Heart failure specialists haven't had a new treatment with the potential to significantly change outcomes for their patients in quite a while.
“For many years, the word on the street was that it was impossible to develop a new drug for heart failure, because these patients are already on too many drugs and it's just too hard,” said Mariell Jessup, MD, a cardiologist at the University of Pennsylvania in Philadelphia.
But in July, the first angiotensin-receptor neprilysin inhibitor (ARNI) was approved by the FDA after a fast-track process. The drug, known as LCZ696 during development and brand-named Entresto, combines the neprilysin inhibitor sacubitril, a new molecular entity, and valsartan, a widely used angiotensin-receptor blocker (ARB).
The new drug sent a wave of excitement through the cardiology community last summer when an international multicenter clinical trial of more than 8,000 patients showed a 20% drop in hospitalizations and heart-failure mortality at a median follow-up of 27 months, compared with the commonly used angiotensin-converting enzyme (ACE) inhibitor enalapril.
Side effects included higher rates of hypotension and non-serious angioedema, but the patients receiving the combination drug also showed less renal impairment, hyperkalemia, and cough than the enalapril group. The trial, called PARADIGM-HF, was halted early because the outcomes were so favorable, and results were published in the Sept. 11, 2014, New England Journal of Medicine.
“This study opens the door to the possibility of being successful with new drug pathways,” said Dr. Jessup, who treats heart failure almost exclusively and is considering using the new ARNI for 30% to 40% of her patients.
In October 2014, the Canadian Cardiovascular Society Heart Failure Guidelines took the unusual step of recommending that the drug be used in patients similar to those in the trial, contingent on its approval, rather than waiting until it was on the market.
“The panel thought hard about it, but the evidence was strong, and because we only update annually, we would have had to wait another year” to make the recommendation, said Gordon Moe, MD, chair of the heart failure guideline, professor of medicine at the University of Toronto and director of the heart failure program at St. Michael's Hospital. At press time, Canada had not approved the drug, but Dr. Moe said Canadian drug approvals usually parallel those of the U.S. Other countries and the European Union are also likely to approve the drug soon, according to news reports.
The FDA approved the ARNI specifically as a treatment for patients with chronic heart failure (New York Heart Association classes II-IV) and reduced ejection fraction. It is intended to be used in place of an ACE inhibitor or other ARBs.
A clinical trial of the drug in patients with heart failure and preserved ejection fraction, PARAGON-HF, is now in progress, although results won't be available for another 3 years, said Milton Packer, MD, a cardiologist at UT-Southwestern Medical Center in Dallas and one of the principal authors of the PARADIGM-HF study, which was funded by the drug's manufacturer, Novartis.
Like stand-alone ARBs, the new drug blocks the renin-angiotensin system to prevent additional damage to the heart, but it also inhibits the enzyme that interferes with the body's own renin-angiotensin blockers, according to Dr. Packer.
“The amazing thing is that these 2 parts of the drug are so complementary that the combination drug is better tolerated than either individually,” he said. The PARADIGM trial included a lead-in period to test how well patients tolerated each drug, during which about 10% of potential participants dropped out, according to Dr. Packer.
Dr. Packer emphasized that the patients in the trial were stable and had been on stable doses of widely used drugs before entering the trial. “If you asked them at the beginning of the study how they were doing, they would say, ‘Not bad,’” he said. “But a patient with heart failure who's ‘not bad’ is still in trouble and is going to have progressive disease. The appearance of stability is just that—an appearance.”
Putting it into practice
Physicians not involved in the trials are beginning to test out the drugs themselves. Clyde Yancy, MD, MACP, chief of cardiology at Northwestern Medicine in Chicago, prescribed the ARNI for the first time within a couple of weeks of its approval, and he expects uptake to be “brisk.”
Real-world use probably can't match the “remarkable” benefits seen in the trial, he said, predicting that more evidence of expected side effects, particularly hypotension, may emerge. The challenge will be figuring out which patients will benefit.
“There are no data to suggest that this should be first-line therapy in newly diagnosed [heart failure] patients,” Dr. Yancy said. More traditional ACE and ARB medications should be tried first, he advised, and physicians may want to be extra cautious prescribing the new drug to patients who weren't well represented in the PARADIGM study, specifically African Americans, patients older than 75, and those with NYHA class IV heart failure.
Hospitalists are most likely to first encounter the new drug on a medication list rather than prescribing it themselves, he predicted. “As more hospitalists become involved in longitudinal care, many may become prescribers for the entire suite of therapies for reduced [ejection fraction] heart failure,” Dr. Yancy said.
However, if the drug has the hoped-for effect of keeping heart failure patients out of the hospital, hospitalists may see a fundamental change in the profile of heart failure patients who are hospitalized, he added.
Not everyone is quite so excited about the drug's potential. Cardiologist John Mandrola, MD, of Louisville Cardiology Group in Kentucky, listed 10 reservations that will keep him off the drug's bandwagon in a column published on Medscape (where he is chief cardiology correspondent) shortly after FDA approval.
Among them was the duration of the trial: only 2.5 years, not long enough to identify possible long-term side effects from a drug that is intended to be taken long term. (Some researchers have suggested that neprilysin inhibition might increase amyloid deposits in the brain over time, thereby posing a risk of dementia.)
Also, the patients in the trial deviated from a real-world population in some important ways. They skewed relatively young with a median age of 63.8 years; 80% were men; and only 6% were black. “How does that cohort generalize to the millions of elderly, female, and nonwhite [heart failure] patients with comorbid diseases?” Dr. Mandrola asked.
While he is willing to prescribe the drug to carefully selected stable patients, particularly those who have high blood pressure, Dr. Mandrola intends to take things slow and not be swayed by hype. “I would recommend extreme caution in starting this drug when patients are acutely ill in the hospital,” he said, because hospitalized patients are already at risk for low blood pressure and a drug with a side effect of hypotension could be particularly dangerous for them.
The hype machine kicked into gear immediately after the FDA's OK, Dr. Mandrola observed. He tweeted a photo of an e-mail pitch from a drug rep that came 2 days after approval. The drug also began shipping immediately, in 3 doses to accommodate a gradual introduction. A Novartis spokeswoman said the company will move quickly to persuade hospitals to add it to their formularies.
Novartis puts the daily cost of the drug at about $12.50, or roughly $4,500 per year, many times the cost of ACE inhibitors and ARBs that are the current standard of care. The cost to the patient will be subject to negotiations between the manufacturer and insurers.
Company executives have proposed a possible “pay for performance” structure where insurers would pay less for the drug initially but give Novartis some type of bonus if the medication reduced overall health care costs for the patients who took it.
Pay for performance could be tricky to execute, predicted cardiologist Harlan Krumholz, MD, a professor of cardiology at Yale School of Medicine in New Haven, Conn.
“I love the spirit of saying you don't have to pay unless we deliver the goods, but in real life it's hard to understand what effect a drug has, and there are lots of different factors that influence outcomes,” he said. “I think it's going to take some time to figure out.”
He's cautiously excited about the initial trial results but would like to see more research, especially in patients with comorbid conditions. In the meantime, the best course is to present the data to patients and work with them to assess the balance of advantages, risks, and potentially substantial out-of-pocket costs compared with standard heart failure drug regimens, Dr. Krumholz said.
The manufacturer is considering bundling the drug with some type of digital health tool to help physicians and patients track its effects, but Dr. Mandrola casts a doubtful eye on such gadgets.
“I don't think they would affect me except to increase my already heightened awareness of pharma marketing,” he said. “I'm not a techie Luddite, but when you're treating CHF, it's hard to beat education, good social support, a scale, and a [blood pressure] cuff.”