Diagnostic and Therapeutic Uses of Natriuretic
Peptides in Patients with Heart Failure

James A. Hill, M.D., M.S., Medical Director, Heart Failure/Transplantation, University of Florida College of Medicine, Gainesville, FL

Both ANP and BNP are released by the heart in response to several stimuli the most prominent of which is increased intravascular volume and, in the case of BNP, increased intraventricular pressure. When intraventricular pressure and intravascular volume are increased, both ANP and BNP are released and act to decrease preload by increasing sodium and water excretion via several effects on the kidney and afterload by direct vasodilation. Neither liver nor kidney metabolism or excretion is necessary for elimination of natriuretic peptides. Both ANP and BNP are cleared by the C-type natriuretic peptide receptor. When bound to this receptor, the peptide is brought into the cell and deactivated. They are also cleared by neutral endopeptidase enzymes ².

Diagnostic Uses

Because natriuretic peptides are released by the heart as counterregulatory hormones to protect against volume overload, levels are elevated in volume overload states, specifically heart failure. Although a number of peptides have been evaluated as markers, it appears that BNP is more specific than ANP for high left ventricular filling pressure. Biosite (San Diego CA) has marketed a desktop device using a flourescent immunoassay that allows rapid BNP measurement using whole blood. At the University of California at San Diego, Dao and colleagues ³ have used this method to make the diagnosis of heart failure in an urgent-care setting. When comparing patients with and without decompensated heart failure, they found a significantly higher BNP level (1,076 + 138 vs 38 + 4 pg/ml, p<0.001) in those with heart failure. They found that at concentrations of 80 pg/ml, BNP level was an accurate predictor (95%) for the presence of congestive heart failure. BNP level improved the diagnosis when added to other clinical variables. They were also able to correlate the severity of heart failure with the level of BNP and found that with the most severe heart failure, the BNP level was highest.

Other investigators have explored the relationship of BNP level to outcome in patients with heart failure. Koglin et al ⁴ studied 78 patients with chronic heart failure and compared their initial BNP level at study entry to their subsequent clinical course. The outcomes measured were death, transplantation, or clinical deterioration. Using the method of Aaronson ⁵, for each patient they derived a prognostic score (heart failure survival score-HFSS) which is a multivariable-derived measure that has been shown to provide useful information regarding prognosis. They then correlated it to the BNP level which was measured using an immunoradiometric assay. In this study, they were able to demonstrate that BNP level provides prognostic information of similar power to the HFSS. This suggests that a simple measurement of BNP provides very cost effective prognostic information.

BNP level has also been shown to be useful in guiding heart failure management. Troughton ⁶ showed, in a study of 69 decompensated heart failure patients, that patients randomized to therapy guided by BNP level had fewer cardiovascular events (death, hospitalization, and heart failure decompensation) compared to those treated with standard clinical methods (19 vs 54 p= 0.02) over a median follow-up period of 9.5 months.

Therapeutic Uses

Because the body secretes natriuretic hormones in a counterregulatory way in order to decrease intravascular volume, it is logical to consider augmenting this mechanism as a treatment for heart failure. Human BNP has been synthesized using recombinant technology, has recently been approved by the FDA as a therapeutic agent, Nesiritide (Natrecor©), and is marketed by Scios (Sunnyvale, CA) for the management of decompensated heart failure. Because the peptide is identical to that which is secreted naturally, the physiologic effects of nesiritide are similar to those of naturally occurring BNP, that is a reduction of afterload and preload, and enhancement of natriuresis and diuresis. There is also evidence from recent data reported by Colucci ⁷ of direct renin-angiotensin system blockade causing a drop in plasma aldosterone level with nesiritide.

Several clinical trials have been reported recently demonstrating the utility of nesiritide in patients with decompensated heart failure. Colucci and colleagues ⁶ presented data from two trials in such patients. The first was a double-blind, placebo-controlled trial designed to assess short term hemodynamic responses to nesiritide. Patients in this trial underwent pulmonary artery pressure monitoring and a pulmonary capillary wedge pressure (PCWP) >18 mm Hg was required for entry. After their oral vasoactive medications and intravenous diuretics were withheld for at least 4 hours, patients (n=127) were randomized to receive either placebo or nesiritide at a dose of 0.015 (following 0.3 mcg bolus) or 0.030 (following 0.6 mcg bolus) mcg/kg/min. At 6 hours, the two doses of nesiritide provided a dose-dependent decrease in PCWP, 6 + 7.2 and 9.6 + 6.2 mm Hg respectively, both significantly (p<0.001) lower than the 2 + 7.2 mm Hg drop with placebo. Nesiritide also provided global improvement in clinical status with both doses compared to placebo (p<0.001). In the second trial, patients were randomized to either nesiritide in the two doses used in the previous trial or standard therapy with a conventional intravenous vasoactive agent (chosen at the discretion of the investigator). Other standard therapy was used at the discretion of the investigator. Patients generally received treatment with vasoactive drugs for one to two days but a small percentage of all treatment groups (9-14%) were treated for more than 5 days. In this trial, although there were no significant differences in global status, dyspnea, or fatigue among the three groups, there was less diuretic given to those patients on nesiritide despite a similar loss of weight. Asymptomatic or mild dose-related hypotension, was the most common adverse effect in both trials.

Additional data was obtained to evaluate the safety of nesiritide. Preliminary data from the PRECEDENT study was reported at the Heart Failure Society of America meeting in September 1999 ⁸. In this open label study, patients requiring hospitalization for decompensated heart failure were randomized to one of two doses of nesiritide (0.015 or 0.03 mcg/kg/min) or dobutamine, minimum dose 5 mcg/kg/min. Assignment to the two dose groups of nesiritide was blinded. Twenty-four ambulatory ECG monitoring was performed before and after initiation of therapy in order to determine drug effects on arrhythmias. Chronic medications, diuretics, ACE inhibitors and digoxin in the large majority of patients, were continued. The preliminary results of this study showed that the number of PVC's/hour increased with dobutamine but did not change significantly with either dose of nesiritide (p<0.002). Repetitive beats increased with dobutamine but not with low dose nesiritide (p<0.001) and heart rate increased significantly with dobutamine but not with either dose of nesiritide (p<0.002).

One of the largest clinical trials ever performed in decompensated heart failure was the VMAC trial (Vasodilatation in the Management of Acute Congestive heart failure). This study was designed when the FDA requested more clinical safety data regarding how nesiritide compared to a standard vasodilator, in this case nitroglycerin. As contrasted to prior trials reported with nesiritide, this trial was designed to evaluate the safety and efficacy of nesiritide when added to standard care in patients with decompensated heart failure. In addition, the dose of nesiritide studied was lower than that previously evaluated, a 2 mcg IV bolus followed by 0.01 mcg/min continuous infusion. Preliminary results of this trial were presented at the 2000 American Heart Association Meeting ⁹ by Dr. James Young.

The primary objective of this trial was to compare the hemodynamic and clinical effects of nesiritide to nitroglycerin and placebo when added to standard heart failure therapy. The primary endpoints were dyspnea assessment at 3 hours in all patients, and reduction of PCWP at 3 hours in those who received right heart catheterization. Right heart catheterization was not randomized and was used at the discretion of the investigator. Patients who received right heart catheterization monitoring (n=246) were randomized to either nitroglycerin, placebo, fixed dose of nesiritide in a dose of 0.01 mcg/kg/min following a 2 mcg per kilogram IV bolus dose, or adjustable dose nesiritide with the same initial starting dose as the fixed dose group. In the non-catheterized group (n=243), patients were randomized to either fixed dose nesiritide, nitroglycerin or placebo. Nitroglycerin could be titrated at investigator discretion in both arms of the trial. After the 3 hour time period, those who were on placebo were randomized to either fixed dose nesiritide or nitroglycerin in a blinded manner. Treatment was continued at the discretion of the investigator. At 3 hours, the mean PCWP had dropped from 28 to 22 mm Hg in the patients on nesiritide, compared to 24 mm Hg on nitroglycerin and 26 mm Hg on placebo (p<0.027, comparing nesiritide to nitroglycerin and placebo). Dyspnea at 3 hours showed a statistically significant improvement in the nesiritide group compared to placebo (p=0.034), whereas no statistically significant improvement was demonstrated with nitroglycerin compared to placebo (p=0.191). In all patients who had PCWP measurements through 24 hours, there was a statistically significant reduction in PCWP in the nesiritide treated group compared to the nitroglycerin treated group. Another difference noted was that in the nesiritide treated group, the dose generally remained the same whereas with nitroglycerin, the dose continued to be increased to maintain the hemodynamic improvement. Analysis of adverse events noted in the first 24 hours in this trial demonstrated a higher overall incidence of adverse effects with nitroglycerin compared to nesiritide (p<0.001). In particular, headache and abdominal pain were more common with nitroglycerin than nesiritide (p< 0.001 and p= 0.032 respectively). There was a very low incidence of symptomatic hypotension with both nesiritide and nitroglycerin. The preliminary report of this study demonstrated that nesiritide, in doses currently recommended, is safer and more effective than nitroglycerin when added to standard therapy for management of decompensated heart failure. The final report of this trial is awaiting publication.

Natriuretic Peptides Compared To Standard Heart Failure Therapy

The table provides a comparison of nesiritide and other intravenous therapy for decompensated heart failure.

As can be seen, contrary to milrinone and dobutamine, there is no increase in arrhythmias or heart rate with nesiritide. Nesiritide is similar to the nitrates in having no inotropic, chronotropic or proarrhythmic effects but differs in that there is neither tolerance nor toxic metabolites that can be seen with nitroglycerin or nitroprusside respectively. In general, with the currently recommended dose of nesiritide (2 mcg/kg IV bolus and 0.01 mcg/kg/min infusion), special monitoring, that is arterial line or right heart catheterization, is not required with nesiritide as is generally the practice with nitroprusside. While telemetry monitoring is generally performed in the hospitalized heart failure patient, because of the lack of proarrhythmic effects, treatment with nesiritide does not require it. What isn't shown in the table is that nesiritide is the only IV infusion agent, other than loop diuretics, that has a primary diuretic effect. Diuretics, however, activate the renin-angiotensin system while nesiritide has some inhibiting effect. This is obviously beneficial in heart failure. While all these vasoactive drugs have relatively short half-lives, their effect can be prolonged, occasionally seeing sustained hypotension with both milrinone and nesiritide for several hours after discontinuation of the drug.

Conclusions

In conclusion, the heart secretes natriuretic peptides in response to volume and pressure overload as counterregulatory hormones. Their physiologic actions of vasodilation and enhancement of sodium and water excretion serve to reduce that overload. Measurement of BNP level appears to be useful for diagnosing and monitoring management of congestive heart failure. While the literature is fairly consistent in this regard, from a variety of investigators using different assays, clinical experience remains limited. As this test becomes more widely used, how it is best integrated into practice will become clear. Measurement of BNP level does not appear useful or necessary in guiding therapy with nesiritide, however. BNP levels will be elevated while nesiritide is infusing, but they should not be used to increase or decrease the dose of drug. Finally, recombinant human BNP (nesiritide) is effective and safe for the management of decompensated heart failure. When compared to other intravenous agents used for heart failure management, specifically nitrates and inotropic agents, nesiritide has some advantages. Over the last several years, vasodilator therapy has been relatively neglected in favor of inotropic therapy. This is partially a result of the difficulty in using an effective intravenous vasodilator outside of an ICU setting. Nesiritide does not require aggressive monitoring and for the first time allows effective vasodilator therapy to be readily utilized. Its role in the management of heart patients needs to be individualized but in general it appears that in any patient felt to be a candidate for intravenous vasodilator therapy, nesiritide is an excellent alternative to standard agents.

References

1. Boland DG, Abraham WT. Natriuretic peptides in heart failure. CHF March/April 1998:23-33
2. Levin ER, Gardner DG, Samson WK. Natriuretic Peptides. . N Engl J Med 1998;339:321-328
3. Dao Q, Krishnaswamy P, Kazanegra R et al. Utility of B-type natriuretic peptide in the diagnosis of congestive heart failure in an urgent-care setting. J Am Coll Cardiol 2001;37:379-385
4. Koglin J, Pehlivanli S, Schwaiblmair M et al. Role of brain natriuretic peptide in risk stratification of patients with congestive heart failure. J Am Coll Cardiol 2001;38:1934-1941
5. Aaronson KD, Schwartz JS, Chen TM et al. Development and prospective validation of a clinical index to predict survival in ambulatory patients referred for cardiac transplant evaluation. Circulation 1997;95:2660-2667
6. Troughton RW, Frampton CM, Yandle TG et al. Treatment of heart failure guided by plasma aminoterminal brain natriuretic peptide (N-BNP) concentrations. Lancet 2000;355:1126-1130
7. Colucci WS, Elkayam U, Horton DP et al. Intravenous nesiritide, a natriuretic peptide, in the treatment of decompensated congestive heart failure. N Engl J Med 2000;343:246-253
8. Burger AJ, Dennish G, Dinerman J et al. Nesiritide therapy for decompensated CHF is not proarrhythmic. (poster presentation) Heart Failure Society of America Annual Scientific Sessions,1999
9. Young JB. Vasodilation in the Management of Acute Congestive Heart Failure (VMAC) study results [oral presentation] 73^rd Scientific Sessions of the American Heart Association; November 12-15, 2000; New Orleans, LA

Jacksonville Medicine / February, 2002

What's New · Northeast Florida Medicine Journal · Know Your Physician · Legal & Legislative
· DCMS Alliance · Academy of Medicine · Member Websites · Community Health
About the DCMS · Meetings Calendar · Member Benefits · Employment Connection · Home

Duval County Medical Society   ·   555 Bishopgate Lane  ·   Jacksonville, FL  32204
Phone: (904) 355-6561   ·     FAX:  (904) 353-5848   
General Email: dcms@dcmsonline.org    ·   Webmaster's Email: mdoran@dcmsonline.org
Privacy Policy and Disclaimers