Canine Chronic Mitral Valve Disease--The Search for the Silver Bullet
ACVIM 2008
Paul D. Pion; Mark Rishniw
Davis, CA, USA

Introduction

Chronic myxomatous mitral valve disease (MMVD) is the most common cardiac disease in dogs. Although veterinarians have been diagnosing and managing dogs with MMVD for more than 50 years, the cause of MMVD remains unknown.1-7 Over the last 40 years, a more detailed description of the inheritance, breed predisposition, natural history, functional consequences and pathology of the disease has emerged.8-16

Breed predispositions strongly support the notion that genetic determinants play a pivotal role in development of MMVD.8,13 However, despite being recognized as highly prevalent, especially among small breed dogs, little progress has been made in understanding the most basic questions that might lead to a reduction in the incidence of MMVD or true progress in the prevention or slowed progression of MMVD.

Dogs are not little people. Still, it is worth noting that mitral valve repair in humans was first performed in 1923 (Elliot Cutler), and prosthetic valve replacement was first performed in the 1960s. It has long been recognized that within the context of medicine in the 20th and early 21st centuries, clinically significant mitral regurgitation, a physical/mechanical lesion requires a mechanical solution in humans. Consequently, various prostheses have been developed, and various repair techniques have been employed and are still being investigated (Everest, Everest II) as ways of controlling progression of disease in humans. Of critical importance is the realization that surgical intervention in humans is often undertaken with relatively early-stage disease, because prognosis appears to be directly related to the preservation of myocardial function.17

Availability of trained surgeons, need for cardiopulmonary bypass, substantial cost, different pathophysiology of MMVD in dogs (compared to humans) and patient size have largely precluded the adoption of surgical techniques for addressing MMVD in dogs. In select cases, surgical therapy has been used as a last resort, usually in patients with severe disease, often with less-than-favorable outcomes.18-21 Justifiably, the high cost and poor outcomes have dissuaded most veterinary clinicians from pursuing surgical options for dogs with MMVD. Instead, we as a profession have sought to ameliorate clinical signs and alter disease progression medically--in a never ending search for the silver bullet that will effectively "treat" MMVD.

Here's How You Treat It--What You Have Heard at VMA Meetings for the Last 40 Years.

The first descriptions of treatment of CHF in dogs in the US date back to the 1960s.3,21,22 Hindsight is 20-20, but examination of the "evolution" of treatment of MMVD in dogs reveals interesting, almost predictable and repeatable behaviors with regard to therapeutic recommendations and outcomes.

Clinicians from successive generations have been taught very specific and often dogmatic therapeutic approaches. The earliest recommendations dealt primarily with the treatment of CHF, and were based on acute therapeutic results or extrapolations from human data. Subsequently, as more and more clinicians recognized the disease and clients became more receptive (some might say demanding) of earlier intervention with the hope of delaying the onset of clinical signs, recurrence of CHF and ultimately prolonging life, several novel medical strategies were examined, became ingrained in the veterinary culture and despite growing evidence that refute or limit their efficacy, the desire for a silver bullet in the form of a "pill" remains the focus of most clinical investigations and pharmacological investments, possibly at the expense of resources to address the issues that might someday lead to a truly effective therapeutic strategy for retarding or preventing progression of subclinical disease.

It is our hope that reviewing this search for the silver bullet will bring into focus the advances we have made and the potential barriers to true progress we have created by our willingness to want to believe that the solution to this problem can be found in a pill bottle. If only we can find the right pill. The silver bullet!

Approach #1--Volume Reduction. The Age of the Diuretic.

Studies in humans and experimental animals with CHF from multiple causes demonstrated that acute plasma volume reduction was life-saving.22 In veterinary practice, this strategy translates largely to one word: furosemide (or frusemide if you are of British descent). The first mention of furosemide for the management of canine CHF that we could find appears in 1967.23,24 However, subsequent to these early reports, virtually no data exist demonstrating the benefit of furosemide in managing canine CHF patients. We are not arguing that this is a huge gap in the justification of the use of furosemide. Few would argue that double-blinded placebo controlled clinical trials are necessary when outcomes are as dichotomous as those seen with diuretic use in CHF--all veterinarians know that diuretics work, and no clinical trials are necessary to document this. No drug is perfect and although the most popular, it is worth exploring whether other diuretics or combinations of diuretics might be more effective in dogs with MMVD.25

Spironolactone has been used in humans with CHF since the late 1950s, but little mention is made of use in dogs with CHF over the last 40 years.26 More recently, spironolactone has regained popularity as a neurohormonal modulator, and several studies have emerged examining its effect as a diuretic.27-31 These studies have unanimously failed to demonstrate diuresis in normal dogs, but have not looked at dogs with MMVD.

Thiazide diuretics have at least as long a history of use in humans with CHF as spironolactone.26 However, virtually no mention is made of thiazides in the treatment of canine MMVD in the scientific literature. All recommendations for use of thiazides seem to be extrapolated from clinical experience in humans or from their effects as diuretics in normal (experimental) dogs.

Attempts at reducing the adverse impact of individual diuretics, or maximizing diuretic potential by simultaneously targeting multiple segments of the nephron grew in popularity in the mid-1990s, but no studies demonstrate any benefit of "diuretic stacking" over single-agent therapy in uncomplicated CHF. Management of the refractory CHF patient with multiple diuretics has similarly been guided by "gut feeling" and "personal experience" or personal preference.32

Approach #2--Inotropic Support. The Age of the Glycoside.

In the mid 1960s, Ettinger published the first paper describing digitalization of canine patients with CHF.2 However, the rationale for the use of digitalis glycosides in MMVD was not critically examined at that time--digoxin was a useful drug in humans with CHF so clinicians assumed it would be a useful drug in dogs with CHF. In other words, little thought was given to the mechanistic basis for the use of digitoxin or digoxin (personal communication, Buchanan 2008). Many hypothesized as to the potential benefits of digoxin for dogs with MMVD, but no trials documented quality of life or survival benefit.2 Others questioned its use.33 During the 1980's, with the rise of vasodilators and increasing concern regarding digoxin toxicity, digoxin fell out of favor. Digoxin subsequently regained popularity in the 1990s as a neurohormonal modulator.34 The veterinary resurgence was again based solely upon theoretical benefits and evidence from human trials.35

Approach #3--Afterload Reduction. The Age of the Vasodilator.

In the early 1980s, Kittleson demonstrated the benefit of acute and chronic afterload reduction in MMVD with hydralazine, a pure arteriodilator.35,36 The rationale behind this approach was that reducing afterload would increase forward ejection fraction and reduce regurgitant fraction. While this therapy proved effective in acute or short-term management, no studies were conducted demonstrating long-term survival benefits (one study did show a delay in disease progression with hydralazine, compared to ACE-I).37 Additionally, side effects associated with hydralazine administration resulted in a decline in the popularity of this therapeutic strategy. In the mid and late 1980's angiotensin-converting-enzyme inhibitors were introduced as balanced vasodilators and (see below) inhibitors of the renin-angiotensin-aldosterone system. Importantly, these were the first cardiac drugs that major pharmaceutical companies successfully invested large sums to license for use in dogs with heart failure. It is probably this fact, more than any other that has spawned the large number of clinical trials examining the efficacy of ACE-I in MMVD.

More recently, amlodipine has been recommended in for the management of refractory CHF, based exclusively on its action as a vasodilator similar to hydralazine.38 However, no data demonstrating benefits in dogs with MMVD have been published.

Approach #4--Neurohormonal Modulation. The Age of the ACE-Inhibitor and Beta Blocker and Rebirth of Digoxin.

Trials in the late 1980s and early 1990s in humans with both CHF and subclinical disease showed (questionably) improved patient outcomes with therapies aimed at modulating the neurohormonal response and secondary cardiac remodeling.39 The rationale was that normalizing the neurohormonal status or blocking neurohormonal imbalances would prevent mal-adaptation of the heart and either delay progression of disease, or aid in treatment of CHF. Drugs examined in humans with left ventricular dysfunction and DCM included digoxin, ACE-I, beta blockers, and spironolactone.34,39-42 Based on these studies, several studies were performed in dogs with MMVD with or without CHF. It is interesting to note that virtually all studies that have been published on canine MMVD involve the use of ACE-I, despite equal or even greater benefits being demonstrated in humans with other classes of drugs.14,15,43-51 The outcomes from these studies have varied, showing modest benefit in dogs with CHF, but no benefit in subclinical dogs.

Based on the current evidence provided by the SVEP and VETPROOF trials, we believe there is adequate data to conclude that prior to the onset of CHF, we can discount ACE-I as the "silver bullet".14,15

Carvedilol gained popularity in human cardiology in the late 1990s when it was shown to impact heart failure.52 This lead to promotion of carvedilol in veterinary patients, justified exclusively on theoretical benefits and extrapolation, but no conclusive clinical benefit has been demonstrated in dogs with MMVD.50 Interestingly, studies comparing beta blockers in humans with heart failure (but not necessarily CHF) show varied benefit of carvedilol over other beta blockers.

Approach #5--Inodilation. The Age of Milrinone and Pimobendan.

Oral milrinone, a PDE III inhibitor, was introduced in the mid-1980s, and was examined in dogs with CHF both with DCM and MMVD.53,54 However, due to its withdrawal from the human market in the 1990s, it was never marketed for use in dogs.

Most recently, pimobendan has been promoted for use in treatment of CHF secondary to MMVD.55-59 A calcium-sensitizing agent and PDE III inhibitor, it was initially promoted for use in DCM, but has subsequently been shown to be beneficial in treating dogs with advanced MMVD. Pimobendan, like ACE-I, has undergone extensive clinical trials prior to and subsequent to approval by US and European drug regulatory agencies. Its role in earlier stages of MMVD (and DCM) is still under investigation.60

Approach #6--Dietary Sodium Restriction.

While cardiac diets were marketed since the 1960s, no studies have shown a clinical benefit of dietary modification in terms of recurrence of CHF or prevention of disease.61-64

Conclusion

It is apparent that veterinarians have been presented with ever-changing recommendations for the management of MMVD in dogs both with and without CHF. From your earliest cardiology classes in veterinary school, through to your most recent CE, journal or textbook perusal or pharmaceutical representative's presentation, "experts" have delivered information about management of all stages of MMVD. This information is often dogmatic, leaving you, the primary care clinician, believing that (i) the expert has the magic key to managing this disease and (ii) the basis of the recommendations is well founded in clinical trials.

The propagation and practice of these beliefs is compounded by the practicing clinician's desire for effective therapeutic options they can offer clients and patients for canine MMVD, editorial pressure for "black & white" articles, and speaker popularity based on similar criteria.

It is important that clinicians treating dogs with MMVD realize that much of what is "known" about managing MMVD is built on a house of cards and, in recent times, underwritten by pharmaceutical companies with vested interests in promoting particular approaches, at the expense of potentially equally effective, but economically unattractive alternatives.

Where does this leave us? Although this might appear be a dire situation, we believe there is cause for great hope. Our understanding of the complexity of MMVD is maturing at a rapid rate. Increasingly veterinarians are recognizing that although we are able to accurately and noninvasively diagnose all phases of MMVD, no silver bullet in the form of a pill likely exists.

Armed with this understanding, clinicians can increasingly resist the temptation to distract themselves and their clients with false hope that a pill will delay the progress of MMVD in dogs in a clinically relevant manner.

Admitting that we do not yet have an effective therapy for the early stages of MMVD and that we are unlikely to find such a therapy in the form of a pill is an important first step that we hope will lead to increased attention and resources being turned toward discovering the underlying basis of the primary valve lesion and a greater chance of is discovering genetic or pharmacologic strategies that address this process directly.

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Speaker Information
(click the speaker's name to view other papers and abstracts submitted by this speaker)

Paul Pion
Davis, CA

Mark Rishniw
Cornell University
Ithaca, NY


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