Chronic Subcutaneous BNP Therapy in Asymptomatic Systolic Heart Failure

Abstract

Aim

We have previously reported that asymptomatic systolic heart failure (HF) is characterized by an impaired renal response to volume expansion due to lack of activation of urinary cGMP which is corrected by subcutaneous B-type natriuretic peptide (BNP). In the current study we sought to define the cardiorenal response to intravascular volume expansion after 12 weeks of subcutaneous BNP therapy.

Methods and Results

We utilized a double-blinded, placebo controlled study to compare 12 weeks of twice daily subcutaneous BNP 10 ug/kg (n=22) or placebo (n=12) in asymptomatic systolic HF. Subjects underwent two study visits: baseline and after 12 weeks of therapy. At each study visit, echocardiography, renal, and neurohumoral assessments were performed before and after intravascular volume expansion. The primary endpoint was change in urinary sodium excretion in response to volume expansion at 12 weeks and we observed a greater increase in urinary sodium excretion (166 [77, 290] vs 15 [−39, 72] mEq/min; p=0.02) with SQ BNP treatment versus placebo. Secondary endpoints included change in urine flow and GFR in response to volume expansion at 12 weeks. We observed a significant increase in urine flow (p<0.01) and trend for differential response in GFR (p=0.08) with SQ BNP treatment versus placebo.

Conclusion

Among patients with asymptomatic systolic HF, twice daily SQ BNP therapy improved the cardiorenal response to volume expansion at 12 week follow-up. Further studies are warranted to determine if these beneficial physiologic observations with chronic natriuretic peptide administration translate into a delay in the progression to symptomatic HF.

INTRODUCTION

Asymptomatic systolic HF is an increasingly common phenotype which commonly progresses to symptomatic HF and is associated with significant morbidity and mortality.^1–4 Currently, the ACC / AHA HF and the European Society of Cardiology HF guidelines recommend angiotensin converting enzyme (ACE) inhibitor and beta blocker therapy in asymptomatic systolic HF.^{2, 5, 6} As the burden of HF continues to progress^{7, 8}, there is an unmet therapeutic need for new pharmacologic agents aimed at delaying or preventing the progression of asymptomatic HF to symptomatic HF.

It is well established that the kidney plays a key role in the pathophysiology of HF.^9–11 Atrial and B-type natriuretic peptides (ANP and BNP) are regulated by both the heart and kidney and play a critical role in the regulation of volume status.^{12, 13} We and others have previously demonstrated that the natriuretic peptide system is implicated in an impaired renal response to volume expansion in asymptomatic systolic HF.^{14, 15} Specifically, there is a lack of renal cGMP activation resulting in impaired natriuresis and diuresis. This lack of activation of renal cGMP is in contrast to normal subjects where intravascular volume expansion activates the natriuretic peptide system, resulting in increased renal cGMP, ultimately contributing to natriuresis and diuresis. Importantly, the administration of a single dose of subcutaneous (SQ) BNP overcomes this renal cGMP impairment and increases natriuresis and diuresis following volume expansion in asymptomatic systolic HF. Volpe and colleagues have also demonstrated that pre-treatment with ACE inhibitor therapy improves the cardiorenal response to volume expansion in asymptomatic and mildly symptomatic HF patients.¹⁶

The observation that acute SQ BNP corrects the impaired renal cGMP and natriuretic response to intravascular volume expansion among subjects with asymptomatic systolic HF underscores the therapeutic potential of chronic administration of SQ BNP. Intervention in early, asymptomatic stages of HF may ultimately reduce the burden of HF in the community. However, chronic administration of a peptide may result in tolerance and lack of beneficial actions.^17–19 The current study was therefore designed to assess the cardiorenal response to intravascular volume expansion after 12 weeks of SQ BNP versus placebo among subjects with asymptomatic systolic HF. We hypothesized that after 12 weeks of therapy, SQ BNP would continue to enhance the cardiorenal response to volume expansion in asymptomatic systolic HF.

METHODS

Study Design

We utilized a double-blinded, placebo controlled design to compare the cardiorenal and endocrine response to acute volume expansion (0.9% normal saline, 0.25 ml/kg/min for 1 hour) before and after 12 weeks of either twice daily SQ placebo or BNP administration (Figure 1A). The primary endpoint was change in urinary sodium excretion in response to volume expansion at 12 weeks. Secondary endpoints included change in urine flow and GFR in response to volume expansion and the change in left ventricular mass index at 12 weeks. This study was approved by the Mayo Foundation Institutional Review Board and was performed at the Center for Clinical and Translational Science at Mayo Clinic, Rochester, Minnesota. ClinicalTrials.gov Identifier: NCT00405639. All participants provided written informed consent.

Figure 1.

Enrollment, randomization, and follow up of study subjects (A). The volume expansion protocol at study visit 1 and study visit 2 (B).

Study Population

Subjects with asymptomatic systolic HF (n=42) were recruited from November 2007 to April 2011. Asymptomatic systolic HF was defined as 1) an ejection fraction (EF) <45%; 2) no clinical signs or symptoms or previous diagnosis of congestive HF (subjects’ medical records were extensively reviewed for a prior diagnosis of HF or symptomatic volume overload); and 3) a minimal distance on 6-minute walk of ≥450 meters. Subjects who had a 6-minute walk distance < 450 m due to an orthopedic limitation but no dyspnea or fatigue as assessed by the investigators were included in the study. If on cardiovascular medications, all doses were stable for at least two weeks prior to the study. Some subjects were receiving a beta blocker, aldosterone antagonist, or loop diuretic; indications for these medications were coronary artery disease, prior myocardial infarction, or hypertension.

Exclusion criteria included a myocardial infarction within 3 months, unstable angina within 14 days, moderate or greater valvular stenosis, restrictive cardiomyopathy, hypertrophic cardiomyopathy, primary pulmonary hypertension, sustained ventricular arrhythmia within 14 days, 2^nd or 3^rd degree heart block without a permanent pacemaker, a systolic blood pressure < 85 mm Hg, and a cerebrovascular accident within 3 months. Subjects with a total bilirubin > 1.5 mg/dL, liver enzymes > 1.5 times the upper limit of normal, creatinine > 3.0, sodium < 125 or > 160 mEq/dL, digoxin >2.0 ng/ml, or a hemoglobin < 10 gm/dL were also excluded.

Echocardiographic Assessment

Echocardiographic images were obtained from standard acoustic windows according to the recommendations of the American Society of Echocardiography.²⁰ Linear dimensions were obtained from correctly aligned 2D images. Left ventricular (LV) ejection fraction was determined by the simplified method of Quinones. LV mass was determined from this method: LV mass =0.8 × (1.04[(Dd + PW + VS)3 − (Dd)3] + 0.6g (where Dd = diastolic dimension, PW = posterior wall thickness, and VS =septal thickness). LV mass as indexed to body surface area as recommended by the European Association of Cardiac Imaging.²¹ Stroke volume (SV) was determined from this method: SV = CSA × TVI (where CSA is the area of the aortic annulus which is derived from the annulus diameter measured in the parasternal long-axis view; TVI is time-velocity integral of the LV outflow tract). Assessment of LV diastolic function and LV filling pressures was performed by pulsed wave Doppler examination of mitral as well as Doppler tissue imaging of the mitral annulus was performed.^{3, 22–24} All echocardiographic data was obtained by certified echo sonographer and interpreted by HHC who was blinded to the assigned treatment.

Study Protocol

Study Visit 1

Following one week of a no added salt diet (120 mEq sodium per day) which was continued throughout the 12 week study protocol, subjects presented to the Center for Clinical and Translational Science at 07:00 for study visit 1 (Figure 1B). All subjects were given dietary instructions by a dietitian and adherence to the sodium controlled diet was verified with a 24-hour urine sodium at visit 1 and visit 2. Subjects were given their usual morning medications and were placed in the supine position for an equilibration period of 60 minutes. Subjects were asked to empty their bladder spontaneously every thirty minutes. If unable to void every thirty minutes, a urinary catheter was placed. Adequate bladder emptying was insured by bladder ultrasound. Every 30 minutes subjects drank an amount of water equivalent to the sum of the blood losses and urine flow. After the 60 minute equilibration period, baseline echocardiography was performed followed by a 30 minute baseline clearance. The clearance included urine collection over the 30 minutes and venous blood sampling at the end of the 30 minute clearance. Blood pressure was measured using an automatic blood pressure cuff, and heart rate was continuously monitored by electrocardiography. Immediately after the 30 minute baseline clearance was performed, an acute intravenous saline infusion was administered (normal saline 0.9% 0.25 ml/kg/min for 60 minutes). A clearance including urine collection and venous blood sampling was performed during saline infusion and an echocardiography was performed immediately after the saline infusion.

Randomization and 12 weeks of SQ BNP or Placebo Therapy

After the volume expansion protocol in study visit 1, study participants were randomized to receive either twice daily SQ placebo (0.9% normal saline) or SQ BNP (10µg/kg) (Scios Inc., Mountain View, CA) which was administered in abdominal SQ tissue. Randomization was 2:1 for SQ BNP and SQ placebo, respectively. The randomization schedule was provided by the Mayo Clinic Division of Biomedical Statistics & Informatics and implemented by the Mayo Clinic Pharmacy. The investigators were not aware as to which randomization arm subjects were assigned.

Subjects were instructed on the proper technique for diluting the BNP or placebo and the SQ injection in the anterior abdominal wall. The first and second doses were self-administered by study subjects under direct supervision of a study coordinator. Subjects were monitored for adverse effects and hypotension for 12 hours after each dose. If hypotension (defined as systolic blood pressure < 85 mm Hg) occurred after the first dose, the second dose was cut in half. Subjects were dismissed from the clinical research unit 12 hours after the second dose with instructions and supplies for 12 weeks of SQ administration twice daily.

Study visit 2

After 12 weeks of either SQ placebo or BNP, subjects returned for a second study visit (Figure 1B). This study visit was identical to study visit 1 with the exception that after the baseline echocardiogram and clearance subjects received either SQ BNP or placebo. Fifteen minutes after receiving SQ BNP or placebo the volume expansion was performed in an identical fashion as described for study visit 1. At the completion of study visit 2, participants resumed their usual cardiovascular care.

Neurohormonal and Electrolyte Analysis

ANP²⁵ and plasma/urine cGMP²⁶ were measured by radioimmunoassay as previously described. Plasma BNP was measured by fluorescence immunoassay (Biosite Diagnostics) as described previously.²⁷

Renal Assessment

During the first 15 minutes of the equilibration period, two standard intravenous catheters were placed (one in each arm). One catheter was used for infusion and the other (in the contralateral arm) for blood sampling. A priming dose of iothalamate (0.0053 mL/Kg) to measure glomerular filtration rate (GFR) was infused, followed by a constant rate intravenous sustaining dose (calculated according to estimated kidney function) of iothalamate to achieve steady-state plasma concentrations of 15 to 20 mg/L. After the equilibration period of 60 minutes, urine and blood samples were collected as described in study protocol, to determine GFR. Plasma and urine concentration of iothalmate as well as creatinine were measured by the Mayo Core Renal lab. GFR was calculated using the following equation (U = urine concentration; P = plasma concentration; V = urine flow (mL/ min):

$$GFR(ml/\mathit{\text{min}})=\frac{U_{\mathit{\text{iothalamate}}}\times V}{P_{\mathit{\text{iothalamate}}}}$$

Statistical Analysis

Sample size calculation: Based on our previous study on the acute cardiorenal and humoral effects of acute SQ BNP in asymptomatic systolic HF, we were able to construct the magnitude of difference that could be detected for sodium excretion and urine flow in response to volume expansion. It was assumed that the standard deviation in the untreated group would be only ½ of that in the treated group, since the treated group is composed of responders and non-responders, while the untreated group response data is largely due to biological and measurement variability between 2 occasions, with little or no actual signal. In light of this argument, allocation was unequal in order to optimize the precision of the group comparison. Specifically, there were 2 treated subjects per 1 placebo subject. Power calculations were done with these assumptions. With a total of 40 subjects and power of 85%, the detectable difference between raw (and percent) group mean changes for urinary sodium excretion and urinary flow were 131 uEq/min (100%) and 1.89 ml/min (54%) respectively. Power calculated with 34 patients was over 80% power (versus the anticipated 85% power with 40 patient) to detect our primary endpoint.

Echo parameters are presented as mean ± standard deviation, while other continuous variables with non-normal distribution are presented as median (interquartile range). Categorical variables are presented as percentage. Comparisons between the two treatment groups (SQ BNP and SQ placebo) were made by t-tests for normally distributed continuous variables, the rank-sum test for continuous variables with a skewed distribution, and the Chi-square test for independence for categorical variables. Comparisons within groups (between visits or between baseline and volume expansion within the same visit) were made using a paired t-test. To investigate the changes across time and between drug groups, a 2-way repeated measures ANOVA with repeated measures on the time factor was completed. For all analyses, statistical significance was accepted as P<0.05. Data analysis was performed using SAS software (SAS Institute, Cary, NC)..

RESULTS

Study Cohort Baseline Characteristics

Forty two subjects were consented for the study. Five subjects withdrew consent prior to the start of the study and 3 subjects did not complete the study (Figure 1A). Thirty four subjects completed the study and are included in the analysis. Baseline characteristics of the study population (n=34) and SQ BNP (n=22) and SQ placebo (n=12) subgroups at visit 1 are shown in Table 1. The median (25^th, 75^th percentile) age was 64 (53, 72) years and the cohort was predominately male (85%). The mean (SD) EF was 40 (9) % and as stipulated in the inclusion criteria study subjects were both currently and previously asymptomatic from a HF standpoint. The median (25^th, 75^th percentile) BNP was 102 (58, 234) pg / ml. Approximately 90% of subjects were on both a beta blocker and an angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker. 97% of subjects were on either an ACE inhibitor or beta blocker. There were no significant differences (p>0.05) between the baseline characteristics of the SQ BNP and SQ placebo subgroups.

Table 1.

Baseline characteristics at Visit 1

Variable	Overall (N=34)	BNP (N=22)	Placebo (N=12)	P- value
Age, yrs	64 (53,72)	67 (53,75)	59 (51,70)	.40
Female, n (%)	5 (15%)	3 (14%)	2 (17%)	.81
Body mass index, kg/m2	30 (27,33)	30 (26,32)	32 (28,33)	.45
Ejection fraction, %	40 (9)	39 (9)	42 (8)	.23
E/e'	14 (6)	14 (5)	15 (6)	.51
RV systolic pressure, mm Hg	30 (7)	31 (8)	29 (5)	.82
Systolic blood pressure, mm Hg	122 (110,132)	120 (108,128)	124 (118,135)	12
Diastolic blood pressure, mm Hg	72 (66,80)	72 (64,78)	78 (70,80)	.43
Heart Rate, beats per min	64 (54,72)	64 (52,72)	62 (59,70)	.93
Hypertension, n (%)	17 (50%)	11 (50%)	6 (50%)	1.0
Diabetes Mellitus, n (%)	11 (32%)	6 (27%)	5 (42%)	.39
Coronary Artery Disease, n (%)	27 (79%)	17 (77%)	10 (83%)	.68
Atrial Fibrillation, n (%)	4 (12%)	4 (18%)	0 (0%)	.12
Creatinine, mg/dL	1.0 (0.9,1.2)	1.0 (0.9,1.1)	1.1 (0.9,1.3)	.32
Blood Urea Nitrogen, mg/dL	20 (15,23)	21 (17,22)	18 (13,30)	.88
B-type natriuretic peptide, pg/ml	102 (58,234)	128 (58,253)	87 (63,169)	.64
6-Minute Walk Distance (m)	465 (442,488)	458 (442,487)	488 (442,496)	.28
ACEI, ARB or Beta Blocker, n (%)	33 (97%)	21 (95%)	12 (100%)	.45
.  ACEI or ARB, n (%)	30 (88%)	20 (91%)	10 (83%)	.51
.  Beta Blocker, n (%)	31 (91%)	20 (91%)	11 (92%)	.94
Aldosterone Antagonist, n (%)	5 (15%)	4 (18%)	1 (8%)	.44
Nitrates, n (%)	1 (3%)	1 (5%)	0 (0%)	.45
Digoxin, n (%)	4 (12%)	3 (14%)	1 (8%)	.65
Thiazide Diuretic, n (%)	2 (6%)	1 (5%)	1 (8%)	.65
Loop Diuretic, n (%)	10 (29%)	8 (36%)	2 (17%)	.23

Data presented as mean±SD for normally distributed data, median (interquartile range) for non-normally distributed data, and n (%) for categorical variables.

^†Some subjects had 6 minute walk distance less than 450 meters due to orthopedic limitations.

Cardiorenal Response to Volume Expansion at Visit 1

Cardiorenal assessment was performed at baseline and after intravascular volume expansion (normal saline 0.9% at 0.25 ml/kg/min for 1 hour) prior to receiving the assigned treatment (SQ BNP or placebo). Cardiorenal assessment results before and after the volume expansion at visit 1 are reported in Supplemental Table 1. While the results are displayed according to randomization to either the SQ BNP or placebo groups, the volume expansion at visit 1 was performed prior to receiving the assigned treatment (SQ BNP or placebo). The results confirm our published observation¹⁴ that there is a lack of activation of renal cGMP and an impaired diuretic and natriuretic response to volume expansion in subjects with asymptomatic systolic HF.

Cardiorenal Assessment after 12 weeks of SQ BNP or Placebo

Following 12 weeks of either SQ BNP (n=22) or placebo (n=12) therapy, cardiorenal function was reassessed before the last dose of SQ injection was administered (Figure 1B) and the results are reported in Table 2. There was a trend (p=0.045) for a greater reduction of LV mass index with SQ BNP (− 5.8 ± 15.7 g/m²) from visit 1 to visit 2 as compared to placebo (+ 2.0± 5.4 g/m²). Systemic blood pressure and heart rate, LV EF, E/e’, right ventricular systolic pressure, and SV index were not significantly altered by chronic SQ BNP and renal function was preserved (as assessed by iothalmate GFR, renal plasma flow, and creatinine). ANP, BNP, and weight were not significantly changed in either treatment group.

Table 2.

Cardiorenal and humoral assessment at visit 1 and visit 2^* t

	SQ BNP (n=22)		Placebo (n=12)
	Visit 1	Visit 2	Visit 1	Visit 2	p-value†
Left ventricular mass index, g/m2	126±29	120±25	133±36	137±37	0.045
LV Ejection fraction, %	39±9	41±9	42±8	45±7	0.43
LV End systolic diameter, mm	48±7	46±8	49±6	47±6	1.00
LV End diastolic diameter, mm	61±5	59±6	62±6	62±8	0.50
Stroke volume index, ml/m2	46±9	49±8	47±9	53±9	0.23
Right ventricular systolic pressure, mm Hg	31±8	29±10	29±5	30±5	0.57
E/e’	14±5	14±5	15±6	14±5	0.72
Creatinine, mg/dL	1.0 (0.9, 1.1)	1.0 (0.9, 1.2)	1.1 (0.8, 1.4)	1.1 (0.9, 1.4)	0.56
Glomerular filtration rate, m1/min/1.732	79 (66, 98)	80 (64, 96)	87 (50, 99)	90 (69, 103)	0.67
Renal plasma flow, ml/min	391 (260, 450)	381 (303, 473)	336 (251, 482)	393 (262, 488)	1.00
24-hour urine sodium excretion, mmol/24 hrs	134 (102, 159)	160 (89, 225)	156 (118, 199)	147 (127, 194)	0.48
Plasma atrial natriuretic peptide, pg/ml	74 (48, 137)	71 (47, 156)	97 (75, 174)	78 (64, 140)	0.47
Plasma B-type natriuretic peptide, pg/ml	128 (58, 253)	139 (77, 202)	87 (63, 169)	100 (58, 155)	0.34
Systolic blood pressure, mm Hg	119 (110, 132)	129 (111, 133)	107 (105, 125)	116 (114, 127)	0.86
Diastolic blood pressure, mm Hg	65 (55, 73)	66 (60, 74)	63 (60, 70)	59 (58, 67)	0.27
Heart rate, beats per minute	60 (53, 67)	59 (55, 70)	58 (54, 66)	57 (47, 70)	0.19
Weight, kilograms	93 (87, 100)	93 (87, 101)	95 (89, 101)	95 (89, 99)	0.16

Data presented as mean±SD for normally distributed data and median (interquartile range) for non-normally distributed data.

^*Data was collected at visit 1 and 2 prior to volume expansion.

^†p-value comparing change from visit 1 to visit 2 between the SQ BNP and placebo groups

Cardiorenal Response to Volume Expansion after 12 weeks of SQ BNP or Placebo

Intravenous volume expansion (normal saline 0.9% 0.25 ml/kg/min for 1 hour) was repeated after 12 weeks of SQ BNP or placebo treatment. Results are reported in Figures 2/3 and Table 3. At visit 2, in contrast to visit 1, among subjects in the SQ BNP cohort, urinary sodium excretion, urine flow and urinary cGMP excretion significantly increased following volume expansion (Figure 2) whereas there was no significant change in the placebo cohort. The change from baseline to volume expansion in sodium excretion (166 [77, 290] vs 15 [−39, 72] mEq/min; p=0.02), urine flow (3.6 [−0.4, 5.2] vs −0.3 [−2.0, 1.7] ml/min; p=0.01), and urinary cGMP (1880 [1093, 2738] vs −206 [−471, −26] pmol/min; p<0.01) were significantly greater with SQ BNP compared to placebo. There was a trend for a differential GFR response to volume expansion with SQ BNP versus placebo (p=0.08) where GFR was maintained in the SQ BNP group and reduced in the placebo group. Importantly, there was no evidence of BNP tolerance as demonstrated by significant increases in both plasma BNP and cGMP following SQ BNP administration in the BNP cohort (Figure 3). There was a significant decrease in systolic blood pressure in the SQ BNP group as compared to the placebo group in response to volume expansion. (p<0.01 SQ BNP versus placebo)

Figure 2.

Urinary sodium excretion (A), urine flow (B), and urinary cGMP excretion (C) at baseline (BL) and following volume expansion (VE) at visit 2 in the SQ BNP (shaded; n=22) and placebo (open; n=12) groups. Data presented as Tukey box plots, which show the median, interquartile range (the range from the 25th to the 75th percentile for values in the cohort), and “whiskers” for each variable (whiskers are 1.5 times the interquartile range and spread out from the first and third quartiles; by definition, they cannot extend beyond the smallest or largest observed value). P-value comparing change from BL to VE between the placebo and SQ BNP groups was 0.02 for urinary sodium excretion, 0.01 for urine flow, and <0.01 for urinary cGMP excretion (2-way ANOVA).

Figure 3.

Plasma BNP (A) and plasma cGMP (B) at baseline (BL) and following volume expansion (VE) at visit 2 in the SQ BNP (shaded; n=22) and placebo (open, n=12) groups. Data presented as Tukey box plots, which show the median, interquartile range (the range from the 25th to the 75th percentile for values in the cohort), and “whiskers” for each variable (whiskers are 1.5 times the interquartile range and spread out from the first and third quartiles; by definition, they cannot extend beyond the smallest or largest observed value). P-value comparing change from BL to VE between the placebo and SQ BNP groups was <0.01 for plasma BNP and plasma cGMP.

Table 3.

Cardiorenal response to volume expansion at visit 2 (after 12 weeks of SQ BNP or placebo)

	SQ BNP (n=22)		Placebo (n=12)
	Baseline	Volume Expansion	Baseline	Volume Expansion	P-value*
Glomerular filtration rate, ml/min/1.732	80 (64, 96)	80 (64, 96)	90 (69, 103)	71 (64, 91)‡	.08
Renal plasma flow, ml/min	381 (303, 473)	346 (254, 406)†	393 (262, 488)	377 (235, 414)	.90
End diastolic diameter, mm	59±6	59±8	62±8	62±4	.52
End systolic diameter, mm	46±8	44±9†	47±6	46±5	.30
Stroke volume index, ml/m2	49±8	52±8†	53±9	53±12	.29
Right ventricular systolic pressure, mm Hg	29±10	29±6	30±5	33±6	.05
E/e’	14±5	12±6	14±5	15±3	.20
Systolic blood pressure, mm Hg	129 (111, 133)	118 (105, 124)†	116 (114, 127)	122 (111, 132)†	<.01
Diastolic blood pressure, mm Hg	66 (60, 74)	63 (54, 74)	59 (58, 67)	59 (54, 71)	0.29
Heart rate, beats per min	59 (55, 70)	56 (48, 63)	57 (47, 70)	56 (44, 70)	.13

Data presented as mean±SD for normally distributed data and median (interquartile range) for non-normally distributed data. Baseline measurements performed prior to volume expansion. Volume expansion measurements performed 1 hour after volume expansion (see methods for further details).

^*p-value comparing change from baseline to volume expansion between the SQ BNP and placebo groups

^†p<0.05 and

^‡p=0.08 value comparing baseline to volume expansion within the SQ BNP and placebo groups

Adverse Events

Adverse events are documented in Table 4. No subjects withdrew from the study due to an adverse event. There was also a trend for more symptomatic hypotension (p=0.19) among SQ BNP treated subjects compared to SQ placebo. Among subjects with hypotension the SQ BNP or placebo dose was decreased by 50% and all subjects who started treatment completed 12 weeks of treatment as randomized.

Table 4.

Adverse Events

	SQ BNP (n=22)	Placebo (n=12)	p-value*
Hospitalization, n (%)	1 (5%)	0	0.45
Heart failure symptoms, n (%)	2 (9%)	0	0.28
Hypotension, n (%)	6 (27%)	1 (8%)	0.19
Tachycardia, n (%)	2 (9%)	0	0.28
Decreased dose, n (%)	6 (27%)	1 (8%)	0.19
Thromboembolism, n (%)	0	1 (8%)	0.17
Hyperkalemia, n (%)	1 (5%)	1 (8%)	0.65
Flank pain, n (%)	1 (5%)	0	0.45
Gout, n (%)	1 (5%)	0	0.45
Urinary tract infection, n (%)	0	1 (8%)	0.17
Blurred vision, n (%)	0	1 (8%)	0.17

^*p-value comparing SQ BNP and placebo groups

DISCUSSION

In the current proof of concept study our main objective was to define the cardiorenal response and assess for tolerance to acute subcutaneous BNP administration and intravascular volume expansion after 12 weeks of subcutaneous BNP therapy in asymptomatic HF.. The results have important implications as loss of therapeutic actions as seen with other peptide therapies^17–19 would render chronic exogenous BNP therapy ineffective in asymptomatic HF. We have previously reported in asymptomatic systolic HF that the natriuretic peptide system is implicated in an impaired diuretic/natriuretic response to volume expansion. This impairment was overcome by a single dose of SQ BNP.¹⁴ In the current study we extend our previous findings and demonstrate preserved cardiorenal actions of SQ BNP after 12 weeks of SQ BNP therapy. Further studies are warranted to determine if these physiologic observations with chronic natriuretic peptide system augmentation can be translated into a delay in the progression of asymptomatic systolic HF to symptomatic HF.

While the ASCEND-HF²⁸ and ROSE AHF²⁹ studies do not support the routine use of intravenous BNP therapy in acute decompensated HF, chronic BNP in asymptomatic and symptomatic HF may represent a new therapeutic paradigm.³⁰ Supplementation of the natriuretic peptide/cGMP system in HF is important as there is evidence of relative impairment of the system in both early and advanced HF. This impairment is due to several factors including enhanced degradation of the natriuretic peptides and production of altered molecular forms which are relatively biologically inactive.^31–34 In symptomatic systolic HF, the recent PARADIGM-HF study demonstrated that inhibition of natriuretic peptide degradation by LCZ 696 reduces mortality compared to the current standard of care.³⁵ Further, chronic SQ BNP in stage C systolic HF was associated with favorable LV remodeling and improvement of clinical status.³⁶ The beneficial actions of BNP in chronic HF may in part be secondary to sympatho-inhibitory actions of BNP³⁷ as sympathetic nerve activation is an important pathophysiologic pathway in chronic HF, particularly in response to increased preload.^{38, 39} These studies underscore the therapeutic potential of chronic natriuretic peptide system augmentation in symptomatic HF.

Beyond symptomatic HF, in asymptomatic HF there is also evidence for impairment on the natriuretic peptide / cGMP system.^{14, 15} This impairment serves as the therapeutic rationale for chronic natriuretic peptide augmentation in asymptomatic systolic HF. One potential concern with chronic protein therapeutics is the lack of beneficial actions with chronic therapy. In the current study, 12 weeks of chronic SQ BNP, acute SQ BNP resulted in preserved enhancement of diuresis, natriuresis and maintained GFR in response to volume expansion compared to placebo. These beneficial renal actions may be due to the direct effect of BNP on the distal tubules to decrease sodium reabsorption and the inhibitory action of BNP on tubular glomerular feedback to maintain GFR.⁴⁰

From a safety standpoint, no subjects withdrew from adverse effects of SQ BNP. Beyond hypotension, a known physiologic effect of BNP which is responsive to dose lowering, there were no signals towards increased adverse events. However, the study was not designed to assess safety beyond 12 weeks. Importantly, there was no deleterious effort on renal function in the BNP treated group as assessed by creatinine, BUN, and iothalmate GFR assessment.

There are several limitations to the current study. First, it is a proof of concept study with small numbers which was powered to detect changes in renal function in response to volume expansion. Additional studies are required to determine if these physiologic observations translate into clinically meaningful results in subjects with asymptomatic systolic HF. Second, subjects were predominantly male and therefore caution should be made when generalizing the results to women. It will also be important for future studies should also measure anti-BNP antibodies. Finally, there was a non-statistically (p=0.21) higher rate of furosemide use in the BNP treated group versus placebo treated group. Despite the higher rate of furosemide use in the BNP assigned group there was no significant difference in sodium excretion or urine flow in response to volumes expansion as compared to the placebo assigned group at visit 1 (Supplemental Table 1). However after 12 weeks of BNP therapy, there was a significant increase in both sodium excretion and urine flow in the BNP as compare to the placebo group in response to volume expansion.

CONCLUSION

Acute SQ BNP continues to enhance renal function in response to volume expansion following 12 weeks of SQ BNP therapy. These results suggest chronic BNP may serve as a potential therapeutic to improve cardiorenal function in asymptomatic systolic HF. Further studies are warranted to determine if these physiologic observations with chronic natriuretic peptide system augmentation can be translated into a delay in the progression to symptomatic heart failure

ABBREVIATIONS

ACE

angiotensin converting enzyme

ANP

atrial natriuretic peptide

BNP

B-type natriuretic peptide

EF

ejection fraction

GFR

glomerular filtration rate

HF

heart failure

LV

left ventricle

SQ

subcutaneous

SV

stroke volume