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Effect of Pimobendan on Survival in Dogs with Congestive Heart Failure Due to Myxomatous Mitral Valve Disease Jens Häggström1, DVM, PhD, DECVIM-CA (Cardiology); Adrian Boswood2, MA, VetMB, DECVIM-CA (Cardiology); Michael O'Grady3, DVM, MSc, DACVIM-CA (Cardiology); Olaf Jöns3, DVM, Dr.Med.Vet. 1 Uppsala, Sweden; 2London, UK; 3Guelph, ON, Canada

INTRODUCTION Mitral regurgitation secondary to myxomatous degeneration of the mitral valve apparatus is the most common cause of heart failure in dogs.(1) This is usually a disease affecting older animals therefore those dogs with a more slowly progressive course of their disease may succumb to a co-morbid condition before ever demonstrating any signs of ill health attributable to their valvular heart disease. For those animals that do develop signs of CHF secondary to their valvular heart disease the signs are usually progressive with the majority of animals dying within a year of the development of clinical signs.(2,3) Although the exact role of the Renin-Angiotensin-Aldosterone system in the progression of mitral regurgitation is still the subject of some debate(4) earlier clinical trials have demonstrated that treatment of dogs in heart failure secondary to MMVD with angiotensin converting enzyme inhibitors (ACEI) confers a favourable effect on survival.(2,3) Thus, rather than compare the effect of Pimobendan against placebo a true test of its potential benefit would be to compare its effect on outcome against a positive control i.e., against ACEI.

PIMOBENDAN

IN

CLINICAL TRIALS

There have been several studies previously undertaken evaluating the effect of Pimobendan in dogs with mitral valve disease and heart failure. Most of these studies have demonstrated a favourable effect of treatment but they have either evaluated the effect of therapy on endpoints other than survival(5) or allowed for the use of Pimobendan in conjunction with an ACEI.(6,7) Some investigators have questioned the rationale behind using a drug with inotropic effects in dogs with valvular disease and have even claimed a potentially detrimental effect of therapy when used prior to the onset of clinical signs. These investigators have however studied endpoints other than quality of life variables or survival(8) and their results are of questionable value when one is trying to make decisions regarding the optimal long-term therapy for prolongation of survival in dogs with clinical signs caused by this common disease.

THE QUEST TRIAL The recently completed QUEST (Quality of life and Extension of Survival Time) study was undertaken in order to evaluate the impact of Pimobendan on survival in a large group of dogs with heart failure secondary to myxomatous mitral valve disease. The aim of the study was to compare the time taken to reach the primary endpoint for dogs receiving either pimobendan or benazepril in conjunction with other therapy. The primary endpoint was a composite of spontaneous cardiac death, euthanasia for cardiac reasons or withdrawal from the study due to treatment failure. On the basis of a power calculation informed by previous studies(2,6) 260 dogs were recruited to the study making it, to our knowledge, the largest prospective, blinded survival study so far undertaken in canine cardiology. Recruitment took place between 2003 and early 2006 and the study was concluded in late 2006. Dogs were of small and medium breeds and were only included in the study if they had, at some point, demonstrated convincing radiographic evidence of left-sided congestive heart failure. Dogs underwent a full cardiovascular examination at the time of recruitment. After enrolment to the study they were randomised to receive either Pimobendan plus standard therapy or Benazepril plus standard therapy. They were then re-evaluated at regular intervals and followed until they reached the study endpoint, were censored from the study for other reasons, or the study was concluded (whichever occurred first). No dogs were lost to follow up. Three quarters of all the dogs enrolled reached the primary endpoint. Throughout the study the investigators undertaking the examinations of patients were blinded to the treatment that the patient was receiving. Dogs receiving pimobendan plus standard therapy had a longer survival time compared to those receiving Benazepril plus standard therapy. The benefit of pimobendan persisted after adjusting for all baseline variables. Several other baseline variables were shown to influence survival time. Most of these were direct or indirect indicators of disease severity. The incidence of potential adverse effects was comparable between the two groups, indicating that pimobendan was equally well tolerated. The QUEST study offers the most compelling evidence to date demonstrating the beneficial effect of pimobendan when compared to benazepril for extending survival in dogs with CHF due to MMVD when used in

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conjunction with other standard therapy. Because ACE-inhibitors, when administered as adjunct therapy to other heart failure therapy (i.e., diuretic), have been shown to increase survival times in dogs with CHF due to MMVD, it can be assumed that pimobendan would also increase survival times when compared to a placebo. The current study included an extensive analysis of covariates. It demonstrated that the benefit of pimobendan persisted after adjusting for multiple historical, clinical and therapeutic covariates. However, further studies are required to address the impact of combined pimobendan and ACEI therapy and to address the importance of pimobendan in large breed dogs with CHF secondary to MMVD.

CONCLUSIONS Pimobendan prolongs survival in dogs with CHF attributable to MMVD when it is used together with other heart failure drugs (i.e., diuretics). References 1. Buchanan JW. Prevalence of Cardiovascular Disorders. In: Fox PR, Sisson D, Moise NS, eds. Textbook of Canine and Feline Cardiology. Philadelphia: Saunders, W.B.; 1999:457-470. 2. BENCH Study Group. The 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. 3. Ettinger SJ, Benitz AM, Ericsson GF, et al. Effects of enalapril maleate on survival of dogs with naturally acquired heart failure. The Long-Term Investigation of Veterinary Enalapril (LIVE) Study Group. J Am Vet Med Assoc 1998;213:1573-1577. 4. Dell'Italia LJ. The Renin-Angiotensin system in mitral regurgitation: a typical example of tissue activation. Curr Cardiol Rep 2002;4:97-103. 5. Smith PJ, French AT, Van Israel N, 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. 6. Lombard CW, Clinical experience with Pimobendan, Proc of the Veterinary Cardiovascular Society, 2001Birmingham England. 7. 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. 8. 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;21(4):742-53.

SPEAKER INFORMATION (click the speaker's name to view other papers and abstracts submitted by this speaker ) Jens Haggstrom, DVM, PhD, DECVIM-CA (Cardiology) Faculty of Veterinary Medicine Uppsala, Sweden

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