Editorial: J Vet Intern Med 2008;22:1076–1078

A Q UEST Begi ns As important is the quest for certainty, so is the quest for clarity—Jean-Franc¸ois Gautier

ore than 40 years since canine degenerative mitral valve disease (DMVD) was first systematically described, treatment of this highly prevalent condition remains an immense challenge. Despite myriad advances in the diagnosis, imaging, and pharmaceutics, morbidity and case fatality rate of dogs with congestive heart failure remain surprisingly high. Treatment of DMVD targets restitution of multiple hemodynamic and neurohormonal derangements, including elevated venous pressures, decreased systolic pump function, and heightened activity of the sympathetic and renin-angiotensin-aldosterone systems. In this regard, diuretics, vasodilators, and positive inotropes form the bedrocks of treatment. Diuretic administration is undeniably an effective and life-saving treatment based on decades of success in alleviating respiratory distress caused by congestive heart failure. ACE inhibitors improve hemodynamics, alleviate clinical signs, and improve outcome, as demonstrated in series of landmark studies published between 1995 and 1999. And now, in this issue of Journal of Veterinary Internal Medicine, Haggstrom et al present results of the QUEST trial1 indicating that pimobendan, a dual-acting positive inotrope and vasodilator, improves outcome in dogs with congestive heart failure secondary to DMVD. The investigators report that the combined risk of natural death, euthanasia, or resistance to maximal diuretic therapy was reduced by 32% in dogs receiving pimobendan and furosemide versus dogs receiving the ACE inhibitor benazepril and furosemide. Consequently, the time from study enrollment to endpoint in dogs receiving pimobendan was 91% longer than in those receiving benazepril. These results present a persuasive case for the beneficial effects of pimobendan in dogs with heart failure caused by DMVD, as well as raise a number of intriguing issues. Positive inotropes are drugs that increase the inherent ability of the myocyte to contract. Interestingly, the annals of human medical research are filled with positive inotropic drugs that failed to improve survival when chronically administered. These agents include such failures as milrinone, enoximone, vesnarinone, xamoterol, ibopamine, and flosequinan. Not only did these agents fail to improve survival, they actually increased risk of death when given chronically! Pimobendan tended to increase risk of death, and even the stalwart and venerable positive inotrope, digoxin, failed to favorably affect longevity. The inability of positive inotropes to improve outcome was unexpected, and even more striking when viewed against the incontrovertible benefits of ACE inhibitors and b-adrenergic blockers in humans. How can this be? How could improved contractility and improved cardiac hemodynamics not produce a more favorable outcome? The answer was stated simply by an eminent cardiologist in 1992: ‘‘. . . although hemodynamic abnormalities may explain the symptoms of heart failure, they

M

are not sufficient to explain the progression of heart failure and, ultimately, the death of the patient . . . [inotropic agents] may improve the hemodynamic status of patients but adversely affect their long-term outcome . . . these observations support the formulation of a neurohormonal hypothesis of heart failure.’’2 We now know that the neurohormonal systems that lie at the core of cardiac dysfunction include, among others, the renin-angiotensin-aldosterone, sympathetic nervous, cytokine, and vasopressin systems. Thus, the ‘‘ideal’’ treatment of heart failure in dogs with DMVD likely involves a combination of several agents, some of which offer hemodynamic benefits (ie, diuretics, positive inotropes, vasodilators) and some of which (ie, ACE inhibitors, b-blockers, and so on) tilt the balance of neurohormonal activity toward a more favorable equilibrium. And so this is not necessarily the time to forever banish the ACE inhibitors to the hinterlands in favor of a positive inotrope such as pimobendan; however, if the neurohormonal approach to heart failure is indeed correct, why the apparent superiority of pimobendan over ACE inhibitor in the study by Haggstrom et al? There are several potential explanations. The positive inotropic effect of pimobendan is unique from that of ‘‘traditional’’ positive inotropes such as digoxin. Most of pimobendan’s effect on contractility is accomplished through sensitization of the myocyte’s contractile elements to calcium ion binding as opposed to simply increasing the intracellular concentration of free calcium. The failures of the past are likely related to detrimental effects of the latter mechanism on arrhythmia formation, energy expenditure, and cell viability. Moreover, pimobendan, in addition to increasing contractility, elicits arterial vasodilation and reduces afterload and myocardial work. Thus, perhaps it is through these combined ‘‘inodilator’’ effects that pimobendan improves outcome. Clinical experience with pimobendan reveals that most dogs experience an improved quality of life with respect to appetite, activity level, resolution of clinical signs, and enhanced interaction with the owner when receiving this agent. This phenomenon is not lost on clients. In fact, quality of life may be of greater immediate importance to pet owner than longevity. As such, any agent that improves quality of life has great value, despite even a neutral (or negative) effect on survival. This is where veterinary medicine and human medicine diverge, and thankfully veterinarians have great latitude in this respect. In veterinary patients, the intersection of quality and quantity of life is forever intertwined by the ability to provide humane euthanasia. It is exceedingly rational to conclude that agents that improve quality of life are likely to delay euthanasia and thereby automatically prolong ‘‘survival’’. Accordingly, subsequent reports of QUEST data, which include quality of life parameters, are highly anticipated.

Editorial

Studies that compare 2 approved drug treatments typically do so without a negative control group and with good reason. It would be highly unethical to include a control group of dogs that received no drugs, and as such, the outcome of the treatment groups must be viewed in relative terms. We can safely state that dual therapy with pimobendan and furosemide yielded better outcome than ACE inhibitor and furosemide, but what were the absolute benefits of either agent? Dogs receiving pimobendan faired better than those receiving ACE inhibitor; however, the median survival time of dogs receiving the superior protocol (ie, pimobendan) was only 267 days, or approximately 8.9 months. In a retrospective study of 558 dogs with DMVD, Borgarelli et al3 report that the median survival time of dogs with mild and severe heart failure was 28 and 9 months, respectively, with only 5.6% of the dogs having received pimobendan. Thus, a skeptic might conclude that the dogs receiving pimobendan performed quite average, whereas the dogs receiving ACE-I faired worse than expected. Indeed, in the study by Haggstrom et al, the median survival time (140 days, or 4.7 months) of dogs receiving ACE-I is very sobering. The imperfections of comparing populations of dogs from two different studies notwithstanding, this underscores the limitations of our knowledge even when presented with well-designed, executed, and reported clinical studies. And hence, despite the ‘‘sturm und drang’’ of these types of conundrums, is it likely that the results of Haggstrom et al are the result of adverse effects of ACE-I in dogs with DMVD? The answer is ‘‘extremely unlikely,’’ given the wealth of positive data from human, experimental, and naturally occurring disease ACE inhibitor studies. Which brings us to perhaps the most important question of all: How should the report by Haggstrom et al influence our decision-making when we are standing in front of the pharmacy shelf? Here, as one might expect, we lack absolute certainty, but Haggstrom et al have provided us with sharpened clarity. First, the effectiveness demonstrated by this report does not give license for use of pimobendan in any and all dogs with DMVD. This cannot be overstated. The benefits of pimobendan are achieved in dogs with symptomatic disease (ie, heart failure) secondary to DMVD (or dilated cardiomyopathy). In the overwhelming majority of dogs with DMVD, this will mean dogs with left-sided congestive heart failure in the form of pulmonary edema. How can one be sure that a geriatric coughing dog with a heart murmur has pulmonary edema and is thus a candidate for pimobendan therapy? Dogs with a history of DMVD and respiratory signs should undergo thoracic radiography to discern significant left-sided heart enlargement, distended pulmonary veins, and a perihilar and caudodorsal interstitial pattern (ie, the radiographic hallmarks of left-sided congestive heart failure) from other comorbidities such as collapsing trachea or chronic bronchitis that could be a confounding source of clinical signs. What of dogs that are already receiving ACE inhibitors? In its strictest interpretation, the relative benefits reported by Haggstrom et al apply only to dogs receiving dual treatment with pimobendan and furosemide.

1077

Should we now preferentially use pimobendan over ACE inhibitors? Should we withdraw ACE inhibitors in dogs and replace with pimobendan? The answer to this question is an admittedly indecisive ‘‘probably not.’’ Here again, we lack certainty, but ever clearer answers are emerging from the haze. In cases where circumstances dictate an ‘‘either-or’’ approach (ie, financial restraints, recalcitrant pets who are difficult to medicate), the data from Haggstrom et al clearly favor the use of pimobendan. In all other cases of dogs with heart failure caused by DMVD, the most reasonable course of action is combined therapy with pimobendan, ACE inhibitor, and diuretics. Just how much greater effectiveness this combination might have over the either-or approach requires further trials, but in the absence of these data, there is every theoretic and practical reason to assume that these agents retain their individual beneficial effects when coadministered. The United States was one of the last major veterinary markets to receive pimobendan. Like with any new drug, practitioners will travel through a continuum of thought and action that begins with skepticism, proceeds slowly to wary curiosity, then to hopeful experimentation, and finally, depending on its effectiveness, to either embracement or rejection. I too have traveled down that path, and currently consider pimobendan the single most important addition to the medical therapy of dogs with symptomatic DMVD and dilated cardiomyopathy since becoming a veterinary cardiologist more than a decade ago. But whatever one’s clinical experience, it is clear (as this editorial hopes to convey) that a bounty of unanswered questions remain. For instance, there are significant unknowns about pimobendan’s utility in preclinical disease; little is known about pimobendan use in cases of congenital heart disease, pericardial disease, or myocarditis, and we have yet to fully understand pimobendan’s interaction with traditional positive inotropes such as digoxin. This quest for clarity involves many aspects of DMVD, and not just issues surrounding optimal use of pimobendan. For instance, large-scale trials assessing efficacy of b-blockers and spironolactone remain undone; the impact of nonpharmaceutical interventions such as transvenous mitral valve repair or replacement has yet to be felt in veterinary medicine, but is not too far distant, and ultimately, advances in molecular biology yield hope that the pathophysiology and the etiology of DMVD will eventually be understood, thereby relegating discussion of medical therapy to the dustbin of history (perhaps wildly optimistic, but let us set our sights high). Until such a time, we will have to depend on the totality of evidence gathered in the past 10 years that both ACE inhibitors and pimobendan have a role in treatment of symptomatic DMVD. Finally, the study by Haggstrom et al is to be commended not only for its ambition and meticulous reporting but also for its ultimately successful multicentered design. The questions of efficacy, which are so critical to advancing veterinary care, are best addressed by cooperative efforts that employ ‘‘large’’ populations of patients (large being a relative term). Indeed, it is sobering to note that survival studies in human cardiology

1078

Editorial

typically enroll thousands of patients and are designed to produce results that are as ‘‘certain’’ as can be humanly achieved. The obstacles of this type of definitive mega trial in veterinary medicine notwithstanding, future studies will certainly benefit from the example set forth herein; and through the cumulative result of this and other clinical studies, our ‘‘quest’’ will move ever closer to the elusive goal of certainty.

References 1. Haggstrom J. Effect of pimobendan versus benazepril hydrochloride on survival times in dogs with congestive heart failure due to naturally occurring myxomatous mitral valve disease: Results of the QUEST study. J Vet Intern Med 2008; DOI: 10.1111/j.19391676.2008.0150.x Published online 11 July 2008.

2. Packer M. The neurohormonal hypothesis: A theory to explain the mechanism of disease progression in heart failure. J Am Coll Cardiol 1992;20:248–254. 3. Borgarelli M, Savarino P, Crosara S, et al. Survival characteristics and prognostic variables of dogs with mitral regurgitation attributable to myxomatous valve disease. J Vet Intern Med 2008; 22:120–128.

Mark A. Oyama, DVM, DACVIM-Cardiology Department of Clinical Studies School of Veterinary Medicine University of Pennsylvania PA