Effect of nesiritide on renal function in patients admitted for decompensated heart failure
From the Departments of 1Cardiovascular Disease and 2Internal Medicine, Western Pennsylvania Hospital/Temple University, Pittsburgh, USA
Address correspondence to Dr S. Arora, Department of Cardiovascular Disease, Suite 3411 North Western Pennsylvania Hospital/Temple University Program, 4800 Friendship Avenue, Pittsburgh, PA 15224, USA. email: sandeeparora24{at}hotmail.com
Received 13 May 2007 Accepted for publication 11 July 2007.
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Summary |
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Background: Studies addressing the effect of nesiritide on renal function in patients hospitalized for decompensated heart failure (HF) are limited, with conflicting results.
Aim: To study the effect of nesiritide on renal function in patients admitted for acute decompensated HF.
Methods: We retrospectively reviewed charts of patients admitted with decompensated HF, comparing those who received nesiritide along with conventional therapy vs. those who received conventional therapy alone. Serum creatinine levels and body weight were measured on admission, and were compared with levels at day 3 to estimate deterioration in renal function. Worsening renal function (WRF) was defined as a rise in serum creatinine of 
0.3 mg/dl from baseline, with final creatinine level >1.5 mg/dl.
Results: We reviewed 206 charts (116 controls, 90 nesiritide group). WRF developed in 28/90 (31.1%) in the nesiritide group and 37/116 (31.9%) controls (p = 1.0). Mean change in creatinine in the nesiritide group was 0.15 ± 0.37 mg/dl, compared to 0.17 ± 0.25 mg/dl in controls (p = 0.75). Using an alternative cut-off increase in serum creatinine of 0.5 mg/dl, 16/90 (17.7%) patients in the nesiritide group developed WRF compared to 18/116 (15.5%) controls (p = 0.80). If WRF was defined as elevation in serum creatinine levels by 0.3 mg/dl anytime during hospitalization, the incidence of WRF in the nesiritide group remained similar to that of controls (42.2% vs. 41.3%, p = 0.90). On multivariate analysis, nesiritide therapy was not associated with WRF (OR 0.8, 95% CI 0.4–1.6, p = 0.48).
Discussion: We failed to detect any significant risk of WRF in patients treated with nesiritide compared to conventional therapy in patients with decompensated HF during index hospitalization. Larger randomized, placebo-controlled trials are required to further elucidate the effect of nesiritide on renal function in these patients.
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Introduction |
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Several studies have reported an association between impaired renal function and unfavourable outcomes in patients with heart failure.1–3 Renal insufficiency may not only be a marker of severity of underlying disease, but may also confer increase risk of heart failure progression. Moreover, worsening of renal function (WRF) is seen in around one-third of patients hospitalized for acute decompensated HF, and this may be associated with poorer outcomes, including longer hospital stay, higher in-hospital mortality, and increased likelihood of readmission.4–6 Even transient and minor elevations in serum creatinine levels of 0.1 mg/dl may predict poorer outcomes, independent of baseline renal function.7
Nesiritide is a recombinant human brain or B-type natriuretic peptide that is identical to the endogenous hormone produced by the ventricles in response to increased wall tension, hypertrophy or volume overload. The drug mediates its effect by binding to the A-type natriuretic peptide receptor (NPR-A) present on the surface of vascular smooth muscle and endothelial cells to produce vasodilation. Various studies have shown improved symptoms and haemodynamic functions in patients treated with nesiritide in addition to standard therapy.8–10 However, recent meta-analyses have reported WRF and higher short-term mortality associated with nesiritide,11,12 and use of nesiritide for acute decompensated heart failure has significantly decreased after these publications.13 However, in the meta-analysis, other potentially confounding variables could not be adjusted beyond treatment group assignment. There was also limited information available on the events or interventions occurring after the treatment period that may have adversely affected renal function.11 Studies specifically addressing the effect of nesiritide on renal function in patients with HF are limited, and have shown conflicting results.11,14–18 We therefore conducted a retrospective study to evaluate the effect of nesiritide on renal function, as measured by serum creatinine levels, in patients admitted for decompensated HF.
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Methods |
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Study population
We retrospectively reviewed the charts of patients hospitalized in our Institution for acute decompensated HF from January 2004 to December 2004. Patients with HF were identified using the 9th International Classification of Disease Clinical Modification (ICD-9-CM) principal discharge diagnoses codes 428.0, 428.1, 402.11, 402.91, 404.01, 404.03, 404.11, 404.13, 404.91, and 404.93. Patients who received nesiritide in addition to standard therapy (including diuretics) were compared to those who did not receive nesiritide. Patients were excluded from the analysis if they: (i) were on haemodialysis; (ii) had cardiogenic shock anytime during hospitalization, or required vasoactive or inotropic medications, including dopamine, dobutamine, milrinone and norephinephrine; (iii) had severe infection or sepsis, defined as hypotension with systolic BP <90 mmHg and positive blood cultures; (iv) received nephrotoxic medications such as aminoglycosides or intravenous contrast agents; (v) received chemotherapeutic agents; or (vi) received nesiritide at least 24 h after initiating standard heart failure therapy. The latter category was excluded because standard heart failure therapy (including loop diuretics) may affect renal function prior to initiating nesiritide therapy.
Nesiritide was administered as an intravenous bolus of 2 µg/kg/min followed by continuous infusion in doses varying from of 0.01–0.03 µg/kg/min for a period of 1–5 days. Patients who received nesiritide were identified by retrospectively querying the hospital's pharmacy database. The study was approved by the Institutional Review Board. The investigation conforms with the principles outlined in the Declaration of Helsinki.
Definitions
Patients with CRI were defined as those with baseline serum creatinine 1.5 mg/dl, as determined by patient's electronic medical records and prior creatinine levels. Serum creatinine levels on admission (either before or within 4 h of administration of diuretics/drug) were compared with levels at day 3 to estimate the deterioration in renal function. Day 3 was chosen because previous studies show that the majority of patients develop WRF within 3 days of admission.6 WRF was defined as a rise in serum creatinine of 0.3 mg/dl from baseline, with final creatinine levels >1.5 mg/dl. This was based on studies showing that such mild elevation in serum creatinine level is associated with worse outcomes in these patients.7 We chose a final creatinine level >1.5 mg/dl to exclude those patients who developed an increase in serum creatinine of 0.3 mg/dl from baseline, but with final levels still being within normal range. It seems unreasonable to categorize these patients as 'WRF' in the presence of normal renal function. We also analysed the incidence of WRF using a less strict definition of increase in serum creatinine levels (0.5 mg/dl), as done in some previous studies. Furthermore, data were collected for peak creatinine levels to estimate the incidence of WRF occurring anytime during hospitalization. To study the dose-dependent effect of diuretics in the development of WRF, diuretic dose was categorized as low (equivalent intravenous furosemide dose <80 mg/day), moderate (80–160 mg/day) and high dose (use of 2 diuretics or i.v. furosemide 160 mg/day).
Data collection
The following data were collected for both groups: age, sex, race, functional class (NYHA) of HF on admission, history of HF, co-morbidities such as diabetes, hypertension, chronic obstructive pulmonary disease (COPD), peripheral vascular disease (PVD), BNP levels on admission, medications used (including total daily dose of diuretics), left ventricular ejection fraction (LVEF) as determined by echocardiography, haemoglobin level on admission, sodium levels, systolic blood pressure on admission (as measured by mean of at least three readings), serum creatinine levels on admission and at day 3, peak creatinine levels during hospitalization, body weight on admission and at day 3 and length of hospitalization. Co-morbidities were ascertained and confirmed by documented history and examination, evaluation of patient's electronic records and prior objective studies.
Primary outcome of the study was the percentage of patients who developed WRF. Mean increase in creatinine levels and mean change in weight, measured on the third day, were reported as secondary outcomes.
Statistical analysis
Patients were divided into groups and compared according to exposure/non-exposure to nesiritide. Continuous variables were described in terms of means±SD; discrete variables were reported as frequencies and percentage. For univariate analyses, two-sample t-tests were used to compare continuous variables, while the 
2 test or Fisher's exact test was used to compare categorical variables between the two groups. A p value <0.05 was considered statistically significant. For power calculations, we assumed that around 50% of the patients admitted for decompensated HF who received nesiritide would develop WRF, compared to about 30% of controls. Based upon two-sided test with an alpha value of 0.05, it was estimated that at least 95 patients in each group would be required to provide a statistical power of 0.8.
To evaluate the effect of nesiritide administration on WRF while adjusting for patients’ baseline characteristics, we developed a logistic regression model. The model considered demographic and clinical variables, co-morbidities and medication usage as potential predictor variables. Model selection used a backward step search strategy. For final multivariate analysis, the three levels of diuretic doses were collapsed into two levels: low dose, including patients who got either no diuretics or a low dose; and higher dose, which grouped together patients receiving moderate and high doses. Also, exploratory analyses lead to the collapse of categories of ethnicity into Black and non-Black. Data analyses used SAS/STAT software, version 9.1 (SAS Institute).
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Results |
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A total of 206 charts were reviewed, of whom 90 (41.6%) received nesiritide. The mean age of the patients was 72 ± 12 years, with 51.5% being female and 43.2% being Black. Overall, 65/206 patients (30.1%) developed WRF. Baseline characteristics of the patients, co-morbidities and medication usage in the two groups are listed in Table 1.
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The mean duration of nesiritide administration was 1.97 ± 0.58 days. The two groups were similar in their baseline characteristics, except for a higher incidence of CRI (54.4% vs. 35.3%, p = 0.009) and lower haemoglobin levels (11.5 ± 1.6 vs. 12.1 ± 1.7 g/dl, p = 0.008) in the nesiritide group. Patients in the nesiritide group had higher baseline creatinine levels compared to controls (1.8 ± 0.85 vs. 1.42 ± 0.63 mg/dl, p = 0.0003). There was also a trend towards lower LVEF, higher BNP levels and longer hospital stay in patients who received nesiritide, but it did not reach statistical significance.
Primary and secondary outcomes
The primary and secondary outcomes of the study are listed in Table 2. The incidence of WRF was similar in both groups (31.1% vs. 31.9%, p = NS). Overall mean change in creatinine levels were also similar in both the groups (0.15 ± 0.37 mg/dl vs. 0.17 ± 0.25 mg/dl, p = 0.75). There was a non-significant trend towards better diuresis in the nesiritide group, as determined by weight loss over 3 days (–1.5 kg vs. –1.17 kg, p = 0.23).
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Since the definitions of WRF and selection of day 3 to estimate the deterioration in renal function were to some extent arbitrary, we reanalysed the data using a less strict definition of WRF as an increase in serum creatinine levels
0.5 mg/dl on day 3. Using this cut-off, 16/90 patients in the nesiritide group developed WRF compared to 18/116 controls (17.7% vs. 15.5%, p = 0.80). If WRF was defined as elevation in serum creatinine levels by 0.3 mg/dl at any time during hospitalization, the incidence of WRF in the nesiritide group was again similar to that in controls (42.2% vs. 41.3%, p = 0.90).
To adjust for potential confounding variables such as CRI, multivariate regression analysis was used to determine the independent predictors of WRF. On univariate analysis, Black ethnicity, CRI, PVD, lower haemoglobin, ACE inhibitors, angiotensin receptor blockers and higher doses (moderate/high dose) of diuretics were associated with WRF (Table 3). However on multivariate analysis, only CRI (OR 3.3, 95%CI 1.6–6.8, p < 0.001), PVD (OR 3.3, 95%CI 1.2–8.7, p = 0.02), and higher dose of diuretics (OR 6.2, 95%CI 2.9–12.8, p < 0.001) emerged as independent predictors of WRF (Table 4). Model diagnostics showed no unusual influential or outlying observations that would lead to questions of model validity. Also the Hosmer-Lemeshow overall goodness of fit test showed adequate fit (2 = 0.87, 2 df, p = 0.65).
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Nesiritide administration was equally prevalent in patients who developed WRF (43.1%) than in those who did not (44%). On multivariate analysis, use of nesiritide yielded a non-significant reduction in WRF (OR 0.8, 95%CI 0.4–1.6, p = 0.48). The odds ratios of WRF for nesiritide for the entire study sample and in various subgroups are listed in Figure 1. In the subgroup of patients with CRI, nesiritide therapy was again not associated with WRF (OR 0.5, 95%CI 0.2–1.4, p = 0.20). Also, in patients with DM, nesiritide was associated with a non-significant reduction in WRF (OR 0.4, 95%CI 0.1–1.1, p = 0.07).
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Most of the patients in our study received a low dose of nesiritide, with only 12.2% of the patients receiving >0.01 µg/kg/min. There was no statistical difference in the incidence of WRF in patients who received low dose vs. a higher doses of nesiritide, as evaluated by univariate analysis. Nesiritide was well tolerated and only 2/90 patients developed transient hypotension, compared to 1/116 controls (p > 0.05). No patient in the study population required dialysis for renal failure. There was one death during hospitalization in the nesiritide group, secondary to end-stage cardiomyopathy and respiratory failure.
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Discussion |
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Worsening of renal function is associated with poor outcomes in patients admitted for decompensated HF. The pathophysiology of renal dysfunction in the setting of HF is complex, and not completely understood. Some of the recent studies have reported a decline in renal function11 and increased mortality within 30 days after hospitalization12 with the use of nesiritide, especially when used in higher doses.
The results of our study are in contrast to the above meta-analysis, suggesting that nesiritide therapy is not an independent predictor of WRF during index hospitalization. This could be the result of our study design, relatively small sample size, patient population studied and the definitions of WRF used in our study. Unlike our study, where data were collected retrospectively, the meta-analyses evaluating the risk of WRF was based on randomized controlled trials in a larger patient population where renal data were collected prospectively. The definitions of CRI and WRF used in our study, although rough estimates and also used by similar non-randomized studies, are somewhat arbitrary. The two groups of patients in our study were different in their baseline characteristics and other co-morbidities, and patients in the nesiritide group appeared to be sicker and had worse renal function at baseline as determined by creatinine levels. Nevertheless, in our study we did not see any specific trend towards WRF with nesiritide therapy. Larger prospective randomized controlled trials are required to assess the effect of nesiritide on renal function in these patients.
Nesiritide was approved by the FDA in 2001 for the ‘intravenous treatment of patients with acutely decompensated congestive heart failure who have dyspnea at rest or with minimal activity’. Since then, many physicians have begun to use nesiritide as a routine therapy for these patients, especially in those with underlying chronic renal insufficiency, in the hope that nesiritide therapy might preserve renal functions in these patients. This is probably the reason that nesiritide was used as an initial therapy in patients who appeared to be sicker by the treating physicians in our study. Also, over 54% of patients treated with nesiritide therapy had baseline renal insufficiency, many more than those treated with standard therapy. The package insert of nesiritide states ‘Nesiritide may affect renal functions in susceptible individuals. In patients with severe heart failure whose renal functions may depend on the activity of the renin-angiotensin-aldosterone system, treatment with nesiritide may be associated with azotemia’. Although the results of our study may suggest a lack of significant risk, we do not recommend routine use of nesiritide therapy, particularly in patients with underlying CRI. Also, the results of the study should not be interpreted to demonstrate a lack of clinical concern, only difficulty in detecting any risk. While this may imply that any potential risk associated with nesiritide therapy is relatively small, nesiritide should still be used very judiciously in patients with HF until the safety of this therapeutic intervention is better established.
Our study is in accord with some other recent studies in patients with HF.15,16,18 In a study of patients with decompensated HF, nesiritide use was not a significant independent risk factor for WRF in patients with HF, as determined by serum creatinine levels.15 Two randomized controlled trials assessing the safety and efficacy of nesiritide infusion for patients with advanced HF in the out-patient setting found no significant WRF associated with nesiritide therapy.16,18 Also, a double-blind, placebo-controlled crossover study done to evaluate renal functions in patients with acute decompensated HF and mild chronic renal failure with recent worsening of serum creatinine showed that there was no difference in GFR, effective renal plasma flow, urine output or sodium excretion between the two groups,19 although this study involved only 15 patients and there was no wash-out period between the cross-over. Finally, in a recent meta-analysis of seven randomized controlled trials, nesiritide therapy was not associated with increased risk of short-term or long-term (up to 6 months) mortality in patients with HF.20 These findings suggest that relationship between nesiritide and its effect on renal functions and/or mortality is complex, and requires further investigation.
We used day 3 for the estimation of WRF, based upon previous observations that most of the patients with HF have highest elevation in serum creatinine levels within 3 days of admission. While this may hold good for patients treated with diuretics, it might not be true for nesiritide therapy, which may adversely affect renal function later on in the course of hospitalization. However, the results were unchanged when WRF was defined based upon deterioration in renal function during anytime during hospitalization.
In this study, CRI, PVD and higher doses (including both moderate and high doses) of diuretics were independent risk factors for WRF. CRI is an established risk factor for WRF, well substantiated by other studies.6 These patients have diminished baseline renal blood flow and poor renal reserves. Moreover, they have profound activation of RAAS, and ACE inhibitors may blunt the efferent arteriolar constriction caused by RAAS, thereby decreasing renal perfusion pressure. It is thus not surprising that these patients are more susceptible to develop WRF, especially when treated with ACE inhibitors. Also, patients with HF have impaired renal perfusion, and aggressive diuresis may cause intravascular volume depletion, which may further compromise GFR and therefore result in increased serum creatinine levels. While high-dose diuretic therapy has been shown to be an independent predictor of WRF in patients with HF in previous studies,5 our study suggested that even moderate doses of diuretic therapy might have an adverse effect on renal functions.
Peripheral vascular disease emerged as a risk factor for WRF in our study. Diagnosis of peripheral vascular disease was made based upon documented history, physical examination and prior objective studies. This has not been reported as a predictor of WRF in previous studies. While this may be a chance finding secondary to small sample volume, it is possible that PVD may have unrecognized deleterious effects on renal function in this population. One possible explanation is that these patients may have a higher incidence of concomitant renal artery stenosis, which could have accounted for WRF when treated with diuretics and ACE inhibitors. Further studies with a larger number of patients would be needed to confirm these findings.
Limitations
There are several limitations to our study. It is a retrospective study of relatively small number of patients, which may limit our ability to adjust for other unmeasured confounding variables. These include, but are not limited to, direct estimation of cardiac output or volume status (by Swan Ganz catheter), and presence of renal artery stenosis. In both groups, patients were treated with diuretic therapy based upon volume status, as determined by clinical evaluation and symptoms. While this is the usual methodology adopted in routine clinical practice, impact of over-diuresis on WRF in either group can not be ruled out. This may be especially true in patients in the control group, who tend to have lower BNP values and higher LVEF compared to patients treated with nesiritide. It is possible that over-diuresis in these patients may result in more WRF, thereby underestimating the deleterious effects of nesiritide on renal function. However, the overall incidence of WRF in the whole cohort was comparable to previous studies, suggesting that over-diuresis was probably not a significant factor for WRF.
We measured serum creatinine levels, and did not measure creatinine clearance or GFR to determine WRF. This was done because estimation of GFR by weight-based equations can be misleading when the body weight of these patients is altered in response to diuretics and other pharmacotherapy. Nevertheless, age is a primary determinant of renal functions, and it is possible that estimation of renal functions and its deterioration by more systematic methods (estimation of GFR by Cockcroft-Gault or Modification of Diet in Renal Disease equation) could have led to different results. We did not collect long-term data on renal function or mortality after hospital discharge. This may be important, since the meta-analyses addressing the effect of nesiritide on mortality showed increased risk of death with nesiritide therapy for up to 30 days after hospitalization. It is possible that an adverse effect of nesiritide therapy on renal function manifests long after hospital discharge. Finally, we did not do a multivariate analysis of predictors of WRF in the two groups separately. Since nesiritide may affect renal function by numerous mechanisms, we may potentially find different predictors of WRF in two groups.
Conclusions
WRF is common in patients admitted for acute decompensated HF. In these patients, our study failed to detect any significant risk of WRF from nesiritide therapy during index hospitalization. Larger randomized, placebo-controlled trials powered to evaluate WRF are required to substantiate these findings.
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Acknowledgements |
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We would like to thank Dr Anju Arora, MD and Dr Kamran Khan, MD, for their help in collecting study data.
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References |
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