ARNI therapy trial misses target in heart failure, may have selective benefit only

Heart failure with preserved ejection fraction (HFpEF) is a common condition, affecting millions of people and resulting in significant illness and death. No effective treatments have been developed for this condition.

A drug combination called ARNI successfully reduces hospitalizations and cardiovascular deaths in heart failure associated with reduced ejection fraction (HFrEF). However, this does not extend to HFpEF, according to the findings of a five-year trial reported this week.

However, the researchers noted some improvement in a subset of patients who had heart failure with slightly reduced ejection fraction, as expected from earlier research, and in females.

What is heart failure?

Heart failure, which affects over 5.5 million people in the US alone, is associated with enormous healthcare costs of over $30 billion. This condition is caused by the inability of the heart to pump blood in adequate amounts to supply food and oxygen to the body’s cells. The percentage of blood pumped by the heart with each beat is called the ejection fraction (EF). This depends on how well the heart muscle contracts and also how easily the heart chambers relax and accommodate blood during the off-beats. It is normally 55% or greater.

When heart failure is due to impaired muscle contraction, it is called heart failure with reduced ejection fraction (HFrEF), where the EF is 40% or less. When heart failure is associated with EF higher than 40%, it may be due to poor muscle contraction or due to the abnormal stiffness of the heart muscle. This is called HFpEF.

Many conditions cause heart failure, ranging from conditions like hypertension, obesity and diabetes, to chronic illness of the kidney, lung and heart. HFpEF causes shortness of breath, swelling of the legs, tiredness and reduced capacity for physical exertion. These symptoms are due to the accumulation of fluid in the lungs and the lowest part of the legs as blood backs up in the lung capillary bed. The weakness and fatigue are due to inadequate tissue oxygenation.

The drug combination of sacubitril-valsartan (a neprilysin inhibitor plus an ARB) is known as an angiotensin receptor-neprilysin inhibitor (ARNI). Sacubitril inhibits a neutral endopeptidase enzyme that breaks down several peptides that could benefit the heart, like natriuretic peptide which reduces blood sodium levels. Valsartan is an angiotensin blocker that blocks the renin-angiotensin-aldosterone system, a cascade of reactions that increases blood pressure while reducing kidney blood flow.

A previous trial (PARADIGM-HF) by the same team showed that ARNI helps patients with overt HFrEF, bringing down hospitalization rates and deaths from heart disease. The question is whether it does as well in those with a normal ejection fraction.

The study

The Paragon-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HF With Preserved Ejection Fraction) trial was a large randomized trial comparing the effect of valsartan alone vs. valsartan/sacubitril in over 4800 patients with chronic HFpEF. In this largest HFpEF trial so far, equal numbers of patients were randomly assigned one of these therapies.

All the patients had heart failure, high atrial natriuretic peptide levels, EF of 45% or more, and physical impairment of heart structure. The outcome that was assessed included both hospitalization for heart failure and deaths due to cardiovascular events.

What were the findings?

The investigators found that ARNI failed to significantly reduce the number of deaths in either group. There was a modest dip in the total number of hospitalizations in the sacubitril/valsartan group, but this fell just below statistical significance. Other measures included a slightly improved ability to function and a lower risk of worsening kidney function with the latter. However, these patients also had more cases of hypotension and angioedema.

Analysis of the results by predefined subgroups showed that the effects varied between subgroups. The combination may work best with patients who have EF of 45% to 57%, and in women, who form a high fraction of patients with HFpEF. There is no significant benefit for patients with HFpEF.

Researcher Scott Solomon summed up: “These findings extend our findings with sacubitril/valsartan in patients with frankly reduced ejection fraction to those with ejection fraction that is less reduced, but not normal. Our findings suggest that there may be an important difference among female patients' response to this therapy, and we'll be working over the next several years to understand why.“
The study was published in the New England Journal of Medicine on September 1, 2019.

Journal reference:

Angiotensin–neprilysin inhibition in heart failure with preserved ejection fraction. Scott D. Solomon, John J.V. McMurray, Inder S. Anand, Junbo Ge, Carolyn S.P. Lam, Aldo P. Maggioni, Felipe Martinez, Milton Packer, Marc A. Pfeffer, Burkert Pieske, Margaret M. Redfield, Jean L. Rouleau, Dirk J. van Veldhuisen, Faiez Zannad, Michael R. Zile, Akshay S. Desai, Brian Claggett, Pardeep S. Jhund, Sergey A. Boytsov, Josep Comin-Colet, John Cleland, Hans-Dirk Düngen, Eva Goncalvesova, Tzvetana Katova, Jose F. Kerr Saraiva, Małgorzata Lelonek, Bela Merkely, Michele Senni, Sanjiv J. Shah, Jingmin Zhou, Adel R. Rizkala, Jianjian Gong, Victor C. Shi, and Martin P. Lefkowitz. New England Journal of Medicine. September 1, 2019. DOI: 10.1056/NEJMoa1908655. https://www.nejm.org/doi/full/10.1056/NEJMoa1908655