Researchers Still Looking for Effective Treatment for Heart Failure with Preserved Ejection Fraction

Recent trials involving promising medications to treat patients with heart failure with preserved ejection fraction have not produced significant reductions in mortality.

No treatment has been shown to convincingly reduce mortality in patients with heart failure (HF) with preserved ejection fraction (HFpEF). Clinical trials investigating treatments for this population have been consistently disappointing to date. ACE inhibitors, angiotensin receptor blockers, beta blockers, and mineralocorticoid receptor antagonists have all failed to significantly reduce mortality in HFpEF patients.

At the 2016 annual meeting of the Heart Failure Society of America, Orly Vardeny, PharmD, MS, associate professor at the University of Wisconsin School of Pharmacy and Medicine and a clinical pharmacy specialist at the William S. Middleton Memorial VA Hospital, in Madison, WI, reviewed recent clinical trial data focused on HFpEF.

The TOPCAT spironolactone trial did not meet primary outcome goals, but did result in reduced hospitalizations as compared to placebo. The dramatic regional variation reported between US, Canada, Argentina, and Brazil multicenter trials as compared to Russia and Georgia trials turned out to be due to misrepresentation of compliance, as the expected metabolites were not detected in many of the Russian and Georgian patients. Thus, the Russian and Georgian data is largely ignorable.

Vardeny emphasized that HFpEF is an extremely comorbid condition that usually includes older patients who are more likely to have hypertension (most common), diabetes, renal dysfunction, sleep apnea, and anemia. Accordingly, it is just as important to treat the comorbidities. Beta blocker use, however, has fallen out of favor.

In summary, when it comes to current treatments for HFpEF, Vardeny said physicians have to be extra cautious with diabetes patients, and manage comorbidities with aggressive control of hypertension, diabetes, and ischemic heart disease. Treatment with spironolactone did reduce hospitalizations, and so clinicians may want to use it more frequently for treating HFpEF patients.

Novel burgeoning treatment targets for HFpEF include focusing on nitric oxide (NO) signaling, which is impaired in HFpEF. One strategy is to increase production of NO, according to Vardeny. The NO-dependent cGMP pathway can be targeted by multiple approaches including: (1) PDE5 inhibitors like sildenafil (RELAX trail), (2) sGC activators/inhibitors (LEPHT trial), (3) nitrates (NEAT-HF), or (4) neprilysin inhibitors (PARAMOUNT trial).

In the RELAX trial, 200 patients with HFpEF were treated with sildenafil, but the results were disappointing. There were no significant differences in the primary measure of peak oxygen consumption, nor improvements in secondary outcomes. Direct stimulators of soluble guanylate cyclase (sGC), which increase sensitivity to NO, have now been examined. The SOCRATES-PRESERVED trial showed no significant reduction in log-NT or left ventricular volume after treatment with a variety of doses of the sGC activator vericiguat. However, secondary analysis revealed significantly improved quality of life (QoL) scores at 12 weeks post-treatment. So, even though no apparent improvement in cardiac function was detected, there was an improvement in patient QoL, according to Vardeny. Finally, in the NEAT-HFpEF trials using isosorbide mononitrate, there was no difference seen in the primary or secondary endpoints. There was unfortunately an actual reduction in activity when compared to placebo.

Sacubitril/valsartan is also being examined for HFpEF in several clinical trials. In the phase II PARAMOUNT study (n~200), there was significant reduction at 4 and 12 weeks as measured by the primary outcome of NT pro-BNP. There were also improvements seen in left atrial size and NYHA functional class. High hopes remain for sacubitril/valsartan for treating HFpEF. The ongoing PARAMOUNT study is a phase III study with HFpEF and involves a population of 4,600 patients with structural heart disease, heart failure, and diastolic dysfunction. Patients will be randomized for treatment with sacubitril/valsartan up to 200 mg bid or valsartan 100 mg bid with primary outcome measures of CV death or hospitalizations.

In conclusion, Vardeny stressed that HFpEF treatment includes requires treatment of both congestion and comorbid conditions. Trials with RAS blockers and SMS agents have been disappointing, with the slight exception that spironolactone may reduce hospitalizations and vericiguat may improve QoL. She said we will learn more about sacubitril/valsartan in the coming years.

During the ensuing discussion, Dr. Teerlink was impressed with the improved QoL seen in the SOCRATES trial and asked, “Have we gotten to the point where we don’t care about making people feel better?” Vardeny replied that, in her personal opinion, “of course we all want to make people feel better, but you can’t ignore the fact that we still have a negative outcome based on current data.”