January 08, 2016
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New therapies change landscape of care for patients with HF

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The treatment and management of patients with HF has taken a dramatic leap in the past year. Although HF remains one of the most difficult heart diseases to treat, the introduction of new drugs and new technologies has improved the outlook for many patients with HF.

Much of the optimism is driven by recent FDA approval of two new drugs: ivabradine (Corlanor, Amgen) and sacubitril/valsartan (Entresto, Novartis). Ivabradine was approved in April for reduction of hospitalization for worsening HF in patients with HF with reduced ejection fraction (HFrEF) who have a resting heart rate of at least 70 bpm and are on a maximally tolerated dose of beta-blockers. Sacubitril/valsartan was approved in July for reduction of CV death and HF-related hospitalization in patients with HFrEF. In addition, some experts said the October approval of patiromer (Veltassa, Relypsa) for treatment of hyperkalemia could, ultimately, benefit many patients with HF.

“It is a different landscape today compared to a year ago,” Mary Norine Walsh, MD, FACC, medical director of HF and cardiac transplantation and director of nuclear cardiology at St. Vincent Heart Center, Indianapolis, and vice president of the American College of Cardiology, told Cardiology Today. “We have new therapies that are exciting and have changed our practice dramatically in the last year.”

After decades of relying on the same therapies to treat HF, doctors now have new one options at their disposal, and more are expected soon. Experts interviewed by Cardiology Today said the field is in the midst of an adjustment period due to changes in practice, cost and insurance implications, and patient expectations, but ultimately, 2015 will be thought of as the start of a new era in HF care.

Use of ivabradine

Ivabradine is likely to benefit a subset of patients with HFrEF who have a persistently elevated heart rate despite being in sinus rhythm and receiving the highest dose of beta-blockers that they can tolerate, a condition associated with increased risk for hospitalization.

Mary Norine Walsh, MD, FACC, of St. Vincent Heart Center in Indianapolis, discusses recent developments that have given clinicians more options for treating patients with HF.
Mary Norine Walsh, MD, FACC, of St. Vincent Heart Center in Indianapolis, discusses recent developments that have given clinicians more options for treating patients with HF.

Photo credit: St. Vincent Heart Center; printed with permission.

FDA approval was based in part on the SHIFT study conducted by Karl Swedberg, MD, from the University of Gothenburg in Sweden, and colleagues. Results of SHIFT demonstrated that patients assigned ivabradine had reduced risk for CV death or hospitalization for worsening HF compared with those assigned placebo (HR = 0.82; 95% CI, 0.75-0.9). The results were primarily driven by reductions in risk for hospitalization for worsening HF (HR = 0.74; 95% CI, 0.66-0.83) and HF-related death (HR = 0.74; 95% CI, 0.58-0.94).

In an interview with Cardiology Today, Walsh said this drug could particularly benefit younger patients with HFrEF.

“Many times, patients who are younger have HFrEF with dilated ventricles but persistently elevated heart rates,” she said. “We know from the trials that benefits have been demonstrated in patients in sinus rhythm with resting heart rates over 70 bpm. This is a minority of HFrEF patients, but it is certainly a subset for whom we will see benefit.”

Javed Butler, MD, MPH, chief of cardiology and professor of medicine at Stony Brook University, New York, agrees. “For chronic outpatient HF, that’s where the data are and that’s where the biggest benefit is with ivabradine,” he said.

Butler noted, however, that approval of ivabradine has sparked a debate about whether patients have actually been receiving optimal doses of beta-blockers.

“Now that this drug is available, there are people questioning whether the beta-blocker dose has been maximized, and whether we should start this drug or try again to push the dose of beta-blockers,” said Butler, a member of the Cardiology Today Editorial Board.

Adoption of sacubitril/valsartan

Unlike ivabradine, the expected patient population for sacubitril/valsartan is broad, experts said.

“The approval of Entresto has probably impacted HF practice more than the approval of any medication for a long time,” Walsh said.

Douglas Mann, MD
Douglas Mann

“Entresto has the potential to impact all patients with HF because in the PARADIGM-HF trial, in a head-to-head comparison, it was superior to ACE inhibitors,” Douglas Mann, MD, professor of medicine and chief of cardiology at Washington University School of Medicine, St. Louis, said in an interview. “ACE inhibitors, we recommend for patients with NYHA class I through class IV HF, so the potential impact for Entresto could be far broader than that for ivabradine.”

In PARADIGM-HF, John J.V. McMurray, MD, from University of Glasgow, Scotland, and colleagues found that patients assigned sacubitril/valsartan had lower risk for CV death or first incidence of HF-related hospitalization compared with those assigned the ACE inhibitor enalapril (HR = 0.8; 95% CI, 0.73-0.87). The sacubitril/valsartan group also had lower risk for all-cause mortality (HR = 0.84; 95% CI, 0.76-0.93) and CV mortality (HR = 0.8; 95% CI, 0.71-0.89).

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Further analysis indicated that sacubitril/valsartan has the potential to benefit patients across the HFrEF spectrum, Barry H. Greenberg, MD, distinguished professor of medicine and director of the advanced HF treatment program at University of California–San Diego School of Medicine, told Cardiology Today.

“The clinical data incorporated a large segment of the HF population,” he said. “Based on the analysis of that database, there seems to be efficacy across the board, so the indications included on the package label are broad.”

However, Greenberg noted that this has caused “a bit of consternation” among clinicians. “Some are asking, ‘Do we switch everyone over?’” he said. “My take on the data is that you would consider switching a substantial portion of stable patients with HFrEF who are taking an ACE inhibitor or angiotensin receptor blocker over to the sacubitril/valsartan combination. I’ve heard from clinicians who say, ‘Maybe we’ll only [switch] those patients who are not doing well.’ But that would not be reflective of what the data tell us, in that those patients who were stable ... derived benefit from Entresto compared with standard ACE inhibitor therapy.”

Butler said sacubitril/valsartan represents a rare case in which patients with HF can have one medication substituted for another, instead of having it added on to their therapy. However, he said, this may present challenges with some patients.

“In real life, that becomes a bigger challenge because it takes some time to talk to the patients, especially those who are stable,” he said. “Those who are more symptomatic are looking for changes, but for those who are more stable it takes some time to convince them that it is worth getting off their stable medication and try this new medication because, in the long run, the data suggest that it’s in their favor. Nevertheless, it requires some follow-up visits and blood tests. However, considering the remarkable benefits seen in the PARADIGM-HF trial, this is time well spent by the patients and the health care providers.”

Randall C. Starling, MD, MPH
Randall C. Starling

It will be a few years before the full effect of sacubitril/valsartan is understood, Randall C. Starling, MD, MPH, head of the section of Heart Failure and Cardiac Transplant Medicine, medical director of the Kaufman Center for Heart Failure, staff cardiologist in the Robert and Suzanne Tomsich Department of Cardiovascular Medicine and vice chairman of Cardiovascular Medicine Operations at Cleveland Clinic, told Cardiology Today.

“Time will tell the impact of sacubitril/valsartan for mainstream HFrEF and whether patients at higher risk will tolerate the drug, and whether there will be benefits from reduced dosages not utilized in PARADIGM-HF,” Starling said.

Patiromer approval

The approval of patiromer is not restricted to patients with HF; it is indicated for almost anyone who has hyperkalemia. But for the HF population, the big news is not that it can lower potassium, but that it may enable patients to use drugs that help with HF but raise potassium, Butler said.

Javed Butler, MD, MPH
Javed Butler

“The place where there is an unmet need ... is in chronic therapy for patients with HF and hyperkalemia who are unable to take renin-angiotensin-aldosterone system (RAAS) inhibitors, and taking a chronic therapy will lead to increasing the use of RAAS therapy,” he said. “Although there are data out to a year that it is safe and well tolerated, we don’t have HF-focused studies. We need to know whether putting patients with HF on this therapy so they can have RAAS therapy will lead to improved outcomes. To date, we have not been able to give RAAS inhibitors at all, or at least in recommended doses, because of this risk for hyperkalemia.”

Mann, a Cardiology Today Editorial Board member, said the drug might be appropriate for patients with HF and impaired renal function “who we’ve not been able to get aldosterone antagonists into. When you put those patients on them, they retain potassium. For that group, it may expand the ability to use aldosterone antagonists, which are wonderful drugs and inexpensive. That has the potential to have an impact, but like with ivabradine, it would be in smaller swath of the HF population.”

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Cost, insurance barriers to adoption

Despite promise, immediate widespread uptake has not yet occurred for any of the drugs, and the most prominent reasons have to do with costs and insurance coverage, experts said.

“For some time, we have been used to treating patients with HF with all generic therapies,” Walsh said. “Now, all of a sudden, there are several drug and device therapies that are all more costly. We have to pick and choose which ones to use, as insurance and payment barriers come into play.”

Even early adoption of sacubitril/valsartan has been limited to a subset of patients because of cost and, in many cases, insurance coverage remains uncertain, Mann said.

“The potential for Entresto to be a game-changing drug is significant, but the big hurdle with Entresto is going to be pricing, and whether the patients’ insurance companies will actually be willing to pay for it,” he said. “These things are all being worked out now.”

What is often happening, Walsh said, is that doctors have to work out some form of prior authorization with the insurance companies before prescribing.

“There is a fairly elaborate process for insurance coverage, involving getting patients on samples and then talking to insurance companies and filling out prior authorization paperwork in order to get the medication,” she said. “At least in the region of the country where I work, some insurance companies are not favorably tiering the new drugs, so many patients are out-of-pocket.”

Fewer breakthroughs in HFpEF

Patients with HFrEF have many more options available to them than even a year ago, but the same is not the case for patients with HF with preserved EF (HFpEF).

“There are certainly a number of things that have been tried in patients with HFpEF, but nothing has worked for sure,” Butler said.

Ivabradine and sacubitril/valsartan are approved for HFrEF only. Although patiromer is approved for almost anyone with hyperkalemia, it is not yet clear to what extent it will benefit those with HFpEF.

Barry H. Greenberg, MD
Barry H. Greenberg

The ongoing PARAGON-HF study is evaluating the effects of sacubitril/valsartan in patients with HFpEF. If the outcomes are positive, it could possibly lead to the drug getting a new indication for patients with HFpEF.

“Entresto has been shown in a pilot study to have beneficial effects on surrogate markers in the HFpEF population, and is now being looked at in a larger clinical trial in this population,” said Greenberg, a member of the Cardiology Today Editorial Board. “If the promise that was seen in that smaller trial is translated into clinical benefits in the larger trial, then we will have a HFpEF drug available.”

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Absent any proven alternatives, some clinicians have turned to spironolactone. The overall results of the TOPCAT trial indicated that spironolactone did not reduce risk for CV death, HF hospitalization or aborted cardiac arrest in patients with HFpEF. However, a subgroup analysis by region raised questions about whether the drug was effective in patients enrolled at sites in North America and South America. Spironolactone was associated with a lower rate of the primary outcome in patients from the Americas (HR = 0.82; 95% CI, 0.69-0.98), but not in those from Russia and Georgia (HR = 1.1; 95% CI, 0.79-1.51), Marc A. Pfeffer, MD, PhD, FACEP, FAHA, from Harvard Medical School and Brigham and Women’s Hospital, and colleagues reported.

Marc A. Pfeffer, MD, PhD, FACEP, FAHA
Marc A. Pfeffer

“Many people, and I would likely put myself in that group, actually felt the TOPCAT study had positive information regarding the role of aldosterone agents in patients with HFpEF,” Mann said. “There is a lot of talk that many of the patients in Europe probably didn’t have HFpEF and, therefore, wouldn’t have benefited from the drug. According to the way we look at trials, you can’t just pick the group you want. But I personally am putting patients on aldosterone agents for HFpEF. I’m finding a reason to do it because it’s the only drug we have.”

According to Butler, debate over the regional analysis will likely continue. “From a strictly scientific perspective, the trial was negative, but the data from the Americas are so compelling that, in the absence of any other data or known therapies for these patients, on a clinical judgment basis, spironolactone may be OK to use in this population,” he said.

Other research, developments

The past year also has seen the adoption in some centers of the CardioMEMS HF System (CardioMEMS/St. Jude Medical), which measures pulmonary artery pressure and heart rate in patients with NYHA class III HF previously hospitalized for HF, and which has been shown to reduce the rehospitalization rate in patients with HFrEF and HFpEF. However, Butler said, uptake has been slower than expected because of cost.

“Pricing is an issue, but for people who have difficult-to-manage volume overload issues, and are recently admitted with HF, the CardioMEMS device may help clinicians keep people out of the hospital,” Mann said.

In recent years, many abnormalities related to HF have been identified, and several drugs targeting them are now in development, Greenberg said.

“This will have to be worked out in clinical trials, but some of them are exciting, like the soluble guanylate cyclase stimulators, which seem to be a promising avenue,” he said. “Some of the newer vasodilator drugs with additional properties, like serelaxin and ularitide for acute HF, are promising. A novel inotropic drug, omecamtiv mecarbil (Amgen/Cytokinetics), is also being developed. New drugs coming down the pike augers well for the future.”

A second potassium-lowering agent that could benefit patients with HF, sodium zirconium cyclosilicate (ZS-9, ZS Pharma), is under review by the FDA, which is expected to make a decision by May.

Vericiguat (Bayer/Merck), one of the soluble guanylate cyclase stimulators, is being tested in HFpEF in the ongoing SOCRATES-PRESERVED trial, Butler said.

Walsh also noted that “there is some interesting ongoing work in the mechanical circulatory support realm, with [ventricular assist devices] becoming smaller and being implanted in different ways, such as via lateral thoracotomy rather than sternotomy. As these mechanical therapies continue to be developed and improved, a larger patient group can benefit. As an example, women were not eligible for all VAD therapy, and that’s no longer a barrier.”

However, she said, more trials are needed for therapies for HFpEF, which disproportionately affects women and the elderly.

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Another area of research that could bear fruit is “the role of the autonomic nervous system and modulation in the treatment of HF,” Starling said.

In addition, more work must be done about how to optimize the transition from inpatient care to outpatient care, he said.

“We need to understand how to provide team care and the continuum from inpatient to outpatient, and importantly, transitions of care,” he said. “Not all patients with HF have the same risks and needs, and identifying the risks and solutions that are patient-specific will optimize outcomes and value.”

A world of difference

The care of patients with HF has begun a radical transformation that, if the data hold up for the long term, could make quality of life and outcomes far better than expected.

“These are exciting times, and we’re going to get some good therapies for these patients,” Butler said.

The progress is especially welcomed by long-time veterans of the subspecialty, who have seen novel therapies for HF fail repeatedly until recently.

“If you reflect back over 10 years, this has been a remarkable journey,” Mann said. “The number of different ways we have of treating these patients is just phenomenal. Years ago, we just didn’t have any therapies that worked. Today, we have multiple therapies that have made a huge impact on patient outcomes and quality of life. It’s fun to watch all these new therapies and how they help patients.” – by Erik Swain

Disclosures: Butler reports consulting for Amgen, Bayer, Boehringer Ingelheim, Cardiocell, Janssen Pharmaceuticals, Novartis, Relypsa, Trevena, Zensun and ZS Pharma. Greenberg reports consulting for Novartis, Relypsa and ZS Pharma. Starling reports serving on the steering committee of ROADMAP trial sponsored by Thoratec and the INOVATE HF trial sponsored by BioControl and serving as an investigator on the PARADIGM-HF trial sponsored by Novartis, but receiving no honoraria. Mann and Walsh report no relevant financial disclosures.