost-effective than MMF versus azathioprine in the first 6 months after heart transplantation. Data from a head-to-head trial are required to confirm these results.

The impact of left ventricular reconstruction on survival in patients with ischemic cardiomyopathy.

OBJECTIVE: Left ventricular reconstruction (LVR) is performed to improve the morphologic structure and function of the heart in patients with heart failure. This procedure has been performed at the Cleveland Clinic Foundation since 1997. We assessed mortality, functional status, and predictors of outcome in these patients. METHODS: Data were extracted from multiple prospectively acquired datasets on demographic, clinical, and operative details of 220 consecutive patients who underwent LVR between July 1997 and July 2003, where the indication for surgery was heart failure (of whom 66% had New York Heart Association (NYHA) functional class III or IV symptoms). Mortality, functional status, and postoperative complications were ascertained by reference to the clinical record, social security death index, and by phone contact. Mean preoperative left ventricular ejection fraction (LVEF) was 21.5+/-7.3% and mean left ventricular end-diastolic diameter was 6.4+/-1.0 cm. The mean age was 61.4+/-9.0 years and 80% were male. The majority (86%) of patients underwent concomitant coronary artery bypass grafting and 49% underwent mitral valve surgery. RESULTS: Thirty-day mortality was 1% and survival at 1, 3, and 5 years was 92%, 90%, and 80%, respectively. Of the survivors for whom data on NYHA functional class were available, 85% were in NYHA functional class I or II. Mortality was predicted by reduced preoperative ejection fraction <20% (unadjusted hazard ratio 1.53, p = 0.02), body mass index < or = 24 kg/m2 (unadjusted hazard ratio 1.69, p = 0.01), QRS duration > or = 130 ms (unadjusted hazard ratio 1.66, p = 0.01) and the requirement for renal replacement therapy postoperatively (unadjusted hazard ratio 3.85, p < 0.01). Mean LVEF improved to 24.7+/-8.86% (p < 0.01) and left ventricular volumes were also significantly reduced. CONCLUSIONS: In selected patients with heart failure, LVR, in conjunction with revascularization and valve surgery, is associated with excellent survival, improved symptoms, and improved LVEF and left ventricular dimensions.

Longitudinal assessment of cardiovascular exercise performance after pediatric heart transplantation.

BACKGROUND: No existing longitudinal data document exercise performance after pediatric heart transplantation. We report the exercise performance findings from the longitudinal study of pediatric heart transplantation patients and the association of aerobic capacity with echocardiographic measures of graft function. METHODS: We performed a retrospective analysis of 28 children after heart transplantation who underwent 87 exercise tests and echocardiograms. Subjects exercised using graded cycle or treadmill protocols. Maximal oxygen consumption (VO2), physical working capacity, peak heart rate, and anaerobic threshold were evaluated. To measure systolic and diastolic function, shortening fraction and mitral valve pressure half-time (PHT) respectively, were obtained by echocardiography. RESULTS: The average age at transplantation was 10.9 +/- 5.6 years, at initial exercise test was 13.8 +/- 5.0 years, and at final exercise test was 15.8 +/- 5.2 years. Percent-predicted values at the initial exercise test were VO2, 59.3%; physical working capacity, 60.2%; and peak heart rate, 75.8%; these remained similarly decreased at the final exercise test. Shortening fraction and PHT were within normal limits, but PHT was significantly greater at final test (p < 0.05). The relationship of VO2% with time was statistically significant, described by a quadratic equation that included initial VO2% and time from heart transplantation. This relationship remained significant when the shortening fraction (p < .05) but not PHT was added as a covariate in the equation. CONCLUSIONS: Exercise performance after pediatric heart transplantation is impaired and, despite an initial improvement, declines over time. This can be explained by increasing diastolic dysfunction independent of donor graft age. If confirmed, these findings point the direction to further research aimed at limiting this aerobic capacity decline after heart transplantation.

Noninvasive assessment of cardiac mechanics and clinical outcome after partial left ventriculectomy.

BACKGROUND: Partial left ventriculectomy (PLV) was developed as a therapy for end-stage heart failure, but results were variable with few a priori predictors of outcome. Little is known about its effects on myocardial mechanics and their relation to clinical outcome. METHODS: Twenty-four dilated cardiomyopathy patients underwent cardiac magnetic resonance imaging (MRI) before PLV, and 3 and 12 months after surgery. Left ventricular (LV) circumferential shortening and wall stress were computed at three short-axis levels. Exploratory outcome analysis grouped patients according to the timing of adverse cardiac events postsurgery. RESULTS: LV mass and volume were decreased at each postsurgical time point (all p < 0.01). At 3 months, regional wall stress was reduced at all short-axis levels; but by 12 months stress was reduced from baseline only at the apex. Circumferential shortening was increased significantly at both postsurgical time points at each level. On average, septal shortening was negative (stretching) before surgery, but increased significantly, and was positive, postsurgery. Exploratory outcome analysis found that negative values of basal septum circumferential shortening before surgery increased the probability of event-free survival beyond 6 months. CONCLUSIONS: Regional heterogeneity of LV myocardial function, associated with dilated cardiomyopathy, was diminished after PLV but was also related to patient outcome. MRI with tissue tagging is useful for assessing the efficacy of surgical therapies for congestive heart failure.

The non-invasive assessment of hibernating myocardium in ischaemic cardiomyopathy--a myriad of techniques.

Heart failure is placing an ever-increasing burden on society. Many subjects with heart failure and underlying coronary artery disease have a significant amount of akinetic but viable myocardium that is able to contract should myocardial perfusion improve (hibernating myocardium). Non-randomised studies have shown prognostic benefit in subjects with hibernating myocardium undergoing revascularisation. Several non-invasive techniques have been developed to assess the presence or absence of hibernating myocardium. This review will examine the epidemiology and underlying pathogenesis of hibernating myocardium; evaluate the non-invasive techniques for diagnosing hibernating myocardium, and look at therapeutic intervention in subjects with hibernating myocardium.