Urinary peptidomic biomarkers of renal function in heart transplant recipients.

BACKGROUND: Chronic kidney disease (CKD) is common in patients after heart transplantation (HTx). We assessed whether in HTx recipients the proteomic urinary classifier CKD273 or sequenced urinary peptides revealing the parental proteins correlated with the estimated glomerular filtration rate (eGFR). METHODS: In 368 HTx patients, we measured the urinary peptidome and analysed CKD273 and 48 urinary peptides with a detectable signal in >95% of participants. After 9.1 months (median), eGFR and the urinary biomarkers were reassessed. RESULTS: In multivariable Bonferroni-corrected analyses of the baseline data, a 1-SD increase in CKD273 was associated with a 11.4 [95% confidence interval (CI) 7.25-15.5] mL/min/1.73 m2 lower eGFR and an odds ratio of 2.63 (1.56-4.46) for having eGFR <60 mL/min/1.73 m2. While relating eGFR category at follow-up to baseline urinary biomarkers, CKD273 had higher (P = 0.007) area under the curve (0.75; 95% CI 0.70-0.80) than 24-h proteinuria (0.64; 95% CI 0.58-0.69), but additional adjustment for baseline eGFR removed significance of both biomarkers. In partial least squares analysis, the strongest correlates of the multivariable-adjusted baseline eGFR were fragments of collagen I (positive) and the mucin-1 subunit α (inverse). Associations between the changes in eGFR and the urinary markers were inverse for CKD273 and mucin-1 and positive for urinary collagen I. CONCLUSIONS: With the exception of baseline eGFR, CKD273 was more closer associated with imminent renal dysfunction than 24-h proteinuria. Fragments of collagen I and mucin-1-respectively, positively and inversely associated with eGFR and change in eGFR-are single-peptide markers associated with renal dysfunction.

The evolution and benefit of device therapy in patients listed for heart transplant.

Aims: The latest 2015 ESC Guidelines on the prevention of sudden cardiac death make a Class IIa recommendation for ICD implantation in patients listed for heart transplantation. This recommendation was based on expert consensus in view of the sparsity of data. Methods and results: All patients listed for heart transplantation at the University Hospitals of Leuven from 2002 until 2014 were studied retrospectively. Exclusion criteria were age <16 years, cardiac disease other than ischaemic or dilated cardiomyopathy and re-transplantation. A total of 286 patients were included, of which 140 (49.0%) received an ICD. There was a historical increase of the time on the waiting list before transplantation (P < 0.001) together with an increase of the use of ICDs (P < 0.001) and left ventricular assist devices (LVADs) (P < 0.001). The proportion of patients reaching heart transplant remained unchanged (P = 0.700). The annual appropriate shock rate in patients with ICD was 28.0%/y on the active waiting list. Patients with ICD showed a trend to improved survival (P = 0.070). Independent predictors of mortality or removal from the transplant list because of clinical deterioration were the need for LVAD (HR 4.38, 95%CI 2.11-9.01), a history of stroke (HR 2.95, 95%CI 1.61-5.40), older age (HR 1.03, 95%CI 1.01-1.05) and a worse renal function (HR 1.15, 95%CI 1.00-1.33). Conclusion: The time on the waiting list for heart transplantation significantly increased together with an increased use of device therapy in this population. The proportion of patients reaching transplant remained unchanged. This patient group is prone to life-threatening arrhythmias and the use of an ICD may improve survival.

Clinical usefulness of gene-expression profile to rule out acute rejection after heart transplantation: CARGO II.

AIMS: A non-invasive gene-expression profiling (GEP) test for rejection surveillance of heart transplant recipients originated in the USA. A European-based study, Cardiac Allograft Rejection Gene Expression Observational II Study (CARGO II), was conducted to further clinically validate the GEP test performance. METHODS AND RESULTS: Blood samples for GEP testing (AlloMap(®), CareDx, Brisbane, CA, USA) were collected during post-transplant surveillance. The reference standard for rejection status was based on histopathology grading of tissue from endomyocardial biopsy. The area under the receiver operating characteristic curve (AUC-ROC), negative (NPVs), and positive predictive values (PPVs) for the GEP scores (range 0-39) were computed. Considering the GEP score of 34 as a cut-off (>6 months post-transplantation), 95.5% (381/399) of GEP tests were true negatives, 4.5% (18/399) were false negatives, 10.2% (6/59) were true positives, and 89.8% (53/59) were false positives. Based on 938 paired biopsies, the GEP test score AUC-ROC for distinguishing ≥3A rejection was 0.70 and 0.69 for ≥2-6 and >6 months post-transplantation, respectively. Depending on the chosen threshold score, the NPV and PPV range from 98.1 to 100% and 2.0 to 4.7%, respectively. CONCLUSION: For ≥2-6 and >6 months post-transplantation, CARGO II GEP score performance (AUC-ROC = 0.70 and 0.69) is similar to the CARGO study results (AUC-ROC = 0.71 and 0.67). The low prevalence of ACR contributes to the high NPV and limited PPV of GEP testing. The choice of threshold score for practical use of GEP testing should consider overall clinical assessment of the patient's baseline risk for rejection.

Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure.

BACKGROUND: Clinical trials in heart failure have focused on the improvement in symptoms or decreases in the risk of death and other cardiovascular events. Little is known about the effect of drugs on the risk of clinical deterioration in surviving patients. METHODS AND RESULTS: We compared the angiotensin-neprilysin inhibitor LCZ696 (400 mg daily) with the angiotensin-converting enzyme inhibitor enalapril (20 mg daily) in 8399 patients with heart failure and reduced ejection fraction in a double-blind trial. The analyses focused on prespecified measures of nonfatal clinical deterioration. In comparison with the enalapril group, fewer LCZ696-treated patients required intensification of medical treatment for heart failure (520 versus 604; hazard ratio, 0.84; 95% confidence interval, 0.74-0.94; P=0.003) or an emergency department visit for worsening heart failure (hazard ratio, 0.66; 95% confidence interval, 0.52-0.85; P=0.001). The patients in the LCZ696 group had 23% fewer hospitalizations for worsening heart failure (851 versus 1079; P<0.001) and were less likely to require intensive care (768 versus 879; 18% rate reduction, P=0.005), to receive intravenous positive inotropic agents (31% risk reduction, P<0.001), and to have implantation of a heart failure device or cardiac transplantation (22% risk reduction, P=0.07). The reduction in heart failure hospitalization with LCZ696 was evident within the first 30 days after randomization. Worsening of symptom scores in surviving patients was consistently more common in the enalapril group. LCZ696 led to an early and sustained reduction in biomarkers of myocardial wall stress and injury (N-terminal pro-B-type natriuretic peptide and troponin) versus enalapril. CONCLUSIONS: Angiotensin-neprilysin inhibition prevents the clinical progression of surviving patients with heart failure more effectively than angiotensin-converting enzyme inhibition. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255.

Combined liver-thoracic transplantation: single-center experience with introduction of the 'Liver-first' principle.

Combined liver/thoracic transplantation (cLiThTx) is a complex procedure for end-stage/advanced liver and heart(H)/lung(Lu) disease. To avoid futile use of multiple organs in single recipients, results should be scrutinously analyzed. Single-center cLiThTx (04/2000-12/2015) were reviewed for the following: demographics, indications, surgical technique, complications, rejection, and five-year patient survival. Results are reported as median (range). Fourteen consecutive patients underwent cLiThTx: 3 cLiHTx, 10 cLiLuTx, and 1 cLiHLuTx. Recipient age was 42 years (17-63 years). Most frequent indications were cystic fibrosis (n = 5), hepatopulmonary fibrosis (n = 2), amyloidosis (n = 2), and epithelioid hemangio-endothelioma (n = 2). Thoracic organs were transplanted first, except in three where LiTx preceded LuTx. In the latter, lungs were preserved by normothermic ex vivo lung perfusion. Stenting was performed for stenosis of bile duct (n = 4), hepatic artery (n = 2), and bronchus (n = 2). Abdominal interventions were required for bleeding (n = 3), evisceration (n = 1), and adhesiolysis (n = 1). One liver (cLiLuTx) was lost to hepatic artery thrombosis 3 months post-transplant and successfully retransplanted. One patient (cLiHTx) died 4 months post-transplant (myocardial infarction). Follow-up was 4 years (2 months-16 years). One liver and 5 pulmonary rejections occurred, all mild and reversible. Two patients developed bronchiolitis obliterans, one is clinically well 16 years post-transplant, and the other successfully retransplanted. Estimated 5-year patient survival is 90%. CLiThTx is safe with excellent short-/long-term surgical and immunological results.

Performance of gene-expression profiling test score variability to predict future clinical events in heart transplant recipients.

BACKGROUND: A single non-invasive gene expression profiling (GEP) test (AlloMap®) is often used to discriminate if a heart transplant recipient is at a low risk of acute cellular rejection at time of testing. In a randomized trial, use of the test (a GEP score from 0-40) has been shown to be non-inferior to a routine endomyocardial biopsy for surveillance after heart transplantation in selected low-risk patients with respect to clinical outcomes. Recently, it was suggested that the within-patient variability of consecutive GEP scores may be used to independently predict future clinical events; however, future studies were recommended. Here we performed an analysis of an independent patient population to determine the prognostic utility of within-patient variability of GEP scores in predicting future clinical events. METHODS: We defined the GEP score variability as the standard deviation of four GEP scores collected ≥315 days post-transplantation. Of the 737 patients from the Cardiac Allograft Rejection Gene Expression Observational (CARGO) II trial, 36 were assigned to the composite event group (death, re-transplantation or graft failure ≥315 days post-transplantation and within 3 years of the final GEP test) and 55 were assigned to the control group (non-event patients). In this case-controlled study, the performance of GEP score variability to predict future events was evaluated by the area under the receiver operator characteristics curve (AUC ROC). The negative predictive values (NPV) and positive predictive values (PPV) including 95 % confidence intervals (CI) of GEP score variability were calculated. RESULTS: The estimated prevalence of events was 17 %. Events occurred at a median of 391 (inter-quartile range 376) days after the final GEP test. The GEP variability AUC ROC for the prediction of a composite event was 0.72 (95 % CI 0.6-0.8). The NPV for GEP score variability of 0.6 was 97 % (95 % CI 91.4-100.0); the PPV for GEP score variability of 1.5 was 35.4 % (95 % CI 13.5-75.8). CONCLUSION: In heart transplant recipients, a GEP score variability may be used to predict the probability that a composite event will occur within 3 years after the last GEP score. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT00761787.

Building research initiative group: chronic illness management and adherence in transplantation (BRIGHT) study: study protocol.

AIM: This article describes the rationale, design and methodology of the Building research initiative group: chronic illness management and adherence in transplantation (BRIGHT) study. This study of heart transplant patients will: (1) describe practice patterns relating to chronic illness management; (2) assess prevalence and variability of non-adherence to the treatment regimen; (3) determine the multi-level factors related to immunosuppressive medication non-adherence. BACKGROUND: The unaltered long-term prognosis after heart transplantation underscores an urgent need to identify and improve factors related to survival outcomes. The healthcare system (e.g. level of chronic illness management implemented) and patient self-management are major drivers of outcome improvement. DESIGN: The study uses a survey design in 40 heart transplant centres covering 11 countries in four continents. METHODS: Theoretical frameworks informed variable selection, which are measured by established and investigator-developed instruments. Heart transplant recipients, outpatient clinicians and programme's directors complete a survey. A staged convenience sampling strategy is implemented in heart transplant centres, countries and continents. Depending on the centre's size, a random sample of 25-60 patients is selected (N estimated 1680 heart transplant recipients). Five randomly selected clinicians and the medical director from each centre will be invited to participate. CONCLUSION: This is the first multi-centre, multi-continental study examining healthcare system and heart transplant centres chronic illness management practice patterns and potential correlates of immunosuppressive medication non-adherence. The knowledge gained will inform clinicians, researchers and healthcare policy makers at which level(s) interventions need to be implemented to improve long-term outcomes for transplant recipients.

Matricellular proteins and matrix metalloproteinases mark the inflammatory and fibrotic response in human cardiac allograft rejection.

AIMS: The cardiac extracellular matrix is highly involved in regulating inflammation, remodelling, and function of the heart. Whether matrix alterations relate to the degree of inflammation, fibrosis, and overall rejection in the human transplanted heart remained, until now, unknown. METHODS AND RESULTS: Expression of matricellular proteins, proteoglycans, and metalloproteinases (MMPs) and their inhibitors (TIMPs) were investigated in serial endomyocardial biopsies (n = 102), in a cohort of 39 patients within the first year after cardiac transplantation. Out of 15 matrix-related proteins, intragraft transcript and protein levels of syndecan-1 and MMP-9 showed a strong association with the degree of cardiac allograft rejection (CAR), the expression of pro-inflammatory cytokines tumour necrosis factor (TNF)-α, interleukin (IL)-6 and transforming growth factor (TGF)-ß, and with infiltrating CD3⁺ T-cells and CD68⁺ monocytes. In addition, SPARC, CTGF, TSP-2, MMP-14, TIMP-1, Testican-1, TSP-1, Syndecan-1, MMP-2, -9, and -14, as well as IL-6 and TGF-ß transcript levels and inflammatory infiltrates all strongly relate to collagen expression in the transplanted heart. More importantly, receiver operating characteristic curve analysis demonstrated that syndecan-1 and MMP-9 transcript levels had the highest area under the curve (0.969 and 0.981, respectively), thereby identifying both as a potential decision-making tool to discriminate rejecting from non-rejecting hearts. CONCLUSION: Out of 15 matrix-related proteins, we identified synd-1 and MMP-9 intragraft transcript levels of as strong predictors of human CAR. In addition, a multitude of non-structural matrix-related proteins closely associate with collagen expression in the transplanted heart. Therefore, we are convinced that these findings deserve further investigation and are likely to be of clinical value to prevent human CAR.

Placental growth factor increases regional myocardial blood flow and contractile function in chronic myocardial ischemia.

Placental growth factor (PlGF) has a distinct biological phenotype with a predominant proangiogenic role in disease without affecting quiescent vessels in healthy organs. We tested whether systemic administration of recombinant human (rh)PlGF improves regional myocardial blood flow (MBF) and systolic function recovery in a porcine chronic myocardial ischemia model. We implanted a flow-limiting stent in the proximal left anterior descending coronary artery and measured systemic hemodynamics, regional myocardial function using MRI, and blood flow using colored microspheres 4 wk later. Animals were then randomized in a blinded way to receive an infusion of rhPlGF (15 µg·kg(-1)·day(-1), n = 9) or PBS (control; n = 10) for 2 wk. At 8 wk, myocardial perfusion and function were reassessed. Infusion of rhPlGF transiently increased PlGF serum levels >30-fold (1,153 ± 180 vs. 33 ± 18 pg/ml at baseline, P < 0.001) without affecting systemic hemodynamics. From 4 to 8 wk, rhPlGF increased regional MBF from 0.46 ± 0.11 to 0.85 ± 0.16 ml·min(-1)·g(-1), with a concomitant increase in systolic wall thickening from 11 ± 3% to 26 ± 5% in the ischemic area. In control animals, no significant changes from 4 to 8 wk were observed (MBF: 0.45 ± 0.07 to 0.49 ± 0.08 ml·min(-1)·g(-1) and systolic wall thickening: 14 ± 4% to 18 ± 1%). rhPlGF-induced functional improvement was accompanied by increased myocardial neovascularization, enhanced glycogen utilization, and reduced oxidative stress and cardiomyocyte apoptosis in the ischemic zone. In conclusion, systemic rhPlGF infusion significantly enhances regional blood flow and contractile function of the chronic ischemic myocardium without adverse effects. PlGF protein infusion may represent an attractive therapeutic strategy to increase myocardial perfusion and energetics in chronic ischemic cardiomyopathy.

Survival and heart failure therapy in chronic dialysis patients with heart failure and reduced left ventricular ejection fraction: an observational retrospective study.

AIMS: We retrospectively followed 250 patients who started dialysis between 2005 and 2009 to clarify the prevalence, the prognosis and the prescribed heart failure treatment of systolic heart failure patients on dialysis. METHODS AND RESULTS: This cohort was divided according to left ventricular ejection fraction (LVEF): group A with a reduced LVEF (< or = 45%, n = 45) versus group B with a preserved LVEF (> 45%, n = 205). Patients in group A had a significantly worse survival after 12 and 24 months (68.9% and 55.5% vs. 87.3% and 73.0%, respectively, P = 0.0001). Hazard ratio for all-cause mortality was 2.70 (C.I. 95% 1.6 - 4.56, P = 0.0002). In the subgroup of patients with a LVEF < 30% the hazard ratio increased to 3.45 (C.I. 95% 1.71 - 6.94, P = 0.0005). The cumulative incidence of cardiovascular death was significantly higher in group A (hazard ratio: 4.78 (C.I. 95% 1.99- 11.50, P = 0.0005), especially in the subgroup with a LVEF < 30%. In group A 71%, 31% and 9% of the patients received a beta blocker, an ACE inhibitor and an angiotensin-receptor blocker, respectively. Only 27% were treated with the combination of a beta blocker and a RAAS inhibitor, while 18% did not receive any heart failure therapy. Most patients only received a low dose of neurohormonal blockers (< or = 25% of the recommended daily dose). The use of these heart failure medications was not significantly different between group A and B. CONCLUSION: After initiation of dialysis, patients with heart failure and reduced LVEF have a bad prognosis. Only a minority of these patients receive adequate specific heart failure treatment.

A critical review on telemonitoring in heart failure.

Morbidity and mortality remain high in heart failure despite considerable progress achieved with medical therapy and electrical devices. A multidisciplinary approach is actually strongly recommended. In order to provide optimal care to the ever-growing population of patients with heart failure, telemonitoring has been proposed as a modality to improve usual care. The aim of this review is to provide an overview of the existing evidence on telemonitoring in HF. Despite two major meta-analyses with favourable results, two recent, large, multicentre, randomized controlled trials, one with a sophisticated technical remote telemonitoring approach (TIM-HF) in stable chronic HF and the other with a comprehensive telephone-based interactive voice-response monitoring (Tele-HF) in patients recently hospitalized for heart failure, have been performed and both failed to demonstrate a clinical benefit for telemonitoring. Newer technologies or other modalities, such as collaboration between a general practitioner and a heart failure clinic facilitated by telemonitoring should be further evaluated. Dedicated telemonitoring for heart failure may be a practical adjunct in selective centres and patients, on top of usual care, including education and a multidisciplinary approach. However, prior to being accepted as a standard of care, more evidence from large, randomized clinical trials is required.

The spectrum of nonadherence with medication in heart, liver, and lung transplant patients assessed in various ways.

Adherence to medication regimes is crucial for transplant patients. Addressing methodological limitations and gaps in the literature, we studied: (i) the prevalence of nonadherence (NA) with immunosuppression (IS) using various measurement methods, (ii) NA prevalence regarding intake and timing, (iii) changes in NA over time, (iv) differences in NA across organ transplant populations, (v) NA regarding co-medication. Using a descriptive, prospective, comparative design over 3 months, we included convenience samples of adult heart (n=79), liver (n=55), and lung (n=104) transplant patients. NA with IS was measured using self-report, collateral report, blood assay, electronic monitoring (Helping Hand™ , Bang and Olufsen Medicom, Denmark), and their combinations. In the overall sample, depending on the method used, IS NA ranged from 23.9% to 70.0%. For co-medication, the overall NA rate was 30.1% using self-report. Nonadherence rates remained stable over time. At inclusion, significant NA differences between organ groups were reported via self- and collateral report; lung transplant patients were less adherent than heart or liver transplant recipients, both to IS and to co-medication.

How to test electronic adherence monitoring devices for use in daily life: a conceptual framework.

Electronic monitoring devices are increasingly used in healthcare to monitor health behaviors on a day-to-day basis. As a prerequisite to their application in clinical studies or daily practice, the performance of those electronic monitoring devices should be tested. Such testing includes a demonstration of technically correct function and of correspondence between the recorded data and the actual patient behavior, that is, objective testing of reliability and validity. Furthermore, from the patient's perspective, the operation of these devices should be easy to learn and to perform, and their use should be acceptable. These aspects of usability need to be tested from a user's subjective point of view. We propose a conceptual framework that builds on existing literature, for example, the framework on "obtrusiveness" of Hensel et al [J Am Med Inform Assoc. 2006;13(4):428-431], the assumptions regarding valid electronic monitoring of Denhaerynck et al [BMC Med Res Methodol. 2008;8:5], and empirical evidence. The framework integrates an objective and a subjective dimension. The objective dimension encompasses both reliability (accuracy and precision) and internal and external validity. The subjective dimension describes the user's perspective on usability along subdimensions of user performance, satisfaction, and acceptability. This framework can be used as a road map to test existing and future electronic monitoring devices before their widespread application in clinical studies or daily practice.

Depressive symptoms at 1 year after surgery increase the risk of cardiac allograft vasculopathy and mortality in heart transplant recipients: A prospective cohort study.

OBJECTIVE: To investigate the impact of depressive symptoms at 1-year post-heart transplant (HTx) on cardiac allograft vasculopathy (CAV) and mortality. METHODS: We performed a single-center prospective cohort study of patients 1-year post-HTx consecutively enrolled between January 2001 and September 2015, and followed-up until November 2020. Kaplan-Meier and uni- and multivariate cox proportional hazards models were used to investigate the impact of depressive symptoms (Beck Depression Inventory) on all-cause mortality and clustered CAV events, i.e. time to angiographically detected CAV, revascularizations, retransplantation/CAV-mortality. RESULTS: 23.7% (45/190) (median age 53.5 [IQR 19.3], 77% men) had mild to severe depressive symptoms (BDI 10-63). Forty-four patients (23.2%) died during a 10.4 years median follow-up. Depressive symptoms (BDI ≥ 10) increased all-cause mortality risk (HR = 2.52 [1.35-4.71], p = .004), even after adjusting for confounders (HR = 2.95 [1.50-5.80], p = .002). CAV data were available for 156 patients. During a 9.9 years median follow-up, 51 patients (32.7%) developed CAV or revascularization of which 8 received at least a second revascularization, 3 were re-transplanted, and 9 died from CAV-related causes. Analysis showed a significant increased CAV-risk among depressed patients (HR = 2.27 [1.10-4.69], p = .026), even in adjusted models (HR = 2.25 [1.01-4.98, p = .047). CONCLUSION: Depressive symptoms at 1-year post-HTx unfavorably impact mortality and CAV, highlighting the need for interventions.

Ventricular phosphodiesterase-5 expression is increased in patients with advanced heart failure and contributes to adverse ventricular remodeling after myocardial infarction in mice.

BACKGROUND: Ventricular expression of phosphodiesterase-5 (PDE5), an enzyme responsible for cGMP catabolism, is increased in human right ventricular hypertrophy, but its role in left ventricular (LV) failure remains incompletely understood. We therefore measured LV PDE5 expression in patients with advanced systolic heart failure and characterized LV remodeling after myocardial infarction in transgenic mice with cardiomyocyte-specific overexpression of PDE5 (PDE5-TG). METHODS AND RESULTS: Immunoblot and immunohistochemistry techniques revealed that PDE5 expression was greater in explanted LVs from patients with dilated and ischemic cardiomyopathy than in control hearts. To evaluate the impact of increased ventricular PDE5 levels on cardiac function, PDE5-TG mice were generated. Confocal and immunoelectron microscopy revealed increased PDE5 expression in cardiomyocytes, predominantly localized to Z-bands. At baseline, myocardial cGMP levels, cell shortening, and calcium handling in isolated cardiomyocytes and LV hemodynamic measurements were similar in PDE5-TG and wild-type littermates. Ten days after myocardial infarction, LV cGMP levels had increased to a greater extent in wild-type mice than in PDE5-TG mice (P<0.05). Ten weeks after myocardial infarction, LV end-systolic and end-diastolic volumes were larger in PDE5-TG than in wild-type mice (57+/-5 versus 39+/-4 and 65+/-6 versus 48+/-4 muL, respectively; P<0.01 for both). LV systolic dysfunction and diastolic dysfunction were more marked in PDE5-TG than in wild-type mice, associated with enhanced hypertrophy and reduced contractile function in isolated cardiomyocytes from remote myocardium. CONCLUSIONS: Increased PDE5 expression predisposes mice to adverse LV remodeling after myocardial infarction. Increased myocardial PDE5 expression in patients with advanced cardiomyopathy may contribute to the development of heart failure and represents an important therapeutic target.

Rosuvastatin in older patients with systolic heart failure.

BACKGROUND: Patients with systolic heart failure have generally been excluded from statin trials. Acute coronary events are uncommon in this population, and statins have theoretical risks in these patients. METHODS: A total of 5011 patients at least 60 years of age with New York Heart Association class II, III, or IV ischemic, systolic heart failure were randomly assigned to receive 10 mg of rosuvastatin or placebo per day. The primary composite outcome was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Secondary outcomes included death from any cause, any coronary event, death from cardiovascular causes, and the number of hospitalizations. RESULTS: As compared with the placebo group, patients in the rosuvastatin group had decreased levels of low-density lipoprotein cholesterol (difference between groups, 45.0%; P<0.001) and of high-sensitivity C-reactive protein (difference between groups, 37.1%; P<0.001). During a median follow-up of 32.8 months, the primary outcome occurred in 692 patients in the rosuvastatin group and 732 in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI], 0.83 to 1.02; P=0.12), and 728 patients and 759 patients, respectively, died (hazard ratio, 0.95; 95% CI, 0.86 to 1.05; P=0.31). There were no significant differences between the two groups in the coronary outcome or death from cardiovascular causes. In a prespecified secondary analysis, there were fewer hospitalizations for cardiovascular causes in the rosuvastatin group (2193) than in the placebo group (2564) (P<0.001). No excessive episodes of muscle-related or other adverse events occurred in the rosuvastatin group. CONCLUSIONS: Rosuvastatin did not reduce the primary outcome or the number of deaths from any cause in older patients with systolic heart failure, although the drug did reduce the number of cardiovascular hospitalizations. The drug did not cause safety problems. (ClinicalTrials.gov number, NCT00206310.)

Comparison of perceived health status among solid organ transplant candidates.

INTRODUCTION: In solid organ transplantation (TX), perceived health status (PHS) is a relevant patient-reported outcome. For patients on TX waiting lists, PHS information is limited. The aim of this study was therefore to compare PHS of heart, liver, lung, and renal TX candidates. METHODS: We used a cross-sectional descriptive design, including consecutive heart, liver, lung and renal TX candidates listed at a university hospital in Belgium. PHS was evaluated using the generic EuroQoL instrument, assessing patients' perceptions of their general PHS, and evaluating the health-related domains of mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Data were analyzed using multivariable ordinal logistic regression. RESULTS: The study included 314 TX candidates: 29 heart, 75 liver, 67 lung, and 143 renal. Analyses controlling for possible PHS-impacting variables (age, gender, marital status, education, comorbidities) yielded significantly disparate results between the four candidate groups. Renal candidates reported best PHS, followed by liver candidates, whereas heart and lung candidates, whose score differences were not significant, had worst PHS. CONCLUSION: The EQ-5D seems to be a valuable tool to identify differences in health-related problems in the four different organ candidate groups. The results can be used to create intervention programs focusing on effective clinical management for these patients pre- and post-transplant.

How accurate are electronic monitoring devices? A laboratory study testing two devices to measure medication adherence.

In a prospective descriptive laboratory study, 25 Helping Hand(™) (HH) (10 without and 15 with reminder system) and 50 Medication Event Monitoring Systems (MEMS) (25 with 18-month and 25 with 2-year battery life) were manipulated twice daily following a predefined protocol during 3 consecutive weeks. Accuracy was determined using the fixed manipulation scheme as the reference. Perfect functioning (i.e., total absence of missing registrations and/or overregistrations) was observed in 70% of the HH without, 87% of the HH with reminder, 20% MEMS with 18 months, and 100% with 2-year battery life respectively.

A new electronic monitoring device to measure medication adherence: usability of the Helping Hand™.

The aim of this study was to test the user performance, satisfaction and acceptability of the Helping Hand™ (B&O Medicom) electronic medication adherence monitor. Using a mixed-method design, we studied 11 kidney transplant patients and 10 healthy volunteers during three weeks. Although testing showed positive usability aspects, several areas requiring technical improvement were identified: the most important obstacles to usability and acceptability were the weak sound signal, problems loading the medication, and the fact that only one medication could be used at a time.

Predictors of fatal and non-fatal outcomes in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA): incremental value of apolipoprotein A-1, high-sensitivity C-reactive peptide and N-terminal pro B-type natriuretic peptide.

AIMS: Few prognostic models in heart failure have been developed in typically elderly patients treated with modern pharmacological therapy and even fewer included simple biochemical tests (such as creatinine), new biomarkers (such as natriuretic peptides), or, especially, both. In addition, most models have been developed for the single outcome of all-cause mortality. METHODS AND RESULTS: We built a series of models for nine different fatal and non-fatal outcomes. For each outcome, a model was first built using demographic and clinical variables (Step 1), then with the addition of biochemical measures (serum creatinine, alanine aminotransferase, creatine kinase, thyrotrophin, apolipoproteins A-1 and B, and triglycerides) (Step 2) and finally with the incorporation of high-sensitivity C-reactive protein (hsCRP) and N-terminal pro B-type natriuretic peptide (NT-proBNP). Ranked according to the Wald chi(2) value, age (56), ejection fraction (44), and body mass index (42) were most predictive of all-cause mortality in Step 1 (total model chi(2) 343). Creatinine was the most powerful predictor at Step 2 (48) and ApoA-1 ranked fifth (25), with the overall chi(2) increasing to 440. Log NT-proBNP (167) was the most powerful of the 14 independently predictive variables identified at Step 3 and the overall chi(2) increased to 600. NT-proBNP was the most powerful predictor of each other outcome. hsCRP was not a predictor of all-cause mortality but did predict the composite atherothrombotic outcome. CONCLUSION: Of the two new biomarkers studied in prognostic models in heart failure, NT-proBNP, but not hsCRP, added substantial and independent predictive information, for a range of clinical outcomes, to that provided by simple demographic, clinical, and biochemical measures. ApoA-1 was more predictive than LDL or HDL.