Treating the “In-Between” Patients with Degenerative Valve Disease
Mikaela Mueller, DVM, DACVIM-Cardiology
Degenerative valve disease, or endocardiosis, is a disease that affects many canine patients, particularly small-breed dogs. The vast majority of our patients with degenerative valve disease are at the “in-between” stage, where they have a heart murmur and various levels of left-sided cardiomegaly, but are not yet in congestive heart failure. Many patients stay in this preclinical, in-between stage for their entire lives, but there is still the unlucky handful that do progress to congestive heart failure, typically with pulmonary edema. Studies such as the PREDICT cohort study, along with some common sense, indicate that left atrial enlargement and biomarkers such as NT-proBNP, can signal patients that are at a higher risk of developing congestive heart failure in the near future. However, it is more difficult to predict the clinical course that patients will experience when they are still in the more mild stages of the disease.
As doctors, we want to be able to fix problems for our patients. Sadly, this is one disease that we cannot fix (yet). We have been frustrated alongside our clients with nothing to offer them in this common preclinical stage. One intervention that has gotten a lot of research attention is ACE-inhibitors. We seem to really want them to make a difference in delaying the time to onset of congestive heart failure, maybe because we can make physiological justifications for why ACE-inhibitors should, theoretically, help. Multiple studies have shown “trends” to improvement, but no statistical significance (VETPROOF, SVEP). Many arguments suggest that we simply haven’t performed the right study to find the benefit, but one could also argue that if multiple different studies didn’t show a statistical difference, then the true benefit is likely modest, at best. That said, I think many of us have prescribed ACE-inhibitors in the preclinical stage just in case it does help. It makes us, and our clients, feel like we are doing something that may possibly help, while we are, in all honesty, in a position where our hands are tied. All of that changed with the release of the EPIC study results at ACVIM in June 2016.
Historically, we have found that pimobendan out-performs ACE-inhibitors after the onset of congestive heart failure by reducing heart size and retention of free water (QUEST study). The EPIC study (Evaluation of Pimobendan in Dogs with Cardiomegaly) was a prospective, double-blind, randomized, placebo-controlled, international, multi-center study that was started in June 2010. Pimobendan (or placebo) was administered chronically to small-breed (4.1-15 kg) canine patients with cardiomegaly due to degenerative valve disease (ACVIM Stage B2) to determine if it could delay the onset of congestive heart failure. For the study, 360 patients were enrolled – 180 dogs in the pimobendan group and 180 dogs in the placebo group. The primary endpoint was the development of left-sided congestive heart failure or death due to a cardiac cause.
A planned interim analysis was conducted, showing a significant benefit in the administration of pimobendan prior to the onset of clinical signs, and no concerns over safety were found. The investigators found that the time to the primary endpoint was increased by over a year. Patients in the pimobendan group did not live as long as the placebo group after the onset of congestive heart failure, but overall survival time (all-cause mortality) was increased. Said another way, patients that receive pimobendan starting in the preclinical stage (ACVIM Stage B2) live longer than those who don’t and spend less of their life battling clinical signs of congestive heart failure. The results were significant enough that the study was prematurely discontinued in March 2015.
One of the major concerns with the EPIC study is that many dogs with only mild enlargement never experience clinical signs of congestive heart failure in the first place, so treating them long-term with pimobendan does not change their clinical outcome. Luckily, it appears to be a very safe medication for the majority of patients, but it is not a cheap medication to give for years when it does not change the outcome. Since we do not have a good way of predicting which dogs with mild disease will progress to clinical signs, it becomes difficult to decide whether or not to recommend pimobendan for some patients.
This is where the art of clinical practice comes into play. Each patient is an individual who deserves personalized thought and attention. If a patient has mild cardiomegaly and is already 16 years old, it is far less likely that the patient will progress to congestive heart failure during his or her lifetime than a different patient with similar disease who is only 5 years old. Also, does the patient have other clinical diseases that otherwise limit its lifetime? Potentially, these patients will not be expected to benefit from chronic pimobendan administration. Since the EPIC study was announced, I have started to recommend giving pimobendan with increased urgency to patients of mine with progressive cardiomegaly. When in doubt, I often take the approach of educating the owners on the potential benefits and the downfalls of starting their dog on pimobendan at any given time, empowering them to make the decision that is best for them and their companion.
Questions still remain about the best way to treat patients at various stages of degenerative valve disease, and I imagine that questions will always remain since each patient is a different case to consider. Like the rest of us, I anxiously await publication of the EPIC study results. I have to admit, though, it feels good to have something to offer many of my clients when their patients are “in-between.”