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PANACHE: Neladenoson unsuccessful in improving walking distance in HFpEF
NEW ORLEANS —A partial adenosine A1 receptor agonist in patients with HF with preserved ejection fraction did not have a dose-response effect for 6-minute walk distance at 20 weeks and other endpoints such as activity levels, ECG monitoring and echocardiographic endpoints, according to data from the PANACHE trial presented at the American College of Cardiology Scientific Session.
“This is the first randomized controlled trial of a partial adenosine A1 receptor agonist in HF with preserved ejection fraction,” Sanjiv J. Shah, MD, professor of medicine and director of the T1 Center for Cardiovascular Therapeutics at of Northwestern University Feinberg School of Medicine, said during the presentation.
In this phase 2b trial, researchers analyzed data from 305 patients with a history of chronic HFpEF, NYHA class between II and IV, left ventricular ejection fraction greater than 45% and a 6-minute walk distance between 100 m and 550 m. In addition, within the last 6 months, patients were on diuretics, had an elevated B-type natriuretic peptide and either met structural criteria or had elevated LV filling pressures. Patients in this study had high rates of hypertension, atrial fibrillation, diabetes and obesity, and low rates of CAD.
Patients were assigned 5 mg (n = 27; mean age, 74 years; 59% women), 10 mg (n = 50; mean age, 72 years; 52% women), 20 mg (n = 51; mean age, 74 years; 41% women), 30 mg (n = 50; mean age, 73 years; 64% women) or 40 mg neladenoson bialanate (n = 51; mean age, 73 years; 54% women) or placebo (n = 76; mean age, 74 years; 47% women).
“A partial adenosine A1 receptor agonist has multiple potential beneficial effects, as have been seen in preclinical studies,” Shah said during the presentation. “These include improved mitochondrial function, not only in the heart but in the skeletal muscle, enhanced SERCA2a activity, improved energy substrate utilization, decreased myocardial fibrosis and hypertrophy, increased myocardial capillary density and anti-ischemic cardioprotective effects.”
The primary endpoint was a change in 6-minute walk distance at 20 weeks. Secondary endpoints included continuous ECG monitoring, activity levels, biomarkers and multiple echocardiographic endpoints.
There was a run-in period when patients underwent two 6-minute walk tests to familiarize them with the test, according to the presentation. After patients were assigned a treatment, they were followed up for 20 weeks, during which ECGs and activity levels were assessed. Patients were also followed up for up to 26 weeks for CV events and safety.
At 20 weeks, there were no significant changes between those assigned neladenoson and those assigned placebo regarding 6-minute walk test distance. There were increases in distance in those assigned neladenoson, although they were not statistically significant.
There were also no improvements in the secondary endpoints in both groups.
Both groups had no differences in the low rates of adverse events, including death, symptomatic bradycardia, HF hospitalization and acute kidney injury. There was a slight decline in renal function in patients assigned neladenoson.
“This was to be expected with the mechanism of the drug,” Shah said during the presentation. “With increasing doses of neladenoson, there was a slight decrease in [estimated glomerular filtration rate] such that the 40-mg group had about a 6 mm per minute decrease, and that was statistically significant.”
Heart rate also slightly decreased, although there were no atrioventricular blocks in the neladenoson groups vs. the placebo group.
“While there was a good safety profile at 20 weeks, there were slight decreases in renal function and heart rate,” Shah said during the presentation. – by Darlene Dobkowski
Reference:
Shah SJ, et al. Featured Clinical Research I. Presented at: American College of Cardiology Scientific Session; March 16-18, 2019; New Orleans.
Disclosures: The study was funded by Bayer AG. Shah reports he receives research funding from Actelion, American Heart Association, AstraZeneca, Corvia, NIH and Novartis, and consulting/advisory board/steering committees for Actelion, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cardiora, Coridea, CVRx, Eisai, Ionis, Ironwood, Merck, MyoKardia, Novartis, Pfizer, Sanofi, Tenax and United Therapeutics.
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The PANACHE study is yet another trial in the long list of studies focused on treatment of heart failure with preserved ejection fraction to miss its primary endpoint.
To some extent, we have become very enthusiastic about declaring failure in HFpEF. This is a phase 2 trial, so by definition, this is not a study that one might say is a conclusive result. Still, the problem with the results of the PANACHE study was there was absolutely no appreciable impact on several mechanistic endpoints. Had we seen an encouraging signal, even if not statistically significant, it might have given us enthusiasm to proceed further in the development of this therapy. However, across multiple, very relevant endpoints including change in NT-proBNP, we were not able to see any significant impact of neladenoson on patients treated with the drug.
It is not to say that the drug was not working. In fact, there were some indirect signals of drug efficacy such as a lowering of heart rate and changes in kidney function, which are expected effects of the drug, but there was no obvious benefit for 6-minute walk distance, NT-proBNP and quality of life.
The take-home message from this is that this study, like many of the other studies in HFpEF necessarily indicates that we may need to take a step back and ask just who we are treating when we say that they have “HFpEF.” It is increasingly clear that this is a diagnosis of many phenotypes, some of which may be treatment responsive with drug therapy, some of which may not be. Identifying which patients are treatment responsive and with what drug is going to be the relevant challenge.
We at the Mass General Heart Center are presenting data from a study driven by Hanna Gaggin, MD, that is examining the use of cluster phenotyping in the ACC PINNACLE registry in many hundreds of thousands of patients with heart failure. Gaggin used machine learning to identify individual clusters of clinical phenotypes in patients with heart failure. What was so fascinating about her result is that ejection fraction was not part of the clusters, really implying that EF is probably one of the worst ways to consider patients with heart failure. Although we have been very successful in patients with reduced ejection fraction because they have a consistent set of pathophysiologic targets, with HFpEF, work like Gaggin’s may be a step toward identifying groups of patients in whom therapies might be more effective.
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