doi: 10.1161/01.CIR.0000160855.77331.26
(Circulation. 2005;111:e182-e183.)
© 2005 American Heart Association, Inc.
Correspondence |
Letter Regarding Article by Wang et al, "Nesiritide Does Not Improve Renal Function in Patients With Chronic Heart Failure and Worsening Serum Creatinine"
Keck School of Medicine, University of Southern California, Los Angeles, Calif
I read with interest the study by Wang et al1 examining the effect of nesiritide on renal function in patients with decompensated heart failure and elevated serum creatinine concentrations. The failure of nesiritide to improve renal function in this study is both surprising and disappointing because previous studies of nesiritide have demonstrated significant natriuretic and diuretic effects, as well as diminution of the untoward effects of loop diuretics.2–4 More research is needed to fully understand the renal effects of nesiritide in patients with heart failure. In the meantime, the potential limitations of the study by Wang and associates should be taken into account to help design future studies. These limitations include the possibility that the study was underpowered to detect differences because the power calculation was based on an estimated mean initial glomerular filtration rate (GFR) of 50 mL · min–1 · 1.73 m–2 and a standard deviation (SD) of 7. The mean GFR on enrollment was 44 mL · min–1 · 1.73 m–2, with an SD of 18; this SD increased to 31 during the initial 3 h of the study, indicating larger variability among patients than was previously assumed. The study employed a crossover design but did not have a washout period, which may have introduced a carryover effect into the second treatment period. This action could have enhanced the observed response to placebo and reduced the potential to detect a true treatment difference. Separate analyses by treatment sequence can be used to detect a carryover effect, but small patient numbers in this study made this impractical. In addition, nesiritide is most effective in symptomatic patients requiring intravenous vasoactive medications, but the study of Wang et al specifically excluded these patients. Furthermore, no information is provided on hospital length of stay or treatment received before enrollment. The enrollment of patients after initial stabilization may have resulted in an assessment of patients on the downslope of their response curve to diuretics or nesiritide, a possibility that is supported by the modest mean urine output (
2700 mL/24 h) and the 0.7-kg mean weight loss during the initial 24 h. In addition, it is curious how the construct of the patient’s weight on the second day, which was required to be within 1 kg of the first day, influenced the comparison in urine output between the 2 arms. Finally, the authors do not describe the effect of treatment on blood pressure. A nesiritide-induced reduction in blood pressure could have decreased renal perfusion pressure, having an impact on both renal blood flow and GFR.
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Acknowledgments |
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Dr Elkayam has received research support from Abbott, Actelion, Amgen, Aventis, FlowMedian, GlaxoSmithKline Beecham, Medtronic, Novacardia, Otsuka, and Scios, and consulting fees from Amgen, Aventis, Nitromed, and Scios.
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References |
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 Top References References |
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1. Wang DJ, Dowling TC, Meadows D, Ayala T, Marshall J, Minshall S, Greenberg N, Thattassery E, Fisher ML, Rao K, Gottlieb SS. Nesiritide does not improve renal function in patients with chronic heart failure and worsening serum creatinine. Circulation. 2004; 110: 1620–1625.
2. Colucci WS, Elkayam U, Horton DP, Abraham WT, Bourge RC, Johnson AD, Wagoner LE, Givertz MM, Liang CS, Neibaur M, Haught WH, LeJemtel TH. Intravenous nesiritide, a natriuretic peptide, in the treatment of decompensated congestive heart failure. N Engl J Med. 2000; 343: 246–253.
3. Marcus LS, Hart D, Packer M, Yushak M, Medina N, Danziger RS, Heitjan DF, Katz SD. Hemodynamic and renal excretory effects of human brain natriuretic peptide infusion in patients with congestive heart failure: a double-blind, placebo-controlled, randomized crossover trial. Circulation. 1996; 94: 3184–3189.
4. Cataliotti A, Boerrigter G, Costello-Boerrigter LC, Schirger JA, Tsuruda T, Heublein DM, Chen HH, Malatino LS, Burnett JC Jr. Brain natriuretic peptide enhances renal actions of furosemide and suppresses furosemide-induced aldosterone activation in experimental heart failure. Circulation. 2004; 109: 1680–1685.
Response
Department of Medicine, University of Maryland School of Medicine, Veterans Administration Medical Center, Baltimore, Md, sgottlie{at}medicine.umaryland.edu
We agree with Dr Elkayam’s concern that decreases in blood pressure may have adverse effects on renal blood flow and glomerular filtration rate (GFR). Nesiritide is a vasodilator. The improvement in filling pressures, however, could be at the expense of lower blood pressure and reduced renal plasma flow and/or GFR. This may be the reason for the report of a 15% incidence of a doubling of serum creatinine1 and the suggestion of a meta-analysis that more renal dysfunction occurs in patients receiving nesiritide.2 As demonstrated in our original report,3 the failure of nesiritide to improve GFR is consistent with previous studies.4–6
With regard to diuresis and natriuresis, many studies do not show an increase in urine output.5–8 The studies that Dr Elkayam cites report increased urine output at higher doses than are presently used and in a different patient population. In contrast to the studies cited, we assessed patients with worsening renal function, presumably the patients that physicians want to treat with a drug that could improve renal function.
The variability of the change in GFR is a better indicator of the power of the study than is the variability of the baseline parameters. In our study, the standard deviation of the change in GFR between days was 9. It thus had the power to detect a 21% improvement in GFR (ß=0.8).
Because the number of subjects does not allow for formal analysis of effect-order, the primary end point was the difference in GFR at the 21- to 24-h period; the effects of the previous day’s drug should be eliminated by this time. At the 21- to 24-h period, the GFR did not improve with nesiritide; indeed, it was lower by 6.5 mL · min–1 · 1.73 m–2 (P=NS).
We evaluated patients 23 to 48 h after hospital admission for decompensated but not hemodynamically unstable heart failure. No patients received nesiritide or inotropes before the study. The furosemide dose was chosen to maintain weight so that the effects of nesiritide could be studied. Notably, nesiritide did not lead to additional diuresis or improved renal function in this ill fluid-overloaded population.
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1. Tang WHW, Militello M, Barcelona R, Young JB. Presented at: American College of Cardiology Annual Scientific Session 2004; March 7-10, 2004; New Orleans, La.
2. Sackner-Bernstein JD, Skopicki HA, Aaronson KD. Risk of worsening renal function with nesiritide in patients with acutely decompensated heart failure. Circulation. 2005; 111: 1487–1491.
3. Wang DJ, Dowling TC, Meadows D, Ayala T, Marshall J, Minshall S, Greenberg N, Thattassery E, Fisher ML, Rao K, Gottlieb SS. Nesiritide does not improve renal function in patients with chronic heart failure and worsening serum creatinine. Circulation. 2004; 110: 1620–1625.
4. Marcus L, Hart D, Packer M, Yushak M, Medina N, Danziger RS, Heitjan DF, Katz SD. Hemodynamic and renal excretory effects of human brain natriuretic peptide infusion in patients with congestive heart failure. A double-blind, placebo-controlled, randomized crossover trial. Circulation. 1996; 94: 3184–3189.
5. Jensen KT, Eiskjaer H, Carstens J, Pedersen EB. Renal effects of brain natriuretic peptide in patients with congestive heart failure. Clin Sci (Lond). 1999; 96: 5–15.[Medline] [Order article via Infotrieve]
6. Lainchbury JG, Richards AM, Nicholls MG, Hunt PJ, Ikram H, Espiner EA, Yandle TG, Begg E. The effects of pathophysiological increments in brain natriuretic peptide in left ventricular systolic dysfunction. Hypertension. 1997; 30: 398–404.
7. Publication Committee for the VMAC Investigators (Vasodilatation in the Management of Acute CHF). Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial. JAMA. 2002; 287: 1531–1540.
8. Mills RM, LeJemtel TH, Horton DP, Liang C, Lang R, Silver MA, Lui C, Chatterjee K. Sustained hemodynamic effects of an infusion of nesiritide (human b-type natriuretic peptide) in heart failure: a randomized, double-blind, placebo-controlled clinical trial. Natrecor Study Group. J Am Coll Cardiol. 1999; 34: 155–162.
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Circulation 2005 111: 1729.
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