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LATEST INFORMATION ABOUT CANINE MITRAL VALVE DISEASE: RESULTS OF THE QUEST TRIAL Jens Häggström, DVM, PhD, DECVIM-CA (Cardiology) Faculty of Veterinary Medicine and Animal Science Swedish University of Agricultural Sciences Uppsala, Sweden Mitral regurgitation (MR) caused by myxomatous mitral valve disease (MMVD) is the most common heart disease in dogs. The disease is characterized by chronic progressive lesions on the mitral valve apparatus (leaflets and chordae tendineae) leading to insufficient coaptation of the leaflets and valve regurgitation. The progression of valve leakage leads to a corresponding increase in valve leakage, which, at a certain stage, leads to increased left atrial and ventricular size and recruitment of different compensatory mechanisms. Congestive heart failure (CHF) develops when the MR has become so severe that the compensatory mechanisms have become exhausted. However, MMVD 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. In one study of Cavalier King Charles spaniels (CKCS) the median period of time from diagnosis of disease to the onset of signs of congestive heart failure was over 3 years.1 The median time to the development of heart failure was similarly greater than 2 years in dogs with MMVD not in heart failure, but with evidence of cardiac remodeling.2 Thus, MMVD is a relatively benign condition in some dogs. 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. Medical treatment of CHF is controversial, although most experts agree that furosemide is indicated for managing the pulmonary edema and congestion. Thus, medical treatment consists of a diuretic agent plus various types of adjunct therapy. Commonly used drugs include pimobendan, angiotensin-converting enzyme (ACE) inhibitors (ACEI), digoxin, and spironolactone. 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 favorable effect of treatment but they have either evaluated the effect of therapy on endpoints other than survival3 or allowed for the use of pimobendan in conjunction with an ACEI.4 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.5 These investigators have, however, studied endpoints other than quality of life variables or survival5 and their results are of questionable value when one is trying to

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make decisions regarding the optimal long-term therapy for prolongation of survival in dogs with clinical signs caused by this common disease. Although the exact role of the renin-angiotensin-aldosterone system in the progression of mitral regurgitation is still the subject of some debate,6 earlier clinical trials have demonstrated that treatment of dogs in heart failure secondary to MMVD with ACEI confers a favorable effect on survival.7,8 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, eg, against an ACEI. Because of the continuing controversy surrounding the optimal treatment for patients with heart failure secondary to MMVD we conducted a prospective, randomized, blinded study to compare the outcome of two groups of dogs with heart failure secondary to MMVD9: one group would receive pimobendan and the other would receive benazepril hydrochloride. The study was designed to test the hypothesis that the group receiving pimobendan would have an improved outcome compared with the group receiving benazepril. The study was named the QUEST (QUality of life and Extension of Survival Time) trial.9 THE QUEST STUDY DESIGN On the basis of a power calculation informed by previous studies,8 260 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 at 28 centers in 11 different countries in Europe, Canada, and Australia between 2003 and early 2006 and the study was concluded in late 2006.9 The dogs had to fulfill a set of inclusion criteria in order to be eligible for inclusion in the study: the dog must have been older than 5 years of age, weigh between 5 and 20 kg, had physical, echocardiographic and radiographic evidence of severe MR attributable to MMVD, and had demonstrated convincing clinical radiographic evidence of left-sided congestive heart failure at inclusion or at a previous time point but where the signs had been resolved in the past with treatment that was still being administered and in the opinion of the attending clinician necessary to prevent the return of clinical signs. These inclusion criteria ensured that only dogs with progressed MMVD and MR in need of medical therapy to survive were recruited into the study. The dogs were allocated at random to treatment with either pimobendan (Vetmedin, Boehringer Ingelheim Vetmedica, Germany) orally at a dose of 0.4 to 0.6 mg/kg per day, or benazepril (Fortekor, Novartis, Switzerland) orally at a dose of 0.25 to 0.5 mg/kg once or twice a day, both treatments according to the manufacturer’s recommendations. The trial was designed as a single blinded study, meaning that the owner, but not the investigator was aware of treatment allocation. Standard concomitant therapy for heart failure (such as diuretics and digoxin) was permitted throughout

Small Animal – Cardiology ______________________________________________________________________________________________ the trial. Doses of concomitant treatments could be modified, if needed, throughout the study. The dogs underwent a full cardiovascular examination at the time of recruitment. 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). The primary endpoint was a composite of spontaneous cardiac death, euthanasia for cardiac reasons, or withdrawal from the study due to treatment failure. Where the dog died spontaneously or was euthanized the investigator specified whether they considered the cause of death to be cardiac or noncardiac. In cases where the cause of death was considered non-cardiac the reason for death or euthanasia was noted. Treatment failure was defined as presence of certain signs of CHF despite receiving or failing to tolerate a diuretic dosage of furosemide (12 mg/kg daily per os [PO]) and spironolactone (6 mg/kg daily PO) in addition to other concomitant medications and the test drug. THE QUEST TRIAL RESULTS Of the 260 included dogs, 8 were excluded from statistical analysis because of significant violation of the trial protocol concerning inclusion criteria, medication, or follow up. Thus, 252 dogs were included in the statistical analysis. Of these 252 dogs, 124 dogs were allocated to pimobendan and 128 to benazepril treatment. The most common included breeds were CKCS, Dachshund, poodle, and Yorkshire terrier, but 26 other breeds were represented. Thirty-three different baseline variables (such as signalment variable, pretrial treatment,”quality of life” variables, diagnostic imaging variables (ECG, echocardiography, and radiography), and blood variables) were analyzed with respect to significant differences between the two treatment groups. No major difference was found between the two treatment groups, indicating that the groups were well balanced. Of the 252 included dogs, a total of 190 (75%) dogs reached the primary endpoint, 68 (27%) died spontaneously of cardiac causes, 75 (30%) were euthanized for cardiac reasons, and 47 (19%) reached the treatment failure endpoint. Sixty-two dogs (25%) were censored: 5 (2%) dogs died spontaneously and 19 (7.5%) dogs were euthanized for non-cardiac reasons, 25 (9.9%) dogs were alive at the termination of the trial, and 13 (5%) were removed from the study for various reasons (most commonly owner compliance). No significant differences were found between the two treatment groups concerning the proportion of dogs reaching the primary endpoint or proportion of dogs that were censored. The median time to reach the primary endpoint for all dogs (both treatment groups) in the study was 188 days. There was a significant difference between the two treatment groups concerning the median time from inclusion to the primary endpoint. The dogs receiving pimobendan had a median time of 267 days, whereas dogs in the benazepril group had a median time of 140

days. The difference between the two treatment groups at a given time point during the study was >20% in favor of the pimobendan group between day 159 and day 325. The median time in the study was longer on the pimobendan group for all of the three sub-endpoints (cardiac death, cardiac-related euthanasia, and treatment failure) when analyzed separately. However, these differences did not reach statistical significance for any of the three sub-endpoints. The results were analyzed further using the Cox Proportional Hazard analysis, which is a method that takes both proportion events and the time to reach the endpoint into account. The analysis provides a risk ratio, which is an equivalent to an odds, but it also test for statistical significance. It has the advantage that many variables can be analyzed at the same time, ie, multivariate analysis, which is valuable to detect and correct for any imbalances between the groups that could influence the overall outcome. Test treatment and additional 33 baseline variables were analyzed in a Coxproportional Hazard analysis. Pimobendan treatment was associated with a significant risk reduction for reaching the primary endpoint (P=0.006; Hazard ratio=0.63). Seven other baseline variables had a significant effect on the risk for reaching the primary endpoint: those having a beneficial effect were being a Cavalier King Charles spaniel and having a higher creatinine concentration; those having a detrimental effect were having a greater cardiac silhouette on thoracic radiographs (VHS score), a greater left atrial size on the echocardium (LA/Ao ratio), having greater intolerance of exercise, a greater left ventricular diameter in systole on the echocardiogram (LVIDs corrected for body weight), and receiving a higher daily furosemide dose. WHAT DO THE RESULTS FROM THE QUEST TRIAL MEAN? The QUEST trial is hitherto the largest clinical trial ever conducted in veterinary cardiovascular medicine. The 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 conjunction with other standard therapy. The median time to reach a composite endpoint for the dogs treated with pimobendan was almost twice as great as for dogs treated with benazepril (267 vs. 140 days, respectively).9 This represented a 32% relative risk reduction of reaching the composite endpoint for the pimobendan group. This study also demonstrated that the benefit of pimobendan persisted after adjusting for all baseline variables. Because the drug of comparison, benazepril, when administered as adjunct therapy to other heart failure therapy (ie, 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 with a placebo. The inevitable question in all clinical trials is whether or not the differences found between treatment groups

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NAVC Conference 2009 ______________________________________________________________________________________________ are of genuine clinical importance, or if they are so small that they are only of statistical importance. The QUEST trial is no different. What exactly defines a difference of genuine clinical importance has very little to do with science, but is more a question of attitudes and costbenefit analysis. A difference of days in survival at a high cost for the owner probably does not motivate that particular treatment. However, the QUEST trial showed that pimobendan was associated with roughly a doubling in survival time and a risk reduction of approximately one third to reach the primary endpoint when compared with benazepril. It is our opinion that most owners and clinicians consider this difference to be of genuine clinical importance. Although the primary endpoint in our study was a composite of three possible outcomes we would argue this is a genuine reflection of survival in this population and therefore conclusions about the effect of therapy on survival can be drawn. Two of the three outcomes resulted in the death of the dog (spontaneous death and euthanasia for cardiac reasons). The third component of our composite endpoint was treatment failure. While this latter endpoint lacks the incontrovertible nature of death we had to include it for ethical reasons. Treatment failure, as outlined above, was a predefined endpoint in the study that necessitated the dog having clinical signs of heart failure refractory to maximal diuresis, or failure to tolerate a maximal dose of diuretics while remaining on treatments stipulated in the protocol. The only reason an investigator would consider that a dog had reached this endpoint was that they felt the dog would not survive without receiving further treatment that was precluded within the protocol. This would suggest that at this point dogs had advanced and poorly controlled disease as well as clinical signs of heart failure and that although this is a surrogate for the dog dying, a dog would only reach this end point if they were close to death as a consequence of their progressive disease Most owners find the quality of life of their pet important. In fact, a recently published study10 suggests that a majority of owners are willing to trade survival time for an improved quality of life, and this aspect separates human medicine from veterinary. The QUEST trial focused only on survival data, and prospective data, including quality of life variables, will be published in a separate forthcoming publication. The survival data of the QUEST trial does, however, give some insight how the quality of life of included dogs was experienced by owners and investigators during the trial. Two out of the three sub-endpoints were dependant on how the investigator and the owner assessed the clinical status of the dogs, ie, euthanasia because of cardiac reason and treatment failure. Pets having clinical signs despite maximal doses of diuretics reached the treatment failure endpoint or become euthanized because of CHF. Thus, it is reasonable to assume that dogs treated with pimobendan had a better quality of life during a longer time period of the study. How can the results from the QUEST trial help us in prescribing optimal therapy to a dog with CHF because

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of MMVD? The results of the QUEST trial do NOT indicate that all dogs with MMVD should be treated with pimobendan. The study was not designed to study the treatment effect in asymptomatic MMVD dogs. The beneficial effect found in the QUEST trial concerned symptomatic MMVD dogs only, ie, dogs with severe MR and evidence of CHF (pulmonary edema and congestion), when the drug was administered together with conventional CHF therapy. Respiratory clinical signs may, however, be caused by primary lung disease, such as tracheal instability, chronic bronchitis, and these conditions sometimes coexist with MMVD. Dogs with respiratory signs should therefore be examined by thoracic radiography to verify the presence of CHF (pulmonary edema) and to exclude possible differential diagnoses. Should ACEI therapy be discontinued in dogs already receiving this medication? In cases where the treatment cost is an issue, or there may be another medical or practical reason why combined therapy is not an option, the QUEST trial clearly showed that pimobendan is the superior option. In cases with no such restrictions exists, then the answer is probably not. The QUEST trial was not designed to study the effect of combining pimobendan with ACEI. The two drugs have completely different modes of action, but studies of the possible extra benefit combined treatment might have are currently not available. There are some theoretical arguments in favor of combined therapy, but future studies specifically designed to study this question are warranted. Until results from these studies are published, we will have to settle with the fact that the question the QUEST trial set out to answer was clearly answered: Pimobendan does have a favorable effect on survival in dogs with CHF because of MMVD. REFERENCES 1. 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 regurgitation. J Vet Intern Med. 2002;16:80-88. 2. 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. JAVMA. 2007;231:10611069. 3. Smith P, French A, Van Israël N, et al. Efficacy and safet 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. 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,

Small Animal – Cardiology ______________________________________________________________________________________________ controlled, blinded, and randomized study. J Vet Intern Med. 2007;21:742-753. 6. Dell'Italia L. The renin-angiotensin system in mitral regurgitation: a typical example of tissue activation. Curr Cardiol Rep. 2002;4:97-103. 7. 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. JAVMA. 1998;213:1573-7. 8. The 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, placebocontrolled, long-term clinical trial. J Vet Cardiol. 1999;1:7-18. 9. Haggstrom J, Boswood A, O'Grady M, 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;22:11241135. 10. Oyama MA, Rush JE, O'Sullivan ML, et al. Perceptions and priorities of owners of dogs with heart disease regarding quality versus quantity of life for their pets. JAVMA. 2008;233:104-108.

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