A look at new therapeutic advances for HF management

Issue: November 2016

BOCA RATON, Fla. — New therapeutic advances, in the form of recently approved drugs and others on the horizon, are changing the management of HF, according to a speaker at the American Society for Preventive Cardiology’s Congress on Atherosclerotic Cardiovascular Disease Prevention.

HF is the No. 1 diagnosis for Medicare hospital admissions and the cost of care exceeds $40 billion per year in the United States, Douglas D. Schocken, MD, FASPC, professor of medicine at Duke University School of Medicine and medical director of the Duke Heart Center at Southpoint Duke University Medical Center, told attendees here. Moreover, “the emotional cost [of HF] to the families and society is incalculably large,” he said.

“[HF] is likely to emerge as a major contributor to decline in quality adjusted life years (QALY) in developing countries and for the elderly and worldwide,” he said.

For patients with HF with reduced ejection fraction (HFrEF), angiotensin receptor blockers and ACE inhibitors can reduce mortality by between 10% and 20%, mineralocorticoid receptor antagonists by about 30% and beta-blockers by nearly 40%, according to Schocken. “But, when we combine all of these drugs, we are still not reaching as much as 40% mortality reduction,” he said. “That lets us know that we’ve got a lot more work to do.”

Newer therapeutic options

Two agents were recently approved by the FDA for use in patients with HF: sacubitril/valsartan (Entresto, Novartis) and ivabradine (Corlanor, Amgen).

Neprilysin inhibition potentiates actions of endogenous vasoactive peptides that counter maladaptive mechanisms in HF, Schocken said. Sacubitril/valsartan is an angiotensin receptor-neprilysin inhibitor that received FDA approval in July 2015 for reduction of CV death and HF-related hospitalization among patients with HFrEF. The therapy combines the angiotensin receptor blocker valsartan bonded to the neprilysin inhibitor sacubitril.

Approval of sacubitril/valsartan was based on data from the PARADIGM-HF trial, which included approximately 8,400 adults with NYHA class II, III or IV HFrEF. The trial was stopped early due to significant reductions observed in the risk for CV death and HF-related hospitalization among patients treated with the drug vs. enalapril (HR = 0.8; 95% CI, 0.73-0.87; P = .0000002; number needed to treat = 21). Results also showed improvement in secondary endpoints such as Kansas City Cardiomyopathy Questionnaire clinical summary score at 8 months, he said. Angioedema was observed more in patients who received sacubitril/valsartan; the FDA warned against administering sacubitril/valsartan in combination with an ACE inhibitor due to increased angioedema risk and this was also echoed in the 2016 Update of the 2013 Guidelines for the Management of Chronic HF released by the American College of Cardiology, American Heart Association and Heart Failure Society of America.

In the population with CVD, heart rate is even more directly related to mortality, according to Schocken. Much of the benefit of beta-blockade in the management of HF is attributed to reduction in heart rate, he said. However, many patients with HF are unable to tolerate beta-blockers due to adverse effects such as hypotension. Ivabradine is a specific and selective inhibitor of the I_f ion channel. In April 2015, the FDA approved ivabradine to reduce hospitalization from worsening HF. Ivabradine is indicated for stable patients with symptomatic HF, a normal heartbeat with a resting heart rate of at least 70 bpm and those taking maximally tolerated doses of beta-blockers.

The efficacy of ivabradine was studied in the SHIFT trial of 6,500 patients. Results demonstrated that ivabradine reduced risk for the primary endpoint of CV death or hospitalization for worsening HF by 18% vs. placebo (HR = 0.82; 95% CI, 0.75-0.9; P < .0001) and reduced risk for worsening HF alone by 26% (HR = 0.74; 95% CI, 0.66-0.83; P < .0001). The most common adverse events associated with ivabradine are bradycardia, hypertension, atrial fibrillation and temporary vision disturbance.

According to the ACC/AHA/HFSA updated guideline, sacubitril/valsartan and ivabradine are now included in the drug options for patients with stage C HFrEF along with ACE inhibitors and angiotensin II receptor antagonists, aldosterone antagonists, beta-blockers, combination isosorbide dinitrate and hydralazine, and diuretics.

On the horizon

There are several other new targets and tools on the horizon for management of patients with HF, including:

positive inotropes such as omecamtiv mecarbil (Amgen, Cytokinetics);
soluble guanylate cyclase stimulators such as vericiguat (Merck/Bayer);
third-generation mineralocorticoid receptor antagonists such as finerenone (Bayer);
·vasoactive peptides such as ularitide (Cardiorentis AG) and serelaxin (Novartis);
allogeneic mesenchymal precursor cells, gathered from a single donor with no immunosuppression needed.
gene transfer therapy using recombinant human genetic material delivered with a viral vector.

Schocken also highlighted the possibility of new for “old” drugs, such as:

SGLT2 inhibitors, used to treat type 2 diabetes, may have a role in HF management;
rivaroxaban (Xarelto, Janssen), and other novel oral anticoagulants, may have a role in the treatment of HFrEF in patients with CAD; and
sacubitril/valsartan may have a role in the treatment of HF with preserved EF (HFpEF).

“Current HF management is palliative, and not curative,” Schocken said. “We have made very little progress in the management and prevention of HFpEF … [and] the medical management of acute decompensated HF.”

Looking ahead, Schocken said the field may now be “entering the era of prevention.”

Reference:

Schocken DD. Management of Heart Failure: A Look Back and What’s on the Horizon. Presented at: American Society for Preventive Cardiology Congress on Atherosclerotic Cardiovascular Disease; Sept. 16-18, 2016; Boca Raton, Fla.

Disclosure: Schocken reports contracted research with Novartis.