Pimobendan in the Treatment of Canine Heart Disease: Early vs Late Use?
ACVIM 2008
Eric de Madron, DACVIM (Cardiology), DECVIM (Internal Medicine)
Ottawa, ON, Canada

Pimobendan is the newest addition to the treatment of congestive heart failure (CHF) in dogs. Pimobendan is a benzimidazole with positive inotropic properties. It inhibits the phosphodiesterase (PDE) III (like amrinone and milrinone), but also acts as a calcium sensitizer. It increases the sensitivity of contractile proteins to calcium, and more the troponin C-calcium interaction. This increases contractility without increasing energy consumption. Pimobendan has also vasodilatory properties, because it promotes calcium efflux. This classifies Pimobendan as an inodilator (positive inotrope and vasodilator). Pimobendan may also decrease levels of norepinephrine (NE), natriuretic peptides ANP, BNP), de l'endothelin (ET1), tumor necrosis factor (TNF-α), and interleukins (IL1b, IL6). The properties of Pimobendan (positive inotropy and vasodilation) are particularly interesting in the management of patients with declining or impaired ventricular contractility.

Pimobendan in Patients with CHF

Pimobendan has been initially evaluated in humans patients. Mixed results were obtained. In the North American PICO trial,(11) improved quality of life (QoL) but also a heightened risk of adverse cardiac events were noted in the patients receiving Pimobendan (on top of the classical therapies, including ACEI). In the Japanese EPOCH trial,(12) improved QoL and a lower incidence of adverse cardiac events in the patients receiving pimobendan was noted. These conflicting results might result from the fact that most of the PICO patients had ischemic heart disease, whereas most of Japanese EPOCH patients had non ischemic cardiomyopathy. As a result of these studies, Pimobendan has not been approved for human use except for Japan. It is important to note that in these studies, Pimobendan was added to background therapy (ACEI, vasodilators, diuretics) (and not substituted to ACEI as later done in some veterinary studies).

In veterinary medicine, Pimobendan has been now used in Europe for more than 5 years for the treatment of DCM or valvular disease in dogs. It has been available in Canada for the last 5 years. It has been recently approved by the FDA in 2006 in the United States.

Three veterinary studies have been published. In the first study, 10 Dobermans and 10 Cockers spaniels with dilated cardiomyopathy (DCM) were divided in 2 groups of 5 animals receiving either a placebo, or pimobendan on top of the classical therapy (furosemide, enalapril, digoxin). The survival time of the Dobermans went from 79 days (placebo) to 280 days for the animals receiving pimobendan. No statistically significant difference was seen in the Cockers.(9) The very small number of animals involved in this study makes it pretty weak, however.

In the study of Smith et al,(10) 43 dogs with mild to moderate heart failure due to mitral regurgitation (MR) were studied. 2 groups were made, one receiving ramipril and furosemide, the second receiving pimobendan and furosemide. The Pimobendan dogs were 25% as likely as the ramipril dogs to develop adverse heart failure effect. There was no increase in mortality in the pimobendan dogs. The authors did not report a demonstrable difference in quality of life between the 2 groups. However, the conclusion of this study are weakened by the fact that the ramipril dogs were more severely affected than the pimobendan dogs.

The VETSCOPE study has been recently published.(15) In this multicenter, randomized, double-blinded study, 76 dogs with MR were enrolled. 2 groups were compared: Benazepril and Furosemide versus Pimobendan and Furosemide. The duration of study was 56 days. A survival study was then carried out. The short term study showed an improvement in clinical score with Pimobendan (84% of cases vs 56% in BNZ group). The survival study showed increased survival in dogs with Pimobendan compared to Benazepril (430 days vs 228 days). However, it is important to note that dogs with Pimobendan were allowed to get Benazepril after 56 days, where the dogs initially on Benazepril could not get Pimobendan.

In the 2006 FDA study,(e) designed to approve Pimobendan in the US, 355 dogs (256 MR, 99 DCM) were separated in 2 groups (Pimobendan or Enalapril on top of background therapy (furosemide, digoxin, others). The period during which these 2 drugs were given separately was 56 days. Treatment success was defined as decreased NYHA CHF class, decreased pulmonary edema score, and overall clinical score. The results obtained with Pimobendan were not inferior to those obtained with ACEI. Beyond the 56 days, both drugs could be given concomitantly. Interestingly, the survival of Dobermans with DCM in that study was greatly improved (more than 50% survived more than 6 months).

There are also a number of abstracts or unpublished studies about Pimobendan in veterinary patients.

In one abstract, 105 dogs were evaluated (81 DCM and 24 valvular diseases) and 3 treatment categories were compared: pimobendan alone, benazepril alone, and pimobendan + benazepril. An evaluation of the first 4 weeks of treatment suggests that the pimobendan and pimobendan + benazepril groups responded better than the benazepril group. Survival time, particularly for the DCM patients, was longer with pimobendan.(b)

Some Canadian authors (c) mention their own experience with pimobendan. There again, the number of animals is small:

 Comparison with placebo: 11 Dobermans with DCM and in heart failure. Pimobendan seems to improve survival time and quality of life compared to classical therapy (ACEI, furosemide).

 Open label use without placebo control: 10 Dobermans, some of them in atrial fibrillation and 4 dogs of different breeds: subjective impression of a significant improvement in energy level, appetite, breathing pattern and weight.

 Pimobendan compared to Benazepril in cases of CHF due to mitral valve disease: 9 cases. Improvement of quality of life but not of survival with Pimobendan.

 Open label use without placebo control: 20 dogs with ventricular disease receiving Pimobendan with an ACEI: subjective impression of symptoms improvement, sometimes spectacular and rapid, even in very sick patients.

All these studies seem to indicate the same thing: Pimobendan is very promising. The authors all seem impressed by the rapidity of the improvement. An increased survival seems consistently noted, especially in Dobermans. More studies enrolling bigger number of animals are currently under way.

Pimobendan in Patients without CHF

Recent evidence is showing that Pimobendan may have some disturbing side effects, if prescribed inappropriately prior to CHF. Tissier et al (13) reported 2 cases of dogs in which inappropriate prescription of Pimobendan led to tachycardia, left ventricular hypertrophy, diastolic dysfunction, and mitral regurgitation. These anomalies all reversed after cessation of the pimobendan. Experimental toxicity data has also shown that Pimobendan can induce mitral regurgitation in normal dogs due to its potent inotropic effect.(14) Another study by Chetboul et al has shown that long term administration of Pimobendan (256 days) in mild asymptomatic mitral regurgitation without initial cardiomegaly can WORSEN the mitral regurgitation by Pimobendan (increase in the size of the mitral regurgitation jet, increase in the loudness of the heart murmur).(16)

To be fair, there are a couple of studies that have shown that Pimobendan prescribed in more advanced asymptomatic mitral regurgitation cases did in fact improve the mitral regurgitation and reduced the cardiac size. (d, 17) So it looks that Pimobendan becomes more useful as the disease progresses in severity, but its routine prescription prior to the onset of CHF cannot be recommended at this stage.

Conversely, the benefits of ACEI in asymptomatic patients with heart disease, although clearly established in humans,(1) remain difficult to demonstrate in dogs.(7) The recently published VETPROOF study suggests however a prolongation of the asymptomatic phase and an increased overall survival if ACEI are initiated prior to CHF.(8)

Pimobendan versus ACEI?

The 3 veterinary studies (10,15,e) studied Pimobendan AGAINST an ACEI. In the human studies, Pimobendan was ADDED to the established protocols. The efficacy of ACEI in the management of CHF has been well established by several human and veterinary studies.(1-6) The inhibition of the renin-angiotensin-aldosterone system (RAAS) remains a very valid therapeutic objective, especially if diuretics are being used. At this stage, most veterinary cardiologists are combining Pimobendan to ACEI, yet we have no data to support the superiority of this combination to Pimobendan or ACEI alone. The ability of Pimobendan to blunt the RAAS has not been supported by a recent study in dogs being challenged by furosemide.(f)

Therefore, combined use of Pimobendan and ACEI (on top of the furosemide, of course) still makes more sense that the use of either drug alone.

References

1.  The SOLVD investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. New England J Med 1991; 325: 293.

2.  The CONSENSUS Trail Study Group. Effects of enalapril on mortality in severe congestive heart failure: results of the cooperative North Scandinavian enalapril survival study (CONSENSUS) N Engl J Med 1992; 327: 669.

3.  The IMPROVE Study Investigators. Clinical effects of enalapril maleate in dogs with naturally acquired heart failure: results of the invasive multicenter prospective veterinary evaluation of enalapril. J Vet Intern Med 1995; 9: 234.

4.  COVE Study Group: Controlled clinical evaluation of enalapril in dogs with heart failure: results of the Cooperative Veterinary Study Group. J Vet Intern Med 1995; 9: 243.

5.  Ettinger SJ, Benitz am, Ericson GF et al. Effects of enalapril maleate on survival of dogs with naturally occurring acquired heart failure. The Long-Term Investigation of Veterinary Enalapril (LIVE) Study Group. J Am Vet Med Assoc 1998; 213: 243-252.

6.  BENCH Study Group: Effect of benazepril on survival times and clinical signs of dogs with congestive heart failure: Results of a multicenter, prospective, randomized, double-blinded, placebo-controlled, long term clinical trial" J Vet Cardiol 1999; 1: 7-18.

7.  Kvart C, Haggstrom J, Pedersen HD, et al. Efficacy of Enalapril for prevention of congestive heart failure in dogs with myxomatous valve disease and asymptomatic mitral valve regurgitation. J Vet Int Med 2002, 16 : 80-88.

8.  Atkins CE, Keene BW, Brown WA, et al. Results of the veterinary enalapril trial to prove reduction in onset of heart failure in dogs chronically treated with enalapril alone for compensated, naturally occurring mitral valve insufficiency. J Am Vet Med Assoc 2007; 231: 1061-1069.

9.  Fuentes VL, Corcoran B, French A, et al.A double-blind, randomized, placebo-controlled study of Pimobendan in dogs with dilated cardiomyopathy. J Vet Int Med, 2002; 16: 255-261.

10. Smith PJ, French AT, Van Israel N, et al."Efficacy and safety of Pimobendan in canine heart failure caused by mitral valve disease." J Small Animal Practice, 2005; 46: 121-130.

11. The PICO trial investigators: Effect of Pimobendan on exercise capacity in patients with heart failure: main results from the Pimobendan in congestive heart failure (PICO) trial. Heart 1996; 76: 223-231.

12. The EPOCH study group: Effects of Pimobendan on adverse cardiac effects and physical activities in patients with mild to moderate chronic heart failure. The effect of Pimobendan on chronic heart failure study (EPOCH study). Circ J 2002; 66: 149-157.

13. Tissier R, Chetboul V, Moraillon R, et al. Increased mitral valve regurgitation and myocardial hypertrophy in two dogs with long term Pimobendan therapy. Cardiovascular Toxicology (2005), 05 43-51.

14. Schneider P, Guttner J, Eckenfels, et al. Comparative cardiac toxicity of the IV administered benzimidazole pyridazinon derivative Pimobendan and its eninatomers in female Beagle dogs. Exp Toxic Pathol 1997, 49: 217-224.

15. 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.

16. Chetboul V, Lefebvre HP, Sampedrano CC 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; 27: 742-753.

17. Kanno N, Kuse H, Kawasaki M et al. Effects of Pimobendan for mitral regurgitation in dogs. J Vet Med Sci 2007: 69: 373-377.
b. O'Grady M, Luis Braz Ruivo, Gordon SG. Pimobendan: the North American experience, Forum ACVIM, Dallas, 2002-06-10.
c. Michael O'Grady. Evaluation of the Efficacy of Pimobendan to Reduce Mortality and Morbidity in Doberman Pinchers with Congestive Heart Failure Due to Dilated Cardiomyopathy. Abstract, Proceedings of the 21st ACVIM Forum, Charlotte, NC, USA, 2003.
d. Ouellet M, Di Fruscia R, Belanger MC. Evaluation of Pimobendan in the treatment of early mitral valve disease. ACVIM Forum, Seattle, 2007.
e. FDA approval Pimobednan study, 2006. FDA Web site.
f. Booth MA. Atkins CE, Fujii Y et al. The effect of pimobendan on the rennin-angiotensin-aldosterone system and arrhythmogenesis in the dog. ACVIM Forum, Seattle, 2007.

Speaker Information
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Eric de Madron, DACVIM (Cardiology), DECVIM (Internal Medicine)
Alta Vista Animal Hospital
Ottawa, Canada


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