A new study published in JAMA found an experimental drug did not improve exercise capacity among patients suffering from heart failure with preserved ejection fraction, a common form of heart failure.
Sanjiv Shah, ’00 MD, the Neil J. Stone, MD, Professor of Medicine in the Division of Cardiology and lead author of the study, said that while neladenoson bialanate may be useful for treating other cardiovascular conditions, the results of this study underlined the need for further research into heart failure with preserved ejection fraction (HFpEF).
Heart failure is a large public health burden in the United States: At least six million people nationwide have been diagnosed with the condition.
About half of cases are classified as reduced ejection fraction, meaning the heart is weak and unable to pump blood effectively. According to Shah, this type of heart failure is caused by direct damage to the heart, such as a heart attack, and is easily diagnosable and familiar to clinicians.
On the other hand, a heart with preserved ejection fraction (HFpEF) is pumping normally but the muscle is abnormally stiff, preventing the heart from filling properly. This type of heart failure is more difficult to diagnose using ultrasound, the usual method of diagnosing heart failure.
The proximate cause is less clear, but cardiovascular risk factors like aging, obesity, a sedentary lifestyle, diabetes and high blood pressure appear to have an impact.
“We now understand that HFpEF is really a systemic syndrome,” Shah said. “There’s something going on in the bloodstream that then secondarily makes the heart muscle and other organs sick.”
The ultimate therapy for HFpEF would be a medication that not only improved the heart muscle, but could improve other organs in the body as well. So the investigators turned to neladenoson bialanate, a partial adenosine agonist.
Adenosine is a chemical present in all human cells, combining with phosphate to form various compounds that are crucial for cellular energy transfer, dilating blood vessels, neurotransmission and more. However, high levels of adenosine have adverse effects, including low heart rate and neurological problems.
Because neladenoson bialanate is a partial agonist, it does not fully activate adenosine receptors, thereby avoiding harmful side effects. Accordingly, the drug was effective in early laboratory testing in animal models, Shah said.
“It seemed to be reducing fibrosis in the heart, making the heart muscles less stiff, and it appeared to protect the heart from damage and improve skeletal muscle function,” Shah said.
In the current study, investigators administered varying doses of neladenoson bialanate to 305 patients over a period of 20 weeks, seeking to define the optimal dose to treat patients with HFpEF. They measured the distance study participants could walk in six minutes — a common measure of cardiovascular health and exercise capacity — before and after treatment.
While some patients did see a mild improvement in walk distance — an average of about 20 meters — the study authors determined this distance wasn’t clinically significant.
“We think a significant threshold would be about 40 meters, a distance where patients might really feel like they’re improving,” Shah said.
Shah and colleagues also examined a variety of other outcomes in multiple domains and found that neladenoson did not improve any of those outcomes, either.
While Shah praised the dose-response method and multi-domain approach of the trial, he recognizes that there are still many unknowns with HFpEF, and developing better pre-clinical animal models of the disease should be a priority. However, neladenoson bialanate could have benefits in other patients.
“Thinking about patients with ischemic heart disease, coronary artery disease-associated heart failure or other potential scenarios where the heart muscle is under stress, like cancer cardiovascular toxicity, all might be good places to test this drug in the future,” Shah said.
Nonetheless, a treatment for HFpEF is still needed, and will only become more important, according to Shah.
“We’re getting better at preventing and treating heart attacks, so risk factors for heart failure with reduced ejection fraction are decreasing,” Shah said. “But certain risk factors for HFpEF are increasing in the population, like aging, obesity and diabetes — and those are big epidemics.”
This study was funded by Bayer AG, and Shah reported receiving personal fees from Amgen, Bayer, Boehringer-Ingelheim, Cardiora, Eisai, Ionis, Ironwood, MyoKardia, Merck, Sanofi and United Therapeutics; receiving grants and personal fees from Actelion, AstraZeneca and Novartis; and receiving grants from the National Institutes of Health, the American Heart Association and Corvia.