Pimobendan Possibilities

Rob Sanders DVM, DACVIM (Cardiology) Associate Prof Cardiology Department of Small Animal Clinical Sciences College of Veterinary Medicine Veterinary Medical Center, D212 Michigan State University East Lansing, MI 48824-1314

When should I start using pimobendan in a dog with mitral valve disease?

Okay we have all heard about the EPIC study(J Vet Intern Med. 2016 Nov;30(6):1765- 1779). Here are the conclusions (I have added the bolding)…

” The conclusions of this study are only relevant to dogs with cardiac enlargement secondary to preclinical MMVD (stage B2) as all dogs entering the study met or exceeded 3 different heart size criteria (LA/Ao ≥ 1.6, LVIDDN ≥ 1.7, and VHS > 10.5) and no dogs without cardiac enlargement were recruited to the study. Similarly, the conclusions are only relevant to dogs with a murmur of at least a grade 3/6 in intensity. Treatment with pimobendan of all dogs that have a murmur compatible with the presence of MMVD would not be justified on the basis of the findings of this study.”

I like evidence to base my clinical decisions upon. For the moment lets accept the results as presented. Based on the presented results of the EPIC study dogs with preclinical degenerative valve disease should start getting pimobendan when all of the following criteria have been met… 1. Have at least a grade 3 murmur 2. Meet or exceed ALL three different heart size criteria a. LA/Ao ≥ 1.6 by echocardiography b. LVIDDN ≥ 1.7 by echocardiograpy c. VHS > 10.5 by radiography

Ok…so you have to do an auscultation (easy), you have to do rads (easy) and you have to get an echo done and calculate LVIDDN (normalized end diastolic left ventricular diameter). None of this is impossible but the study showed only when patients with ALL of these changes benefited from pimobendan. This is a key statement. Patients that did not meet ALL these criteria did not show a benefit from the administration of pimobendan. Consequently, in a perfect world, I would not start pimbendan unless I could verify these conditions existed.

I get it. We live in a practical world not a perfect world so what should you really do? I think the echocardiographic changes are most important. Try to get an echo done prior to starting pimobendan.

Is there any risk to an asymptomatic patient taking pimobendan?

This is a tricky question with little solid evidence. Let’s go through a study that suggest pimobendan administration may carry some risk. Chetboul et al. (J Vet Intern Med. 2007 Jul-Aug;21(4):742-53) completed a study in 12 beagle dogs with degenerative valve disease. Dogs were randomized into two groups one receiving benazepril and one receiving pimobendan for 512 days. A significant increase in %FS was noted in the pimo group as early as day 15. No changes noted in benazepril. Histologic grades of mitral valve disease were more severe in the dogs receiving the pimo as compared to benazepril. There are some significant concerns regarding this study. First, very small study with limited data provided. Second, funded by the manufacturer of benazepril in Europe. Okay we should take this with a grain of salt but do these two concerns completely invalidate the results? If being funded by a drug company is grounds for invalidation, then there are more than a couple studies that support pimo use that will need to be invalidated as well.

So what should we do? This study is far from perfect but it does make me want to wait to start pimobendan (and every other drug for that matter) until I believe that the DVD patient is very close to being in heart failure if not in heart failure.

Is it okay to use pimobendan in cats and if so when?

Yes its okay…but be cautious. On the label it say “ Contraindications: Vetmedin should not be given in cases of hypertrophic cardiomyopathy…”. So what happens if you give a cat HCM pimobendan and it dies? Right, be cautious. There are studies that suggest administration of pimobendan to cats is safe and potentially effective. The study Reina- Doreste et al (J Am Vet Med Assoc. 2014 Sep 1;245(5):534-9.) is a retrospective study that suggests therapy with pimo prolongs survival times in cats with HCM that are in CHF. It is not a case controlled study but has value and at least adds to existing data suggesting that pimobendan therapy appears well tolerated in cats. I usually will begin therapy of feline HCM CHF patients with furosemide and if there is not good a response then I will have a conversation with the owners and give them the options to start pimo.

Are there situations I shouldn’t use pimobendan?

The full quote of the pimo label warning includes …aortic stenosis, or any other clinical condition where an augmentation of cardiac output is inappropriate…”

Again, this is where client communication is essential. The good news is most patients with an outflow track obstruction like aortic stenosis do not go into heart failure. So there really is no temptation to begin therapy with pimo. But what if it does happen? Clearly if a CHF patient is known to have arotic stenosis, then I would inform them of the potential risks and offer the option of pimo therapy.

Do I have to monitor any blood work when using pimobendan?

No. That was simple.

Is there any evidence that therapy with pimobendan will cause or worsen arrhythmias?

Good question.

A study by Lake-Bakaar et (J Vet Cardiol. 2015 Jun;17(2):120-8) demonstrated that the was no significant difference in arrhythmia development in canine patients with degenerative valve disease given pimo or a placebo.

Great news…right? Wait a minute what kind of heart disease patients are you worried about worsening or causing arrhythmias? Patients with dilated cardiomyopathy, right? Any information about that? You have to dig deep and get the original document used to gain approval for pimo. This documents states that there was no significant increase in arrhythmias frequency in either the degenerative valve disease group or the DCM group as assessed by ECG but this was not assessed by 24 hour Holter monitoring. In 2006 an abstract was presented by Rosenthal et al (JVIM 2008. 20:3 #76) entitled “Association of pimobendan with ventricular arrhythmias in dogs with congestive heart failure”. The abstract did not state the type of heart disease that these dogs were diagnosed with but performed pre and post pimo Holter monitoring to assess impact of treatment on frequency of ventricular arrhythmias. Unfortunately, it was a small study and the results were not analyzed statistically but there was an increase in total number of ventricular arrhythmias by 102.1% per 24 hour period. Cleary this study suggests that it is possible that dogs with existing ventricular arrhythmias may experience an increase in arrhythmias after being treated with pimo. It is also clear that this is a VERY small study of 8 dogs and further study is required prior to making a definitive statement.

So, what do I do with dogs with ventricular arrhythmias, DCM and CHF? Give them pimobendan because it makes them feel better and do better. I am worried about the arrhythmias, but I am convinced that the dogs do better on it than off it.