George A. Mansoor

Rolofylline, an Adenosine A1−Receptor Antagonist, in Acute Heart Failure

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 patients 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.).

Long-term reproducibility of ambulatory blood pressure.

Objective To compare the reproducibility of ambulatory and office blood pressure readings in established hypertensive subjects when studies are repeated at extended time intervals. Subjects Twenty-five hypertensive patients (office diastolic blood pressure ≥90mmHg) who were off antihypertensive therapy for at least 4 weeks and had repeat office and ambulatory blood pressures at least 3 months apart under similar study conditions. Methods On the same day, patients underwent office blood pressure readings measured by mercury column sphygmomanometry and then by ambulatory blood pressure monitoring. Ambulatory blood pressure monitoring was done for 24 h, and awake and sleep periods were divided according to a diary kept by each patient. A second study was performed in an identical manner at a mean±SD interval of 23 ±24 months (range 3–80, median 15). The agreement between studies was assessed by correlation coefficients, coefficients of variation and standard deviation of the differences (SDD). Results There were no significant differences in office, 24-h, awake and sleep mean blood pressures between the two studies. Mean 24-h systolic and diastolic blood pressures were 16 and 14mmHg lower, respectively, than office blood pressure values. Correlation coefficients were significantly higher for 24-h ambulatory blood pressure than office blood pressure, whereas the SDD between visits was significantly lower for 24-h ambulatory blood pressure than office blood pressure. Conclusions These data demonstrate that long-term reproducibility of ambulatory blood pressure is superior to that for office measurement. One implication of this finding is that, in long-term clinical pharmacology trials utilizing ambulatory blood pressure, fewer subjects would be required than for studies that used office blood pressure end-points.

The Predictive Value of Short-Term Changes in Hemoglobin Concentration in Patients Presenting With Acute Decompensated Heart Failure

OBJECTIVES The study sought to investigate the clinical correlates and prognostic role of anemia and changes in hemoglobin in patients hospitalized for acute decompensated heart failure (AHF). BACKGROUND Anemia is related to a poor outcome in patients with heart failure. In addition, an increase in hemoglobin during hospitalization might be a sign of effective decongestion and therefore related to improved outcome. METHODS This is a post hoc analysis of the PROTECT (Placebo-Controlled Randomized Study of the Selective Adenosine A1 Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function) study in 1,969 patients with AHF and mild to moderate impaired renal function. Hemoglobin levels were measured daily for the first 4 days and at day 7. The endpoint was 180-day all-cause mortality. RESULTS Anemia at baseline was observed in 50.3% of the patients. During follow-up, 359 patients (18.2%) died. Hemoglobin increased in 69.1% and was associated with a better renal function at baseline and more weight loss, but was associated with a deterioration of renal function (p = 0.01), whereas total dose diuretics was lower in patients with hemoconcentration (p < 0.01). Interaction analysis showed that greater weight loss and better baseline renal function were associated with a more rapid increase in hemoglobin concentration (p < 0.01 for both). The absolute change in hemoglobin (g/dl) independently predicted outcome (hazard ratio: 0.66; 95% confidence interval: 0.51 to 0.86; p = 0.002), whereas baseline hemoglobin levels did not. CONCLUSIONS Patients with AHF and preserved renal function are decongested better, as shown by an increase in hemoglobin. A rapid increase in hemoglobin during the first week is independently associated with a favorable outcome, despite a slight decrease in renal function.

The relationship of electronically monitored physical activity to blood pressure, heart rate, and the circadian blood pressure profile*

We studied how closely changes in electronically monitored physical activity are reflected in changes in blood pressure and heart rate in a group of untreated hypertensive subjects. Thirty-nine hypertensive patients (office blood pressure > 140/ 90 mm Hg) of mean age 57 +/- 10 years (mean +/-SD) wore an ambulatory blood pressure monitor and a wrist actigraph simultaneously. Both average and peak activity for 5 min before each valid blood pressure reading were determined, as was average activity for awake and sleep periods, determined by patient kept diaries. For the overall group, awake and 24-h activities were inversely correlated to age (n = 39, r = -0.42; P = 0.01 and n = 39, r = -0.38; P = 0.01, respectively). No correlation was found between group awake activity and group-average blood pressure or heart rate. For individual patients, there was marked variation in the degree of correlation between awake activity measures (both peak and average) and blood pressure and heart rate. The strongest positive correlation was between activity levels and the heart rate-pressure product. Nondipper profile hypertensives had higher sleep activity than dipper hypertensives (44 +/- 28 units/min v 25 +/- 20 units/min, df = 37, t = 2.12; P = 0.04), but awake activity levels were similar. The higher sleep activity remained after adjustment for age. These findings indicate that the relationship between actigraphic activity and hemodynamic parameters is highly variable and that the rate-pressure product is the strongest correlate of short-term activity. Furthermore, hypertensives with the nondipper profile have higher sleep activity than dipper hypertensives. These findings stress the need for further study into the role of day-to-day activity in determining ambulatory blood pressure and heart rate variability.

The PROTECT in-hospital risk model: 7-day outcome in patients hospitalized with acute heart failure and renal dysfunction

In patients with acute heart failure (AHF), early worsening heart failure (WHF) predicts a significant proportion of post‐discharge readmissions and mortality. We aimed to identify the predictors of 7‐day heart failure events or death in patients hospitalized with AHF.

Effects of the Adenosine A1 Receptor Antagonist Rolofylline on Renal Function in Patients With Acute Heart Failure and Renal Dysfunction: Results From 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)

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 A(1) 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 A(1) 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 A(1) 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).

Design and Rationale of the PROTECT Study: A 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 Current treatment for acute decompensated heart failure (ADHF) is associated with incomplete resolution of symptoms and signs, recurrent symptoms of heart failure in-hospital and after discharge and high mortality. Studies have consistently demonstrated an association between worsening renal function in ADHF and adverse outcomes. Adenosine A(1) receptor antagonists, such as rolofylline, appear in preliminary studies to produce potentially beneficial effects on natriuresis, diuresis, renal blood flow, and glomerular filtration rate. In a previous dose-finding study, rolofylline 30 mg intravenously daily for 3 days was associated with symptom improvement, less worsening of renal function, and trends toward lower 60-day rates of death or readmission for cardiovascular or renal causes. METHODS AND RESULTS This manuscript describes the rationale underlying the design of the phase 3 PROTECT (Placebo-controlled Randomized study of the selective A(1) adenosine receptor antagonist rolofylline for patients hospitalized with acute heart failure and volume Overload to assess Treatment Effect on Congestion and renal funcTion) trial. CONCLUSION Rolofylline 30 mg or matching placebo was given intravenously as a 4-hour continuous infusion on 3 consecutive days and the hospital course was assessed by measurements dyspnea, clinical status, renal function, and subsequent morbidity and mortality in a large population of patients with ADHF with renal impairment.

Herbs and alternative therapies in the hypertension clinic

The use of alternative therapies, herbs, and supplements occurs at a very high rate among patients attending a variety of health care settings. Such therapy may cause significant interactions or effects on hypertension and other cardiovascular disorders and needs to be considered by clinicians. In this brief review, we highlight several commonly used alternative therapies that may have a clinical impact in the hypertensive patient. Several problems hinder our complete awareness of these effects. These problems include patients not informing physicians about alternative treatment or herbal use, the lack of consistent scientific standards for the bioactivity of many herbals or supplements, and the multiple names that each bioactive substance is sold under. Specific questioning regarding herbals and alternative therapies in the hypertension clinic is therefore needed. Herbals including ma huang, St. Johns wort, yohimbine, garlic, and licorice all may cause important consequences in the hypertensive patient. Added care is needed in monitoring the use and effects of herbal and alternative therapies in the hypertensive population.

Effects of the adenosine A1 receptor antagonist rolofylline on renal function in patients with acute heart failure and renal dysfunction: results from PROTECT (Placebo-Controlled Randomized Study of the Selective Adenosine A1 Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function).

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 A(1) 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 A(1) 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 A(1) 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).

Predictors of Postdischarge Outcomes From Information Acquired Shortly After Admission for Acute Heart Failure A Report From the 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 (PROTECT) Study

Background —Acute heart failure (AHF) is a common reason for admission and outcome is often poor. Improved prognostic risk stratification may assist in the design of future trials and in patient management. Using data from a large randomized trial, we explored the prognostic value of clinical variables, measured at hospital admission for AHF, to determine whether a few selected variables were inferior to an extended data-set. Methods and Results —The prognostic model included 37 clinical characteristics collected at baseline in PROTECT, a study comparing rolofylline and placebo in 2,033 patients admitted with AHF. Pre-specified outcomes at 30 days were death or re-hospitalization for any reason, death or re-hospitalization for cardiovascular or renal reasons and, at both 30 and 180 days, all-cause mortality. No variable had a c-index >0.70 and few had values >0.60; c-indices were lower for composite outcomes than for mortality. Blood urea was generally the strongest single predictor. Eighteen variables contributed independent prognostic information but a reduced model using only eight items (age, prior heart failure hospitalization, peripheral edema, systolic blood pressure, serum sodium, urea, creatinine and albumin) performed similarly. For all-cause mortality at 180-days, the model C-index using all variables was 0.72 and for the simplified model, also 0.72. Conclusions —A few simple clinical variables measured on admission in patients with AHF predict a variety of adverse outcomes with similar accuracy to more complex models. However, predictive models were of only moderate accuracy, especially for outcomes that included non-fatal events. Better methods of risk-stratification are required. Clinical Trial Registration —URL: http://www.clinicaltrials.gov. Unique identifiers: [NCT00328692][1] and [NCT00354458][2]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00328692&atom=%2Fcirchf%2Fearly%2F2013%2F11%2F26%2FCIRCHEARTFAILURE.113.000284.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00354458&atom=%2Fcirchf%2Fearly%2F2013%2F11%2F26%2FCIRCHEARTFAILURE.113.000284.atom