Looking into the Future of Acute Heart Failure Treatment

SEPTEMBER 20, 2016
W. Todd Penberthy,PhD
At the highly anticipated panel presentation for heart failure (HF) treatment updates at the 2016 Heart Failure Society of America Scientific Meeting, Michael Felker, MD, professor of medicine and member of the Duke Clinical Research Institute, began the first presentation by declaring: “If you were to ask what’s new in acute heart failure pharmacology? The truth is that it has not changed fundamentally much since the 1970s. It is remains mostly diuretics, vasodilators, oxygen, with consideration of inotropic therapies.” With that qualifier, Felker reviewed three promising new heart failure treatments.
 
Serelaxin is a vasodilator that decreases systemic vascular resistance, increases glomerular filtration rate (GFR), increases renal blood flow, decreases collagen synthesis, and increases collagen degradation. Prospective, randomized, placebo-controlled serelaxin trials were the largest of the new HF drug clinical trials performed in recent years, and involved patients with high blood pressure and HF. Dyspnea was measured as the primary endpoint.
 
Serelaxin treatment was associated with approximately a 20% reduction after just 5 days of randomization. Potentially most exciting, an impressive reduction in cardiovascular (CV) death was observed after 180 days (6% compared to 9.5% for placebo). This was originally just a measure for adverse events. Researchers need to confirm this finding with future trials according to Felker.
 
The next new HF drug in the pipeline that was presented was a natriuretic peptide known as ularitide. The human hormone equivalent, urodilatin, is primarily secreted by the kidney and promotes vasodilation with a variety of HF-favorable hormone effects that most profoundly involves increasing renal and myocardial function. Phase II studies (SIRIUUS II), about 10 years old now, revealed ularitide reduces blood pressure, dyspnea, and 30-day mortality, thus supporting implementation of additional future studies (TRUE-HF).
 
The last new pipeline drug update presented by Felker focused on the nitroxyl (HNO) prodrug CXL-1427. In use for nearly 100 years, nitroxyl prodrugs were originally known as Angeli’s salt. It has similar effects as nitric oxide, but distinct differences. Unlike nitric oxide, HNO is not detectable in biological systems, is insensitive to oxygen, and non-enzymatically reversible. HNO has the unique properties of being inotropic and lusitropic by speeding calcium cycling through SERCA-2A, while also increasing calcium sensitivity at the myocyte. Thus, it appears to positively affect all factors controlling contractility. CXL-1427 has been examined previously and determined to reduce the pulmonary capillary wedge pressure and blood pressure, too. These are early data, and new trials are in progress.
 
Furosemide administration has been significantly optimized for greater effectiveness and cost savings. Previously it was only administered intravenously, but now novel buffering has made it possible to perform subcutaneous administration with a pump in an outpatient setting in low-risk patients.
 
In conclusion, Felker pointed out that while we still lack many new established treatments at this point, there remain several medications in the pipeline that appear to have great promise based on preliminary data.
 
During the discussion there was great interest around the most impressive decrease in mortality seen in the serelaxin trials. Favorable shifts were quickly observed shortly after serelaxin administration and so the answer would seem to lie in there. Moreover, it was pointed out that there is this ongoing concept based largely on animal model research, that treating early can cause long-term and lasting improvements via remodeling effects.
 
 
 
Related Coverage:
 
Duke University's Joseph Rogers, MD, on the Benefits of Palliative Care in Heart Failure
 
Providing a New Approach to Patient Care: A Conversation with Pieter Mutendam from scPharmaceuticals
 
Novel Buffered Subcutaneous Furosemide Combines Lower Cost and Therapeutic Benefit for Patients with Heart Failure
 
 

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