Could Entresto® Become the Next Pimobendan?

Part 1: The Science Behind Veterinary Cardiology's Most Exciting Emerging Therapy

By Christina Bové, DVM, MS, DACVIM (Cardiology)

“Every generation of veterinary cardiologists hopes to witness the next major advance in heart disease. Pimobendan fundamentally changed how we treat MMVD. The exciting question now is whether Entresto® could become another important addition to our therapeutic toolbox.”

Why This Conversation Matters

If you've been practicing veterinary medicine for the past two decades, you've already experienced one true paradigm shift in canine cardiology.

Pimobendan changed everything.

Before the publication of the EPIC (Evaluation of Pimobendan in Cardiomegaly) Trial, treatment for dogs with myxomatous mitral valve disease (MMVD) was largely reactive. We diagnosed heart disease, monitored progression, and initiated aggressive therapy only after dogs developed congestive heart failure (CHF).

That approach changed forever in 2016.

The landmark EPIC Trial demonstrated that administering pimobendan to dogs with Stage B2 MMVD significantly prolonged the preclinical period, delaying the composite endpoint of congestive heart failure, cardiac-related death, or euthanasia by a median of approximately 15 months compared with placebo.

Few medications have transformed veterinary cardiology as profoundly.

Because of EPIC, thousands of dogs have lived longer, experienced better quality of life, and enjoyed additional months—or even years—with their families.

That is what a true breakthrough looks like.

The EPIC trial fundamentally changed the way we approach preclinical MMVD. Pimobendan became—and remains—a cornerstone of therapy for dogs with Stage B2 disease.

The question now isn't what should replace pimobendan.

It's what might come next.

Could targeting additional pathways involved in heart failure progression provide even greater benefit when added to the therapies we already know work?

Since EPIC, What's Really Changed?

While our understanding of heart disease has continued to evolve, the medications we rely on every day have remained remarkably familiar.

Today, treatment of canine MMVD still centers around:

• Pimobendan to improve cardiac performance and delay progression in Stage B2 disease.

• Loop diuretics, including furosemide and torsemide, to manage pulmonary edema.

• ACE inhibitors to suppress activation of the renin-angiotensin-aldosterone system (RAAS).

• Spironolactone to provide additional neurohormonal blockade.

• Antiarrhythmic medications when indicated.

• Nutritional management and careful monitoring.

These therapies remain the foundation of evidence-based management. However, they all share one important characteristic:

They represent refinements of existing treatment strategies rather than an entirely new therapeutic approach.

That raises an important question.

Could another medication fundamentally change how we manage canine heart disease?

Enter Entresto®

Over the past several years, one medication has generated increasing excitement among veterinary cardiologists:

Sacubitril/valsartan (Entresto®)

Unlike conventional heart failure medications commonly used in dogs, Entresto belongs to a newer class of drugs known as angiotensin receptor-neprilysin inhibitors (ARNIs). Human studies have demonstrated substantial benefits in patients with heart failure and reduced ejection fraction, and early veterinary investigations suggest the drug is biologically active and generally well tolerated. However, its role in canine MMVD is still being defined through ongoing clinical research.

Rather than simply suppressing harmful neurohormonal pathways, it also enhances the body's own protective compensatory mechanisms.

This concept transformed the management of human heart failure.

Naturally, veterinary cardiologists began asking whether the same physiologic advantages might benefit dogs with naturally occurring MMVD.

Since then, several veterinary studies have evaluated Entresto in dogs, examining:

• Neurohormonal modulation

• Reverse cardiac remodeling

• Safety

• Tolerability

• Long-term clinical outcomes

Collectively, these studies have generated considerable enthusiasm—but they have also highlighted how much remains unknown.

Importantly, I don't view sacubitril/valsartan as a potential substitute for pimobendan.

The two drugs do fundamentally different things.

Pimobendan provides inotropic and vasodilatory effects through calcium sensitization and phosphodiesterase III inhibition. Sacubitril/valsartan targets neurohormonal regulation through neprilysin inhibition and angiotensin-receptor blockade.

That makes them potentially complementary rather than competitive therapies.

The exciting question isn't Entresto or pimobendan?

It's whether Entresto added to contemporary MMVD therapy—including pimobendan—could provide additional benefit.

Could Entresto Be the Next Major Advance in MMVD Therapy?

The honest answer is: We don't know—yet.

And that's exactly where the conversation should begin.

Pimobendan earned its place in veterinary medicine through multiple well-designed clinical studies demonstrating meaningful improvements in outcomes that matter to patients and owners, including delaying congestive heart failure and extending survival.

Entresto has not yet reached that level of evidence.

What it does have is:

• A compelling biologic mechanism

• Outstanding human heart failure data

• Encouraging veterinary pilot studies

• Early evidence of favorable neurohormonal modulation and reverse remodeling

• Growing clinical experience suggesting that the medication is generally well tolerated in carefully selected dogs

That combination makes Entresto one of the most exciting emerging therapies in veterinary cardiology.

It does not, however, make it a replacement for evidence-based medicine.

Evidence vs. Enthusiasm

There is an important difference between showing that a medication changes physiology and demonstrating that adding that medication to current therapy improves outcomes.

With Entresto, we now have evidence supporting biologic activity, favorable changes in cardiac remodeling, tolerability, and encouraging longer-term clinical experience.

The next step is demonstrating incremental clinical benefit.

Does adding sacubitril/valsartan to contemporary MMVD therapy delay disease progression, reduce recurrent CHF, improve quality of life, or extend survival?

Those are the questions that ultimately determine whether Entresto becomes a major addition to our standard treatment protocols.

💬 Cardiologist's Perspective

What excites me about Entresto isn't the possibility of replacing a therapy we already know works.

It's the possibility of adding another one.

Pimobendan remains a cornerstone of MMVD therapy. Sacubitril/valsartan targets different and potentially complementary pathways involved in heart failure progression.

We now have enough canine evidence that I think Entresto deserves serious attention. But enthusiasm needs to remain proportional to the evidence.

The question I want answered is whether adding Entresto to contemporary MMVD therapy can give our patients better outcomes than contemporary therapy alone.

If future prospective trials demonstrate that, then we may truly have another major advance in canine cardiology.

Entresto doesn't need to replace pimobendan to change veterinary cardiology.

If targeting the natriuretic peptide system while simultaneously blocking angiotensin II provides meaningful additional benefit to dogs already receiving contemporary MMVD therapy, that alone could represent an important therapeutic advance.

But before we can decide where Entresto belongs, we need to understand why the drug is so different—and what the veterinary evidence actually shows.

That's where Part 2 begins.

References

1. Boswood A, Häggström J, Gordon SG, et al. Effect of pimobendan in dogs with preclinical myxomatous mitral valve disease and cardiomegaly: The EPIC Study—A randomized clinical trial. J Vet Intern Med. 2016;30(6):1765–1779. doi:10.1111/jvim.14586.

2. Newhard DK, Jung S, Winter RL, Duran SH. A prospective, randomized, double-blind, placebo-controlled pilot study of sacubitril/valsartan (Entresto) in dogs with cardiomegaly secondary to myxomatous mitral valve disease. J Vet Intern Med. 2018;32(5):1555–1563. doi:10.1111/jvim.15240.

3. Saengklub N, Pirintr P, Nampimoon T, Kijtawornrat A, Chaiyabutr N. Short-term effects of sacubitril/valsartan on echocardiographic parameters in dogs with symptomatic myxomatous mitral valve disease. Front Vet Sci. 2021;8:700230. doi:10.3389/fvets.2021.700230.

4. Carlson JA, Stern JA. Long-term sacubitril/valsartan is well tolerated in dogs with heart failure and myxomatous mitral valve disease and suggests excellent survival benefits. Am J Vet Res. 2026;87(8):ajvr.26.02.0048. doi:10.2460/ajvr.26.02.0048.