Nesiritide

Abstract

Nesiritide (Natrecor®¹) is arecombinant form of human B-type (brain) natriuretic peptide that has beneficial vasodilatory, natriuretic, diuretic and neurohormonal effects. The drug is administered intravenously for the management of patients with decompensated congestive heart failure (CHF). In the Vasodilation in the Management of Acute Congestive Heart Failure (VMAC) study, patients hospitalised with acute decompensated CHF who received nesiritide had significantly greater mean reductions from baseline in pulmonary capillary wedge pressure 3 hours after starting treatment than nitroglycerin or placebo recipients (−5.8 vs −3.8 and −2mm Hg, respectively); all patients also received standard therapy (e.g. intravenous diuretics). Improvements in other haemodynamic parameters were also seen in nesiritide recipients. In addition, significantly more nesiritide than placebo recipients reported an improvement in dyspnoea after 3 hours' treatment in VMAC, whereas there was no significant difference between nitroglycerin and placebo recipients. Improvements in global clinical status, dyspnoea and fatigue were also seen with nesiritide in another active-comparator study and in a placebo-controlled study. In VMAC, there was no significant difference between nesiritide and nitroglycerin recipients in 6-month mortality. In the other active-comparator trial, 6-month mortality was significantly lower in recipients of nesiritide 0.015 µg/kg/min than in dobutamine recipients (although mortality was not a pre-specified endpoint and this result should be interpreted with caution). In this same study, the 21-day all-cause hospital readmission rate was significantly lower with nesiritide 0.015 µg/kg/min than with dobutamine and the duration of active drug treatment was significantly shorter with nesiritide than with dobutamine. Nesiritide is generally well tolerated. In VMAC, significantly more adverse events occurred with nitroglycerin than with nesiritide. The most common adverse events reported during the first 24 hours of therapy in nesiritide and nitroglycerin recipients included general pain, abdominal pain, catheter-related pain, headache, nausea, asymptomatic and symptomatic hypotension, nonsustained ventricular tachycardia and angina pectoris. Most episodes of symptomatic hypotension resolved spontaneously or after an intravenous volume challenge of ≤250ml. In addition, nesiritide does not appear to be proarrhythmic. Conclusion: Short-term intravenous infusion of nesiritide is associated with haemodynamic and symptomatic improvements in patients with acutely decompensated CHF. Nesiritide may offer tolerability and practical advantages over currently used vasodilators, inodilators and inotropes in this condition; in particular, nesiritide does not appear to have proarrhythmic effects. Nesiritide also appears to be effective and well tolerated in patients receiving concomitant β-blocker therapy and in patients with renal insufficiency. Thus, nesiritide is a suitable first-line option for the treatment of patients with acutely decompensated CHF and is a welcome addition in an area where intravenous agents are few. Nesiritide is structurally and pharmacologically indistinguishable from human B-type (brain) natriuretic peptide (BNP). The vasodilatory, natriuretic and diuretic effects of nesiritide appear to be primarily mediated by its interaction with natriuretic peptide receptor A on target cells and organs (e.g. vascular smooth muscle cells, endothelial cells, kidney and adrenal gland). Nesiritide does not have a direct inotropic effect on the heart. Nesiritide has beneficial haemodynamic effects in patients with decompensated or severe congestive heart failure (CHF). The drug reduces pulmonary capillary wedge pressure (PCWP) and right atrial pressure (RAP) [both indicating reduced preload] and also reduces systemic vascular resistance (SVR) and increases cardiac index (CI) [reflecting a reduction in afterload]. Nesiritide reduces systemic arterial pressure without evidence of reflex tachycardia. Human BNP has a natriuretic effect and, in general, a diuretic effect in healthy volunteers; it appears that the major effect of nesiritide on sodium handling occurs in the distal nephron. In patients with CHF, nesiritide increased urine output to a significantly greater extent than placebo in two trials in which diuretics were withheld during the period of evaluation. In two active-comparator trials in which diuretics could be administered as needed, significantly fewer nesiritide recipients than nitroglycerin or standard treatment (e.g. dobutamine) recipients received diuretics. Nesiritide or human BNP reduced plasma aldosterone levels in patients with CHF in some studies, which may contribute to its natriuretic effect, and also appeared to inhibit plasma renin activity. Nesiritide was associated with significant improvement from baseline in heart rate variability and parasympathetic modulation in patients with decompensated CHF and highly depressed heart rate variability at baseline. Plasma noradrenaline (norepinephrine) and endothelin-1 levels were significantly reduced from baseline in patients with decompensated CHF who received nesiritide. Nesiritide has a distribution half-life of approximately 2 minutes. The plasma level achieved with nesiritide infusion is proportional to the infused dose. Steadystate nesiritide levels may be reached in 0.5 mg/dl (>44 µmol/L) above levels at study entry occurred in 17 to 28% of nesiritide recipients in the PRECEDENT and VMAC trials (assessed to days 14 and 30, respectively). This laboratory change was seen in 11 and 21% of standard therapy and nitroglycerin recipients in the corresponding trials. In VMAC, 3% of nesiritide recipients and 2% of nitroglycerin recipients required first-time dialysis during 30 days of follow-up (p value not significant). Intravenous nesiritide is approved in the US for...