As clinicians recognize heart failure's neurohormonal component, a biologic agent may prove better than the small molecules.
The United States is in the midst of an epidemic of heart failure arising from the convergence of factors that include the aging population, advanced cardiac salvaging technology, and decades of lifestyle indiscretions that predispose the population to conditions that lead to heart disease: hypertension, dyslipidemia, metabolic syndrome, and diabetes. The sobering fact is that the prevalence of heart failure in the United States is about 4.7 million, with more than half a million new cases added yearly.
Mortality from heart failure is no better — about 50 percent of people diagnosed with heart failure die within five years of diagnosis.
Enter nesiritide (Natrecor), a biologic agent that is a member of a family of natural compounds called B-type natriuretic peptides (BNP). This peptide, made up of 32 amino acids, has been engineered using recombinant DNA technology. The DNA is implanted into E. coli to create the compound, then separated from the organism and purified. The cardiac ventricles produce nesiritide when they experience stress. Plasma levels of this natural hormone are elevated in chronic heart failure in proportion to the severity of left ventricular dysfunction, suggesting that the plasma level of BNP relates in some degree to the state of left ventricular overload. Although questions still arise about the precise mechanisms mediating the biologic effects of BNP, it has been shown to have vasodilatory, diuretic, and natriuretic properties.
Nesiritide reacts with two receptors, natriuretic peptide receptor A and, to a lesser extent, natriuretic peptide receptor B, on vascular smooth muscle, endothelial, kidney, and adrenal cells. This reaction activates the cyclic and noncyclic quanosine monophosphate-mediated pathways. This activation suppresses the renin-angiotensin-aldosterone axis resulting in vasodilatory, diuretic, natriuretic, and cardiovascular effects. The sum of these effects in an emergently symptomatic patient with decompensated heart failure is to rapidly decrease the pulmonary capillary wedge pressure (PCWP) and right atrial pressure, preload, and systemic vascular resistance, and to improve the cardiac index. These effects take place in the absence of tachycardia. In the clinical trials leading to its approval, greater reduction in PCWP was observed in patients given nesiritide than in patients who received intravenous nitroglycerine. This reduction occurred quickly — 15 minutes after infusion. Symptomatic improvement also occurred quickly.
The only side effect observed is a limited amount of easily reversed hypotension, which requires careful monitoring for the first few hours. Thereafter, the patient may be transferred to a telemetry bed, since there isn't the increase in ectopy and heart rate that is associated with dobutamine or milrinone.
Nesiritide does not appear to be associated with tolerance or proarrhythmia effects. With nesiritide, once a patient is stabilized in the emergency room, further titration may be unnecessary and a telemetry bed may be used instead of an ICU bed. In fact, nesiritide has been shown to save considerable ICU time and actually decreases the cost of a typical hospitalization.
Typically nesiritide is administered as an IV bolus followed by a continuous infusion for several days. Although there are no FDA approved uses beyond this, longer exposure to nesiritide as intermittent infusion for NYHA class III and IV patients over a period of more than four months resulted in symptomatic improvement. One patient in a clinical trial received nesiritide for 161 days without evidence of tolerance. These findings open the possibility that nesiritide may eventually be administered on an outpatient basis to prevent hospitalization. Trials are under way to try to determine whether this is a viable option.
AWP is $456 for dosing over a 24-hour period for a patient weighing up to 188 lbs. This drug is not hitting health plan's pharmacy budgets currently, as it is primarily being used in the inpatient setting. But many cutting-edge centers are using this in outpatient settings instead of milrinone, dobutamine, or dopamine infusions.
A neurohormonal disorder
Once thought to be primarily a mechanical disorder (impaired contractility and pump dysfunction), heart failure is increasingly understood to be a neurohormonal disorder.
A myocardial infarction, uncontrolled hypertension, acute myocarditis, or even valvular heart disease, can activate the compensatory neurohormones and inflammatory cytokines. The release of neurohormones leads to progressive remodeling of the left ventricle and progressive symptomatology. Under normal conditions, counter-regulatory endogenous vasodilators and neurohormone antagonists balance these same vasoconstrictive neurohormones. But this compensation cannot continue forever and the chronic exposure to the remodeling neurohormones leads to progression of the disease.
The declining cardiac output associated with a heart attack is accompanied by activation of the RAAS that leads to constriction of the arterioles to maintain glomerular filtration rate. The release of renin from the "starving" kidney, the result of renal artery hypotension, leads to a reduction in sodium delivery and subsequent excretion. Renin also acts upon circulating angiotensinogen to form angiotensin I.
A subsequent response to angiotensin I causes the vascular endothelium to release angiotensin converting enzyme (ACE), leading to the formation of angiotensin II. Angiotensin II also induces oxidative stress and if unopposed leads to vascular injury. The resulting cascade of events leads to hypertrophy of the smooth muscle in the cardiac walls. Angiotensin II also stimulates the adrenal cortex causing the secretion of aldosterone. This in turn leads to increased sodium absorption in exchange for potassium in the renal tubules and decreased release of nitric oxide, reducing arterial compliance. This results in subsequent endothelial dysfunction, myocardial fibrosis, and increased stiffness.
Thus, chronic activation of the RAAS leads to the progression of heart failure due to attempts to restore adequate renal perfusion. Traditional therapy for chronic heart failure has been and continues to be nitroglycerine, diuretics, ACE inhibitors, aldosterone inhibitors and, in the acute care setting, presser agents and more potent vasodilators such as nitroprusside and intravenous nitroglycerine.
Chronic heart failure can now be considered part of the growing list of diseases treated with biologic agents. In this case, nesiritide, a natural human hormone, has been shown in many cases to be better than the traditional small molecules. Future developments may result in long-term administration of this hormone in much the same way that we treat diabetes with an insulin pump. Once more, we are seeing the influence of genomics and biologics in bringing tomorrow's medicine to us ... today.