Sizing Up the First Two New Heart Failure Meds in a Decade

A novel drug for chronic heart failure (CHF) that recently outperformed the standard of care in the pivotal PARADIGM clinical trial is poised to become the treatment of choice in CHF patients who tolerate it. That’s the take of Randall Starling, MD, MPH, assuming the agent gains FDA approval as expected this year.

The drug, known as LCZ696, “would have applicability to all patients with heart failure and a reduced ejection fraction (defined as < 40 percent) who have tolerated a standard dose of ACE inhibitor therapy,” says Dr. Starling, Medical Director of Cleveland Clinic’s Kaufman Center for Heart Failure. He served as U.S. leader of the PARADIGM steering committee. Cleveland Clinic was a participating center in that phase 3 trial, the results of which were recently published in the New England Journal of Medicine.

Combo agent with a novel mechanism: Neprilysin inhibition

LCZ696 (to be marketed as Entresto® by Novartis) is a combination of the angiotensin II receptor blocker valsartan and sacubitril. The latter compound is a neprilysin inhibitor prodrug that augments endogenous natriuretic peptides and other beneficial counter-regulatory systems (ie, bradykinin, adrenomedullin) in CHF.

Inhibiting neprilysin results in significant reductions in systemic vascular resistance, pulmonary artery pressure, pulmonary capillary wedge pressure and right arterial pressure in patients with CHF. Other effects include vasodilation, enhanced sodium and water excretion, and preservation of glomerular filtration.

Superior to ACE inhibition in PARADIGM

These beneficial properties of neprilysin inhibition, when combined with valsartan, translated to a 20 percent relative reduction in the composite primary end point of death from cardiovascular causes and/or hospitalization for heart failure compared with the ACE inhibitor enalapril among the 8,442 patients with CHF and reduced ejection fraction enrolled in PARADIGM.

Each of the components of this composite end point was reduced by about 20 percent in recipients of LCZ696 compared with enalapril, and greater symptomatic improvement was reported. LCZ696 also was associated with a 16 percent reduction in overall mortality relative to enalapril.

The cost question

The improvement in survival and reduction in CHF-related hospitalizations imply that LCZ696 has the potential to be a cost-effective therapy once available, depending on its price, according to Dr. Starling. “I think patients will want this drug and physicians will want to use it,” he says. “But we need to see how it is priced and reimbursed to know whether there may be cost-related obstacles to access.”

Careful blood pressure screening will be key

Because LCZ696 can cause hypotension, patients will require careful blood pressure screening before the drug can be considered, Dr. Starling notes. In PARADIGM, approximately 10 percent of patients had challenges maintaining blood pressure during the screening phase or after trial initiation. Screening involved two single-blind run-in phases — first with enalapril 10 mg twice daily and then, if no unacceptable side effects occurred, with LCZ696 (100 mg twice daily followed by 200 mg twice daily) — before randomization to enalapril at 10 mg twice daily or LCZ696 at 200 mg twice daily.

“The main message is that if a patient is tolerating a standard dose of an ACE inhibitor, he or she will probably tolerate LCZ696 just fine,” Dr. Starling says. “You’ll just want to keep a careful eye on the blood pressure.”

Appropriate institution of LCZ696 in patients with CHF who have been treated with an angiotensin receptor blocker rather than an ACE inhibitor is uncertain, he notes, adding that eventual approval language from the FDA may give some guidance. “I anticipate there will be a role for this drug in that patient population although it has not yet been specifically tested.”

Approval would follow surprise timing of ivabradine clearance

The expected FDA approval of LCZ696 would follow on the heels of the April approval of another first-in-class medication for CHF, ivabradine (Corlanor®), which was the first new CHF agent cleared by the FDA in almost a decade.

Ivabradine works by inhibiting the l(f) current (“funny” current) in the sinoatrial node to slow the heart rate without affecting ventricular repolarization or myocardial contractility. It is indicated for use as add-on therapy to reduce the risk of hospitalization in patients with stable symptomatic CHF who have a resting heart rate of at least 70 beats per minute despite maximally tolerated beta-blocker therapy.

Ivabradine, which is taken orally twice daily, was approved by the European Medicines Agency in 2005 to treat symptoms of angina and in 2012 to treat CHF. Its U.S. approval took many observers by surprise because it came without the usual initial consideration of the drug at a meeting of the Cardiovascular and Renal Drugs Advisory Committee to the FDA.

Approval was based on findings of the international SHIFT study, which randomized more than 6,500 patients to either placebo or ivabradine in addition to standard-of-care therapies for heart failure. Results showed that ivabradine recipients had significantly lower rates of the composite end point of cardiovascular death or hospitalization for worsening CHF.

Adverse events were rare in the clinical trial. The most common — bradycardia, increased blood pressure, atrial fibrillation and luminous phenomena/visual brightness — were reversible by lowering the medication dose.

Long-overdue new options for a recalcitrant disease

These new classes of medications are long overdue for a condition like CHF whose long-term prognosis has remained stubbornly poor, notes W.H. Wilson Tang, MD, Director of Cleveland Clinic’s Center for Clinical Genomics and Research Director in the Section of Heart Failure.

“We’re excited that these new drugs, and others like them, are bringing new options to the treatment of this condition,” he says.