Treating mitral regurgitation -damming up the spill (Proceedings)

ACE inhibition in dogs with mitral regurgitation (MR) but no heart failure

Studies have been performed in humans to determine if early administration of ACE inhibitors to human patients with ischemic dilated cardiomyopathy decreases the progression of myocardial failure and so reduces mortality. In the SAVE study, captopril was found to decrease mortality and morbidity in patients with left ventricular dysfunction following acute myocardial infarction. In a similar study (CONSENSUS II), enalapril did not improve survival in patients after acute myocardial infarction.  Another study (the prevention limb of the SOLVD trial) also examined the issue of early intervention with an ACE inhibitor in patients with left ventricular dysfunction. Patients enrolled in this study had to have moderate to severe myocardial failure (ejection fraction <35% which corresponds to a shortening fraction <15%) and could not have hemodynamically serious valvular disease. This study found that enalapril administration delayed the onset of heart failure symptoms but did not influence mortality. Regardless, acute myocardial infarction is a disease that is very dissimilar to chronic MR and data from these studies cannot be extrapolated to dogs with chronic myxomatous mitral valve degeneration (MMVD).

There have been three studies that have examined the effects of an angiotensin converting enzyme (ACE) inhibitor (enalapril or benazepril) on the progression of mitral regurgitation due to myxomatous valve degeneration to heart failure in dogs – two prospective and one recent retrospective study. The first study (J Vet Intern Med 2002;16:80-88) was reported in 2002. It was carried out in Scandinavia and went by the acronym SVEP. The investigators  enrolled 229 Cavalier King Charles spaniels with MMVD that were not in heart failure. Of these, 116 were randomized to enalapril (0.25 – 0.5 mg/kg /day; average dose = 0.37 mg/kg/day) administration and 113 to placebo. Each dog was evaluated every 12 (+/-1) months using physical examination, electrocardiography, and thoracic radiography. The endpoint was the onset of heart failure. There was no hint of a statistically or clinically significant difference in time to onset of heart failure between the two groups. Even when the groups were subdivided into those that started the study with cardiomegaly vs. those that did not, there still was no hint of a difference. The conclusion was that enalapril does not increase the time that a dog with MMVD is not in heart failure.

Following this report many veterinary cardiologists were skeptical of the results. Most were concerned that this might be a finding that related only to Cavaliers King Charles Spaniels. Some were also concerned that the dose of enalapril may have been too low. Consequently, a second study was devised in the USA to look at other breeds of dogs in a similar fashion but at a dose that was at or near 0.5 mg/kg/day (JAVMA 2007; 231:1061-1069). This study was known by its acronym VETPROOF. The results of this study were published in 2007 although the results were first verbally reported in abstract form in 2002. The investigators in this study enrolled 124 small dogs with MMVD and no heart failure and randomly assigned them to placebo (n=65) or enalapril (n=59). An additional 15 dogs were originally enrolled but died (n=5), developed heart failure (n=7) or dropped out of the study (n=3) within the first 60 days. All 7 that developed heart failure during this stage were in the group on enalapril. This study also examined time to onset of heart failure in dogs administered either enalapril or placebo. Once again there was no statistically or clinically significant difference between groups for this primary endpoint when using the appropriate statistical tests evaluating Kaplan-Meier survival curves. This was true whether all 139 dogs were included in the statistical analysis or the remaining 124 dogs only were included. However, the investigators subsequently decided to try to further analyze the data and looked at only the dogs that were still not in heart failure at the end of the trial and noted that more dogs in the group on enalapril were doing well at that time when compared to the placebo group. These were dogs that were out over 3 years after the onset of the trial and were few in number. Consequently, although this finding was highlighted in the abstract and conclusions, it likely has little bearing on the question being asked. In addition, the investigators then decided to combine survival (death due to any cause) time and the time to onset of heart failure and look at that. Here they did find a significant difference with the advantage going to enalapril. Unfortunately, this is an inappropriate evaluation. Because all-cause mortality was included one would have to believe that enalapril could delay death for any reason (e.g., cancer, renal failure, trauma). Plus, enalapril probably does increase survival in dogs that are in heart failure so combining that positive effect with the negative finding of enalapril's effects on heart failure free time and getting a positive finding only means the positive finding might somehow outweighed the negative finding making for statistical nonsense. So this study was negative with regard to enalapril prolonging the time to the inset of heart failure in the presenter's view.

Finally, a study out of France (J Vet Intern Med  2008;22:905-914) was published in 2008. In this study the investigators retrospectively looked at 141 cases of small dogs that they had previously been diagnosed with MR due to MMVD that were not in heart failure between 1995 and 2006 that had been treated with benazepril (average dose = 0.3 mg/kg/day) or not and for whom they had adequate follow-up. They found 66 dogs that they had placed on benazepril and 75 that they had not. Their population included both Cavalier King Charles Spaniels (n=48) and other small breed dogs (n=93). Presumably their primary question again was whether or not benazepril prolongs the time between initiating ACE inhibition and the onset of heart failure. The answer to this question again was no, it did not. However, this primary answer was not mentioned in the abstract. Neither did benazepril prolong the time until a dog died of heart failure. Because of this the investigators decided to combine time until death due to heart failure along with sudden death. When they did that they found a significant improvement in dogs that were not CKCSs, primarily because all of the sudden deaths happened to occur in dogs not on benazepril. Then, once again, the investigators decided to look at all-cause mortality (death due to heart failure, sudden death and death due to any other cause). Here they found that dogs that were not CKCSs but were on benazepril lived longer. And so once again, to believe that this was a significant finding one would have to believe that benazepril has the power to prevent death from everything from cancer to pyometra. So, once again, the only potential real finding out of this study is that benazepril does not prolong the time until the onset of heart failure. Unfortunately, since a retrospective study like this has so many confounding variables that cannot be accounted for, one certainly cannot say that this study proves that. All one can say is that the negative finding in this study is consistent with the more appropriate prospective studies that have been done.

There are no clinical studies in veterinary medicine to suggest that anything slows the progression of mitral valve degeneration or slows the progression of the altered hemodynamics. Although it is logical, a study to examine the effects of the administration of a potent systemic arteriolar dilator such as hydralazine or amlodipine on the time to onset of heart failure in dogs with MVD has not been performed. One study has examined the effects of amlodipine on regurgitant fraction in dogs with moderate to severe mitral regurgitation, some of which had never been in heart failure. It produced significant reductions in systolic blood pressure, regurgitant fraction, and regurgitant stroke volume. These effects might be expected to prolong the time until heart failure in dogs with MR due to MMVD.

In conclusion, studies to date indicate that there is no indication for the administration of enalapril or benazepril and, by association, any other angiotensin converting enzyme inhibitor to a dog with MMVD that is not in heart failure (i.e., pulmonary edema). A large scale clinical trial looking at amlodipine for this purpose is warranted.

Pimobendan

Pimobendan is a positive inotropic agent with vasodilating properties that increases contractility by inhibiting phosphodiesterase III and by sensitizing intracellular proteins such as troponin C to calcium. It also inhibits the pro-inflammatory effects of cytokines. It is approved for use in human heart failure patients in Japan and for canine patients with heart failure in many countries, including the United States. Pimobendan is a benzimidazole-pyridazinone derivative that is rapidly absorbed following oral administration. The oral bioavailability is approximately 60% when administered without food. It is metabolized in the liver to a metabolite that is an even more potent inhibitor of phosphodiesterase III. Approximately 90% is excreted in the feces. It is highly protein bound.

In vitro, pimobendan increases contractility in myocytes and isolated normal and failing human hearts. The positive inotropic effect is brought about by phosphodiesterase inhibition leading to an increase in cAMP resulting in increased calcium influx through L-type calcium channels in both normal and failing human myocardium and phosphorylation of intracellular proteins via protein kinases. In addition, calcium sensitization occurs, especially with the L-isomer. Pimobendan's major metabolite also inhibits phosphodiesterase III but decreases the sensitivity of myocardial proteins to calcium resulting in no net effect on contractility. The contractile effect of pimobendan is comparable to that of dobutamine in normal and failing hearts with the effect being reduced in failing hearts.  That is to say, it is very potent. Whereas dobutamine increases myocardial oxygen consumption in normal and failing hearts, pimobendan does not.

In normal dogs, pimobendan produces the expected moderate reductions in systemic and pulmonary vascular resistance, a decrease in left ventricular filling pressure, a moderate increase in heart rate, and a moderate increase in cardiac output. It also increases myocardial blood flow and improves diastolic function. In canine models of heart failure, pimobendan improves hemodynamics. In models produced via myocardial ischemia, pimobendan increases contractility. In the rapid pacing model of heart failure pimobendan produces a dose-dependent increase in contractility but to a lesser degree than in normal dogs. The positive effect on myocardial relaxation, however, is similar to normal.  At comparable doses, pimobendan produces a greater improvement in systolic function than does amrinone as well as greater reductions in left atrial and left ventricular diastolic pressures. It also produces a greater positive effect on diastolic properties. Systemic vascular resistance decreases similarly with both drugs. Pimobendan has little effect on heart rate in dogs in heart failure. Electrophysiologically, pimobendan enhances atrioventricular conduction and shortens the refractory periods of atrial, atrioventricular, and ventricular tissue. In one study it increased the incidence of sudden death in a canine model of acute myocardial infarction.

Several clinical studies have been published looking at the effects of pimobendan in dogs with MR due to MMVD that are in heart failure. In one study, 76 dogs with mild to moderate heart failure due to mitral regurgitation due to MMVD were studied prospectively in a double-blind and randomized fashion, comparing pimobendan to benazepril (J Am Anim Hosp Assoc 2006;42:249-261). All dogs were administered 0.25-0.5 mg/kg benazepril q12 hours or 0.2-0.3 mg/kg pimobendan q12 hours initially for 56 days and 64 dogs (37 on pimobendan and 27 on benazepril) were maintained on drug therapy after the initial mandatory period. In a subgroup of dogs with concurrent furosemide treatment (pimobendan [n=31], benazepril [n=25]), the Heart Insufficiency Score improved in favor of pimobendan (P=0.0011), equating to a superior overall efficacy rating (P<0.0001) at day 56. Long-term median survival (i.e., death or treatment failure) for dogs receiving pimobendan was 415 days versus 128 days for dogs not on pimobendan (P=0.0022).

Another study looked at the effects of pimobendan in dogs with slight to moderate heart failure due to myxomatous mitral valve disease compared to dogs treated with ramipril over 6 months (J Small Anim Pract 46:121, 2005). The study was randomized, placebo-controlled, and prospective. The owner was blinded to the drug administered. Dogs were observed for an adverse outcome, including death, euthanasia, or failure to complete the trial, all as the result of heart failure. The maximum dose of furosemide needed to control heart failure and the need for additional hospital visits was also recorded. There was 4 (confidence interval = 1.03-16.3) times the risk of an adverse outcome in dogs treated with ramipril compared to pimobendan although the dogs in the group that were administered ramipril had worse heart failure before entering the trial. There was no difference in the risk of additional hospitalization or in the required maximum dose of furosemide.

The most recent study on the use of pimobendan in dogs with MR due to MMVD was published in 2008 and is known by the acronym QUEST (J Vet Intern Med 2008;22:1124-1135). This study is the largest of the clinical trials using this drug to date. Investigators from 28 clinical practices enrolled 260 dogs with heart failure due to severe MR and randomized them to either pimobendan or benazepril. The investigator in charge of each dog did not know if that dog was on either pimobendan or benazepril (blinded) but the owner did know. The investigators then followed each dog until the dog died or was euthanized due to heart failure, died suddenly, or the treatment failed necessitating removing the dog from the study (primary endpoints), or the study ended. Dogs were allowed to be on other heart failure drugs including furosemide and digoxin at the discretion of each investigator but not any other ACE inhibitor. Ultimately 8 dogs were excluded from analysis while 124 were randomized to pimobendan and 128 to benazepril. Of all the dogs, 190 reached a primary endpoint. The median time for dogs on pimobendan to reach one of the primary endpoints was 267 days while those on benazepril took only 140 days, which was significantly different. Although this study was well done, not having a true placebo group and not allowing the dogs randomized to pimobendan to be on an ACE inhibitor were clear drawbacks.

The role of pimobendan in dogs with MR now appears to be firmly established, especially in small dogs where myocardial function is depressed. Whether the drug increases myocardial contractility further in small dogs with severe MMVD and resultant severe MR when myocardial function is normal to mildly reduced and its effects on the severity of the regurgitation have recently been investigated (J Vet Intern Med 2009;23:258-263). This study found that pimobendan did not decrease regurgitant fraction in dogs with mild to moderate MR but did decrease LV end-systolic diameter and increase ejection fraction (correlate of shortening fraction), which means the drug increased contractility without altering the severity of regurgitation. However, this increase in systolic function was only significant at 30 days after starting the drug and dissipated after that.

The current primary question is whether pimobendan should be reserved for use in dogs that are refractory to other conventional heart failure drugs or should be used in combination with those drugs at the onset of heart failure. Currently we commonly restrict the use of pimobendan in small dogs with severe MR to those patients that are refractory to conventional therapy. These dogs commonly do have a demonstrable increase in end-systolic diameter (i.e., a decrease in myocardial contractility) and clearly need further intervention. However, the QUEST data suggest that pimobendan should be used earlier in the course of the disease.

The only adverse effect of pimobendan has been documented in two dogs with mitral regurgitation due to myxomatous mitral valve disease. The dogs developed concentric hypertrophy, diastolic dysfunction, and increased mitral regurgitation (as assessed by improvement in these variables on discontinuation of the drug). To the author's knowledge, no one else has identified this problem.

Anecdotally, dogs in heart failure that are administered pimobendan often experience improvement in clinical signs beyond what one might expect. This has prompted conjecture that the drug may have other, possibly CNS, effects, along with its cardiovascular effects.

Currently a clinical trial is being pursued to look at the use of pimobendan in dogs with mitral regurgitation due to MMVd that are not in heart failure, similar to the studies done with ACE inhibitors. This study will be randomized, blinded and placebo-controlled and will take approximately 5 years to complete. Until the results of this clinical trial are known it is the expressed opinion of the presenter that pimobendan should not be used in dogs with MMVD prior to the onset of heart failure.