Until only recently, the veterinary community attempted to combat the problem with a coterie of human drugs-ACE inhibitors, beta-blockers, diuretics and even digoxin-monitoring and constantly adjusting combinations and dosages in an attempt to ward off side-effects of the drug combinations before the progressive disease becomes fatal.
Consequently, the arrival of pimobendan (marketed as Vetmedin), a drug specifically developed for dogs and cats (but now given to humans), was heralded as a wonder breakthrough for CHF, and specifically targeted at mitral valve disease, in which the mitral valve degenerates, allowing blood to flow back into the heart.
Developed by Boehringer Ingelheim GmbH, a German drug company, and approved by the US Food and Drug Administration (FDA) in 2007, Vetmedin was hailed as such a brilliant improve-ment over ACE inhibitors and other drugs for CHD that the catch phrase given to it by its manufacturer is 'rewrites the ending'.
Pimobendan is an 'inodilator', which supposedly works by dilating blood vessels to ease resistance of the circulatory system and increase the strength of heart-muscle contractions, improving the pumping action of the heart so that more blood reaches the major organs.
Some glowing reports concluded that pimobendan changes the structure of the heart by reversing the enlargement of the heart's chambers or, in the case
of mitral valve disease, lessening the backflow of blood through the valve. Such was the initial hype surrounding the drug that many vets were using Vetmedin in dogs and cats only suspected of having CHF, and in healthy dogs of a breed with a propensity to develop the disease, but no evidence yet of clinical signs. Vetmedin also enjoys a thriving black-market business, with many dog owners self-medicating their pets with drugs bought over the Internet.
The hard facts
According to the Original New Animal Drug Application submitted to the FDA, the safety and effectiveness of Vetmedin was largely evaluated as a result of a 56-day multicentre study of 355 dogs with moderate-to-severe CHF due to valve problems or enlarged heart chambers.
In the study, the drug was not examin-ed independently, but simply compared against enalapril maleate (Enacard), an ACE inhibitor. Also, when considered necessary, individual dogs were given furosemide (a diuretic) at varying doses, depending upon the severity of disease, and in some cases, digoxin and even beta-blockers; dosage levels of diuretics could also be altered for individual dogs during the two-month study, if considered necessary. Consequently, the canine study participants were hardly uniform, but had widely varying levels of disease severity and widely varying therapies.
Treatment success or failure was primarily determined on day 29 of the programme, and 'success' was defined as any improvement in heart insufficiency, fluid in the lungs and/or any measure of clinical improvement, no matter how slight, in that 29-day window only. On this basis, Vetmedin was determined to have an 80.7-per-cent success rate compared with 76.1-per-cent success with Enacard-an advantage of minimal significance.
What was not highlighted is that dogs with stage IV heart failure (defined as "no capacity for exercise" and "disabling clinical signs are present even at rest") did worse with Vetmedin than with the ACE inhibitors; only 15 per cent of dogs at stage IV improved compared with 24 per cent with Enacard. Furthermore, both drugs had identical scores for improvement in heart insufficiency on day 29. The only difference occurred in pulmonary oedema, which could well have been due to the varying levels of diuretics used on individual dogs.
The dogs given Vetmedin suffered myriad side-effects that had not been present prior to the study, including poor appetite, lethargy, diarrhoea, difficult or laboured breathing, worsening signs of heart failure, death from heart failure, damage to kidney function known as 'azotemia' (increased blood urea nitrogen), weakness or loss of body control, excess fluid in the lungs or abdomen, loss of consciousness caused by a fall in blood pressure and even, ironically, heart murmur. Nevertheless, as dogs in the ACE inhibitor group also suffered a vast range of side-effects, these new developments were written off as 'potentially related' to the disease itself.
The final analysis
The bottom line is that neither drug was shown to enhance survival; the total number of dogs that died (n = 52) over this short time frame was divided similarly between both treatment groups (www.fda.gov/OHRMS/DOCKETS/98fr/2007-141-273-fois001.pdf).
In 2008, the published report of the considerably longer QUEST trial was meant to answer the questions raised by the first study. This 28-centre study of canine mitral valve disease and CHF compared 124 dogs that received Vetmedin with 128 dogs randomly given benazepril, or Lotensin, an angiotensin-converting enzyme (ACE) inhibitor, over a longer period of time.
Of the 244 dogs finally analyzed (eight dogs were ultimately excluded from the analysis), 78 per cent, or 190 dogs, reached the "primary endpoint"-in other words, cardiac death, treatment failure or euthanasia-during the study.
When the results were analyzed, the median time to reach the endpoint was 188 days on average, with 267 days for dogs given Vetmedin and 140 days for those taking benazepril. Consequently, Vetmedin's great breakthrough is to offer dogs an average survival of eight and a half months-a mere four-month advantage over ACE inhibitors (J Vet Intern Med, 2008; 22: 1124-35).
Vetmedin given to healthy dogs or to those with mild mitral valve disease (MVD) and strong heart contractility can cause such powerful pumping action that the major heart strings of the mitral valve may rupture, causing sudden death.
Indeed, the drug can have the very opposite of the intended effect, causing heart enlargement, increased backflow of blood through the mitral valve and rupture.
According to a French study (J Vet Intern Med, 2007; 21: 742-53), mitral valve tissue lesions were more severe in the Vetmedin group than in the benazepril group, as were haemorrhages, and other abnormalities of the heart muscle and heart strings ('chordae tendineae'). The study researchers concluded that pimobendan had "adverse cardiac functional and morphologic effects in dogs with asymptomatic MVD".
In addition, in a case report of two dogs treated with Vetmedin for several months (Cardiovasc Toxicol, 2005; 5: 43-51), mitral valve regurgitation and enlarged heart were revealed on tissue Doppler echocardiography imaging. When the dogs were taken off the drug, mitral valve function improved in both animals, while the heart murmur in one of the dogs disappeared. The study authors were concerned that Vetmedin might have actually caused the dogs' observed heart abnormalities; however, as this was the first such report to describe these clinical abnormalities, it is too early to tell.
Writing in the 6 October 2006 issue of Veterinary Medicine, veterinarian Justin Thomason and colleagues agreed that the main problem with the drug is that it is often administered too early, thereby causing heart flutters or the heart muscle to weaken. As pimobendan's 'durability' may not be all it's cut out to be, noted Thomason, giving the drug too early to dogs with only mild-to-moderate heart failure "caused by dilated cardiomyopathy could result in decreased effectiveness later in the course of the disease".
The bottom line is that pimobendan offers a bit more time in animals with advanced disease-but at a price-and possibly less time for those with only mild illness.
Next month: ACE inhibitors, diuretics and alternatives for heart failure
WDDTY VOL 22 NO 8