By George A. Kramer, DVM, DACVIM (Cardiology)
Chief of Staff
Atlantic Coast Veterinary Specialists
Since the recent licensing and widespread availability of Vetmedin (pimobendan) in the U.S., many claims concerning the drug have been made and it is frequently described as a “wonder drug” on various Internet sites.
As a cardiologist and someone who has used the drug extensively for five years, I´d like to pass along information concerning the drug to our referring veterinarians.
When used appropriately, the drug can be of benefit in treating dogs in heart failure. But it is not a wonder drug and there are concerns that should be taken into account when using the drug.
The manufacturer’s [Boehringer Ingelheim] own FDA licensing studies show that the drug is no better than enalapril in treating heart failure due to chronic valvular disease or dilated cardiomyopathy. As with any drug, the prescriber should be well aware of the drug’s mechanism of action, indications for use, benefits, side effects, and potential negative interactions with other drugs.
Pimobendan is …
… a benzimidazole pyridazinone derivative. It is classified as an inodilator and has a dual mode of action. It causes vasodilation through phosphdiesterase III inhibition and it causes an increase in cardiac contractility through increased Ca++ sensitization of the cardiac myofilaments. There is also mild inhibition of phosphodiesterase V activity. The increase in contractility is achieved by increasing the efficiency within the cardiac myofibrils without an increase in myocardial energy requirements. This is an important distinction from adrenergic agents that increase contractility but cause the cardiac myocyte to use more ATP. The vasodilator effect of pimobendan reduces both afterload and preload of the peripheral and coronary vasculature. The vasodilation that occurs involves both the peripheral and coronary vasculature.
Pimobendan is highly protein-bound and consideration should be give to the animal’s serum albumin concentration when dosing the drug. Additionally, treatment with pimobendan should be monitored carefully if used in conjunction with other drugs that have high protein binding properties. There is first pass hepatic metabolism (O-desmethylation) which produces the active metabolite. The drug is cleared from the body via fecal excretion.
Pimobendan should be used only in dogs that are symptomatic for heart failure (modified NYHA class II-IV). The recommended dose is 0.25mg/kg BID. The drug is used in both dogs with DCM and chronic valvular heart disease. It may have more value in dogs with DCM due to the positive inotropic effect since all dogs with DCM have decreased myocardial contractility. Most dogs with chronic valvular heart disease do not have decreased contractility and do not need positive inotropic support. Both types of heart disease benefit from the vasodilator properties of the drug. According to Boehringer-Ingelheim, “treatment should be initiated only in symptomatic cases which will benefit from increased myocardial contractility (positive inotropy).”
The drug is often used in combination with other cardiac drugs used for the treatment of heart failure (e.g. furosamide, ACE-inhibitors, digoxin, spironolactone, nitrates). It probably should not be used in conjunction with other phosphodiesterase inhibitors (e.g. theophylline, aminophylline, etc.) and should not be used concurrently with sympathomimetic inotropic agents (e.g. dobutamine). Concurrent use with a beta-blocker or calcium channel blocker may attenuate the positive inotropic action of pimobendan.
Adverse side effects that have been reported after clinical use include tachycardia, vomiting, diarrhea, inappetence, incoordination, convulsions, polyuria, and polydypsia.
Dose-dependent cardiotoxic effects include damage to the chordae tendineae that can lead to rupture, thickening of the mitral valve, and jet lesions on the endocardial surfaces. The lesions seem to be associated with the positive inotropic properties of the drug. These findings raise concerns that, used inappropriately in dogs with chronic valvular disease, pimobendan could lead to left atrial tears or rupture of the chordae tendineae.
There is a report out of Europe that documents negative effects on the heart and worsening of the mitral regurgitation in dogs chronically treated with pimobendan for valvular disease. The changes were reversed when the drug was discontinued. There is also a concern that the drug could predispose the heart to tachyarrhythmias and lead to an increased incidence of sudden death. Although pimobendan has been shown to cause a dose-dependent tachycardia, no studies to date have documented an increased risk of sudden death. One study comparing pimobendan to enalapril showed an increase in ventricular ectopy after 14 days of treatment.
Pimobendan augments exocytotic release of insulin secretory granules from pancreatic islet cells in a dose-dependent manner by directly sensitizing the intracellular Ca++-sensitive exocytotic mechanism. It has been suggested by some that this mechanism could lead to an increase in diabetes in patients chronically treated with pimobendan. There have been reports of diabetes developing in a few patients enrolled in pimobendan treatment studies. However, the significance of that occurrence is not clear.
There have been a number of studies over the last few years examining the effects of pimobendan on the treatment of heart failure in dogs. Most have shown that pimobendan is as effective or slightly more effective than ACE-inhibitors in treating heart failure. The most promising study was that of Dr. Christophe Lombard, a veterinary cardiologist from the University of Bern in Switzerland. His study looked at 76 dogs in heart failure caused by atrioventricular valvular disease. Half of the dogs were treated with the ACE-inhibitor benazapril and the other half received pimobendan. The benazapril group had a mean survival of 128 days compared to 415 days for the pimobendan group. This study suggests that dogs in heart failure that are treated with pimobendan live approximately 9 months longer than those treated with an ACE-inhibitor.
This is one of the studies that serves as the basis for many of the “wonder drug” claims. However, the study needs to be evaluated critically. It is a relatively small sample size and stands in contrast to the larger FDA clinical trial that showed pimobendan to be equivalent to the ACE-inhibitor enalapril in treating heart failure. Additionally, the benazapril-treated group seems to have a much shorter median survival than would typically be expected of a population of dogs with heart failure caused by chronic valvular disease when treated by a veterinary cardiologist.
Many new studies are underway that I am sure will help advance our understanding of this drug. There is some debate among veterinary cardiologists about when to use the drug and with what combination of other drugs. There is no single answer. As my friend and former cardiology mentor Dr. Jim Ross always used to say: “It depends.” It depends on the clinical presentation, progression over time of the underlying lesion (i.e. valvular insufficiency or cardiomyopathy), the condition of the heart as seen via echocardiogram, presence or absence of arrhythmias, concurrent diseases, and the clinical response to first-line treatment of the congestive heart failure episode. Only when all of those factors are taken into consideration can an appropriate treatment plan be made.
Pimobendan is an important new drug in our battle against heart disease in dogs when used appropriately, but it should not be added to the drinking water as was once jokingly suggested about enalapril when that was the new “wonder drug” several years ago.