Joanne Marshall

Nesiritide does not improve renal function in patients with chronic heart failure and worsening serum creatinine

Background—Nesiritide (synthetic human brain natriuretic peptide) is approved for the treatment of symptomatic heart failure. However, studies of brain natriuretic peptide in patients with heart failure have come to conflicting conclusions about effects on glomerular filtration rate (GFR), effective renal plasma flow, natriuresis, and diuresis. Methods and Results—To identify a population at high risk of renal dysfunction with conventional treatment, we selected patients with a creatinine level increased from baseline (within 6 months). We examined the effects of nesiritide on GFR (measured by iothalamate clearance), renal plasma flow (measured by para-amino hippurate clearance), urinary sodium excretion, and urine output in a double-blind, placebo-controlled, crossover study. Patients received nesiritide (2 &mgr;g/kg IV bolus followed by an infusion of 0.01 &mgr;g/kg per minute) or placebo for 24 hours on consecutive days. Nesiritide and placebo data were compared by repeated-measures analysis and Student t test. We studied 15 patients with a recent mean baseline creatinine of 1.5±0.4 mg/dL and serum creatinine of 1.8±0.8 mg/dL on admission to the study. There were no differences in GFR, effective renal plasma flow, urine output, or sodium excretion for any time interval or for the entire 24-hour period between the nesiritide and placebo study days. For 24 hours, urine output was 113±51 mL/h with placebo and 110±56 mL/h with nesiritide. GFR during placebo was 40.9±25.9 mL/min and with nesiritide was 40.9±25.8. Conclusions—Nesiritide did not improve renal function in patients with decompensated heart failure, mild chronic renal insufficiency, and renal function that had worsened compared with baseline. The lack of effect may be related to renal insufficiency, hemodynamic alterations, sodium balance, severity of heart failure, or drug dose. Understanding the importance of these issues will permit effective and appropriate use of nesiritide.

Effects of BG9719 (CVT-124), an A1-Adenosine receptor antagonist, and furosemide on glomerular filtration rate and natriuresis in patients with congestive heart failure

OBJECTIVES To determine the effects of furosemide and the selective A1 adenosine receptor BG9719 on renal function in patients with congestive heart failure (CHF). BACKGROUND Studies suggest that adenosine may affect renal function by various mechanisms, but the effects of blockade of this system in humans is unknown. In addition, the effects of a therapeutic dose of furosemide on glomerular filtration rate (GFR) and renal plasma flow (RPF) in heart failure patients are controversial. METHODS On different days, 12 patients received placebo, BG9719 and furosemide. Glomerular filtration rate, RPF and sodium and water excretion were assessed immediately following drug administration. RESULTS Glomerular filtration rate was 84 +/- 23 ml/min/1.73m2 after receiving placebo, 82 +/- 24 following BG9719 administration and a decreased (p < 0.005) 63 +/- 18 following furosemide. Renal plasma flow was unchanged at 293 +/- 124 ml/min/1.73m2 on placebo, 334 +/- 155 after receiving BG9719 and 374 +/- 231 after receiving furosemide. Sodium excretion increased from 8 +/- 8 mEq following placebo administration to 37 +/- 26 mEq following BG9719 administration. In the six patients in whom it was measured, sodium excretion was 104 +/- 78 mEq following furosemide administration. CONCLUSIONS Natriuresis is effectively induced by both furosemide and the adenosine A1 antagonist BG9719 in patients with CHF. Doses of the two drugs used in this study did not cause equivalent sodium and water excretion but only furosemide decreased GFR. These data suggest that adenosine is an important determinant of renal function in patients with heart failure.

A Randomized, Controlled Trial of the Renal Effects of Ultrafiltration as Compared to Furosemide in Patients With Acute Decompensated Heart Failure

OBJECTIVES This study was designed to evaluate the consequences of ultrafiltration (UF) and standard intravenous diuretic (furosemide) therapy on glomerular filtration rate (GFR) and renal plasma flow in patients with acute decompensated heart failure. BACKGROUND It has been hypothesized that treatment with diuretics may worsen renal function as the result of systemic neurohormonal activation and direct renal vascular effects. UF also removes fluid, but its actions on intrarenal hemodynamics, and therefore renal function, are unknown. METHODS Patients hospitalized for acute decompensated heart failure with an ejection fraction less than 40% and two or more signs of hypervolemia were randomized to receive UF or intravenous diuretics. Urine output, GFR (as measured by iothalamate), and renal plasma flow (as measured by para-aminohippurate) were assessed before fluid removal and after 48 hours. RESULTS Nineteen patients (59 +/- 16 years, 68% were male) were randomized to receive UF (n = 9) or intravenous diuretics (n = 10). The change in GFR (-3.4 +/- 7.7 mL/min vs. -3.6 +/- 11.5 mL/min; P = .966), renal plasma flow (26.6 +/- 62.7 mL/min vs. 16.1 +/- 42.0 mL/min; P = .669), and filtration fraction (-6.9 +/- 13.6 mL/min vs. -3.9 +/- 13.6 mL/min; P = .644) after treatment were not significantly different between the UF and furosemide treatment groups, respectively. There was no significant difference in net 48-hour fluid removal between the groups (-3211 +/- 2345 mL for UF and -2725 +/- 2330 mL for furosemide, P = .682). UF removed 3666 +/- 2402 mL. Urine output during 48 hours was significantly greater in the furosemide group (5786 +/- 2587 mL) compared with the UF group (2286 +/- 915 mL, P < .001). CONCLUSIONS During a 48-hour period, UF did not cause any significant differences in renal hemodynamics compared with the standard treatment of intravenous diuretics.

Hypoxia, Not the Frequency of Sleep Apnea, Induces Acute Hemodynamic Stress in Patients With Chronic Heart Failure

OBJECTIVES This study was conducted to evaluate whether brain (B-type) natriuretic peptide (BNP) changes during sleep are associated with the frequency and severity of apneic/hypopneic episodes, intermittent arousals, and hypoxia. BACKGROUND Sleep apnea is strongly associated with heart failure (HF) and could conceivably worsen HF through increased sympathetic activity, hemodynamic stress, hypoxemia, and oxidative stress. If apneic activity does cause acute stress in HF, it should increase BNP. METHODS Sixty-four HF patients with New York Heart Association functional class II and III HF and ejection fraction <40% underwent a baseline sleep study. Five patients with no sleep apnea and 12 with severe sleep apnea underwent repeat sleep studies, during which blood was collected every 20 min for the measurement of BNP. Patients with severe sleep apnea also underwent a third sleep study with frequent BNP measurements while they were administered oxygen. This provided 643 observations with which to relate apnea to BNP. The association of log BNP with each of 6 markers of apnea severity was evaluated with repeated measures regression models. RESULTS There was no relationship between BNP and the number of apneic/hypopneic episodes or the number of arousals. However, the burden of hypoxemia (the time spent with oxygen saturation <90%) significantly predicted BNP concentrations; each 10% increase in duration of hypoxemia increased BNP by 9.6% (95% confidence interval: 1.5% to 17.7%, p = 0.02). CONCLUSIONS Hypoxemia appears to be an important factor that underlies the impact of sleep abnormalities on hemodynamic stress in patients with HF. Prevention of hypoxia might be especially important for these patients.

Test-retest reliability of assessment for intraventricular dyssynchrony by tissue Doppler imaging echocardiography.

The purpose of this study was to evaluate the test-retest reliability of intraventricular dyssynchrony (IVD) assessment by tissue Doppler imaging (TDI) echocardiography. Limited response rates to cardiac resynchronization may improve with TDI screening for appropriate recipients. However, the clinical applicability of TDI will depend on the reliability of the test. Repeat TDI was prospectively performed (11 +/- 11 days apart) in 15 patients with QRS intervals >120 ms and left ventricular ejection fractions <35% and 25 normal controls using the same machine, sonographer, and blinded readers for the 2 tests. There was no change in clinical status or treatment between tests. Established and clinically feasible criteria for IVD were evaluated. These were based on differences of TDI-derived activation time between 2, 4, or 12 left ventricular segments. Reliability was assessed by linear correlation and Bland-Altman analysis for quantified measures, along with percentage agreement and kappa statistics for IVD diagnosis. Despite good intrareader (r = 0.98, p <0.0001) and interreader (2 segments: r = 0.96, p <0.0001; 4 segments: r = 0.85, p <0.0001) reliability, test-retest correlations were uniformly modest for the 2-segment (r = 0.26, p = 0.11), 4-segment (r = 0.36, p = 0.021), and 12-segment (r = 0.50, p = 0.0009) measures. Test-retest agreement for IVD diagnosis by either criterion was equally limited (2 segments: 83%, kappa = 0.27; 4 segments: 75%, kappa = 0.47; 12 segments: 68%, kappa = 0.35). Bland-Altman analysis demonstrated wide confidence intervals, exceeding the diagnostic cutoff values for the respective criteria. In conclusion, the accurate assessment of IVD by TDI may be limited by poor test-retest reliability.

Trastuzumab-Induced Cardiomyopathy: Incidence and Associated Risk Factors in an Inner-City Population

BACKGROUND Although it is known that trastuzumab causes cardiotoxicity, its extent and reversibility are still in question. Earlier studies have not evaluated consecutive patients with reproducible nuclear ventriculography. OBJECTIVE We sought to evaluate the baseline characteristics which predispose patients to increased risk of trastuzumab cardiotoxicity and to determine the natural history of the cardiotoxicity. METHODS AND RESULTS Left ventricular ejection fraction (LVEF) was measured in 76 women aged 36-73 years who had been treated with trastuzumab at the University of Maryland Greenebaum Cancer Center. LVEF was determined at baseline and then 3, 6, 9, and 12 months after treatment initiation. Cardiotoxicity was defined as ≥ 16% decrease in LVEF or ≥ 10% decrease in LVEF to <50%. There were no differences in comorbidities, earlier treatment, or demographics between patients with and without trastuzumab-induced cardiomyopathy except that African Americans were more likely to develop decreased LVEF (P < .05). Twenty-one patients (28%) met criteria for cardiotoxicity. Four of those patients were continued on trastuzumab and 17 patients had therapy withheld at some point. Only 1 patient developed symptomatic heart failure requiring inpatient hospitalization. LVEF improved in most patients regardless of whether or not trastuzumab was continued. CONCLUSIONS Decreased LVEF while undergoing trastuzumab therapy occurs frequently and is usually reversible. African Americans had a higher risk of developing decreased LVEF. These findings raise clinically important questions as to whether it is necessary to discontinue trastuzumab for asymptomatic decrease in LVEF and whether African Americans are more predisposed to a decrease in LVEF while receiving trastuzumab. Further studies carefully assessing LVEF should address these hypotheses.

Torsades de Pointes with Administration of High‐Dose Intravenous d‐Sotalol to a Patient with Congestive Heart Failure

A patient with heart failure was administered d‐sotalol 3.0 mg/kg infused over 2 minutes. The patient had normal electrolytes and baseline QT. Six minutes after drug administration the QT prolonged to 600 msec, and the patient developed torsades de pointes and required electrical cardioversion. This emphasizes the need to consider both rate of administration and the dosage when evaluating the safety and efficacy of a new class III antiarrhythmic drug.