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Aims: The course of patients following admission for acute heart failure (AHF) is of major importance to patients and healthcare providers. We examined predictors and associations of length of stay (LOS), 30-day post-discharge readmission and 90-day post-discharge mortality in 1990 patients enrolled in the PROTECT study., Methods and Results: PROTECT was a randomized study that examined the effect of the adenosine blocker rolofylline in patients within 24 h of admission for AHF with mild to moderate renal impairment. Geographic-region-adjusted multivariable models showed that LOS was only partly explained by the severity of heart failure (HF), comorbidities (diabetes mellitus, renal impairment, ischaemic heart disease) and degree of metabolic dysfunction (cholesterol and albumin) at baseline (adjusted R(2) 0.27). Addition of in-hospital worsening heart failure (WHF) and changes in metabolic markers contributed significantly to prediction of LOS [R(2) difference 0.050, 95% confidence interval (CI) 0.0282-0.072]. Thirty-day HF readmission was associated with more severe HF and previous HF admission but not with LOS (odds ratios 1.00, 95% CI 0.97-1.04). Death within 90 days after discharge was associated with older age, more severe HF, worse renal function, and lower sodium and bicarbonate at admission; LOS was a strong predictor of 90-day post-discharge mortality., Conclusions: In patients admitted for AHF, LOS is not well-predicted by traditional markers of disease severity, but strongly associated with the occurrence of in-hospital WHF. Longer LOS is a strong predictor of early mortality after discharge but not of readmission. These findings may help focus efforts to reduce LOS and post-discharge outcomes on patients' subgroups at increased risk., (© 2016 The Authors. European Journal of Heart Failure © 2016 European Society of Cardiology.)

Aims: Previous heart failure (HF) trials suggested that age influences patient characteristics and outcome; however, under-representation of elderly patients has limited characterization of this cohort. Whether standard prognostic variables have differential utility in various age groups is unclear., Methods and Results: The PROTECT trial investigated 2033 patients (median age 72 years) with acute HF randomized to rolofylline or placebo. Patients were divided into five groups based on the quintiles of age: ≤59, 60-68, 69-74, 75-79, and ≥80 years. Baseline characteristics, medications, and outcomes (30-day death or cardiovascular/renal hospitalization, and death at 30 and 180 days) were explored. The prognostic utility of baseline characteristics for outcomes was investigated in the different groups and in those aged <80 years vs. ≥80 years. With increasing age, patients were more likely to be women with hypertension, AF, and higher EF. Increased age was associated with increased risk of 30- and 180-day outcomes, which persisted after multivariable adjustment (hazard ratio for 180-day death = 1.17; 95% confidence interval 1.11-1.24 for each 5-year increase). The prognostic utility of baseline characteristics such as previous HF hospitalization and serum sodium, systolic blood pressure, and NYHA class was attenuated in the elderly for the endpoint of 180-day mortality. An increase in albumin was associated with a greater reduction in risk in patients aged ≥80 years vs. <80 years., Conclusions: In a large trial of acute HF, there were differences in baseline characteristics and outcomes amongst patients of different ages. Standard prognostic variables exhibit different utility in elderly patients., (© 2014 The Authors. European Journal of Heart Failure © 2014 European Society of Cardiology.)

Aims: The implications of geographical variation are unknown following adjustment for hospital length of stay (LOS) in heart failure (HF) trials that included patients whether or not they had systolic dysfunction. We investigated regional differences in an international acute HF trial., Methods and Results: The PROTECT trial investigated 2033 patients with acute HF and renal dysfunction hospitalized at 173 sites in 17 countries with randomization to rolofylline or placebo. We grouped enrolling countries into six regions. Baseline characteristics, in-hospital management, and outcomes were explored by region. The primary study outcome was 60-day mortality or cardiovascular/renal hospitalization. Secondary outcomes included 180-day mortality. Of 2033 patients, 33% were from Eastern Europe, 19% from Western Europe, 16% from Israel, 15% from North America, 14% from Russia, and 3% from Argentina. Marked differences in baseline characteristics, HF phenotype, in-hospital diuretic and vasodilator strategies, and LOS were observed by region. LOS was shortest in North America and Israel (median 5 days) and longest in Russia (median 15 days). Regional event rates varied significantly. Following multivariable adjustment, region was an independent predictor of the risk of mortality/hospitalization at 60 days, with the lowest risk in Russia (hazard ratio 0.39, 95% confidence interval 0.23-0.64 vs. Western Europe) due to lower rehospitalization; mortality differences were attenuated by 180 days., Conclusions: In an international HF trial, there were differences in baseline characteristics, treatments, LOS, and rehospitalization amongst regions, but little difference in longer term mortality. Rehospitalization differences exist independent of LOS. This analysis may help inform future trial design and should be externally validated., (© 2014 The Authors. European Journal of Heart Failure © 2014 European Society of Cardiology.)

Aims: Differences in manifestation, treatment, and outcomes of acute heart failure between men and women have not been well studied. The objective of this analysis was to characterize differences in clinical presentation, and in-hospital and post-discharge outcomes between sexes in acute heart failure patients., Methods and Results: Clinical profiles, treatment characteristics, and outcomes were compared between sexes in 2033 patients hospitalized for acute heart failure and impaired renal function. Women comprised 33% of the study population and were older, had higher body mass index, LVEF, and systolic blood pressure, and a greater prevalence of diabetes. At baseline, women showed signs and symptoms of congestion comparable with men, but more often had rales, orthopnoea, and worse renal function. Women were less intensively diuresed, as indicated by lower oral and intravenous diuretic doses used, fewer dose increases, and less total weight loss during hospitalization. Furthermore, hospitalization was slightly but significantly prolonged in women (11.04 ± 7.8 vs. 10.65 ± 8.86 days; P = 0.024). Age-adjusted 180-day mortality was lower in women (15.8% vs. 18.5%, hazard ratio 0.74; 95% confidence interval 0.59-0.93, P = 0.010), but multivariable risk-adjusted mortality was similar in both sexes, mainly attributable to lower blood urea nitrogen, higher LVEF, and higher systolic blood pressure in women compared with men., Conclusions: Women with acute heart failure present with a clinical profile different from that of men, with more hypertension, diabetes, and depression, and a preserved LVEF. During hospitalization, they were less intensively diuresed. Nevertheless, risk-adjusted 180-day outcome was similar between sexes.

Aims: The direct effects of adenosine A1 receptor antagonists on haemodynamic parameters in patients with acute heart failure (HF) remain largely unknown., Methods and Results: We evaluated the haemodynamic effects of the AA(1)RA rolofylline in 59 HF patients with concomitant renal impairment (estimated creatinine clearance 20-80 mL/min). Placebo or rolofylline 30 mg was administered as a 4 h infusion followed by intravenous (i.v.) loop diuretic administration. Haemodynamic measurements were carried out hourly up to 8 h post-dosing by pulmonary artery catheterization. Urine output, fractional excretion of sodium, potassium, urea, and uric acid, and blood urea nitrogen (BUN) and creatinine levels were also measured. In both groups, the changes from baseline in all haemodynamic indices except mean pulmonary artery pressure (PAP) were not clinically significant. Mean [95% confidence interval (CI)] PAP showed a placebo-adjusted decrease with rolofylline of -1.5 (-4.1, 1.1)mmHg at Hour 4 and -3.5 mmHg (95% CI: -6.2, -0.2) at Hour 8. There was a significant increase with rolofylline in diuresis [placebo-corrected mean (95% CI) change of 68 (20, 116)mL/h at Hour 2-4 and 103 (21, 185)mL/h at Hour 4-8] and in fractional excretion of sodium, potassium, and uric acid. Placebo-corrected changes in plasma levels of creatinine and BUN with rolofylline were non-significant., Conclusion: Single administration of rolofylline in patients with HF and impaired renal function produced a slight decrease in mean PAP and consistently increased diuresis and natriuresis without compromising renal function, both before and after administration of i.v. loop diuretics.

Background: Worsening renal function, which is associated with adverse outcomes, often develops in patients with acute heart failure. Experimental and clinical studies suggest that counterregulatory responses mediated by adenosine may be involved. We tested the hypothesis that the use of rolofylline, an adenosine A1-receptor antagonist, would improve dyspnea, reduce the risk of worsening renal function, and lead to a more favorable clinical course in patients with acute heart failure., Methods: We conducted a multicenter, double-blind, placebo-controlled trial involving patients hospitalized for acute heart failure with impaired renal function. Within 24 hours after presentation, 2033 patients were randomly assigned, in a 2:1 ratio, to receive daily intravenous rolofylline (30 mg) or placebo for up to 3 days. The primary end point was treatment success, treatment failure, or no change in the patient's clinical condition; this end point was defined according to survival, heart-failure status, and changes in renal function. Secondary end points were the post-treatment development of persistent renal impairment and the 60-day rate of death or readmission for cardiovascular or renal causes., Results: Rolofylline, as compared with placebo, did not provide a benefit with respect to the primary end point (odds ratio, 0.92; 95% confidence interval, 0.78 to 1.09; P=0.35). Persistent renal impairment developed in 15.0% of patients in the rolofylline group and in 13.7% of patients in the placebo group (P=0.44). By 60 days, death or readmission for cardiovascular or renal causes had occurred in similar proportions of patients assigned to rolofylline and placebo (30.7% and 31.9%, respectively; P=0.86). Adverse-event rates were similar overall; however, only patients in the rolofylline group had seizures, a known potential adverse effect of A1-receptor antagonists., Conclusions: Rolofylline did not have a favorable effect with respect to the primary clinical composite end point, nor did it improve renal function or 60-day outcomes. It does not show promise in the treatment of acute heart failure with renal dysfunction. (Funded by NovaCardia, a subsidiary of Merck; ClinicalTrials.gov numbers, NCT00328692 and NCT00354458.).

Objectives: This study sought to evaluate the dose-dependent effects of adenosine A1-receptor blockade on diuresis and renal function in patients with acute decompensated heart failure (ADHF) and renal impairment or diuretic resistance., Background: Intravenous loop diuretics are the mainstay of therapy for patients with ADHF. Treatment, however, may be complicated by diuretic resistance and/or worsening renal function., Methods: We carried out a pair of randomized, double-blind, placebo-controlled, proof-of-concept studies in 2 clinically challenging ADHF populations., Results: In the ADHF protocol, 146 patients with volume overload and an estimated creatinine clearance (CrCl) of 20 to 80 ml/min were randomized to placebo or 1 of 4 doses of KW-3902 (rolofylline) infused over 2 h daily for up to 3 days. On day 1, KW-3902 monotherapy increased urine output during the first 6 h (445, 531, 631, and 570 ml in the 2.5-, 15-, 30-, and 60-mg groups, respectively) compared with placebo (374 ml; p = 0.02). On day 2, serum creatinine decreased in all KW-3902 groups and increased with placebo (p = 0.04). By day 4 or day of discharge if earlier, intravenous furosemide administration tended to be lower in the KW-3902 groups compared with placebo (p = 0.10). In the diuretic-resistant protocol, 35 patients with an average CrCl of 34 ml/min were randomized to a single infusion of placebo, 10, 30, or 60 mg of KW-3902. Compared with placebo, KW-3902 increased hourly urine volume and estimated CrCl with peak effects occurring at 2 to 3 h and at 24 h, respectively. Adverse events were not different between placebo and KW-3902., Conclusions: In patients with ADHF and volume overload, KW-3902, an adenosine A1-receptor antagonist, enhances the response to loop diuretics and may have a renal protective effect.

Background: Among patients who are hospitalized with heart failure (HF), worsening renal function (WRF) is associated with worse outcomes. Whether treatment for HF contributes to WRF is unknown. In this study, we sought to assess whether acute treatment for patients who were hospitalized with HF contributes to WRF., Methods: Data were collected in a nested case-control study on 382 subjects who were hospitalized with HF (191 patients with WRF, defined as a rise in serum creatinine level >26.5 micromol/L [0.3 mg/dL], and 191 control subjects). The association of medications, fluid intake/output, and weight with WRF was assessed., Results: Calcium channel blocker (CCB) use and loop diuretic doses were higher in patients on the day before WRF (25% vs 10% for CCB; 199 +/- 195 mg vs 143 +/- 119 mg for loop diuretics; both P <.05). There were no significant differences in the fluid intake/output or weight changes in the 2 groups. Angiotensin-converting enzyme (ACE) inhibitor use was not associated with WRF. Other predictors of WRF included elevated creatinine level at admission, uncontrolled hypertension, and history of HF or diabetes mellitus. Higher hematocrit levels were associated with a lower risk. Vasodilator use was higher among patients on the day before WRF (46% vs 35%, P <.05), but was not an independent predictor in the multivariable analysis., Conclusions: Several medical strategies, including the use of CCBs and a higher dose of loop diuretics, but not ACE inhibitors, were associated with a higher risk of WRF. Although assessment of inhospital diuresis was limited, WRF could not be explained by greater fluid loss in these patients. Determining whether these interventions are responsible for WRF or are markers of higher risk requires further investigation.

Byline: Nihir B. Shah, Elaine Der, Chris Ruggerio, Paul A. Heidenreich, Barry M. Massie Abstract: Congestive heart failure is the most common cause of hospitalization for the older population. A previous study demonstrated that rehospitalizations, undertaken by 30% to 50% of elderly patients, can be prevented with intensive multidisciplinary intervention. A pilot study was designed to determine whether a less intensive program with patient education materials, automated reminders for medication compliance, self-monitoring of daily weights and vital signs, and facilitated telephone communication with a nurse-monitor could reduce hospitalizations and whether this benefit could be extended to younger outpatients. Twenty-seven male patients (mean age 62 years) with New York Heart Association class II to IV congestive heart failure caused by dilated cardiomyopathy underwent follow-up with an independent service, which provided the primary cardiologist with information concerning changes in vital signs or symptoms. The number of hospitalizations and hospital days during the mean value of 8.5 months in the program was compared patient by patient with the number during the equivalent period before entrance in the program. The number of hospitalizations for cardiovascular diagnoses and hospital days was reduced from 0.6 to 0.2 (p = 0.09) per patient year of follow-up and 7.8 to 0.7 days per patient per year (p < 0.05). Hospitalizations for all causes fell from 0.8 to 0.4 per patient per year (p = not significant) and 9.5 to 0.8 days per patient per year (p < 0.05). The greatest absolute and relative benefit was observed among patients with more severe congestive heart failure. The most frequent indication for intervention was an increase in weight, which was managed with adjustment of diuretic dosages. This preliminary experience suggests that close telephone monitoring by personnel from an independent service can prevent hospitalizations for heart failure among both recently discharged patients and ambulatory outpatients and among both elderly and middle-aged persons. (Am Heart J 1998;135:373-8.) Author Affiliation: San Francisco, Calif. Article History: Received 28 January 1997; Accepted 17 July 1997 Article Note: (footnote) [star] From the Department of Medicine and Cardiovascular Research Institute of the University of California, San Francisco, and the Cardiology Section of the Department of Veterans Affairs Medical Center., [star][star] Supported in part by the Department of Veterans Affairs Research Service., a Reprint requests: Barry M. Massie, MD, Cardiology Section (111-C), Veterans Affairs Medical Center, 4150 Clement St., San Francisco, CA 94121., aa 0002-8703/98/$5.00 + 0 4/1/86044

Abstract: Background: Renal function is a powerful prognostic variable in patients with heart failure (HF). Hospitalisations for acute HF (AHF) may be associated with further worsening of renal function (WRF). Methods and results: We analysed the clinical significance of WRF in 318 consecutive patients admitted at our institute for AHF. WRF was defined as the occurrence, at any time during the hospitalisation, of both a ≥25% and a ≥0.3 mg/dL increase in serum creatinine (s-Cr) from admission (WRF-Abs-%). Results: Patients were followed for 480±363 days. Fifty-three patients (17%) died and 132 (41%) were rehospitalised for HF. WRF-Abs-% occurred in 107 (34%) patients. At multivariable survival analysis, WRF-Abs-% was an independent predictor of death or HF rehospitalisation (adjusted HR, 1.47; 95%CI, 1.13–1.81; p =0.024). The independent predictors of WRF-Abs-%, evaluated using multivariable logistic regression, were history of chronic kidney disease (p =0.002), LV ejection fraction (p =0.012), furosemide daily dose (p =0.03) and NYHA class (p =0.05) on admission. Conclusion: WRF is a frequent finding in patients hospitalised for AHF and is associated with a poor prognosis. Severity of HF and daily furosemide dose are the most important predictors of the occurrence of WRF. [Copyright &y& Elsevier]

Discusses the first-line therapy for hypertension among the elderly. Report of Systolic Hypertension in the Elderly Program; Usage of diuretics and beta blockers; Key questions to consider when treating middle-aged or older patient with elevated blood pressure; Required levels of blood pressure; Appropriate goal for blood pressure lowering; Prescribed of medication.

Objectives: This study sought to assess the effects of rolofylline on renal function in patients with acute heart failure (AHF) and renal dysfunction randomized in PROTECT (Placebo-Controlled Randomized Study of the Selective A1 Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized With Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function). Background: Small studies have indicated that adenosine A1 receptor antagonists enhance diuresis and may improve renal function in patients with chronic heart failure or AHF. Methods: A total of 2,033 patients with AHF, volume overload, estimated creatinine clearance between 20 and 80 ml/min, and elevated natriuretic peptide levels were randomized (2:1) within 24 h of hospital presentation to rolofylline 30 mg/day or intravenous placebo for up to 3 days. Creatinine was measured daily until discharge or day 7 and on day 14. Persistent worsening renal function was defined as an increase in serum creatinine ≥0.3 mg/dl at both days 7 and 14, or initiation of hemofiltration or dialysis or death by day 7. Results: At baseline, mean ± SD estimated creatinine clearance was 51.0 ± 20.5 ml/min in the placebo group and 50.4 ± 20.0 ml/min in the rolofylline group. Changes in creatinine and estimated creatinine clearance were similar between placebo- and rolofylline-treated patients during hospitalization and at day 14. After 4 days, mean body weight was reduced by 2.6 and 3.0 kg in placebo and rolofylline patients, respectively (p = 0.005). Persistent worsening renal function occurred in 13.7% of the placebo group and 15.0% of the rolofylline group (odds ratio vs. placebo: 1.11 [95% confidence interval: 0.85 to 1.46]; p = 0.44). Conclusions: In this large, phase III clinical trial, the adenosine A1 receptor antagonist rolofylline did not prevent persistent worsening renal function in AHF patients with volume overload and renal dysfunction. (A Study of the Selective A1 Adenosine Receptor Antagonist KW-3902 for Patients Hospitalized With Acute HF and Volume Overload to Assess Treatment Effect on Congestion and Renal Function [PROTECT-1], NCT00328692; and [PROTECT-2], NCT00354458) [Copyright &y& Elsevier]

Background-In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), a randomized, double-blind, practice-based, active-control, comparative effectiveness trial in high-risk hypertensive participant , risk of new-onset heart failure (HF) was higher in the arnlodipine (2.5-10 mg/d) and lisinopril (10-40 mg/d) arms compared with the chlorthalidone (12.5-25 mg/d) arm. Similar to other studie , mortality rates following new-onset HF were very high (≥50% at 5 years), and were similar across randomized treatment arms. After the randomized phase of the trial ended in 2002, outcomes were determined from administrative databases. Methods and Results-With the use of national databases, posttrial follow-up mortality through 2006 was obtained on participants who developed new-onset HF during the randomized (in-trial) phase of ALLHAT. Mean follow-up for the entire period was 8.9 years. Of 1761 participants with incident HF in-trial, 1348 died. Post-HF all-cause mortality was similar across treatment groups, with adjusted hazard ratios (95% confidence intervals) of 0.95 (0.81-1.12) and 1.05 (0.89 - 1.25), respectively, for arnlodipine and lisinopril compared with chlorthalidone, and 10-year adjusted rates of 86%, 87%, and 83%, respectively. All-cause mortality rates were also similar among those with reduced ejection fraction (84%) and preserved ejection fractions (81 %), with no significant difference by randomized treatment arm. Conclusions-Once HF develops, risk of death is high and consistent across randomized treatment group . Measure to prevent the development of HF, especially blood presure control, must be a priority if mortality asociated with the development of HF is to be addressed. Clinical Trial Registration-http://www.clinicaltrials.gov. Unique identifier: NCT00000542. (Circulation. 2011;124:1811-1818.) [ABSTRACT FROM AUTHOR]