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Improving outcomes of myxomatous mitral valve disease in dogs
  1. Adrian Boswood

Abstract

Now that treatment has been shown to slow the onset of clinical signs of myxomatous mitral valve disease (MMVD), recommendations are focusing on diagnosing the condition before clinical signs manifest so that dogs can be maintained free of signs for longer. This article summarises the published evidence and outlines optimal management for dogs at each disease stage. It covers pharmacological and other strategies, with a view to maintaining dogs in the early stages of the disease for as long as possible and effectively managing their clinical signs when they develop.

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Adrian Boswood, Department of Clinical Science and Services, Royal Veterinary College, Hatfield, Hertfordshire, UK e-mail: aboswood@rvc.ac.uk

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Adrian Boswood graduated from Cambridge university veterinary school in 1989. He spent a year in mixed practice before joining the RVC as an intern. He is currently professor of veterinary cardiology and vice principal for learning, teaching and assessment there. He holds the RCVS certificate in small animal cardiology, the RCVS diploma in veterinary cardiology and the ECVIM cardiology diploma.

MYXOMATOUS mitral valve disease (MMVD) is the cardiac disease that most commonly affects dogs and, as such, is a common cause of morbidity and mortality in the ageing dog population. It typically affects older small breed dogs and some breeds of dog are very strongly predisposed to the development of the disease. In order to understand the optimal management of the disease it is first necessary to understand a little about the pathophysiology and staging of the disease. This is covered comprehensively in other articles in this supplement, but I will very briefly review the progression and staging of the disease here.

MMVD is characterised initially by a degeneration of the normal structure of the mitral valve. In the earliest stage of the disease the only abnormality present is the leak in the valve. In many dogs the leak is small, well-tolerated and necessitates no significant adaptation of the cardiovascular system for the patient to compensate. In some patients the disease progresses and the leak in the valve worsens. The heart enlarges in order to compensate for the inefficiency that a larger leak introduces into the function of the heart.

Cardiac enlargement (cardiomegaly), although helping the patient to compensate for their disease, is an indicator of progressive disease that usually precedes the manifestation of any outward sign of disease. Eventually, in some dogs, the leak in the valve progresses to the extent that the dog’s capacity to compensate is overwhelmed by the severity of the disease, resulting in the development of outward signs. These are typically signs of heart failure, either signs of poor cardiac output (such as exercise intolerance and collapse) or signs of congestive heart failure (CHF) (increased respiratory rate due to pulmonary congestion and oedema, or ascites).

The whole process described typically takes several years in those patients that progress through all stages of the disease. Some patients have non-progressive disease and older patients may succumb to concurrent diseases of old age before their heart disease results in cardiomegaly or clinical signs. This means that development of the initial stages of the disease does not make it inevitable that a patient will progress to the latter stages. Some studies have estimated that fewer than half of affected dogs will die as a direct consequence of MMVD.

The most useful classification of these different stages of the disease was proposed by the American College of Veterinary Internal Medicine (ACVIM) Speciality of Cardiology consensus panel (Atkins and others 2009). It uses an alphabetic system to classify dogs into disease stages A, B, C and D. In stage A dogs are considered predisposed to the disease but do not yet have it. In stage B dogs have evidence of disease but have not yet developed signs of heart failure. In stage C dogs are showing, or have previously shown, signs of CHF. Stage D dogs demonstrate signs of heart failure despite receiving appropriate treatment; they are considered to have refractory signs of heart failure. When practitioners understand and apply this classification system it enables them to appropriately manage the animals under their care affected by, or predisposed to, this condition.

Pharmacological management

The remainder of this article will describe the management of patients with MMVD according to the classification system outlined in this article and supplement (Table 1). This advice is based on the current best evidence available from the published literature. As such, it is likely to be superseded by further advances in the management of the disease, but represents a current method of management that can be usefully employed in practice.

Table 1:

Drug doses and appropriate stages at which to administer them

Stage A disease

As the oft used proverb states, prevention is better than cure. A lot of emphasis on the management of human patients at risk of cardiovascular disease is aimed at preventing disease rather than managing patients that already have it.

There is no medication that is known to delay the onset of MMVD in dogs. In some of the breeds of dog most strongly predisposed to developing MMVD there have been efforts to identify genetic markers associated with early onset disease and also to employ breed surveillance programmes to attempt to avoid or delay the onset of disease.

Although some associations between specific genetic polymorphisms and early onset disease have been suggested in cavalier King Charles spaniels (CKCS) (Madsen and others 2011), genetic tests are not yet available to identify high-risk dogs. Breeding schemes have so far relied upon echocardiographic and/ or physical examination findings to identify affected dogs. Recently published evidence has suggested that a breeding scheme combining echocardiographic examination and auscultation can, over approximately a decade, reduce the incidence of MMVD in a high-risk breed of dog – the CKCS (Birkegård and others 2016). A voluntary breeding scheme, also in CKCS, reliant on auscultation alone that has been applied in the UK has had more mixed success in reducing the age of onset of the disease (Swift and others 2017). Practitioners with clients who breed dogs at risk of development of MMVD should consider advising those clients of the breed surveillance schemes available. Current information on the schemes in the UK is available through the Veterinary Cardiovascular Society (www. vet-cardio.co.uk).

It is possible that in future a more concerted effort at selecting away from the disease with breeding programmes may reduce the prevalence, or at least increase the age of onset, of MMVD in high-risk breeds. Given how prevalent the disease is in numerous ageing small-breed dogs, and not just those from breeds considered to be at highest risk, it seems unlikely that selective breeding in specific breeds will markedly reduce the overall prevalence of this disease in the foreseeable future. Therefore, management of patients that have already acquired the disease remains the most significant consideration for most practitioners.

Stage B disease

Stage B of MMVD is a lengthy phase of the disease and represents a spectrum of disease severity varying from dogs with very early valvular lesions and a miniscule mitral regurgitant jet, to dogs with advanced disease characterised by a large regurgitant jet and considerable evidence of ventricular and atrial remodelling (enlargement). It is helpful for the purposes of management of these patients to subdivide this stage into those dogs that have no evidence of cardiac enlargement (stage B1) and those that have evidence of enlargement (stage B2). This is still, in effect, to dichotomise a spectrum of disease severity into two groups that are still heterogeneous, with there being a diversity of disease severity within B1 and a different diversity within B2.

One of the reasons this dichotomy is particularly useful is that the evidence for effectiveness of interventions to treat MMVD is quite different in these two groups of dogs.

In order to accurately classify a dog as having stage B1 or stage B2 disease, the dog will need to undergo diagnostic imaging to establish whether its heart is enlarged. Ideally, all dogs with a heart murmur should undergo diagnostic imaging. Realistically, the cost of such testing will be prohibitive for some clients and access to appropriate equipment and expertise may be limited in some settings. Of the diagnostic imaging methods available, echocardiography is likely to be the most accurate in determining whether cardiomegaly is present. It is the diagnostic test of choice if one is to be performed in the patient with preclinical disease.

Stage B1 disease

Any dog with a leak in its mitral valve caused by degeneration of that valve, but without evidence of secondary cardiac enlargement, can be considered to be a dog with stage B1 disease. Dogs with this stage are the most numerous group of dogs with MMVD in cross-sectional studies undertaken in primary care practice. They therefore represent the majority of dogs with MMVD that will be managed by primary care practitioners.

Few studies have sought to demonstrate the effectiveness of medical therapy in stage B1 dogs. The only prospective blinded placebo controlled study undertaken including stage B1 dogs evaluated the effect of angiotensin-converting enzyme inhibitors (ACE inhibitors) in a population of CKCS. This study showed no favourable (or detrimental) effect of treatment at this stage (Kvart and others 2002). No other treatment has been systematically evaluated in stage B1 dogs. The current best evidence suggests that there is no benefit to medical management of patients with stage B1 disease.

Questions arise about other aspects of management of these patients relating to diet and exercise. These aspects of management will be considered separately.

Stage B2 disease

The conclusions of the EPIC study (evaluation of pimobendan in dogs with cardiomegaly caused by preclinical mitral valve disease) (Boswood and others 2016) have significantly altered the treatment of dogs with stage B2 disease. In this large prospective blinded randomised study, dogs with cardiac enlargement receiving pimobendan were significantly less likely to reach the primary endpoint of the study (ie, develop CHF or experience cardiac-related death), compared with those receiving placebo.

The majority of the observed benefit was attributable to a delay in the onset of CHF. The risk of developing the primary endpoint was reduced by approximately one third, and the estimated median time to the primary endpoint was approximately 15 months longer in the pimobendan group compared with the placebo group. The dose of pimobendan used in the EPIC study was in the range 0.4 to 0.6 mg/kg/day, with the total dose being divided and administered twice daily. The evidence from the study was considered sufficiently convincing for recently updated ACVIM treatment guidelines (yet to be published but outlined at the ACVIM forum in 2017) to recommend the administration of pimobendan to dogs with stage B2 disease.

The important point regarding the use of pimobendan is that it has only been shown to be effective in dogs that have enlargement of their heart. This means that before pimobendan is administered to a dog with preclinical MMVD, that dog should have undergone diagnostic imaging to ensure that there is evidence of cardiac enlargement. Three criteria were used to establish cardiac enlargement before a dog was enrolled in the EPIC study: dogs needed to have a normalised left ventricular internal diameter in diastole (LVIDDN) of greater than or equal to 1.7, a left atrial to aortic ratio (LA:Ao) of greater than or equal to 1.6, both shown on echocardiographic evaluation, and a vertebral heart sum (VHS) of more than 10.5, shown on radiographic evaluation. I therefore recommend, as a minimum, that a dog should have undergone an echocardiographic examination and be shown to meet the LVIDDN and LA:Ao criteria before pimobendan therapy is initiated. It is debatable whether dogs should also be shown to have met the radiographic criterion of a VHS of more than 10.5 in addition to the echocardiographic criteria. Due to variability of VHS within breeds, a VHS of more than 10.5 is probably not, as a single measurement, sufficient evidence to warrant therapy; however, it is likely that a dog with a VHS considerably greater than this (for example, more than 11.5) will also have echocardiographic evidence of enlargement.

On the basis of the results of the EPIC study I now routinely recommend the use of pimobendan in dogs with preclinical MMVD and evidence of cardiac enlargement (sufficient to meet the EPIC inclusion criteria) at a dose of approximately 0.5 mg/kg/day divided into two doses (0.25 mg/kg twice a day).

Historically, there has been considerable controversy regarding the use of ACE inhibitors in dogs with stage B2 disease. Two prospective clinical trials attempted to determine whether ACE inhibitors would benefit dogs at this stage of disease (Atkins and others 2007, Kvart and others 2002). Neither study conclusively demonstrated a significant benefit with respect to their primary endpoint. The ongoing controversy was reflected in the lack of consensus with respect to the use of ACE inhibitors in this stage of the disease reported in the 2009 ACVIM treatment guidelines (Atkins and others 2009). On the basis of a critical reading, I have never believed that the evidence for treatment was sufficiently compelling to warrant treatment and have not recommended the use of ACE inhibitors in dogs with stage B2 disease.

There is currently no clear evidence to support the use of other drugs in dogs with stage B2 disease, although there are other ongoing studies that may provide evidence for the benefit of other medications in future.

Once treatment with pimobendan has been started it should be continued indefinitely and the dog should be monitored for progression of disease. The most likely way in which a dog’s disease will progress is for them to develop signs of CHF (ie, progress to stage C of the disease). One of the most consistent and reliable indicators of the development of stage C disease is an increase in the patient’s resting respiratory rate. It is therefore useful to teach the owners of dogs with stage B2 disease to monitor resting respiratory rate and keep a record of their dog’s respiratory rate over time.

Although a dog’s heart is likely to increase further in size as their disease progresses, an increase in heart size alone is not sufficient to warrant intensifying therapy once a dog is receiving pimobendan. Only the development of further clinical signs is likely to indicate that further treatment is necessary. This raises a question regarding the routine re-examination of these patients, particularly regular performance of tests evaluating heart size.

There is undoubtedly a benefit to maintaining regular contact with the owners of dogs with stage B2 disease. As well as ensuring continuity of care, re-examination at three- to six-month intervals may help with early detection of disease progression. It will also help to ensure that medication continues to be administered and that the owners are monitoring their dog as advised.

If a dog is suspected to be developing signs of congestion, particularly if they are suspected to have pulmonary congestion and oedema, then the diagnostic test of choice is thoracic radiography. Once signs attributable to congestion have developed, a dog is considered to be at stage C of their disease.

Stage C disease

A dog with stage C disease has progressed to the point where there are evident clinical signs as a consequence of CHF. These are most likely to be signs of left-sided CHF, although rarely some dogs will develop right-sided CHF, ascites, as their first sign of CHF. A dog will also be considered to be in stage C disease if they have previously shown evidence of congestion and need to continue to receive heart failure treatment in order to prevent the recurrence of signs. This reflects the irreversible nature of many of the changes associated with the disease. If a dog’s disease is bad enough to necessitate introduction of heart failure therapy it is likely that they will need to continue to receive this therapy throughout their life.

Once signs of CHF have developed, it is widely accepted that diuretics should be administered; the first-line diuretic usually used is furosemide. There is surprisingly little published evidence-base for this widely used treatment, which is probably a consequence of its use predating the use of clinical trials to establish the effectiveness of therapy. Furosemide is administered at a dose of 1 to 4 mg/kg twice to three times a day according to the severity of clinical signs and the ease with which they can be controlled.

A recently published large clinical trial (Chetboul and others 2017) established that torasemide, another loop diuretic, was ‘non-inferior’ to furosemide in its effectiveness at managing dogs with CHF. In doing so it also described a large population of dogs receiving furosemide for the treatment of CHF.

Several studies have established the usefulness of different classes of drug in the management of dogs with heart failure secondary to MMVD. These include pimobendan (Häggström and others 2008), ACE inhibitors (Ettinger and others 1998, Pouchelon and others 1999) and spironolactone (Bernay and others 2010).

Most of the published studies establishing the effectiveness of ACE inhibitors predated the availability of pimobendan and therefore dogs in these studies did not receive pimobendan in addition to ACE inhibitors. The QUEST study (Häggström and others 2008) compared the efficacy of pimobendan and benazepril in the treatment of dogs with stage C disease. The conclusion of this study was that pimobendan was superior to benazepril, but no conclusions could be drawn about the effects of administering the drugs together.

Similarly the study which established the effectiveness of spironolactone in the treatment of dogs with MMVD (Bernay and others 2010) precluded the concurrent administration of pimobendan. This means there has not been a prospective blinded study which specifically evaluates the effectiveness of the combination of these four commonly used drugs together. Despite this, most cardiologists (including me) now recommend the administration of four medications for the treatment of stage C MMVD: furosemide, pimobendan, an ACE inhibitor and spironolactone. Where for reasons of cost or compliance it is not possible to administer all of these drugs then at a minimum the combination of furosemide and pimobendan should be administered. ACE inhibitors and spironolactone should be added into the treatment regime if possible or if clinical deterioration in an animal previously stable on fewer medications occurs.

The above discussion only covers the chronic management of dogs with stage C MMVD with oral medication. The emergency management of heart failure patients is not covered here and interested readers are referred to a book chapter which covers more general consideration of the treatment of patients with heart failure (Boswood 2017).

Modifying therapy to manage clinical signs

Stage D disease

A dog with stage D disease will be showing clinical signs of heart failure despite receiving therapy. There is little evidence-based guidance that can be offered at this stage, although there are case reports and case series published in the literature describing relatively low numbers of such cases and their treatment.

The nature of the clinical signs the patient is showing and any obvious underlying reasons for those signs being shown will determine what sort of modification to therapy may be made at this stage. It is important to check that the patient is receiving optimal doses of the four drugs recommended above for administration in stage C disease. If the predominant clinical signs being shown by the patient are due to congestion (for example, breathlessness or ascites) then escalation of the diuretic dose or switching a dog on furosemide to torasemide can be considered (Oyama and others 2011).

Clinical signs may be exacerbated at this stage by the development of arrhythmias, such as atrial fibrillation, and therapy specifically targeted at managing an arrhythmia might be required, for instance digoxin can be administered to control the rate of atrial fibrillation. If the signs being shown are due to poor cardiac output it might be necessary to consider the administration of drugs that can increase cardiac output. These might include drugs with inotropic effects or additional vasodilators such as amlodipine. However, vasodilators should be used with care in dogs with evidence of hypotension.

When a dog continues to have clinical signs despite optimal therapy one should always consider the welfare of the patient being treated. There is a ‘law of diminishing returns’ in the management of patients with advanced heart failure where progressively more intensive therapy is required and yet the benefits of any intensification of therapy might be small and short lived. At this stage the owners of affected dogs should be appraised of the very guarded long-term prognosis. It might be appropriate to discuss euthanasia rather than prolong the distress of a dog with refractory heart failure.

Non-pharmacological management

Surgery

Surgical management of mitral valve disease is the norm in people. In recent years the successful surgical management of MMVD in dogs has been described. Most of the successful cases reported in the literature have been managed by a single team, highly specialised in this technique (Uechi 2012, Uechi and others 2012). Other veterinary centres across the world are now beginning to undertake this operation. This is a highly specialised technique that is likely to mean it can only be offered to a limited number of patients due to the high cost and limited number of centres in which it can be performed. Questions remain about the optimal timing of surgery and the dogs that are most likely to benefit from it. In people, surgery in patients with progressive disease before the onset of signs of heart failure (the equivalent of late-stage B2 disease in dogs) seems the most effective and it is likely that this will be the case in dogs.

Diet

Although cardiac diets have been available for a long time there is limited published evidence to suggest that meaningful outcomes can be improved by their use. Studies of their short-term administration have suggested possible benefits in early mitral valve disease (Freeman and others 2006), but no long-term study evaluating outcomes such as development of heart failure or survival has been undertaken.

Loss of weight, loss of body condition and loss of appetite all seem to be associated with progression of heart disease in dogs with mitral valve disease (Lopez-Alvarez and others 2015, Boswood and others 2017). It is therefore important that the diet offered to dogs with progressive disease (those with stage B2 or more advanced disease) should be highly palatable and adequately calorific. Moderate restriction of sodium, or at least avoidance of high sodium levels and marked fluctuating sodium intake, is likely to be important in dogs with signs of more advanced disease, although this has not been clearly established.

Dietary supplements have been suggested in dogs with heart disease and there is some evidence of omega-3 fatty acids being beneficial in some cardiac diseases. Again, no clear evidence of benefit has been demonstrated in a prospective longitudinal study specifically conducted in dogs with mitral valve disease.

I tend not to emphasise dietary management of dogs with mitral valve disease, although this might change in future if clearer evidence of benefit emerges.

Exercise

No study has clearly demonstrated a beneficial or detrimental effect of exercise in dogs with MMVD. There is strong evidence of several benefits associated with physical activity in people with heart disease (Piña and others 2003). I tend to advise owners to maintain a level of exercise that the dog can easily cope with. In stage B1 disease I advise that the dog should be regarded as normal for the purposes of exercise. In more advanced stage B2, and beyond, I advise that dogs should be exercised ‘submaximally’, in other words avoiding strenuous exertion such as competitive events or prolonged retrieving of a ball.

It may be an important early warning sign of progressive disease if a dog develops intolerance of exercise with which it could previously easily cope. As MMVD advances from stage B2 to stage C, exercise tolerance deteriorates in the majority of dogs (Boswood and others 2017). Thus, although exercise should not be limited by the owner, if the dog’s capacity to exercise deteriorates this should be interpreted as a potentially significant sign.

Summary

Patients with MMVD can be most effectively managed when the heart failure classification system outlined above is applied. Many dogs with early disease do not, and may never, require treatment for their disease. In dogs with progressive disease, treatment before the onset of clinical signs might delay the onset of those signs. Dogs that develop signs of CHF are very likely to ultimately succumb to their disease, but their clinical signs can be controlled and their lives prolonged by appropriate treatment.

References

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