Pulmonary Artery Catheterization Effectiveness Research Articles

Building the evidentiary framework for pharmacogenetic testing: is it time to move beyond randomized controlled trials?

There is a rapidly expanding evidentiary gap between new molecular markers predictive of drug response and data that supports using such molecular markers (e.g., DNA, RNA or smallmolecule-based tests) in clinical practice. This evidence gap is a barrier to realizing the promise of personalized medicine where treatments are tailored to a patient’s individual characteristics. Randomized controlled trials (RCTs) are the ‘gold-standard’ metric for establishing the evidence that a particular intervention is superior to the current standard of care. However, the RCT is not without limitations and may not be the appropriate level of evidence required to support the clinical use of pharmacogenomic testing. We live in an environment where it is impractical to expect a RCT for each new marker. We should not abandon evidence-based practices when deciding to use a new pharmaco genomic marker; instead, clinicians and researchers must decide the appropriate level of evidence, short of the RCT, that supports the use of a novel pharmacogenomic marker in clinical care.

Symptoms in heart failure correlate poorly with objective haemodynamic parameters

Even though heart failure (HF) is a very common condition, surprisingly little is known regarding association between patient's symptoms and objective data. The purpose of this study was to evaluate for any correlations between haemodynamic, echocardiographic and laboratory data of presenting symptoms in HF patients. This study is a retrospective analysis of the limited access dataset from the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial provided by the National Heart, Lung and Blood Institute. Symptoms including dyspnoea, orthopnoea, fatigue and gastrointestinal (GI) discomfort were graded by their severity from minimal (0) to maximal (3) on admission, at discharge, at 3 months and at 6 months from the admission. Results of Minnesota Living with Heart Failure (MLHF) score and assigned New York Heart Association (NYHA) functional class were available at the same time points. A total of 433 patients with decompensated HF and decreased systolic function (ejection fraction < 30%) were included in this trial. Orthopnoea, dyspnoea and fatigue had weak correlation with invasive pulmonary artery systolic and diastolic pressure and negative correlation with serum creatinine, albumin, sodium, total bilirubin, haemoglobin and haematocrit; fatigue showed positive correlation to pulmonary artery pressures. Abdominal discomfort had no correlation to symptoms. There was no correlation of symptoms, NYHA class, or MLHF scores with age, gender, peak VO(2) on cardiopulmonary stress test, body mass index, either right or left ventricular systolic function, B-type natriuretic peptide, cardiac output or cardiac index, troponin level, velocity of tricuspid regurgitation and multiple other factors predicting morbidity and mortality in HF. Overall, the correlation between symptoms and objective parameters was weak. Because of low magnitude of relationship between symptoms to objective parameters, it was concluded that there are likely other factors determining the perception of symptoms in HF patients.

Relationship of Hemoglobin and Hematocrit to Systolic Function in Advanced Heart Failure

Objectives: The dataset from the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial provides a rare opportunity to evaluate the whole spectrum of associations of hemoglobin (HB) and hematocrit (HCT) in heart failure (HF). In that trial, subjective and objective data were recorded at multiple time points when HB and HCT were also measured. We investigated the relationship between anemia and ventricular systolic function. Methods: A limited access dataset from the ESCAPE trial, provided by the National Heart, Lung and Blood Institute, was analyzed. Linear regression analysis, correlation coefficients and Student’s t test were utilized. Results: Besides the known association of anemia with poor prognosis, more severe symptoms, decreased functional capacity and impaired kidney function, we found a significant and very consistent inverse correlation between HB and HCT and ventricular contractility. Both left ventricular ejection fraction and right ventricular fractional area change improved with a decrease in HB and vice versa. We hypothesize that this effect can result from a change in viscosity, which decreases with a decrease in HCT, and may facilitate adaptation of the heart to a volume overload state accompanied by hemodilution. Conclusions: In HF, anemia is associated with poor prognosis and functional impairment, but also with mildly improved systolic function. It may represent an adaptive reaction to congestion.

The Worst Symptom as Defined By Patients During Heart Failure Hospitalization: Implications for Response to Therapy

BackgroundPatients perceive different symptoms of heart failure decompensation. It is not known whether the nature of the worst symptom relates to hemodynamic profile, response to therapy, or improvement in clinical trials. Methods and ResultsPatients in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness trial were hospitalized with advanced heart failure, ejection fraction ≤30%, and at least 1 sign and 1 symptom of elevated filling pressures. Visual analog scales (VAS) for symptoms were completed by 371 patients, who selected their worst symptom as difficulty breathing, fatigue, abdominal discomfort, or body swelling and also scored breathing and global condition at baseline and discharge. The dominant symptom identified was difficulty breathing by 193 (52%) patients, fatigue by 118 (32%), and abdominal discomfort and swelling each by 30 (8%) patients, combined as right-sided congestion for analysis. Clinical and hemodynamic assessments were not different between groups except that right-sided congestion was associated with more hepatomegaly, ascites, third heart sounds, and jugular venous distention. This group also had greater reduction in jugular venous distention and trend toward higher blood urea nitrogen after therapy. By discharge, average improvements in worst symptom and global score were 28 points and 24 points. For those with ≥10 points in improvement in worst symptom, 84% also improved global assessment ≥10 points. Initial fatigue was associated with less improvement (P = .002) during and after hospitalization, but improvements in symptom scores were sustained when re-measured during 6 months after discharge. ConclusionIn most patients hospitalized with clinical congestion, therapy will improve symptoms regardless of the worst symptom perceived, with more evidence of baseline fluid retention and reduction during therapy for worst symptoms of abdominal discomfort or edema. Improvement in trials should be similar when tracking worst symptom, dyspnea, or global assessment.

Predictors of Right Ventricular Systolic Dysfunction in Compensated and Decompensated Heart Failure

Current understanding of the mechanisms of right ventricular (RV) systolic dysfunction in heart failure (HF) is limited. The authors analyzed a limited access dataset from the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) provided by the National Heart, Lung, and Blood Institute (NHLBI). RV systolic function was measured by echocardiography at baseline and at 3-month follow-up using fractional area change. Univariate and multivariate analysis was performed with linear regression. Of 433 patients enrolled in the ESCAPE trial, 190 had RV systolic function measured at baseline (decompensated HF) and 147 had it measured at 3-month follow-up. On both occasions, parameters of congestion were associated with RV systolic function. Interestingly, lower hematocrit level was also associated with better RV systolic function. In multivariate analysis, only wedge pressure remained a statistically significant predictor of RV dysfunction. In summary, cardiac diastolic pressures and corresponding echocardiographic parameters, as well as hematocrit level, predicted RV systolic function in both compensated and decompensated systolic HF.

Influence of renal dysfunction phenotype on mortality in the setting of cardiac dysfunction: analysis of three randomized controlled trials

Renal neurohormonal activation leading to a reduction in glomerular filtration rate (GFR) has been suggested as a mechanism for renal insufficiency (RI) in the setting of heart failure. We hypothesized that RI occurring in the presence of renal neurohormonal activation may be prognostically more important than RI in the absence of renal neurohormonal activation. Subjects in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial (n = 429), Beta-Blocker Evaluation of Survival Trial (BEST) (n = 2691), and Studies Of Left Ventricular Dysfunction (SOLVD) trial (n = 6782) limited datasets were studied. The blood urea nitrogen to creatinine ratio (BUN/Creatinine) was employed as a surrogate for renal neurohormonal activation and the primary outcome was the interaction between BUN/Creatinine and RI associated mortality. Baseline RI (GFR < 60 mL/min/1.73 m&sup2;) was associated with mortality in all study populations (P < 0.001). In patients with higher BUN/Creatinine, the risk of mortality was consistently greater in patients with RI [adjusted hazard ratio (HR) ESCAPE = 2.8, 95% confidence interval (CI) 1.3-14.3, P = 0.019; BEST = 1.6, 95% CI 1.2-2.2, P = 0.002; SOLVD = 1.6, 95% CI 1.3-2.0, P = 0.001]. However, in patients with lower BUN/Creatinine, the risk of mortality was not elevated in patients with RI (adjusted HR ESCAPE = 0.94, 95% CI 0.35-2.4, P = 0.90, P interaction = 0.005; BEST = 0.97, 95% CI 0.64-1.4, P = 0.90, P interaction = 0.02; SOLVD = 1.0, 95% CI 0.8-1.3, P = 0.71, P interaction = 0.005). The association between RI and poor survival observed in heart failure populations appears to be contingent not simply on the presence of a reduced GFR, but possibly on the mechanism by which GFR is reduced.

Right Ventricular Dysfunction Compromises Accuracy of Echocardiographic Diagnosis of Pulmonary Hypertension in Heart Failure

Background The Swan-Ganz catheter and echocardiography (ECHO) are commonly used to measure pulmonary artery systolic pressure. It is unknown how right ventricular dysfunction influences the accuracy of ECHO-derived estimation of pulmonary hypertension in patients with severe left ventricular systolic dysfunction. Methods and Results We analyzed a limited-access dataset from the ESCAPE (Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness) trial provided by the National Heart, Lung, and Blood Institute. Patients enrolled in this trial had left ventricular ejection fraction <30% and decompensated heart failure (HF). Preserved and depressed right ventricular function was defined as fractional area change ≥30% and <30%, respectively. Pearson correlation coefficient, sensitivity, and specificity were calculated. In 106 patients, there were serial measurements of pulmonary artery systolic pressure with both Swan-Ganz catheter and ECHO. For all points of time, including admission for HF decompensation, next day (subcompensation), and the last day of hemodynamic measurements (compensation), correlation was better for preserved than for depressed right ventricular function. Conclusions Accuracy of echocardiographic estimation of pulmonary hypertension in patients with systolic HF is better when right ventricular systolic function is preserved.

Impact of changes in blood pressure during the treatment of acute decompensated heart failure on renal and clinical outcomes†

One of the primary determinants of blood flow in regional vascular beds is perfusion pressure. Our aim was to investigate if reduction in blood pressure during the treatment of decompensated heart failure would be associated with worsening renal function (WRF). Our secondary aim was to evaluate the prognostic significance of this potentially treatment-induced form of WRF. Subjects included in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial limited data were studied (386 patients). Reduction in systolic blood pressure (SBP) was greater in patients experiencing WRF (-10.3 ± 18.5 vs. -2.8 ± 16.0 mmHg, P < 0.001) with larger reductions associated with greater odds for WRF (odds ratio = 1.3 per 10 mmHg reduction, P < 0.001). Systolic blood pressure reduction (relative change > median) was associated with greater doses of in-hospital oral vasodilators (P ≤ 0.017), thiazide diuretic use (P = 0.035), and greater weight reduction (P = 0.023). In patients with SBP-reduction, WRF was not associated with worsened survival [adjusted hazard ratio (HR) = 0.76, P = 0.58]. However, in patients without SBP-reduction, WRF was strongly associated with increased mortality (adjusted HR = 5.3, P < 0.001, P interaction = 0.001). During the treatment of decompensated heart failure, significant blood pressure reduction is strongly associated with WRF. However, WRF that occurs in the setting of SBP-reduction is not associated with an adverse prognosis, whereas WRF in the absence of this provocation is strongly associated with increased mortality. These data suggest that WRF may represent the final common pathway of several mechanistically distinct processes, each with potentially different prognostic implications.

Malnutrition, anemia and renal dysfunction in patients with Chagasic cardiomyopathy

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Characteristics of Patients With Improvement or Worsening in Renal Function During Treatment of Acute Decompensated Heart Failure

Worsening renal function (RF) and improved RF during the treatment of decompensated heart failure have traditionally been thought of as hemodynamically distinct events. We hypothesized that if the pulmonary artery catheter-derived measures are relevant in the evaluation of cardiorenal interactions, the comparison of patients with improved versus worsening RF should highlight any important hemodynamic differences. All subjects in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness trial limited data set with admission and discharge creatinine values available were included (n = 401). No differences were found in the baseline, final, or change in pulmonary artery catheter-derived hemodynamic variables, inotrope and intravenous vasodilator use, or survival between patients with improved versus worsening RF (p = NS for all). Both groups were equally likely to be in the bottom quartile of cardiac index (p = 0.32), have a 25% improvement in cardiac index (p = 0.97), or have any worsening in cardiac index (p = 0.90). When patients with any significant change in renal function (positive or negative) were compared to those with stable renal function, strong associations between variables such as a reduced cardiac index (odds ratio 2.2, p = 0.02), increased intravenous inotrope and vasodilator use (odds ratio 2.9, p <0.001), and worsened all-cause mortality (hazard ratio 1.8, p = 0.01) became apparent. In contrast to traditionally held views, the patients with improved RF and those with worsening RF had similar hemodynamic parameters and outcomes. Combining these groups identified a hemodynamically compromised population with significantly worse survival than patients with stable renal function. In conclusion, the changes in renal function, regardless of the direction, likely identify a population with an advanced disease state and a poor prognosis.

Hemoconcentration, Heart Failure, and Survival

Background: Overly aggressive diuresis leading to intravascular volume depletion has been proposed as a cause for worsening renal function during the treatment of decompensated heart failure .I f diuresis occurs at ar ate greater than extravascular fluid can refill the intravascular space, the concentration of such intravascular substances as hemoglobin and plasma proteins increases. We hypothesized that hemoconcentration would be associated with worsening renal function and possibly would provide insight into the relationship between aggressive decongestion and outcomes. Methods and Results: Subjects in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness trial limited data set with a baseline/ discharge pair of hematocrit, albumin, or total protein values were included (336 patients). Baseline-to-discharge increases in these parameters were evaluated, and patients with ≥2 in the top tertile were considered to have evidence of hemoconcentration. The group experiencing hemoconcentration received higher doses of loop diuretics, lost more weight/fluid, and had greater reductions in filling pressures (P<0.05 for all). Hemoconcentration was strongly associated with worsening renal function (odds ratio, 5.3; P<0.001), whereas changes in right atrial pressure (P=0.36) and pulmonary capillary wedge pressure (P=0.53) were not. Patients with hemoconcentration had significantly lower 180-day mortality (hazard ratio, 0.31; P=0.013). This relationship persisted after adjustment for baseline characteristics (hazard ratio, 0.16; P=0.001). Conclusion: Hemoconcentration is significantly associated with measures of aggressive fluid removal and deterioration in renal function. Despite this relationship, hemoconcentration is associated with substantially improved survival. These observations raise the question of whether aggressive decongestion, even in the setting of worsening renal function, can positively affect survival.

Potential Effects of Aggressive Decongestion during the Treatment of Decompensated Heart Failure on Renal Function and Survival: Insights from the ESCAPE Trial Limited Dataset

Background: Overly aggressive diuresis leading to intravascular volume depletion has been proposed as a cause for worsening renal function (WRF) during the treatment of decompensated heart failure. If diuresis occurs at a rate greater than extravascular fluid can refill the intravascular space, intravascular substances such as hemoglobin and plasma proteins increase in concentration. We hypothesized that hemoconcentration would be associated with WRF and possibly provide insight into the relationship between aggressive decongestion and outcomes. Methods: Subjects in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness trial limited dataset with a baseline/discharge pair of hematocrit, albumin, or total protein values were included (336 patients). Baseline to discharge increases in these parameters were evaluated and patients with ≥2 in the top tertile were considered to have evidence of hemoconcentration. Results: The group experiencing hemoconcentration received higher doses of loop diuretics, lost more weight/fluid, and had greater reductions in filling pressures (p < 0.05 for all). Hemoconcentration was strongly associated with WRF (OR = 5.3, p < 0.001) whereas change in right atrial pressure (p = 0.36) and change in pulmonary capillary wedge pressure (p = 0.53) were not. Patients with hemoconcentration had significantly lower 180 day mortality (HR = 0.31, p = 0.013). This relationship persisted after adjustment for baseline characteristics (HR = 0.16, p = 0.001). Conclusion: Hemoconcentration is significantly associated with measures of aggressive fluid removal and deterioration in renal function. Despite this relationship, hemoconcentration is associated with substantially improved survival. These observations raise the question whether aggressive decongestion, even in the setting of WRF, can positively impact survival.

Potential Effects of Aggressive Decongestion During the Treatment of Decompensated Heart Failure on Renal Function and Survival

Overly aggressive diuresis leading to intravascular volume depletion has been proposed as a cause for worsening renal function during the treatment of decompensated heart failure. If diuresis occurs at a rate greater than extravascular fluid can refill the intravascular space, the concentration of such intravascular substances as hemoglobin and plasma proteins increases. We hypothesized that hemoconcentration would be associated with worsening renal function and possibly would provide insight into the relationship between aggressive decongestion and outcomes. Subjects in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness trial limited data set with a baseline/discharge pair of hematocrit, albumin, or total protein values were included (336 patients). Baseline-to-discharge increases in these parameters were evaluated, and patients with >or=2 in the top tertile were considered to have evidence of hemoconcentration. The group experiencing hemoconcentration received higher doses of loop diuretics, lost more weight/fluid, and had greater reductions in filling pressures (P<0.05 for all). Hemoconcentration was strongly associated with worsening renal function (odds ratio, 5.3; P<0.001), whereas changes in right atrial pressure (P=0.36) and pulmonary capillary wedge pressure (P=0.53) were not. Patients with hemoconcentration had significantly lower 180-day mortality (hazard ratio, 0.31; P=0.013). This relationship persisted after adjustment for baseline characteristics (hazard ratio, 0.16; P=0.001). Hemoconcentration is significantly associated with measures of aggressive fluid removal and deterioration in renal function. Despite this relationship, hemoconcentration is associated with substantially improved survival. These observations raise the question of whether aggressive decongestion, even in the setting of worsening renal function, can positively affect survival.

Triage After Hospitalization With Advanced Heart Failure: The ESCAPE (Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness) Risk Model and Discharge Score

Identifying high-risk heart failure (HF) patients at hospital discharge may allow more effective triage to management strategies. Heart failure severity at presentation predicts outcomes, but the prognostic importance of clinical status changes due to interventions is less well described. Predictive models using variables obtained during hospitalization were created using data from the ESCAPE (Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness) trial and internally validated by the bootstrapping method. Model coefficients were converted to an additive risk score. Additionally, data from FIRST (Flolan International Randomized Survival Trial) was used to externally validate this model. Patients discharged with complete data (n = 423) had 6-month mortality and death and rehospitalization rates of 18.7% and 64%, respectively. Discharge risk factors for mortality included BNP, per doubling (hazard ratio [HR]: 1.42, 95% confidence interval [CI]: 1.15 to 1.75), cardiopulmonary resuscitation or mechanical ventilation during hospitalization (HR: 2.54, 95% CI: 1.12 to 5.78), blood urea nitrogen, per 20-U increase (HR: 1.22, 95% CI: 0.96 to 1.55), serum sodium, per unit increase (HR: 0.93, 95% CI: 0.87 to 0.99), age >70 years (HR: 1.05, 95% CI: 0.51 to 2.17), daily loop diuretic, furosemide equivalents >240 mg (HR: 1.49, 95% CI: 0.68 to 3.26), lack of beta-blocker (HR: 1.28, 95% CI: 0.68 to 2.41), and 6-min walk, per 100-foot increase (HR: 0.955, 95% CI: 0.99 to 1.00; c-index 0.76). A simplified discharge score discriminated mortality risk from 5% (score = 0) to 94% (score = 8). Bootstrap validation demonstrated good internal validation of the model (c-index 0.78, 95% CI: 0.68 to 0.83). The ESCAPE study discharge risk model and score refine risk assessment after in-hospital therapy for advanced decompensated systolic HF, allowing clinicians to focus surveillance and triage for early life-saving interventions in this high-risk population. (Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness [ESCAPE]; NCT00000619).

Correlation of impedance cardiography with invasive hemodynamic measurements in patients with advanced heart failure: The BioImpedance CardioGraphy (BIG) substudy of the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) Trial

Impedance cardiography (ICG) is a noninvasive modality that uses changes in impedance across the thorax to assess hemodynamic parameters, including cardiac output (CO). The utility of ICG in patients hospitalized with heart failure is uncertain. The BioImpedance CardioGraphy in Advanced Heart Failure study was a prospective substudy of the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness. A total of 170 subjects underwent blinded ICG measurements using BioZ (CardioDynamics, San Diego, CA); of these, 82 underwent right heart catheterization. We compared ICG with invasively measured hemodynamics by simple correlation and compared overall ICG hemodynamic profiles ("wet" [thoracic fluid content > or =47/kOhm in men and > or =37/kOhm in women] and "cold" [cardiac index < or =2.2 L min(-1)m(-2)) versus those determined by invasive measurements (wet [pulmonary capillary wedge pressure > or =22 mm Hg] and cold [cardiac index < or =2.2 L min(-1)m(-2)). We also determined whether ICG measurements were associated with subsequent death or hospitalization within 6 months. There was modest correlation between ICG and invasively measured CO (r = 0.4 to 0.6 on serial measurement). Thoracic fluid content measured by ICG was not a reliable measure of pulmonary capillary wedge pressure. There was poor agreement between ICG and invasively measured hemodynamic profiles (kappa < or =0.1). No ICG variable alone or in combination was associated with outcome. In hospitalized patients with advanced heart failure, ICG provides some information about CO but not left-sided filling pressures. Impedance cardiography did not have prognostic utility in this patient population.

Effect of pulmonary hypertension on clinical outcomes in advanced heart failure: Analysis of the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) database

Pulmonary hypertension has been shown to predict hospitalizations and mortality in patients with heart failure. We aimed to define the prevalence of mixed pulmonary hypertension (MPH; mean pulmonary artery pressure > or = 25 mm Hg, pulmonary capillary wedge pressure >15 mm Hg, and pulmonary vascular resistance > or = 3 Wood units), identify clinical predictors of MPH, and determine whether MPH predicts adverse outcomes in patients hospitalized with severe heart failure. This is a subgroup analysis of patients assigned to pulmonary artery catheter placement in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial. Patients with and without MPH were compared with respect to baseline characteristics and clinical outcomes, including NYHA class, 6-minute walk distance, quality of life, days hospitalized, and 6-month mortality. Of the 171 patients studied, 80 (47%) had MPH. Older age was the only significant predictor of MPH. MPH patients had lower cardiac index (1.8 +/- 0.5 L/min vs 2.1 +/- 0.5 L/min, P = .001) and higher systemic vascular resistance index (3,179 +/- 1,454 vs 2,550 +/- 927 dynes x s/cm5 x m2, P < .001) compared to those without MPH. Importantly, right ventricular function was relatively preserved (median RVSWI 8.7 gm-m/m2/beat) in MPH patients. There were no significant differences in clinical outcomes between the two groups. Mixed pulmonary hypertension is common in patients hospitalized with advanced heart failure and is not associated with adverse short-term clinical outcomes over and above the poor prognosis of ADHF patients without MPH.

Loop Diuretics in Acute Decompensated Heart Failure

Acute decompensated heart failure (ADHF) is a common and highly morbid cardiovascular disorder. Most hospitalizations for ADHF are related to symptoms of congestion, and the vast majority of ADHF patients are treated with intravenous loop diuretics. Despite this nearly ubiquitous use, data supporting the safety and efficacy of loop diuretics in ADHF are limited, and controversy exists about the best way to use loop diuretics with regard to both dosing and means of administration (continuous infusion vs. intermittent boluses). We reviewed the data supporting the safety and efficacy of loop diuretics in patients with ADHF. A large body of observational literature suggests that loop diuretics, especially at higher doses, may be associated with increased mortality in patients with heart failure even after detailed adjustment for other measures of disease severity. Additionally, multiple small underpowered trials suggest that continuous infusion may be equivalent or superior to intermittent bolus dosing. In summary, there is a critical need to develop more robust data on the use of loop diuretics in ADHF. In that context, the NIH Heart Failure Clinical Research Network has begun the Diuretics Optimization Strategies Evaluation (DOSE) study, a multi-center, double-blind, randomized controlled trial that will enroll 300 patients with ADHF. The DOSE study will randomize patients using a 2 × 2 factorial design to low dose vs. high dose furosemide, and intermittent bolus vs. continuous infusion. Successful completion of the DOSE study will provide important data on the optimal clinical use of loop diuretics in ADHF.

Association of Weight Change With Subsequent Outcomes in Patients Hospitalized With Acute Decompensated Heart Failure

The association of weight loss achieved through various decongestive strategies with clinical outcomes in patients with acute decompensated heart failure (HF) is not well described. The aim of this study was to determine the relation between weight change during hospitalization and subsequent clinical events in patients with decompensated HF. Data from 433 patients hospitalized with advanced HF enrolled in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial were evaluated. The influence of change in weight during hospitalization to clinical outcomes (days alive out of the hospital in the first 6 months; death; death or rehospitalization; and death, rehospitalization, or cardiac transplantation) was evaluated. On average, patients lost approximately 3.6 kg during hospitalization. When categorized into 3 weight loss tertiles, those in the highest tertile were more likely to be older, women, and smokers, with higher body weights, previous percutaneous coronary interventions, baseline heart rates, and brain natriuretic peptide and blood urea nitrogen values but lower ejection fractions and peak oxygen consumption. No significant differences were observed between weight change and any in-hospital or follow-up events (days well: hazard ratio 0.995, 95% confidence interval 0.975 to 1.016; 180-day death: hazard ratio 1.012, 95% confidence interval 0.969 to 1.057; death or rehospitalization at 180 days: hazard ratio 1.014, 95% confidence interval 0.990 to 1.038). In conclusion, weight loss in patients with acute decompensated HF during hospitalization was not related to clinical end points. These data challenge the merit of using weight as a surrogate end point for more important clinical events (i.e., death and/or rehospitalization) in patients with HF in the design of treatment strategies for novel therapeutic agents in randomized controlled clinical trials.

High Mortality Without ESCAPE: The Registry of Heart Failure Patients Receiving Pulmonary Artery Catheters Without Randomization

Background In the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE), there was no difference in days alive and out of the hospital for patients with decompensated heart failure randomly assigned to therapy guided by pulmonary artery catheter (PAC) plus clinical assessment versus clinical assessment alone. The external validity of these findings is debated. Methods and Results ESCAPE sites enrolled 439 patients receiving PAC without randomization in a prospective registry. Baseline characteristics, pertinent trial exclusion criteria, reasons for PAC use, hemodynamics, and complications were collected. Survival was determined from the National Death Index and the Alberta Registry. On average, registry patients had lower blood pressure, worse renal function, less neurohormonal antagonist therapy, and higher use of intravenous inotropes compared with trial patients. Although clinical assessment anticipated less volume overload and greater hypoperfusion among the registry population, measured filling pressures were similarly elevated in the registry and trial patients, whereas measured perfusion was slightly higher among registry patients. Registry patients had longer hospitalization (13 vs 6 days, P < .001) and higher 6-month mortality (34% vs 20%, P < .001) than trial patients. Conclusions The decision to use PAC without randomization identified a population with higher disease severity and risk of mortality. This prospective registry highlights the complex context of patient selection for randomized trials.

Cardiorenal Interactions: Insights From the ESCAPE Trial

We examined the ESCAPE (Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness) database to understand the impact and pathophysiology of renal dysfunction in patients hospitalized with advanced decompensated heart failure (HF). Baseline renal insufficiency (RI) (estimated glomerular filtration rate [eGFR] <60 ml/min) and worsening renal function (WRF) (upward arrow serum creatinine [SCr] >or=0.3 mg/dl) during treatment of decompensated HF are associated with adverse outcomes. We used a Cox proportional hazards model to evaluate the impact of renal function on 6-month outcomes. Renal parameters were correlated with hemodynamic measurements. The impact of a strategy using pulmonary artery catheter (PAC) guidance on WRF and outcomes in patients with baseline RI was compared with treatment based on clinical assessment alone. Baseline and discharge RI, but not WRF, were associated with an increased risk of death and death or rehospitalization. Among the hemodynamic parameters measured in patients randomized to the PAC arm (n = 194), only right atrial pressure correlated weakly with baseline SCr (r = 0.165, p = 0.03). There was no correlation between baseline hemodynamics or change in hemodynamics and WRF. A PAC-guided strategy was associated with less average increase in creatinine but did not decrease the incidence of defined WRF during hospitalization or affect renal function after discharge relative to clinical assessment alone. Among patients with advanced decompensated HF, baseline RI impacts outcomes more than WRF. Poor forward flow alone does not appear to account for the development of RI or WRF in these patients. The addition of hemodynamic monitoring to clinical assessment does not prevent WRF or improve renal function after discharge.