Brief Comunication |
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Nesiritide: First use in India
Ayush Manchanda, vikas Kohli
Pediatric Cardiology & Congenital Cardiac Surgery, Indraprastha Apollo Hospital, New Delhi, India
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Introduction
Natriuretic peptides have been of research interest for more than 2 decades but gained real clinical importance within just the past several years (1,2). Atrial natriuretic factor was extracted in 1981 (3). In 1988, a second natriuretic peptide was identified in porcine brain. Initially, it was called brain natriuretic peptide, but after the ventricular myocardium was noted as the main source, it is now typically referred to as B-type natriuretic peptide (BNP). Right and left ventricular myocardium excretes BNP in response to fluid overload and wall stress in congestive heart failure (4). Its pharmacologic effects include hemodynamic, neurohormonal, and renal.
Nesiritide is a recombinant BNP having the same amino acid sequence as the naturally occurring human BNP. Nesiritide has been approved by the Food and Drug Administration for the intravenous treatment of patients with acute decompensated congestive heart failure. Nesiritide has been studied in infants and children with heart failure.
Case Report
3 month old baby presented to us in shock. A diagnosis of fulminant myocarditis was suspected and confirmed by Troponin I and echocardiography. Ventilatory support and inotropes in form of dopamine, dobutamine and milrinone were initiatied. In addition, the child had low cardiac output resulting in renal failure and renal shut down requiring peritoneal dialysis. The option of mechanical circulatory support option was considered at this stage but metabolic acidosis reversed with ventilatory and inotropic support and cardiac output improved.
On day 5 the urine output improved minimally, the heart function improved from 5% on admission to 20%. Cardiac output increased too. Inotropes were on lesser doses at this time. Peritoneal dialysis was still needed but was not effectively functioning at this time. Ultrafiltration was initiated at this stage. On day 3 the patient was initiated on nesiritide infusion. The dose it was started on was 0.005 mcg/kg/min and increased to 0.02 mcg/kg/min. The urine output and cardiac output further increased after initiation of nesiritide and the SVR dropped further. The child could finally be weaned off the ventilator though was still on inotropes and on peritoneal dialysis.
On day 7 the child while on ultrafiltration, had a cardiac arrest which retrospectively was diagnosed to be due to hyperkalemia. The child could not be revived from the cardiac arrest. |
Pharmacology
Interaction of nesiritide with natriuretic peptide receptor A, located on the cells of target organs, results in vasodilation (including coronary vasodilation), natriuresis, and diuresis. BNP and therefore nesiritide also appears to decrease aldosterone, norepinephrine, and endothelin 1 levels. It has inhibiting properties on the renin-angiotensin-aldosterone system (5,6). The diagnostic value of endogenous BNP levels in the differential diagnosis and management of heart failure has been the focus of multiple recent studies. A second large area of interest focuses on the therapeutic properties of BNP given as continuous infusion in congestive heart failure.
Nesiritide (Natrecor, Scios Inc, Fremont, California, USA) is produced using recombinant DNA techniques and is structurally identical to natural human BNP. It has the same pharmacologic properties and same metabolism. It is available in intravenous form. The average half-life elimination time is about 18 minutes which leads to a steady-state plasma concentration about 90 minutes after starting a continuous infusion. Adjustment in dosage for patients with renal impairment is usually not necessary (6).
Nesirite related Trials
The Nesiritide Study Group evaluated 432 patients who required hospitalization and intravenous therapy for decompensated heart failure. Inotropic medications were discontinued, and patients were assigned to different groups, including placebo, nesiritide at 0.015, nesiritide at 0.03 mcg/kg/min, and standard therapy consisting of a single intravenous vasoactive agent. In comparison to placebo, nesiritide decreased capillary wedge pressure, dyspnea, and fatigue. Clinical status improved in more than 60% of patients. The most common side effect was asymptomatic hypotension (7).
The Vasodilation in the Management of Acute Congestive Heart Failure trial compared 489 patients with congestive heart failure and dyspnea at rest. Dyspnea was significantly improved with nesiritide in comparison to placebo at 3 hours, but no difference was present compared to nitroglycerin at 3 or 24 hours (8).
The Prospective Randomized Evaluation of Cardiac Ectopy with Dobutamine or Natrecor Therapy trial evaluated 255 adult patients with congestive heart failure in New York Heart Association class III and IV. Nesiritide resulted in a greater reduction in blood pressure, but there were significantly less premature ventricular beats, less |
Correspondence: Dr. Vikas Kohli, c-116 Sarita Vihar new Delhi-110044, India
E-mail : vkohli_md@yahoo.com |
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Indian Heart J. 2009; 61:371-372 |
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Ayush Manchanda et al |
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ventricular tachycardia, and no increase in heart rate from baseline (9).
Multivariate analysis of more than 33,000 patients enrolled in the Acute Decompensated Heart Failure National Registry showed a significantly lower mortality for patients treated with nesiritide in comparison to milrinone and dobutamine. Preliminary data showed good tolerance of the medication with improved diuresis and improved hemodynamic status.
Nesiritide in Pediatrics
Some data exists related to use of nesiritide in the pediatric population. Sehra and Underwood used nesiritide at doses of 0.005 to 0.02 mcg/kg/min in 7 pediatric patients awaiting heart transplantation. Nesiritide was added to standard therapy. The patients showed improvement in urine output of 22% to 24% from baseline. No significant hypotensive complications were noted (10).
Pediatric patients with cardiomyopathy due to congenital heart disease or myocarditis form a smaller patient population in which nesiritide could be very helpful, assuming that nesiritide produces similar physiologic effects as in the adult population. A potentially larger field of application for nesiritide in pediatrics consists of patients after open heart surgery. Vasodilatation, diuresis, and decreases in aldosterone, norepinephrine, and endothelin 1 levels make nesiritide an attractive alternative to other medications. In addition, its neutral effect on heart rate appears very desirable after complex pediatric intracardiac surgeries where tachycardia (e.g. junctional ectopic tachycardia) is rather common. Inotropic medications may actually result in decreased cardiac output due to disproportionate increase in heart rate, which impairs diastolic relaxation and filling.
The studies by Marshall et al (11) and Sehra and Underwood (10), clearly demonstrate a role for nesiritide in the pediatric population.
Renal function and Nesiritide
Nesiritide may affect renal function in susceptible individuals. In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with nesiritide may be associated with azotemia. When nesiritide was initiated at doses higher than 0.01 mcg/kg/min (0.015 and 0.030 mcg/kg/min), there was an increased rate of elevated serum creatinine over baseline compared with standard therapies, although the rate of acute renal failure and need for dialysis was not increased. In the 30-day follow-up period in the VMAC trial, 5 patients in the nitroglycerin group (2%) and 9 patients in the Natrecor group (3%) required first-time dialysis (12).
Increases in creatinine do not necessarily portend a poor outcome, as the trials with angiotensin-converting enzyme inhibitors have taught. Furthermore, multiple confounders, such as hypotension and overdiuresis, may be responsible for the increased creatinine. Ultimately, transient increases in creatinine may have no clinical significance, unless they serve as a harbinger of worse clinical outcomes (13). |
Controversies and Forthcoming Trials
There has been significant controversy in literature about several issues related to nesiritide. Questions have been raised about potential of higher mortality with the use of nesiritide; with potential of worsening of renal dysfunction and possibly no benefit to the outcome (as compared to symptomatic benefit to patient). In addition, there are several articles in literature questioning the premature approval of the drug by FDA and in addition over-aggressive marketing of the drug by manufacturer for “off-label” uses. Topol highlights these issues in an editorial. Incidentally, European Medicines Agency has not approved this drug for use in Europe and is awaiting results of the European Trial of Nesiritide in Acute Decompensated Heart Failure, that will enroll 1900 patients before considering it for approval for the European market (14).
References
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2. Sudoh T, Kangawa K, Minamino N, Matsuo H. A new natriuretic peptide in porcine brain. Nature. 1988;332:78-81.
3. DeBold AJ, Borenstein HB, Veress AT, Sonnenberg H. A rapid and potent natriuretic response to intravenous injection of atrial myocardial extracts in rats. Life Sci. 1981;28:89-94.
4. Yasue H, Yoshimura H, Sumida H, et al. Localization and mechanism of secretion of B-type natriuretic peptide in comparison with those of A-type natriuretic peptide in normal subjects and patients with heart failure. Circulation. 1994;90:195-203.
5. Silver MA, Horton DP, Ghali JK, Elkayam U. Effect of nesiritide versus dobutamine on short-term outcomes in the treatment of patients with acutely decompensated heart failure. J Am Coll Cardiol. 2002;39(5):798-803.
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8. Publication Committee for the VMAC Investigators. Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure. JAMA.
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9. Burger AJ, Horton DP, LeJemtel T, et al. Effect of nesiritide (B-type natriuretic peptide) and dobutamine on ventricular arrhythmias in the treatment of patients with acutely decompensated congestive heart failure: the PRECEDENT study. Am Heart J. 2002;144(6):1102-1108.
10. Sehra R, Underwood KR. Nesiritide improves urine output in severely ill pediatric patients awaiting heart transplantation without severe hypotension. J Card Fail. 2003;9(5
suppl 1):175.
11. Marshall J, Berkenbosch JW, Russo P, Tobias JD. Preliminary experience with nesiritide in the pediatric population. J Intensive Care Med. 2004;19:164-170.
12. Jonathan D. Sackner-Bernstein ; Hal A. Skopicki ; Keith D. Aaronson. Circulation 2005; 111:1487-1491 (ref for renal & nesiritide)
13. Teerlink JR, Massie BM. Nesiritide and Worsening of Renal Function: The Emperor’s New Clothes? Circulation. 2005;111:1459-1461
14. Topol EJ. Nesiritide - Not Verified. NEJM. 2005:353(2):113-116. |
Indian Heart J. 2009; 61:371-372 |
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