Pimobendan - Help or Hype?
World Small Animal Veterinary Association World Congress Proceedings, 2014
Mark D. Kittleson, DVM, PhD, DACVIM (Cardiology)
Davis, CA, USA

Pimobendan (PB) is a pyridazinone benzimidazole derivative with positive inotropic and vasodilating properties. The positive inotropic properties are known to be due to a combination of sensitization of sarcomeric proteins to calcium and phosphodiesterase (PDE) III inhibition. PB is metabolized in the liver by a cytochrome p450 isoenzyme (CYP1A2) to desmethylpimobendan (DMP). DMP is an active metabolite that has approximately 100 times the PDE III inhibiting capability as PB. PB is solely responsible for sensitizing proteins to calcium.

Surprisingly, there are few (and no large) clinical trials looking at the use of PB in dogs with heart failure due to dilated cardiomyopathy (DCM), the disease one would think would have the primary indication for the drug. The few small clinical trials do suggest that PB prolongs survival in Doberman Pinschers with heart failure due to DCM.1,2

There are several clinical studies that have looked at the use of pimobendan in dogs with heart failure due to mitral regurgitation due to myxomatous mitral valve degeneration (MMVD).3,4 The largest of these is termed the QUEST study and was performed in Europe.5 In this study, 260 dogs in heart failure were randomized to either PB (n = 124) or benazepril (n = 128). Dogs were followed until they died suddenly, were euthanized due to their cardiac disease (e.g., heart failure), or the treatment failed leading the clinician to withdraw the dog from the study. All dogs were on furosemide at an average dose of around 4.5 mg/kg/day at the start of the trial. The Kaplan-Meier survival curve is shown below. Dogs on PB lived a significantly longer time than those on benazepril. Note on the two curves that there is no difference between the two for the first 30 days or so. After that, the curves parallel diverge nicely up until approximately 1 year (300–350 days). After that, the curves parallel one another and then converge up to a point at around 1.5 years (550 days). At the end, there are 15–20% of dogs that continue to live for several years. These dogs almost assuredly weren't actually in heart failure, elucidating how difficult it is for even experts to diagnose heart failure in older small bred dogs. So it would appear that close to all of those dogs that were actually in heart failure on benazepril were dead by 12 months and almost all of those on PB were dead by 18 months.

Most recently, a study termed the PROTECT study was reported that looked at administering pimobendan to Doberman Pinschers with DCM prior to the onset of heart failure to see if the drug would slow the progression to heart failure and/or prevent sudden death.6 Approximately 1,000 dogs were screened echocardiographically and 76 were chosen for the study. Since DCM is thought to be much more prevalent in this breed, it is unclear why so many dogs had to be screened to identify such a small number. The endpoints of the study were the onset of congestive heart failure or sudden death. A flowchart of the study is below.

The important points to note are that 19 dogs died suddenly or went into heart failure in the group on pimobendan and 25 did the same in the group on placebo. Almost an identical number died suddenly in both groups (7 on pimobendan and 8 on placebo) while 17 on placebo developed heart failure during the study and 12 on pimobendan did the same. However, total numbers don't take into account the time it took before either endpoint occurred. For that a Kaplan-Meier survival curve is needed (see below).

It is clear that when using a combined endpoint of time to heart failure and time to sudden death (seen in the graph above) that pimobendan slows the time to that combined event. The problem is that time to sudden death and time to onset of heart failure are two very different endpoints and when looked at individually, neither was statistically significant. In other words, pimobendan did not prolong the time until a dog died suddenly (and did not decrease the total number that died suddenly either) and did not prolong the time until a dog went into heart failure, but if those two modes of death were combined, the time was significant. Unfortunately, and obviously, that means the data are uninterpretable. It is certainly possible that if more dogs had been included in the study and the trend that was present continued in the same direction that one or the other of these could have become significant. But it appears we'll never know.

A more recent study reexamined the dogs in the QUEST study to see if pimobendan improved the quality of life of dogs in heart failure.7 Surprisingly it did not, at least for the group. As expected, pimobendan did prolong the time until heart failure therapy needed to be intensified. It also reduced free water retention. When a positive inotropic drug is administered to a dog with mitral regurgitation, the expectation is that the end-systolic diameter of the left ventricle (LVIDs) will decrease as a result of the increase in contractility, that the LV diastolic diameter will also decrease but to a lesser extent and so the shortening fraction will increase. In this study, when compared to the dogs on benazepril, pimobendan produced a smaller LVIDs (as expected), a smaller LVIDd (again as expected but unexpectedly it was reduced to a similar degree as the LVIDs) and so shortening fraction was not increased in the dog on pimobendan, which is unexpected.

Currently, there is an ongoing clinical trial that is looking to see if pimobendan slows the progression to heart failure in dogs with mitral regurgitation due to MMVD. It is named EPIC (www.epictrial.com). The study's aim is to enroll 300 dogs, half on placebo and half on pimobendan and so a similar design to the PROTECT study. It is supposed to finish in 2015. Currently, there is only one study that has looked at the effects of pimobendan in dogs with MMVD prior to the onset of heart failure.8 This study looked at 12 Beagles from a research colony with mild MMVD where half were placed on pimobendan and half on benazepril for 512 days. As expected, the shortening fraction increased in the dogs on pimobendan. However, the severity of the mitral regurgitation appeared to worsen and, more importantly, the myxomatous degeneration worsened when examined histologically. Because this study found pimobendan to be detrimental to dogs with MMVD, it is the opinion of the author that further study was warranted prior to exposing 150 dogs to it in a large clinical trial (the EPIC study). Primum non nocere (first do no harm).9 It is also the opinion of the author that pimobendan should not be administered to dogs with MMVD prior to the onset of heart failure until the results of the EPCI trial are published.

In conclusion, there is no doubt that pimobendan prolongs survival in dogs in heart failure due to MMVD and little doubt it does the same for Doberman Pinschers with DCM. Does it prolong the time until a Doberman Pinscher with DCM that is not in heart failure goes into heart failure? I believe that's still an unknown. Does it prolong the time until a Doberman Pinscher with DCM that is not in heart failure dies suddenly? I think that is also still unknown. Will it prolong the time until a dog with MMVD goes into heart failure? That remains to be seen. Given the one study that has been done to date, I don't believe you can give this anything more than a 50:50 chance. And so, once again, it is my recommendation that pimobendan not be administered to dogs with mitral regurgitation due to MMVD prior to the results of the EPIC study being published in a peer-reviewed journal.

References

1.  Fuentes VL, Corcoran B, French A, Schober KE, Kleemann R, Justus C. A double-blind, randomized, placebo-controlled study of pimobendan in dogs with dilated cardiomyopathy. J Vet Intern Med. 2002;16:255–261.

2.  O'Grady MR, Minors SL, O'Sullivan ML, Horne R. Effect of pimobendan on case fatality rate in Doberman Pinschers with congestive heart failure caused by dilated cardiomyopathy. J Vet Intern Med. 2008;22(4):897–904.

3.  Smith PJ, French AT, Van Israel N, Smith SG, Swift ST, Lee AJ, et al. Efficacy and safety of pimobendan in canine heart failure caused by myxomatous mitral valve disease. J Small Anim Pract. 2005;46:121–130.

4.  Lombard CW, Jons O, Bussadori CM. Clinical efficacy of pimobendan versus benazepril for the treatment of acquired atrioventricular valvular disease in dogs. J Am Anim Hosp Assoc. 2006;42:249–261.

5.  Häggström J, Boswood A, O'Grady M, Jons O, Smith S, Swift S, et al. Effect of pimobendan or benazepril hydrochloride on survival times in dogs with congestive heart failure caused by naturally occurring myxomatous mitral valve disease: the QUEST study. J Vet Intern Med. 2008;22:1124–1135.

6.  Summerfield NJ, Boswood A, O'Grady MR, Gordon SG, Dukes-McEwan J, Oyama MA, et al. Efficacy of pimobendan in the prevention of congestive heart failure or sudden death in Doberman Pinschers with preclinical dilated cardiomyopathy (The PROTECT Study). J Vet Intern Med. 2012; 26(6):1337–1349.

7.  Häggström J, Boswood A, O'Grady M, Jöns O, Smith S, Swift S, et al. Longitudinal analysis of quality of life, clinical, radiographic, echocardiographic, and laboratory variables in dogs with myxomatous mitral valve disease receiving pimobendan or benazepril: the QUEST study. J Vet Intern Med. 2013;27(6):1441–1151.

8.  Chetboul V, Lefebvre HP, Sampedrano CC, Gouni V, Saponaro V, Serres F, et al. Comparative adverse cardiac effects of pimobendan and benazepril monotherapy in dogs with mild degenerative mitral valve disease: a prospective, controlled, blinded, and randomized study. J Vet Intern Med. 2007;21:742–1753.

9.  Smith CM. Origin and uses of primum non nocere - above all, do no harm! J Clin Pharmacol. 2005;45(4):371–377.

  

Speaker Information
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Mark D. Kittleson, DVM, PhD, DACVIM (Cardiology)
Davis, CA, USA


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