The effect of tablet computer-based telemonitoring added to an established telephone disease management program on heart failure hospitalizations: The Specialized Primary and Networked Care in Heart Failure (SPAN-CHF) III Randomized Controlled Trial.

BACKGROUND: Mobile health applications are becoming increasingly common. Prior work has demonstrated reduced heart failure (HF) hospitalizations with HF disease management programs; however, few of these programs have used tablet computer-based technology. METHODS: Participants with a diagnosis of HF and at least 1 high risk feature for hospitalization were randomized to either an established telephone-based disease management program or the same disease management program with the addition of remote monitoring of weight, blood pressure, heart rate and symptoms via a tablet computer for 90 days. The primary endpoint was the number of days hospitalized for HF assessed at 90 days. RESULTS: From August 2014 to April 2019, 212 participants from 3 hospitals in Massachusetts were randomized 3:1 to telemonitoring-based HF disease management (n = 159) or telephone-based HF disease management (n = 53) with 98% of individuals in both study groups completing the 90 days of follow-up. There was no significant difference in the number of days hospitalized for HF between the telemonitoring disease management group (0.88 ± 3.28 days per patient-90 days) and the telephone-based disease management group (1.00 ± 2.97 days per patient-90 days); incidence rate ratio 0.82 (95% confidence interval, 0.43-1.58; P = .442). CONCLUSIONS: The addition of tablet-based telemonitoring to an established HF telephone-based disease management program did not reduce HF hospitalizations; however, study power was limited.

Activities and Compensation of Advanced Heart Failure Specialists: Results of the Heart Failure Society of America (HFSA) Survey.

BACKGROUND: In the current era, where advanced heart failure (AHF) has become an American Board of Internal Medicine-certified subspecialty, new data are needed to benchmark and value levels of clinical effort performed by AHF specialists (AHFMDs). METHODS AND RESULTS: A 36-question survey was sent to 728 AHFMDs, members of the Heart Failure Society of America, and 224 (31%) responded. Overall, 56% worked in academic medical centers (AMCs) and were younger (48 ± 9 y vs 52 ± 10 y; P < .01) and were represented by a higher proportion of women (34% vs 21%, P < .01) compared with non-AMCs. The percentage of time in clinical care was lower in AMCs (64 ± 19% vs 78 ± 18%; P = .002), with similar concentration on evaluation and management services (79 ± 18% in AMCs vs 72 ± 18 % in non-AMCs; P = NS). The majority of nonclinical time was spent in program administration (10% in both AMCs and non-AMCs) and education/research (15% in AMC vs 5% in non-AMCs). Although 69% of respondents were compensated by work-relative value units (wRVUs), only a small percentage knew their target or the amount of RVUs generated. The mean annual wRVUs generated were lower in AMCs compared to non-AMCs (5,452 ± 1,961 vs 9,071 ± 3,484; P < .001). The annual compensation in AMCs was lower than in non-AMCs (45% vs 10% <$250,000 and 17% vs 61% >$350,000; P < .001) and the satisfaction with compensation was higher in non-AMCs. CONCLUSIONS: AHFMDs' compensation is largely dependent by practice type (AMC vs non-AMC) and clinical productivity as measured by wRVUs. These data provide an opportunity for benchmarking work effort and compensation for AHFMDs, allowing distinction from segments of cardiologists with greater opportunity to accrue procedural wRVUs. They also show several differences between AMCs and non-AMCs that should be considered when formulating work assignment and compensation for AHFMDs.

Advances in Our Clinical Understanding of Autonomic Regulation Therapy Using Vagal Nerve Stimulation in Patients Living With Heart Failure.

The ANTHEM-HF, INOVATE-HF, and NECTAR-HF clinical studies of autonomic regulation therapy (ART) using vagus nerve stimulation (VNS) systems have collectively provided dose-ranging information enabling the development of several working hypotheses on how stimulation frequency can be utilized during VNS for tolerability and improving cardiovascular outcomes in patients living with heart failure (HF) and reduced ejection fraction (HFrEF). Changes in heart rate dynamics, comprising reduced heart rate (HR) and increased HR variability, are a biomarker of autonomic nerve system engagement and cardiac control, and appear to be sensitive to VNS that is delivered using a stimulation frequency that is similar to the natural operating frequency of the vagus nerve. Among prior studies, the ANTHEM-HF Pilot Study has provided the clearest evidence of autonomic engagement with VNS that was delivered using a stimulation frequency that was within the operating range of the vagus nerve. Achieving autonomic engagement was accompanied by improvement from baseline in six-minute walk duration (6MWD), health-related quality of life, and left ventricular EF (LVEF), over and above those achieved by concomitant guideline-directed medical therapy (GDMT) administered to counteract harmful neurohormonal activation, with relative freedom from deleterious effects. Autonomic engagement and positive directional changes have persisted over time, and an exploratory analysis suggests that improvement in autonomic tone, symptoms, and physical capacity may be independent of baseline NT-proBNP values. Based upon these encouraging observations, prospective, randomized controlled trials examining the effects on symptoms and cardiac function as well as natural history have been warranted. A multi-national, large-scale, randomized, controlled trial is well underway to determine the outcomes associated with ART using autonomic nervous system engagement as a guide for VNS delivery.

CD34(+) cell infusion after ST elevation myocardial infarction is associated with improved perfusion and is dose dependent.

BACKGROUND: the objective of the study was to determine whether the effects of infarct-related artery (IRA) infusion of autologous bone marrow-derived CD34(+) cells after ST elevation myocardial infarction (STEMI) are dependent on the dose (quantity and mobility) of the cells infused. Beneficial effects of IRA infusion of mononuclear cells after STEMI have been inconsistent, possibly because of differences in timing, cell type, quantity, and mobility of infused cells. METHODS: patients were randomized to bone marrow harvest (n = 16) or control (n = 15). At a median of 8.3 days after coronary stenting for STEMI, CD34(+) cells were infused via the IRA at 3 dose levels (5, 10, and 15 × 10(6)) in cohorts of 5 patients each. Baseline and follow-up imaging and ex vivo CD34(+) cell mobility were performed. RESULTS: Cell harvest and infusion were safe. Quantitative rest hypoperfusion score measured by single-photon emission computed tomography improved at 6 months in the ≥ 10 million cohorts compared with controls (-256 vs +14, P = .02). There was a trend toward improved ejection fraction at 6 months (+4.5%) in the ≥ 10 million cohorts compared with no change in the controls and 5 million cohort (+0.7%). Improved perfusion and infarct size reduction correlated with the quantity and mobility of the infused CD34(+) cells. CONCLUSIONS: the effects of CD34(+) cell IRA infusion during the repair phase after STEMI are dose dependent and, at a threshold dose of 10 million CD34(+) cells, associated with a significant improvement in perfusion that may limit deterioration in cardiac function (IRA infusion of CD34(+) cells in patients with acute myocardial infarction [AMR-01] NCT00313339).

Health-related quality of life in a multicenter randomized controlled comparison of telephonic disease management and automated home monitoring in patients recently hospitalized with heart failure: SPAN-CHF II trial.

BACKGROUND: Although disease management programs have been shown to provide a number of clinical benefits to patients with heart failure (HF), the incremental impact of an automated home monitoring (AHM) system on health-related quality of life (HRQL) is unknown. METHODS AND RESULTS: We performed a prospective randomized investigation, examining the additive value of AHM to a previously described nurse-directed HF disease management program (SPAN-CHF), with attention to HRQL, in patients with a recent history of decompensated HF. A total of 188 patients were randomized to receive the SPAN-CHF intervention for 90 days, either with (AHM group) or without (NAHM, standard-care group) AHM, with a 1:1 randomization ratio after HF-related hospitalization. HRQL, measured by the Minnesota Living With Heart Failure Questionnaire (MLHFQ) (Physical, Emotional, and Total scores on MLHFQ) was assessed at 3 time points: baseline, 45 days, and 90 days. Although both treatments (AHM and NAHM) improved HRQL at 45 and 90 days compared with baseline with respect to Physical, Emotional, and Total domain scales, no significant difference emerged between AHM and NAHM groups. CONCLUSIONS: AHM and NAHM treatments demonstrated improved HRQL scores at 45 and 90 days after baseline assessment. When comparing 2 state-of the-art disease management programs regarding HRQL outcomes, our results did not support the added value of AHM.

Therapeutic responsiveness to vagus nerve stimulation in patients receiving beta-blockade for heart failure with reduced ejection fraction.

BACKGROUND: The effect of beta-blockade (BB) on response to vagus nerve stimulation (VNS) has not been reported in patients with heart failure and reduced ejection fraction (HFrEF). In the ANTHEM-HF Study, 60 patients received chronic cervical VNS. Background pharmacological therapy remained unchanged during the study, and VNS intensity was stable once up-titrated. Significant improvement from baseline occurred in resting 24-hour heart rate (HR), 24-hour HR variability (SDNN), left ventricular EF (LVEF), 6-minute walk distance (6MWD), and quality of life (MLWHFS) at 6 months post-titration. We evaluated whether response to VNS was related to percentage of target BB dose (PTBBD) at baseline. METHODS: Patients were categorized by baseline PTBBD, then analyzed for changes from baseline in symptoms and function at 6 months after VNS titration. RESULTS: All patients received BB, either PTBBD ≥ 50 % (16 patients, 27 %; group 1) or PTBBD < 50 % (44 patients, 73 %; group 2). Heart rate, systolic blood pressure, LVEF, use of ACE/ARB, and use of MRA were similar between the two groups at baseline. Six months after up-titration, VNS reduced HR and significantly improved SDNN, LVEF, 6MWD, and MLWHFS equally in both groups. CONCLUSIONS: In the ANTHEM-HF study, VNS responsiveness appeared to be independent of the baseline BB dose administered.

A multicenter randomized controlled evaluation of automated home monitoring and telephonic disease management in patients recently hospitalized for congestive heart failure: the SPAN-CHF II trial.

BACKGROUND: We performed a prospective, randomized investigation assessing the incremental effect of automated health monitoring (AHM) technology over and above that of a previously described nurse directed heart failure (HF) disease management program. The AHM system measured and transmitted body weight, blood pressure, and heart rate data as well as subjective patient self-assessments via a standard telephone line to a central server. METHODS AND RESULTS: A total of 188 consented and eligible patients were randomized between intervention and control groups in 1:1 ratio. Subjects randomized to the control arm received the Specialized Primary and Networked Care in Heart Failure (SPAN-CHF) heart failure disease management program. Subjects randomized to the intervention arm received the SPAN-CHF disease management program in conjunction with the AHM system. The primary end point was prespecified as the relative event rate of HF hospitalization between intervention and control groups at 90 days. The relative event rate of HF hospitalization for the intervention group compared with controls was 0.50 (95%CI [0.25-0.99], P = .05). CONCLUSIONS: Short-term reductions in the heart failure hospitalization rate were associated with the use of automated home monitoring equipment. Long-term benefits in this model remain to be studied.

Allostery in oligomeric receptor models.

We show how equilibrium binding curves of receptor homodimers can be expressed as rational polynomial functions of the equilibrium binding curves of the constituent monomers, without approximation and without assuming independence of receptor monomers. Using a distinguished spanning tree construction for reduced graph powers, the method properly accounts for thermodynamic constraints and allosteric interactions between receptor monomers (i.e. conformational coupling). The method is completely general; it begins with an arbitrary undirected graph representing the topology of a monomer state-transition diagram and ends with an algebraic expression for the equilibrium binding curve of a receptor oligomer composed of two or more identical and indistinguishable monomers. Several specific examples are analysed, including guanine nucleotide-binding protein-coupled receptor dimers and tetramers composed of multiple 'ternary complex' monomers.

Comparison of symptomatic and functional responses to vagus nerve stimulation in ANTHEM-HF, INOVATE-HF, and NECTAR-HF.

AIMS: Clinical studies of vagal nerve stimulation (VNS) for heart failure with reduced ejection fraction have had mixed results to date. We sought to compare VNS delivery and associated changes in symptoms and function in autonomic regulation therapy via left or right cervical vagus nerve stimulation in patients with chronic heart failure (ANTHEM-HF), increase of vagal tone in heart failure (INOVATE-HF), and neural cardiac therapy for heart failure (NECTAR-HF) for hypothesis generation. METHODS AND RESULTS: Descriptive statistics were used to analyse data from the public domain for differences in proportions using Pearson's chi-square test, differences in mean values using Student's unpaired t-test, and differences in changes of mean values using two-sample t-tests. Guideline-directed medical therapy recommendations were similar across studies. Fewer patients were in New York Heart Association 3, and baseline heart rate (HR) was higher in ANTHEM-HF. In INOVATE-HF, VNS was aimed at peripheral neural targets, using closed-loop delivery that required synchronization of VNS to R-wave sensing by an intracardiac lead. Pulse frequency was low (1-2 Hz) because of a timing schedule allowing ≤3 pulses of VNS following at most 25% of detected R waves. NECTAR-HF and ANTHEM-HF used open-loop VNS delivery (i.e. independent of any external signal) aimed at both central and peripheral targets. In NECTAR-HF, VNS delivery at 20 Hz caused off-target effects that limited VNS up-titration in a majority of patients. In ANTHEM-HF, VNS delivery at 10 Hz allowed up-titration until changes in HR dynamics were confirmed. Six months after VNS titration, significant improvements in both HR and HR variability occurred only in ANTHEM-HF. When ANTHEM-HF and NECTAR-HF were compared, greater improvements from baseline were observed in ANTHEM-HF in standard deviation in normal-to-normal R-R intervals (94 ± 26 to 111 ± 50 vs. 146 ± 48 to 130 ± 52 ms; P < 0.001), left ventricular ejection fraction (32 ± 7 to 37 ± 0.4 vs. 31 ± 6 to 33 ± 6; P < 0.05), and Minnesota Living with Heart Failure mean score (40 ± 14 to 21 ± 10 vs. 44 ± 22 to 36 ± 21; P < 0.002). When compared with INOVATE-HF, greater improvement in 6-min walk distance was observed in ANTHEM-HF (287 ± 66 to 346 ± 78 vs. 304 ± 111 to 334 ± 111 m; P < 0.04). CONCLUSIONS: In this post-hoc analysis, differences in patient demographics were seen and may have caused the differential responses in symptoms and function observed in association with VNS. Major differences in technology platforms, neural targets, VNS delivery, and HR and HR variability responses could have also potentially played a very important role. Further study is underway in a randomized controlled trial with these considerations in mind.

A cost-saving strategy for inpatient management of advanced decompensated heart failure patients: the Cardiomyopathy Unit.

BACKGROUND: This article analyzes the relative costs and revenues of the Tufts Medical Center Cardiomyopathy Unit (CMU), a recent innovation for grouping and managing advanced decompensated heart failure patients. METHODS AND RESULTS: We selected a retrospective sample of all patients with the primary diagnosis of heart failure, primary procedure of pulmonary artery catheterization, and with no other hospitalization procedures, admitted to Tufts Medical Center between 2000 and 2006. Regression models were used to estimate the cost for the intervention group and controls. Propensity analysis was used to test for selection bias in the comparison groups. We identified 114 hospitalizations meeting these criteria. Patients in the CMU group were well-balanced compared with controls with respect to demographic and clinical variables. Estimated direct medical costs for CMU and control groups were $11,817 (95% CI $7678-$16,106) and $17,236 (95% CI $11,199-$23,493), respectively. A similar pattern of cost differentials was displayed among propensity-matched sample groups. Net revenue was $12,609 (95% CI $9578-$16,845) and $15,627 (95% CI $11,871-$20,877) in the CMU and control groups, respectively. CONCLUSIONS: The inpatient CMU may offer a lower cost and higher contribution margin alternative for the management of advanced heart failure patients requiring hemodynamic monitoring without other major inpatient procedures.

Background pharmacological therapy in the ANTHEM-HF: comparison to contemporary trials of novel heart failure therapies.

AIMS: Clinical trials of new heart failure (HF) therapies administer guideline-directed medical therapy (GDMT) as background pharmacologic treatment (BPT). In the ANTHEM-HF Pilot Study, addition of autonomic regulation therapy to GDMT significantly improved left ventricular function, New York Heart Association (NYHA) class, 6 min walk distance, and quality of life in patients with HF with reduced ejection fraction (HFrEF). A post hoc analysis was performed to compare BPT in ANTHEM-HF with two other trials of novel HF therapies: the PARADIGM-HF study of sacubitril-valsartan and the SHIFT study of ivadrabine. All three studies evaluated patients with HFrEF, and the recommendations for use of GDMT were similar. A left ventricular ejection fraction ≤40% was required for entry into ANTHEM-HF and PARADIGM-HF and ≤35% for SHIFT. NYHA 2 or 3 symptoms were required for entry into ANTHEM-HF, and patients with predominantly NYHA 2 or 3 symptoms were enrolled in PARADIGM-HF and SHIFT. METHODS AND RESULTS: Data on BPT were obtained from peer-reviewed publications and the public domain. Pearson's χ2 test was used to evaluate differences in proportions, and Student's unpaired t-test was used to evaluate differences in mean values. The minimum period of stable GDMT required before randomization was longer in ANTHEM-HF: 3 months vs. 1 month in PARADIGM-HF and SHIFT, respectively. When compared with PARADIGM-HF and SHIFT, more patients in ANTHEM-HF received beta-blockers (100% vs. 93% and 89%, P < 0.04 and P < 0.007) and mineralocorticoid receptor antagonists (75% vs. 55% and 61%, P < 0.002 and P < 0.03). More patients in PARADIGM-HF received an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker than in ANTHEM-HF or SHIFT (100% vs. 85%, P < 0.0001, and 100% vs. 91%, P < 0.001), which was related to PARADIGM's design. When beta-blocker doses in ANTHEM-HF and SHIFT were compared, significantly fewer patients in ANTHEM-HF received doses ≥100% of target (10% vs. 23%, P < 0.02), and fewer patients tended to receive doses ≥50% of target (17% vs. 26%, P = 0.11). When ANTHEM-HF and PARADIGM-HF were compared, more patients in ANTHEM-HF tended to receive doses ≥100% of target (10% vs. 7%, P = 0.36), and fewer patients tended to receive doses ≥50% of target (17% vs. 20%, P = 0.56). CONCLUSIONS: Background treatment with GDMT in ANTHEM-HF compared favourably with that in two other contemporary trials of new HF therapies. The minimum period of stable GDMT required before randomization was longer, and GDMT remained unchanged for the study's duration. These findings serve to further support the potential role of autonomic regulation therapy as an adjunct to GDMT for patients with HFrEF.

The heart failure clinic: a consensus statement of the Heart Failure Society of America.

BACKGROUND: Outpatient care accounts for a significant proportion of total heart failure (HF) expenditures. This observation, plus an expanding list of treatment options, has led to the development of the disease-specific HF clinic. METHODS AND RESULTS: The goals of the HF clinic are to reduce mortality and rehospitalization rates and improve quality of life for patients with HF through individualized patient care. A variety of staffing configurations can serve to meet these goals. Successful HF clinics require an ongoing commitment of resources, the application of established clinical practice guidelines, an appropriate infrastructure, and a culture of quality assessment. CONCLUSIONS: This consensus statement will identify the components of HF clinics, focusing on systems and procedures most likely to contribute to the consistent application of guidelines and, consequently, optimal patient care. The domains addressed are: disease management, functional assessment, quality of life assessment, medical therapy and drug evaluation, device evaluation, nutritional assessment, follow-up, advance planning, communication, provider education, and quality assessment.

Short-Term Effects of Tolvaptan in Patients With Acute Heart Failure and Volume Overload.

BACKGROUND: In patients with acute heart failure (AHF), dyspnea relief is the most immediate goal. Renal dysfunction, diuretic resistance, and hyponatremia represent treatment impediments. OBJECTIVES: It was hypothesized that the addition of tolvaptan to a background diuretic improved dyspnea early in patients selected for an enhanced vasopressin antagonism response. METHODS: In a double-blind trial, patients were randomized to tolvaptan 30 mg/day or placebo. Study entry required hospitalization within the previous 36 h, active dyspnea, and any of the following: 1) estimated glomerular filtration rate <60 ml/min/1.73 m2; 2) hyponatremia; or 3) diuretic resistance (urine output ≤125 ml/h following intravenous furosemide ≥40 mg). The primary endpoint was a 7-point change in self-assessed dyspnea at 8 and 16 h, using a novel standardized approach. RESULTS: We randomized 250 patients. There was no difference in the primary endpoint of day 1 dyspnea reduction, despite significantly greater weight reduction with tolvaptan (-2.4 ± 2.1 kg vs. -0.9 ± 1.8 kg; p < 0.001). At day 3, dyspnea reduction was greater with tolvaptan (p = 0.01). There were 2 significant treatment-by-subgroup interactions: patients without elevated jugular venous pressure and those without ascites showed directional favorability of tolvaptan over placebo for the primary endpoint compared with patients with these findings. CONCLUSIONS: Despite rapid and persistent weight loss with tolvaptan compared with placebo, in patients with AHF who were selected for greater potential benefit from vasopressin receptor inhibition, tolvaptan was not associated with greater early improvement in dyspnea. Apparent subsequent differences in dyspnea warrant further exploration of the temporal relationship between diuresis and dyspnea relief and a possible clinical role for tolvaptan. (Randomized, Double-Blind, Placebo Controlled Study of the Short Term Clinical Effects of Tolvaptan in Patients Hospitalized for Worsening Heart Failure With Challenging Volume Management [SECRET of CHF]; NCT01584557).

The economic effect of a tertiary hospital-based heart failure program.

OBJECTIVES: This study was designed to determine the economic effect of a tertiary heart failure (HF) program at an academic medical center. BACKGROUND: Most hospitals use cross-sectional financial models to analyze the economic contribution of clinical programs for a budget period. We estimated the incremental value of a tertiary hospital HF program on the basis of the longitudinal utilization of a sample of HF patients. METHODS: The primary data source was a sample of 82 HF patients referred for cardiac transplant evaluation at an academic medical center during calendar years 2000 to 2001. Cumulative recurrent rates of utilization, cost, and reimbursement for hospital services were computed as functions of time using reliability models. The economic contribution of patients transplanted was contrasted with those not transplanted. RESULTS: Mean hospitalizations and outpatient encounters per patient at the end of the first year of follow-up for those transplanted were 2.1 (95% confidence interval [CI] 1.6 to 2.7) and 11.9 (95% CI 9.2 to 15.4), compared with 1.1 (95% CI 0.8 to 1.6) and 6.0 (95% CI 4.8 to 7.6), respectively, for those not transplanted. Mean revenue and direct cost per patient were 194,470 dollars (95% CI 136,683 dollars to 276,689 dollars) and 146,623 dollars (95% CI 96,377 dollars to 233,065 dollars), respectively, for transplanted patients and 43,587 dollars (95% CI 28,149 dollars to 67,503 dollars) and 33,424 dollars (95% CI 21,584 dollars to 51,760 dollars), respectively, for non-transplanted patients. The point estimates of first-year contribution margins per patient for transplanted and non-transplanted patients were 47,847 dollars and 10,163 dollars, respectively. CONCLUSIONS: Newly evaluated patients for cardiac transplantation at an academic medical center generated substantial incident demands for inpatient and outpatient services over a two-year follow-up period. The estimated contribution margin associated with these services was positive. Hospitals without cardiac transplantation that serve high-acuity HF patients may generate favorable long-term contribution margins, on the basis of the results for the non-transplant group.

Hospital cost effect of a heart failure disease management program: the Specialized Primary and Networked Care in Heart Failure (SPAN-CHF) trial.

BACKGROUND: Determine the effect on hospitalization cost of a heart failure disease management (HFDM) program delivered within a diverse provider network as demonstrated in the SPAN-CHF randomized controlled trial. METHODS: The SPAN-CHF trial was a prospective randomized assessment of the effectiveness of HFDM delivered for 90 days across a diverse provider network in a heterogeneous population of 200 patients. Baseline clinical and demographic data were obtained on each patient, mortality was monitored, and hospitalizations were tracked for 90 days. Cost estimates for each hospitalization were based on a subsample of patients seen at Tufts-New England Medical Center for whom hospitalization costs were calculated. Heart failure disease management program costs were estimated using a programmatic budget model. Hospital utilization and cost data were combined to estimate medical costs for intervention and control groups. RESULTS: Heart failure disease management had a favorable effect on heart failure hospitalization, which was partially offset by noncardiac hospitalizations. The relative odds of at least one all-cause hospitalization during the intervention period trended less for the intervention group compared with the control group (0.76 [95% CI 0.38-1.51]). The point estimate of the differential hospitalization cost between control and intervention groups was a reduction in cost of $375 per patient. The net effect including the costs of the program was an increase of $488 per patient for the intervention group compared with the control group. The program would have been cost saving if HFDM costs had been 24% lower. CONCLUSION: The HFDM intervention, administered over 90 days to patients hospitalized for heart failure, succeeded in reducing the rate of heart failure hospitalizations, although this effect was partially offset by an increase in non-heart failure hospitalizations. The resulting modest reduction in all-cause hospitalization costs was exceeded by the cost of the intervention. Thus, although the reduction in heart failure may be interpreted as an improvement in health status, it could not be considered cost saving.

Lack of circadian change of concentration of C-type natriuretic peptide in rabbit aqueous humor.

PURPOSE: To determine whether there is a circadian change of the concentration of C-type natriuretic peptide (CNP) in rabbit aqueous humor. METHODS: Forty-one male white New Zealand rabbits were submitted to a 12 h light and 12 dark lighting schedule; lights on was at 0 h, lights off at 12 h. C-type natriuretic peptide was assayed at 3 light (2 h, 6 h and 10 h) and 3 dark (14,18 and 22 h) times. All groups consisted of four animals but two had more animals to increase the power of tests (6 h, n = 12; 22 h, n = 13). Dependence between the two eyes was tested by Pearson's correlation. The mean of two eyes was considered for analysis. Differences in concentration in pg/200 ml were evaluated by one-way ANOVA, t test and COSINOR analysis. RESULTS: There were no significant differences between the 6 analyzed groups (one-way ANOVA p = 0.157). Pooled into two groups (light and dark), the C-type natriuretic peptide concentration of the light group was lower, 2.626 +/- 0.92 pg/200 ml compared with the dark group 3.02 +/- 1.16 pg/200 ml but did not reach a significant difference (t test; p = 0.23). COSINOR analysis was not statistically significant (R% = 7.72 p = 0.209). CONCLUSION: These data demonstrate that the concentration of CNP in aqueous humor did not show a statistically significant circadian change in rabbits entrained to a 12 h light: 12 h dark lighting schedule.

Randomized, controlled evaluation of short- and long-term benefits of heart failure disease management within a diverse provider network: the SPAN-CHF trial.

BACKGROUND: Several trials support the usefulness of disease management (DM) for improving clinical outcomes in heart failure (HF). Most of these studies are limited by small sample size; absence of concurrent, randomized controls; limited follow-up; restriction to urban academic centers; and low baseline use of effective medications. METHODS AND RESULTS: We performed a prospective, randomized assessment of the effectiveness of HF DM delivered for 90 days across a diverse provider network in a heterogeneous population of 200 patients with high baseline use of approved HF pharmacotherapy. During a 90-day follow-up, patients randomized to DM experienced fewer hospitalizations for HF [primary end point, 0.55+/-0.15 per patient-year alive versus 1.14+/-0.22 per patient-year alive in control subjects; relative risk (RR), 0.48, P=0.027]. Intervention patients experienced reductions in hospital days related to a primary diagnosis of HF (4.3+/-0.4 versus 7.8+/-0.6 days hospitalized per patient-year; RR, 0.54; P<0.001), cardiovascular hospitalizations (0.81+/-0.19 versus 1.43+/-0.24 per patient-year alive; RR, 0.57; P=0.043), and days in hospital per patient-year alive for cardiovascular cause (RR, 0.64; P<0.001). Intervention patients showed a trend toward reduced all-cause hospitalizations and total hospital days. On long-term (mean, 283 days) follow-up, there was substantial attrition of the 3-month gain in outcomes, with sustained significant reduction only in days in hospital for cardiac cause. CONCLUSIONS: In a population with high background use of standard HF therapy, a DM intervention, uniformly delivered across varied clinical sites, produced significant short-term improvement in HF-related clinical outcomes. Longer-term benefit likely requires more active chronic intervention, even among patients who appear clinically stable.

Early and late effects of high- versus low-dose angiotensin receptor blockade on renal function and outcomes in patients with chronic heart failure.

OBJECTIVES: This study investigated the dose-related effect of losartan on changes in renal function using data from the HEAAL (Heart failure Endpoint evaluation of Angiotensin II Antagonist Losartan) trial. BACKGROUND: Angiotensin receptor blockers adversely affect renal function in patients with heart failure (HF). The time course and dose dependency of this time course, as well as the clinical implications of these changes in renal function, are not well described. METHODS: Subjects in the HEAAL dataset (n = 3,843) were studied. Changes in estimated glomerular filtration rate (eGFR) over time were compared between dose groups. The association between the timing of incident increases in serum creatinine (SCr) >0.3 mg/dl and clinical outcomes was explored. RESULTS: Compared with 50 mg, 150 mg losartan led to a greater reduction in eGFR across time (mean difference:-3.76 ml/min/1.73 m(2); p < 0.0001). This difference was driven by early changes, and differences in eGFRafter 4 months were not significant (mean difference: 0.42 ml/min/1.73 m(2); p = 0.15) [corrected]. Although an increase in SCr >0.3 mg/dl from baseline was associated with increased risk of death or hospitalization for HF (hazard ratio [HR]: 1.36; p < 0.0001), the relationship was not significant if the change occurred before 4 months (HR: 1.09; p = 0.20). Despite increased risk of worsening renal function, 150 mg losartan was associated with reduced risk of death or hospitalization for HF compared with 50 mg (HR: 0.85; p < 0.0001). CONCLUSIONS: Compared with 50 mg, 150 mg losartan is associated with an increased risk of acute rise in SCr, as well as with greater long-term reductions in eGFR. Despite these effects, high-dose losartan retains its net clinical benefit and is associated with reduced risk of death or hospitalization for HF. (Study to Evaluate Potential Decrease in Hospitalization Events, Time Between Events, and Increasing Longevity in Patients With Symptomatic Heart Failure; NCT00090259).

Tolvaptan in Patients Hospitalized With Acute Heart Failure: Rationale and Design of the TACTICS and the SECRET of CHF Trials.

Congestion is a primary reason for hospitalization in patients with acute heart failure (AHF). Despite inpatient diuretics and vasodilators targeting decongestion, persistent congestion is present in many AHF patients at discharge and more severe congestion is associated with increased morbidity and mortality. Moreover, hospitalized AHF patients may have renal insufficiency, hyponatremia, or an inadequate response to traditional diuretic therapy despite dose escalation. Current alternative treatment strategies to relieve congestion, such as ultrafiltration, may also result in renal dysfunction to a greater extent than medical therapy in certain AHF populations. Truly novel approaches to volume management would be advantageous to improve dyspnea and clinical outcomes while minimizing the risks of worsening renal function and electrolyte abnormalities. One effective new strategy may be utilization of aquaretic vasopressin antagonists. A member of this class, the oral vasopressin-2 receptor antagonist tolvaptan, provides benefits related to decongestion and symptom relief in AHF patients. Tolvaptan may allow for less intensification of loop diuretic therapy and a lower incidence of worsening renal function during decongestion. In this article, we summarize evidence for decongestion benefits with tolvaptan in AHF and describe the design of the Targeting Acute Congestion With Tolvaptan in Congestive Heart Failure Study (TACTICS) and Study to Evaluate Challenging Responses to Therapy in Congestive Heart Failure (SECRET of CHF) trials.