Lee R. Goldberg

Randomized trial of a daily electronic home monitoring system in patients with advanced heart failure: the Weight Monitoring in Heart Failure (WHARF) trial.

BACKGROUND Heart failure treatment guidelines emphasize daily weight monitoring for patients with heart failure, but data to support this practice are lacking. Using a technology-based heart failure monitoring system, we determined whether daily reporting of weight and symptoms in patients with advanced heart failure would reduce rehospitalization and mortality rates despite aggressive guideline-driven heart failure care. METHODS This was a randomized, controlled trial. Patients hospitalized with New York Heart Association class III or IV heart failure, with a left ventricular ejection fraction < or =35% were randomized to receive heart failure program care or heart failure program care plus the AlereNet system (Alere Medical, Reno, Nev) and followed-up for 6 months. The primary end point was 6-month hospital readmission rate. Secondary end points included mortality, heart failure hospitalization readmission rate, emergency room visitation rate, and quality of life. RESULTS Two hundred eighty patients from 16 heart failure centers across the United States were randomized: 138 received the AlereNet system and 142 received standard care. Mean age was 59 +/- 15 years and 68% were male. The population had very advanced heart failure, New York Heart Association class III (75%) or IV (25%), as evidenced by serum norepinepherine levels, 6-minute walk distance and outcomes. No differences in hospitalization rates were observed. There was a 56.2% reduction in mortality (P <.003) for patients randomized to the AlereNet group. CONCLUSIONS This is the largest multicenter, randomized trial of a technology-based daily weight and symptom-monitoring system for patients with advanced heart failure. Despite no difference in the primary end point of rehospitalization rates, mortality was significantly reduced for patients randomized to the AlereNet system without an increase in utilization, despite specialized and aggressive heart failure care in both groups.

Tacrolimus with mycophenolate mofetil (MMF) or sirolimus vs. cyclosporine with MMF in cardiac transplant patients: 1-year report.

The most advantageous combination of immunosuppressive agents for cardiac transplant recipients has not yet been established. Between November 2001 and June 2003, 343 de novo cardiac transplant recipients were randomized to receive steroids and either tacrolimus (TAC) + sirolimus (SRL), TAC + mycophenolate mofetil (MMF) or cyclosporine (CYA) + MMF. Antilymphocyte induction therapy was allowed for up to 5 days. The primary endpoint of ≥3A rejection or hemodynamic compromise rejection requiring treatment showed no significant difference at 6 months (TAC/MMF 22.4%, TAC/SRL 24.3%, CYA/MMF 31.6%, p = 0.271) and 1 year (p = 0.056), but it was significantly lower in the TAC/MMF group when compared only to the CYA/MMF group at 1 year (23.4% vs. 36.8%; p = 0.029). Differences in the incidence of any treated rejection were significant (TAC/SRL = 35%, TAC/MMF = 42%, CYA/MMF = 59%; p < 0.001), as were median levels of serum creatinine (TAC/SRL = 1.5 mg/dL, TAC/MMF = 1.3 mg/dL, CYA/MMF = 1.5 mg/dL; p = 0.032) and triglycerides (TAC/SRL = 162 mg/dL, TAC/MMF = 126 mg/dL, CYA/MMF = 154 mg/dL; p = 0.028). The TAC/SRL group encountered fewer viral infections but more fungal infections and impaired wound healing. These secondary endpoints suggest that the TAC/MMF combination appears to offer more advantages than TAC/SRL or CYA/MMF in cardiac transplant patients, including fewer ≥3A rejections or hemodynamic compromise rejections and an improved side‐effect profile.

High-Sensitivity ST2 for Prediction of Adverse Outcomes in Chronic Heart Failure

Background—Soluble ST2 reflects activity of an interleukin-33–dependent cardioprotective signaling axis and is a diagnostic and prognostic marker in acute heart failure. The use of ST2 in chronic heart failure has not been well defined. Our objective was to determine whether plasma ST2 levels predict adverse outcomes in chronic heart failure in the context of current approaches. Methods and Results—We determined the association between ST2 level and risk of death or transplantation in a multicenter, prospective cohort of 1141 chronic heart failure outpatients. Adjusted Cox models, receiver operating characteristic analyses, and risk reclassification metrics were used to assess the value of ST2 in predicting risk beyond currently used factors. After a median of 2.8 years, 267 patients (23%) died or underwent heart transplantation. Patients in the highest ST2 tertile (ST2 >36.3 ng/mL) had a markedly increased risk of adverse outcomes compared with the lowest tertile (ST2 ⩽22.3 ng/mL), with an unadjusted hazard ratio of 3.2 (95% confidence interval [CI], 2.2 to 4.7; P<0.0001) that remained significant after multivariable adjustment (adjusted hazard ratio, 1.9; 95% CI, 1.3 to 2.9; P=0.002). In receiver operating characteristic analyses, the area under the curve for ST2 was 0.75 (95% CI, 0.69 to 0.79), which was similar to N-terminal pro-B–type natriuretic peptide (NT-proBNP) (area under the curve, 0.77; 95% CI, 0.72 to 0.81; P=0.24 versus ST2) but lower than the Seattle Heart Failure Model (area under the curve, 0.81 (95% CI, 0.77 to 0.85; P=0.014 versus ST2). Addition of ST2 and NT-proBNP to the Seattle Heart Failure Model reclassified 14.9% of patients into more appropriate risk categories (P=0.017). Conclusions—ST2 is a potent marker of risk in chronic heart failure and when used in combination with NT-proBNP offers moderate improvement in assessing prognosis beyond clinical risk scores.

Mycophenolic acid pharmacodynamics and pharmacokinetics provide a basis for rational monitoring strategies.

Mycophenolic acid (MPA), the active immunosuppressant form of the pro-drug mycophenolate mofetil (MMF), is a widely used component of immunosuppressive regimens in organ transplantation. This immunosuppressant is commonly administered in combination with a calcineurin inhibitor (CIN)+ corticosteroid with or without induction therapy in the form of a polyclonal anti-T lymphocyte preparation or one of the available humanized monoclonal interleukin 2 inhibitors. There is strong evidence that maintenance CIN-MMFsteroid-based triple therapy, initiated in the early posttransplant period significantly reduces the risk of acute rejection in the first post-transplant year, when compared to double therapy regimens comprising CIN and steroids alone. After the initial phase of graft stabilization, there are several therapeuticapproachescurrentlyemployed in transplantpractice, including: (1) maintenance of a three-drug regimen, at reduced doses compared to the early post-transplant period; (2) elimination of corticosteroid; (3) reduction or elimination of CIN; (4) replacement of CIN with sirolimus in patients who are especially sensitive to the nephrotoxic effects of these agents; or (5) reduction or discontinuation of MMF, while retaining full-dose CIN or sirolimus and maintenance corticosteroids are among the other therapeutic options under investigation. Dose individualization of CIN is facilitated by target drug concentration monitoring, whereas for MMF, empiric dosing is most commonly practiced.

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.

Factors associated with the development of expertise in heart failure self-care.

Background: Self-care is vital for successful heart failure (HF) management. Mastering self-care is challenging; few patients develop sufficient expertise to avoid repeated hospitalization. Objective: To describe and understand how expertise in HF self-care develops. Methods: Extreme case sampling was used to identify 29 chronic HF patients predominately poor or particularly good in self-care. Using a mixed-methods (qualitative and quantitative) design, participants were interviewed about HF self-care, surveyed to measure factors anticipated to influence self-care, and tested for cognitive functioning. Audiotaped interviews were analyzed using content analysis. Qualitative and quantitative data were combined to produce a multidimensional typology of patients poor, good, or expert in HF self-care. Results: Only 10.3% of the sample was expert in HF self-care. Patients poor in HF self-care had worse cognition, more sleepiness, higher depression, and poorer family functioning. The primary factors distinguishing those good versus expert in self-care were sleepiness and family engagement. Experts had less daytime sleepiness and more support from engaged loved ones who fostered self-care skill development. Conclusion: Engaged supporters can help persons with chronic HF to overcome seemingly insurmountable barriers to self-care. Research is needed to understand the effects of excessive daytime sleepiness on HF self-care.

Multiple Biomarkers for Risk Prediction in Chronic Heart Failure

Background—Prior studies have suggested using a panel of biomarkers that measure diverse biological processes as a prognostic tool in chronic heart failure. Whether this approach improves risk prediction beyond clinical evaluation is unknown. Methods and Results—In a multicenter cohort of 1513 chronic systolic heart failure patients, we measured a contemporary biomarker panel consisting of high-sensitivity C-reactive protein, myeloperoxidase, B-type natriuretic peptide, soluble fms-like tyrosine kinase receptor-1, troponin I, soluble toll-like receptor-2, creatinine, and uric acid. From this panel, we calculated a parsimonious multimarker score and assessed its performance in predicting risk of death, cardiac transplantation, or ventricular assist device placement in comparison to an established clinical risk score, the Seattle Heart Failure Model (SHFM). During a median follow-up of 2.5 years, there were 317 outcomes: 187 patients died; 99 were transplanted; and 31 had a ventricular assist device placed. In unadjusted Cox models, patients in the highest tertile of the multimarker score had a 13.7-fold increased risk of adverse outcomes compared with the lowest tertile (95% confidence interval, 8.75–21.5). These effects were independent of the SHFM (adjusted hazard ratio, 6.80; 95% confidence interval, 4.18–11.1). Addition of the multimarker score to the SHFM led to a significantly improved area under the receiver operating characteristic curve of 0.803 versus 0.756 (P=0.003) and appropriately reclassified a significant number of patients who had the outcome into a higher risk category (net reclassification improvement, 25.2%; 95% confidence interval, 14.2–36.2%; P<0.001). Conclusions—In ambulatory chronic heart failure patients, a score derived from multiple biomarkers integrating diverse biological pathways substantially improves prediction of adverse events beyond current metrics.

Stage B Heart Failure Management of Asymptomatic Left Ventricular Systolic Dysfunction

Heart failure (HF) is a clinical syndrome characterized by symptoms of effort intolerance (eg, dyspnea and fatigue) and/or signs of fluid retention (eg, pulmonary congestion and peripheral edema) due to a variety of pathological processes that perturb normal cardiac function. Approximately 50% of HF patients present with evidence of left ventricular systolic dysfunction (LVSD) manifested as a low left ventricular ejection fraction (LVEF); the remaining half are found to have preserved left ventricular (LV) function.1 HF with either low or normal LVEF represents a significant contemporary medical problem that affects an estimated 5 million people in the United States, with an annual mortality rate approaching 20%.2 HF is considered a progressive disorder that can be represented as a clinical continuum. The American College of Cardiology/American Heart Association (ACC/AHA) updated 2005 guidelines for the management of chronic HF identify 4 stages in this continuum (Figure 1)3 and link the stages in the natural history of HF to therapeutic recommendations for each stage. Previously, the New York Heart Association (NYHA) functional classification, based solely on the severity of symptoms (primarily of patients in ACC/AHA stage C or D), was used as a criteria to initiate or change HF therapy. NYHA classification can change over a relatively short period of time even in the absence of medication changes. Nearly every patient who presents to an emergency department for care has at least NYHA class III or IV symptoms; however, at discharge after treatment, many patients are minimally symptomatic. Clinicians must then decide whether to apply NYHA class IV therapies or only class II therapies, which leads to some uncertainty. This approach may result in the undertreatment of some patients with severe LV dysfunction who might be only mildly symptomatic. Figure 1. ACC/AHA guidelines for the evaluation and management of …

Reduction of Immunosuppression as Initial Therapy for Posttransplantation Lymphoproliferative Disorder

Reduction of immunosuppression (RI) is commonly used to treat posttransplant lymphoproliferative disorder (PTLD) in solid organ transplant recipients. We investigated the efficacy, safety and predictors of response to RI in adult patients with PTLD. Sixty‐seven patients were managed with RI alone and 30 patients were treated with surgical excision followed by adjuvant RI. The response rate to RI alone was 45% (complete response—37%, partial response—8%). The relapse rate in complete responders was 17%. Adjuvant RI resulted in a 27% relapse rate. The acute rejection rate following RI‐containing strategies was 32% and a second transplant was feasible without relapse of PTLD. The median survival was 44 months in patients treated with RI alone and 9.5 months in patients who remained on full immunosuppression (p = 0.07). Bulky disease, advanced stage and older age predicted lack of response to RI. Survival analysis demonstrated predictors of poor outcome—age, dyspnea, B symptoms, LDH level, hepatitis C, bone marrow and liver involvement. Patients with none or one of these factors had a 3‐year overall survival of 100% and 79%, respectively. These findings support the use of RI alone in low‐risk PTLD and suggest factors that predict response and survival.

Modest Increase in Peak VO2 Is Related to Better Clinical Outcomes in Chronic Heart Failure Patients Results From Heart Failure and a Controlled Trial to Investigate Outcomes of Exercise Training

Background—The prognostic ability of a single measurement of peak oxygen uptake (VO2) is well established in patients with chronic heart failure. The relation between a change in peak VO2 and clinical outcomes is not well defined. Methods and Results—This investigation determined whether an increase in peak VO2 was associated with a lower risk of the primary end point of time to all-cause mortality or all-cause hospitalization and 3 secondary end points. In Heart Failure and a Controlled Trial to Investigate Outcomes of Exercise Training, an exercise training trial for patients with systolic heart failure, cardiopulmonary exercise tests were performed at baseline and ≈3 months later in 1620 participants. Median peak VO2 in the combined sample increased from 15.0 (11.9–18.0 Q1–Q3) to 15.4 (12.3–18.7 Q1–Q3) mL·kg−1·min−1. Every 6% increase in peak VO2, adjusted for other significant predictors, was associated with a 5% lower risk of the primary end point (hazard ratio=0.95; CI=0.93–0.98; P<0.001); a 4% lower risk of the secondary end point of time to cardiovascular mortality or cardiovascular hospitalization (hazard ratio=0.96; CI=0.94–0.99; P<0.001); an 8% lower risk of cardiovascular mortality or heart failure hospitalization (hazard ratio=0.92; CI=0.88–0.96; P<0.001); and a 7% lower all-cause mortality (hazard ratio=0.93; CI=0.90–0.97; P<0.001). Conclusions—Among patients with chronic systolic heart failure, a modest increase in peak VO2 over 3 months was associated with a more favorable outcome. Monitoring the change in peak VO2 for such patients may have benefit in assessing prognosis. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00047437.