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Effect of Pimobendan in Dogs with Preclinical Myxomatous Mitral Valve Disease and Cardiomegaly: The EPIC Study – A Randomized Clinical Trial
IN S M ALL ANI M AL M E D ICINE AN D S U R G ERY
www.advancesinsmallanimal.com
Volume 30, Issue 4 • April 2017
Effect of Pimobendan in Dogs with Preclinical Myxomatous Mitral Valve Disease and Cardiomegaly: The EPIC Study – A Randomized Clinical Trial Mark Rishniw, BVSc, MS, DACVIM Cornell University, Ithaca, NY Over the last 20 years, studies have demonstrated that certain drugs can prolong lifespan of dogs with myxomatous mitral valve disease (MMVD) once they develop congestive heart failure (CHF). Studies first suggested that angiotensinconverting-enzyme (ACE) inhibitors could improve survival (although these have been subsequently challenged 1-2) and almost a decade ago, a large randomized controlled trial (RCT) showed that dogs receiving pimobendan with furosemide lived longer than those receiving an ACE inhibitor with furosemide.3 But once a dog has developed CHF, survival is measured in months. So, the Holy Grail has been the ability to alter the course of MVD in small breed dogs before they develop CHF – to either prevent it from occurring at all or at least delay its inevitability by some meaningful extent. STUDY DESIGN At least 3 studies have examined the ability of ACE inhibitors in this respect. All failed to demonstrate a protective effect of early ACE inhibitor therapy.4-6 Thus, the search for the magic bullet continues. The latest attempt was published last year.7 This large study examined the ability of pimobendan to delay the onset of CHF, cardiac death or euthanasia (for cardiac reasons) in small breed dogs with MMVD. The large study was well designed and conducted and demonstrated that dogs with cardiomegaly secondary to MMVD, but not yet in CHF, tend to benefit from administration of pimobendan, with an approximately 1-year prolongation of subclinical dis-
ease. The study was terminated early, after approximately 80% of the patients had been recruited, when an interim analysis was scheduled and demonstrated the benefit of pimobendan.
“Essentially, the risk of developing CHF or dying was almost halved, regardless of how bad the dog’s disease was going into the study.” This is the first study to demonstrate a benefit of medication in subclinical MMVD in small-breed dogs. As such, clinicians are likely to begin prescribing this drug to many patients with this disease. However, several caveats exist, some of which were addressed by the authors and some which are addressed below. The authors selected dogs that had evidence of left atrial and left ventricular enlargement according to both echocardiographic and radiographic criteria. Given that many clinicians struggle to correctly identify cardiomegaly in small-breed dogs from radiographs and tend to over-interpret cardiac enlargement, the investigators stressed that the diagnosis should be made with the benefit of echocardiography. Obviously, many clients will not be able to afford echocardiography, and clinicians will be faced with the decision based on radiographic evidence alone. DIAGNOSTIC REQUIREMENTS The authors also stress that dogs without cardiomegaly might not benefit, therefore,
clinicians should avoid the temptation to treat every old small-breed dog with an apical murmur with pimobendan. The investigators claimed that the benefit was apparent across the range of disease severities, based on a lack of interaction between variables in the proportional hazard models (in plain English, dogs with mild left atrial enlargement had the same benefit as those with marked left atrial enlargement). But the story is more complicated than this. The survival curves show a sudden spate of events in the placebo group at around 180 to 200 days, while dogs in the pimobendan group remain in the study because
P age 2
A D V ANCES
they haven’t died or gone into CHF. After this divergence, the two arms then run parallel to each other for the next couple of years and diverge slightly at around 750 days. This sudden early divergence in events could be argued to represent a protective benefit of pimobendan in the most severely affected dogs. It included those which were going to develop CHF or die relatively soon after enrollment in the study, because they had severe disease and were protected by the pimobendan. This was not observed in the placebo. This effect is then maintained in both groups for much of the study. We will come back to this momentarily. It should be noted that all the benefit was in delaying CHF, not in preventing cardiac (sudden) death. The authors argued that the lack of interaction between disease severity (left atrial size) and treatment shows the effect was sustained across all levels of severity once cardiomegaly had begun. Assuming that this is true, dogs in the pimobendan group had a 40% lower probability of developing CHF during the study (hazard ratio of approximately 0.6), regardless of disease severity. Essentially, the risk of developing CHF or dying was almost halved, regardless of how bad the dog’s disease was going into the study. On the face of it, this sounds great. Based
on this information alone, every dog with MMVD and left atrial enlargement (correctly identified!) would benefit from pimobendan treatment. POSITIVE OBSERVATIONS Not so fast! The decision to treat a dog requires additional information to be considered. First, the baseline risk of developing CHF needs to be determined, i.e., what is the chance that this dog will actually develop CHF at some point in the future? If the risk of developing CHF is 80%, then reducing this risk by 40% has a dramatic effect. Delaying this event by 1 year is also a good value for the client and dog. This is what we would expect with a dog that has severe subclinical disease when we first see it and decide to treat with pimobendan. However, what if the underlying probability of developing CHF is small, e.g., 5%, over the dog’s remaining lifetime? Is reducing this risk by 40% to 3% really worth it? We are now in the realm of costbenefit analysis – the cost and risk of the treatment versus the potential benefit of reducing the chance of CHF from “really unlikely to happen” to “really, really unlikely to happen.” An analogous way to look at this is to consider a lottery. If you have a 50% chance of winning a lottery, and an extra ticket increases this prob-
ability by 40%, you would buy the extra ticket. But if you have a 1% chance of winning, then the extra ticket will increase your probability to 1.5%. At that point, you have to ask yourself – is the cost of the extra ticket worth the 0.5% gain? It all depends on the cost of the ticket. And in this case, the ticket (the cost of the drug) can be thousands of dollars over the course of this dog’s life, which may prevent something that was really unlikely to happen. WHY ALL SUSPECT DOGS SHOULD NOT BE TREATED Could we wait and see whether a dog with mild disease and a very low probability of developing CHF is going to progress to more advanced disease, giving us a better idea about the likely outcome? For example, if we have 10 such dogs and follow them, maybe 2 or 3 will progress over time and we become more worried about these 2 or 3 dogs, but we are unconcerned about the other 7 or 8, because they are either stable or end up dying of something else (remember, these are mostly old dogs, and old dogs die!). Or, will waiting end up harming those 2 or 3 dogs that did progress? Is “earlier” treatment better than “later” treatment? The survival curves provide clues to
A D V ANCES
this answer. If we assume that the survival curve is in some way an estimate of the initial disease severity, then the most severely affected dogs are in the upper left corner, and the least severely affected dogs are in the lower right of the curve. As an analogy, if you have bad disease, you are probably going to die from it. If you have mild disease, you are likely to keep living for years and years. Now, if there was a clear benefit of “earlier” rather than “later,” we might expect the survival curves to diverge, ie., continue to move further and further apart. But they don’t. For the majority of the study, they remain parallel. So, the benefit with more severely affected dogs is about 300 days, and the benefit with the least severely affected dogs is about 300 days. This suggests that taking the more measured approach of waiting until a dog exhibits evidence of disease progression before instituting therapy is not compromising that dog nor reducing the benefit of the drug. And, dogs that were never going to progress to more severe disease and never develop CHF would not be subjected to needless drug administration (and needless expenses). These are the sorts of considerations clinicians will have to discuss with their clients when they are thinking of instituting pimobendan therapy prior to the onset of CHF in dogs with MMVD. References 1. Ettinger SJ, Benitz AM, Ericsson GF, Cifelli S, 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;213:1573-1577. 2. [No authors listed] Controlled clinical evaluation of enalapril in dogs with heart failure: results of the Cooperative Veterinary Enalapril Study Group. The COVE Study Group. JVIM 1995;9:243-252. 3. Häggström 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. JVIM 2008;22:1124-1135. 4. Kvart C, Häggström J, Pedersen HD, et al. Efficacy of enalapril for prevention of congestive heart failure in dogs with myxomatous valve disease and asymptomatic mitral regurgitation. JVIM 2002;16:80-88. 5. 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.
6. Pouchelon JL, Jamet N, Gouni V, et al. Effect of benazepril on survival and cardiac events in dogs with asymptomatic mitral valve disease: a retrospective study of 141 cases. JVIM 2008;22:905-914. 7. Boswood A, Haggstrom J, Gordon SG, et al. JVIM 2016;30:1765-1779.
P age 3
www.advancesinsmallanimal.com
Volume 30, Issue 4 • April 2017
Effect of Pimobendan in Dogs with Preclinical Myxomatous Mitral Valve Disease and Cardiomegaly: The EPIC Study – A Randomized Clinical Trial Mark Rishniw, BVSc, MS, DACVIM Cornell University, Ithaca, NY Over the last 20 years, studies have demonstrated that certain drugs can prolong lifespan of dogs with myxomatous mitral valve disease (MMVD) once they develop congestive heart failure (CHF). Studies first suggested that angiotensinconverting-enzyme (ACE) inhibitors could improve survival (although these have been subsequently challenged 1-2) and almost a decade ago, a large randomized controlled trial (RCT) showed that dogs receiving pimobendan with furosemide lived longer than those receiving an ACE inhibitor with furosemide.3 But once a dog has developed CHF, survival is measured in months. So, the Holy Grail has been the ability to alter the course of MVD in small breed dogs before they develop CHF – to either prevent it from occurring at all or at least delay its inevitability by some meaningful extent. STUDY DESIGN At least 3 studies have examined the ability of ACE inhibitors in this respect. All failed to demonstrate a protective effect of early ACE inhibitor therapy.4-6 Thus, the search for the magic bullet continues. The latest attempt was published last year.7 This large study examined the ability of pimobendan to delay the onset of CHF, cardiac death or euthanasia (for cardiac reasons) in small breed dogs with MMVD. The large study was well designed and conducted and demonstrated that dogs with cardiomegaly secondary to MMVD, but not yet in CHF, tend to benefit from administration of pimobendan, with an approximately 1-year prolongation of subclinical dis-
ease. The study was terminated early, after approximately 80% of the patients had been recruited, when an interim analysis was scheduled and demonstrated the benefit of pimobendan.
“Essentially, the risk of developing CHF or dying was almost halved, regardless of how bad the dog’s disease was going into the study.” This is the first study to demonstrate a benefit of medication in subclinical MMVD in small-breed dogs. As such, clinicians are likely to begin prescribing this drug to many patients with this disease. However, several caveats exist, some of which were addressed by the authors and some which are addressed below. The authors selected dogs that had evidence of left atrial and left ventricular enlargement according to both echocardiographic and radiographic criteria. Given that many clinicians struggle to correctly identify cardiomegaly in small-breed dogs from radiographs and tend to over-interpret cardiac enlargement, the investigators stressed that the diagnosis should be made with the benefit of echocardiography. Obviously, many clients will not be able to afford echocardiography, and clinicians will be faced with the decision based on radiographic evidence alone. DIAGNOSTIC REQUIREMENTS The authors also stress that dogs without cardiomegaly might not benefit, therefore,
clinicians should avoid the temptation to treat every old small-breed dog with an apical murmur with pimobendan. The investigators claimed that the benefit was apparent across the range of disease severities, based on a lack of interaction between variables in the proportional hazard models (in plain English, dogs with mild left atrial enlargement had the same benefit as those with marked left atrial enlargement). But the story is more complicated than this. The survival curves show a sudden spate of events in the placebo group at around 180 to 200 days, while dogs in the pimobendan group remain in the study because
P age 2
A D V ANCES
they haven’t died or gone into CHF. After this divergence, the two arms then run parallel to each other for the next couple of years and diverge slightly at around 750 days. This sudden early divergence in events could be argued to represent a protective benefit of pimobendan in the most severely affected dogs. It included those which were going to develop CHF or die relatively soon after enrollment in the study, because they had severe disease and were protected by the pimobendan. This was not observed in the placebo. This effect is then maintained in both groups for much of the study. We will come back to this momentarily. It should be noted that all the benefit was in delaying CHF, not in preventing cardiac (sudden) death. The authors argued that the lack of interaction between disease severity (left atrial size) and treatment shows the effect was sustained across all levels of severity once cardiomegaly had begun. Assuming that this is true, dogs in the pimobendan group had a 40% lower probability of developing CHF during the study (hazard ratio of approximately 0.6), regardless of disease severity. Essentially, the risk of developing CHF or dying was almost halved, regardless of how bad the dog’s disease was going into the study. On the face of it, this sounds great. Based
on this information alone, every dog with MMVD and left atrial enlargement (correctly identified!) would benefit from pimobendan treatment. POSITIVE OBSERVATIONS Not so fast! The decision to treat a dog requires additional information to be considered. First, the baseline risk of developing CHF needs to be determined, i.e., what is the chance that this dog will actually develop CHF at some point in the future? If the risk of developing CHF is 80%, then reducing this risk by 40% has a dramatic effect. Delaying this event by 1 year is also a good value for the client and dog. This is what we would expect with a dog that has severe subclinical disease when we first see it and decide to treat with pimobendan. However, what if the underlying probability of developing CHF is small, e.g., 5%, over the dog’s remaining lifetime? Is reducing this risk by 40% to 3% really worth it? We are now in the realm of costbenefit analysis – the cost and risk of the treatment versus the potential benefit of reducing the chance of CHF from “really unlikely to happen” to “really, really unlikely to happen.” An analogous way to look at this is to consider a lottery. If you have a 50% chance of winning a lottery, and an extra ticket increases this prob-
ability by 40%, you would buy the extra ticket. But if you have a 1% chance of winning, then the extra ticket will increase your probability to 1.5%. At that point, you have to ask yourself – is the cost of the extra ticket worth the 0.5% gain? It all depends on the cost of the ticket. And in this case, the ticket (the cost of the drug) can be thousands of dollars over the course of this dog’s life, which may prevent something that was really unlikely to happen. WHY ALL SUSPECT DOGS SHOULD NOT BE TREATED Could we wait and see whether a dog with mild disease and a very low probability of developing CHF is going to progress to more advanced disease, giving us a better idea about the likely outcome? For example, if we have 10 such dogs and follow them, maybe 2 or 3 will progress over time and we become more worried about these 2 or 3 dogs, but we are unconcerned about the other 7 or 8, because they are either stable or end up dying of something else (remember, these are mostly old dogs, and old dogs die!). Or, will waiting end up harming those 2 or 3 dogs that did progress? Is “earlier” treatment better than “later” treatment? The survival curves provide clues to
A D V ANCES
this answer. If we assume that the survival curve is in some way an estimate of the initial disease severity, then the most severely affected dogs are in the upper left corner, and the least severely affected dogs are in the lower right of the curve. As an analogy, if you have bad disease, you are probably going to die from it. If you have mild disease, you are likely to keep living for years and years. Now, if there was a clear benefit of “earlier” rather than “later,” we might expect the survival curves to diverge, ie., continue to move further and further apart. But they don’t. For the majority of the study, they remain parallel. So, the benefit with more severely affected dogs is about 300 days, and the benefit with the least severely affected dogs is about 300 days. This suggests that taking the more measured approach of waiting until a dog exhibits evidence of disease progression before instituting therapy is not compromising that dog nor reducing the benefit of the drug. And, dogs that were never going to progress to more severe disease and never develop CHF would not be subjected to needless drug administration (and needless expenses). These are the sorts of considerations clinicians will have to discuss with their clients when they are thinking of instituting pimobendan therapy prior to the onset of CHF in dogs with MMVD. References 1. Ettinger SJ, Benitz AM, Ericsson GF, Cifelli S, 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;213:1573-1577. 2. [No authors listed] Controlled clinical evaluation of enalapril in dogs with heart failure: results of the Cooperative Veterinary Enalapril Study Group. The COVE Study Group. JVIM 1995;9:243-252. 3. Häggström 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. JVIM 2008;22:1124-1135. 4. Kvart C, Häggström J, Pedersen HD, et al. Efficacy of enalapril for prevention of congestive heart failure in dogs with myxomatous valve disease and asymptomatic mitral regurgitation. JVIM 2002;16:80-88. 5. 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.
6. Pouchelon JL, Jamet N, Gouni V, et al. Effect of benazepril on survival and cardiac events in dogs with asymptomatic mitral valve disease: a retrospective study of 141 cases. JVIM 2008;22:905-914. 7. Boswood A, Haggstrom J, Gordon SG, et al. JVIM 2016;30:1765-1779.
P age 3