Thomas Morrow, MD

As clinicians recognize heart failure's neurohormonal component, a biologic agent may prove better than the small molecules.

Thomas Morrow, MD

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.

Administration

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.

Thomas Morrow, MD, is president of the National Association of Managed Care Physicians and vice president and medical director of Matria Health Care. He has 20 years of managed care experience at the payer or health plan level.

Managed Care’s Top Ten Articles of 2016

There’s a lot more going on in health care than mergers (Aetna-Humana, Anthem-Cigna) creating huge players. Hundreds of insurers operate in 50 different states. Self-insured employers, ACA public exchanges, Medicare Advantage, and Medicaid managed care plans crowd an increasingly complex market.

Major health care players are determined to make health information exchanges (HIEs) work. The push toward value-based payment alone almost guarantees that HIEs will be tweaked, poked, prodded, and overhauled until they deliver on their promise. The goal: straight talk from and among tech systems.

They bring a different mindset. They’re willing to work in teams and focus on the sort of evidence-based medicine that can guide health care’s transformation into a system based on value. One question: How well will this new generation of data-driven MDs deal with patients?

The surge of new MS treatments have been for the relapsing-remitting form of the disease. There’s hope for sufferers of a different form of MS. By homing in on CD20-positive B cells, ocrelizumab is able to knock them out and other aberrant B cells circulating in the bloodstream.

A flood of tests have insurers ramping up prior authorization and utilization review. Information overload is a problem. As doctors struggle to keep up, health plans need to get ahead of the development of the technology in order to successfully manage genetic testing appropriately.

Having the data is one thing. Knowing how to use it is another. Applying its computational power to the data, a company called RowdMap puts providers into high-, medium-, and low-value buckets compared with peers in their markets, using specific benchmarks to show why outliers differ from the norm.
Competition among manufacturers, industry consolidation, and capitalization on me-too drugs are cranking up generic and branded drug prices. This increase has compelled PBMs, health plan sponsors, and retail pharmacies to find novel ways to turn a profit, often at the expense of the consumer.
The development of recombinant DNA and other technologies has added a new dimension to care. These medications have revolutionized the treatment of rheumatoid arthritis and many of the other 80 or so autoimmune diseases. But they can be budget busters and have a tricky side effect profile.

Shelley Slade
Vogel, Slade & Goldstein

Hub programs have emerged as a profitable new line of business in the sales and distribution side of the pharmaceutical industry that has got more than its fair share of wheeling and dealing. But they spell trouble if they spark collusion, threaten patients, or waste federal dollars.

More companies are self-insuring—and it’s not just large employers that are striking out on their own. The percentage of employers who fully self-insure increased by 44% in 1999 to 63% in 2015. Self-insurance may give employers more control over benefit packages, and stop-loss protects them against uncapped liability.