Jeffrey M. Testani

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

Interaction between loop diuretic-associated mortality and blood urea nitrogen concentration in chronic heart failure.

OBJECTIVES The purpose of this study was to investigate whether a surrogate for renal neurohormonal activation, blood urea nitrogen (BUN), could identify patients destined to experience adverse outcomes associated with the use of high-dose loop diuretics (HDLD). BACKGROUND Loop diuretics are commonly used to control congestive symptoms in heart failure; however, these agents cause neurohormonal activation and have been associated with worsened survival. METHODS Subjects in the BEST (Beta-Blocker Evaluation of Survival Trial) receiving loop diuretics at baseline were analyzed (N = 2,456). The primary outcome was the interaction between BUN- and HDLD-associated mortality. RESULTS In the overall cohort, HDLD use (≥160 mg/day) was associated with increased mortality (hazard ratio [HR]: 1.56; 95% confidence interval [CI]: 1.35 to 1.80). However, after extensively controlling for baseline characteristics, this association did not persist (HR: 1.06; 95% CI: 0.89 to 1.25). In subjects with BUN levels above the median (21.0 mg/dl), both the unadjusted (HR: 1.59; 95% CI: 1.34 to 1.88) and adjusted (HR: 1.29; 95% CI: 1.07 to 1.60) risk of death was higher in the HDLD group. In patients with BUN levels below the median, there was no associated risk with HDLD (HR: 0.99; 95% CI: 0.75 to 1.34) and after controlling for baseline characteristics, the HDLD group had significantly improved survival (HR: 0.71; 95% CI: 0.49 to 0.96) (p interaction = 0.018). CONCLUSIONS The risk associated with HDLD use is strongly dependent on BUN concentrations with reduced survival in patients with an elevated BUN level and improved survival in patients with a normal BUN level. These data suggest a role for neurohormonal activation in loop diuretic-associated mortality.

Effect of Right Ventricular Function and Venous Congestion on Cardiorenal Interactions During the Treatment of Decompensated Heart Failure

Recent reports have demonstrated the adverse effects of venous congestion on renal function (RF) and challenged the assumption that worsening RF is driven by decreased cardiac output (CO). We hypothesized that diuresis in patients with right ventricular (RV) dysfunction, despite decreased CO, would lead to a decrease in venous congestion and resultant improvement in RF. We reviewed consecutive admissions with a discharge diagnosis of heart failure. RV function was assessed by multiple echocardiographic methods and those with >or=2 measurements of RV dysfunction were considered to have significant RV dysfunction. Worsening RF was defined as an increase in creatinine of >or=0.3 mg/dl and improved RF as improvement in glomerular filtration rate >or=25%. A total of 141 admissions met eligibility criteria; 34% developed worsening RF. Venous congestion was more common in those with RV dysfunction (odds ratio [OR] 3.3, p = 0.009). All measurements of RV dysfunction excluding RV dilation correlated with CO (p <0.05). Significant RV dysfunction predicted a lower incidence of worsening RF (OR 0.21, p <0.001) and a higher incidence of improved RF (OR 6.4, p <0.001). CO emerged as a significant predictor of change in glomerular filtration rate during hospitalization in those without significant RV dysfunction (r = 0.38, p <0.001). In conclusion, RV dysfunction is a strong predictor of improved renal outcomes in patients with acute decompensated heart failure, an effect likely mediated by relief of venous congestion.

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.

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.

Worsening renal function defined as an absolute increase in serum creatinine is a biased metric for the study of cardio-renal interactions.

Objectives: Worsening renal function (WRF) during the treatment of decompensated heart failure, frequently defined as an absolute increase in serum creatinine ≧0.3 mg/dl, has been reported as a strong adverse prognostic factor in several studies. We hypothesized that this definition of WRF is biased by baseline renal function secondary to the exponential relationship between creatinine and renal function. Methods: We reviewed consecutive admissions with a discharge diagnosis of heart failure. An increase in creatinine ≧0.3 mg/dl (WRFCREAT) was compared to a decrease in GFR ≧20% (WRFGFR). Results: Overall, 993 admissions met eligibility. WRFCREAT occurred in 31.5% and WRFGFR in 32.7%. WRFCREAT and WRFGFR had opposing relationships with baseline renal function (OR = 1.9 vs. OR = 0.51, respectively, p < 0.001). Both definitions had similar unadjusted associations with death at 30 days [WRFGFR OR = 2.3 (95% CI 1.1–4.8), p = 0.026; WRFCREAT OR = 2.1 (95% CI 1.0–4.4), p = 0.047]. Controlling for baseline renal insufficiency, WRFGFR added incrementally in the prediction of mortality (p = 0.009); however, WRFCREAT did not (p = 0.11). Conclusions: WRF, defined as an absolute change in serum creatinine, is heavily biased by baseline renal function. An alternative definition of WRF should be considered for future studies of cardio-renal interactions.

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.

Accuracy of Noninvasively Determined Pulmonary Artery Systolic Pressure

The noninvasive estimation of pulmonary artery systolic pressure (PASP) has become a standard component of the echocardiographic examination. Our aim was to evaluate the accuracy of this modality in a large series of unselected studies obtained in clinical practice. All right heart catheterizations during a 4-year period were reviewed. Studies with echocardiographic findings available within 48 hours were evaluated for PASP agreement. In an effort to mirror clinical practice, the right heart catheterization findings were used as the reference standard and the PASP values were taken directly from the respective clinical reports. Overall, 792 right heart catheterization-echocardiogram pairs were identified. Echocardiographic PASP could not be estimated in 174 of these studies (22.0%). The correlation between modalities was moderate, but agreement was poor (bias 9.0%, 95% limits of agreement -53.2% to 71.2%, r = 0.52, p <0.001). Misclassification of clinical PASP categories occurred more often than not (54.4%). Multivariate analysis using multiple potential sources of error could only account for 3.2% of the total variation in the discrepancy between the study modalities (p = 0.003). In conclusion, noninvasively estimated PASP had limited agreement with the invasively determined PASP, and misclassification of PASP clinical categories occurred frequently. Given the widespread use of echocardiographically determined PASP, these data are in need of replication in a large prospective study.

Impact of worsening renal function during the treatment of decompensated heart failure on changes in renal function during subsequent hospitalization

BACKGROUND Worsening renal function (WRF) commonly complicates the treatment of acute decompensated heart failure. Despite considerable investigation in this area, it remains unclear to what degree WRF is a reflection of treatment- versus patient-related factors. We hypothesized that if WRF is significantly influenced by factors intrinsic to the patient, then WRF during an index hospitalization should predict WRF during subsequent hospitalization. METHODS Consecutive admissions to the Hospital of the University of Pennsylvania with a discharge diagnosis of congestive heart failure were reviewed. Patients with >1 hospitalization were retained for analysis. RESULTS In total, 181 hospitalization pairs met the inclusion criteria. Baseline patient characteristics demonstrated significant correlation between hospitalizations (P ≤ .002 for all) but minimal association with WRF. In contrast, variables related to the aggressiveness of diuresis were weakly correlated between hospitalizations but significantly associated with WRF (P ≤ .024 for all). Consistent with the primary hypothesis, WRF during the index hospitalization was strongly associated with WRF during subsequent hospitalization (odds ratio [OR] 2.7, P = .003). This association was minimally altered after controlling for traditional baseline characteristics (OR 2.5, P = .006) and in-hospital treatment-related parameters (OR 2.8, P = .005). CONCLUSIONS A prior history of WRF is strongly associated with subsequent episodes of WRF, independent of in-hospital treatment received. These results suggest that baseline factors intrinsic to the patients cardiorenal pathophysiology have substantial influence on the subsequent development of WRF.

Who wants a left ventricular assist device for ambulatory heart failure? Early insights from the MEDAMACS screening pilot

Who wants a left ventricular assist device for ambulatory heart failure? Early insights from the MEDAMACS screening pilot Garrick C. Stewart, MD, MPH, Michelle M. Kittleson, MD, PhD, Jennifer A. Cowger, MD, Frances L. Johnson, MD, Chetan B. Patel, MD, Maria M. Mountis, DO, Parag C. Patel, MD, J. Eduardo Rame, MD, Jeffrey Testani, MD, Maya E. Guglin, MD, Jeffrey J. Teuteberg, MD, and Lynne W. Stevenson, MD From the Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, Massachusetts; Cedars-Sinai Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California; Cardiovascular Center, University of Michigan, Ann Arbor, Michigan; Division of Cardiology, University of Iowa, Iowa City, Iowa; Division of Cardiology, Duke University, Durham, North Carolina; Division of Cardiology, Cleveland Clinic Foundation, Cleveland, Ohio; Division of Cardiology, University of Texas Southwestern, Dallas, Texas; Heart and Vascular Center, University of Pennsylvania, Philadelphia, Pennsylvania; Division of Cardiology, University of South Florida, Tampa, Florida; and the Heart and Vascular Institute, University of Pittsburgh, Pittsburgh, Pennsylvania