Christophe W. Lombard, DACVIM (Cardiology), DECVIM-CA
Professor, Dept. of Clinical Veterinary Medicine, Vetsuisse Faculty, University of Berne
The recent two decades have seen revolutionary changes in the concept of treating congestive heart failure in man and animals. The recognition of overshooting neuroendocrine mechanisms, in particular excessive activation of the renin-angiotensin-aldosterone system (RAAS) with increased angiotensin-II levels elevating afterload and stimulating excessive myocardial hypertrophy (cardiac remodeling), is now well established, Increased afterload damages an already failing heart even further. Inhibitors of the angiotensin-converting enzyme (ACE-inhibitors) have been developed to counteract these adaptations and have proven their efficacy for treating congestive heart failure in man and in dogs. They have also demonstrated efficacy in combination with digoxin and diuretics. Additionally, ACE-inhibitors have shown to prolong survival in man and in dogs with endocardiosis with mitral and/or tricuspid insufficiency compared to placebo-controls on conventional therapy. Efficacy- and improved survival data have been published for enalapril (the COVE trial 1995, the LIVE trial 1998) and for benazepril (the BENCH trial 1999).Increasing contractile function of the failing heart in cardiomyopathy continues to be a goal for therapeutic intervention (Endoh 2001). Attention has focused on drugs using other than direct stimulation via adrenergic receptors and the adenylate cyclase pathway. Phosphodiesterase III-inhibitors such as milrinone are potent positive inotropes, but their regrettable side effect of increasing mortality in humans through arrhythmogenesis (the "PROMISE" trial, Packer et al 1991) prevented their successful registration and release for treatment.
The recent development of inodilator drugs has addressed this problem in an elegant and successful way. These substances utilise a new mode of action, the sensitisation of cardiac troponin C to calcium, to improve contractility. Such compounds are referred to as "Calcium-Sensitizers" and have been described to have a positive impact on myocardial energetics (Hasenfuss et al 1989, Remme et al 1994). The ideal positive inotropic drug should have some negative chronotropic effects, should be mediated by other than increases in calcium transients, and should decelerate cross-bridge kinetics (Holubarsch 1997). Mixtures of the d- and l-isomers of Pimobendan were shown to cause stereospecific increases of the calcium sensitivity of cardiac myofilaments, specifically at the regulatory calcium binding sites of troponin C (Solaro et al 1989), besides having vasodilatatory properties mediated by the phosphodiesterase III-effects on vascular smooth muscle. The inodilator drug Pimobendan has been used successfully for the treatment of heart failure in humans in Japan (Kato, 1997). A recent study revealed significantly less adverse cardiac events, defined as death or hospitalisation due to heart failure, in human patients under Pimobendan therapy (EPOCH Study Group, 2002). Clinical studies performed in dogs revealed an efficacy at doses between 0.2 to 0.6 mg/kg/day (Kleemann and others 1998a), as well as clearly superior clinical benefits over digoxin (Kleemann et al 1998b, Poulsen Nautrup et al 1998). In these studies, dogs with chronic valvular disease (endocardiosis with mitral and/or tricuspid regurgitation) as well as dilated cardiomyopathy in advanced stages of heart failure were included. They improved their clinical condition under therapy. Furthermore, Pimobendan was shown to clearly and highly significantly prolong the survival time in a small number of Dobermans with dilated cardiomyopathy, increasing the median survival time from 50 days to 329 days (Luis Fuentes et al 2002).
We are going to review the major blinded, placebo-controlled multicenter studies of the last few years that have investigated the efficacy of Pimobendan for the treatment of congestive heart failure in dogs. Some of the above-mentioned investigations and data led to the licensing of Pimobendan for the therapy of canine CHF in the majority of European countries over last few years, an achievement that no other veterinary drug can claim so far.
The PITCH Study is a multicenter randomised positive-controlled study that was conceived in the late 90ies and tested the concept that dogs in congestive heart failure due to mitral regurgitation or dilated cardiomyopathy could be treated with either Pimobendan, Benazepril or both drugs together with the additional diuretic Furosemide where needed due to pulmonary congestion. 105 Dogs with moderately to severe CHF were included and blindly randomised to one of the 3 treatment groups. The initial efficacy study period over 28 days revealed a significantly higher drop-out rate of 34% for the Benazepril group vs. 11% for the Pimobendan group and 9% for the combination group. On a clinical scoring system based on signs such as dyspnea/cough, nocturnal restlessness, appetite, general activity etc. both groups with Pimobendan outperformed the Benazepril group. The combination of Pimobendan with Benazepril did not provide significant better results than Pimobendan alone. A voluntary longevity study followed, during which the dogs could receive, upon request of the owner when their dogs deteriorated, the drug that they hadn't gotten before as an addition to their therapy. The survival time was determined until such addition of drug or death or euthanasia occurred and compared Benazepril-treated dogs against dogs receiving Pimobendan alone or both drugs. A significantly longer survival time resulted for the dogs on Pimobendan. This study contained several weaknesses, namely an (unnecessary) combination-TX group and an unfortunately small number of dogs with mitral regurgitation that lead to small group numbers preventing meaningful statistical evaluation and power of the study.
The Vetscope study is a multicenter double-blinded trial which sought to compare the advantages of Pimobendan against Benazepril in dogs with moderately to severe congestive heart failure (ISACHC-classes 2 and 3) due to valvular disease/mitral regurgitation. A total of 76 dogs were enrolled. The study parameters and the set-up were similar to the PITCH study. Furosemide was allowed and used equally (ca. 2/3 of the cases) in both treatment groups.
Overall efficacy was rated as very good or good in 85% of the Pimobendan cases versus 41% of the Benazepril cases (P<0.0001). In the 56-day study period, 2 dogs in the Pimobendan group and 7 in the Benazepril group died or were euthanised due to cardiac reasons. The group mean of radiographically determined heart size diminished in the Pimobendan group, while it increased slightly in the Benazepril group (p = 0.0329). Survival analysis according to Kaplan-Meier for the 56-day period revealed significant differences in favour of Pimobendan (P=0.0386). Median survival time for Pimobendan treated dogs was 430 days versus 228 days for dogs receiving no Pimobendan. Again, survival analysis according to Kaplan-Meier revealed significant differences in favour of pimobendan (P=0.002). The complete study report will appear in the Journal of the American Animal Hospital Association in the summer of this year 2006.
Another study by Smith et al 2005 evaluated 43 dogs suffering from mitral regurgitation and mild to moderately severe congestive heart failure in a prospective randomised, single-blind parallel-group trial against Ramipril over a study period of 6 months. All dogs received variable dosages of Furosemide. Study endpoints were completion of the entire study period, and the need for hospitalisation and therapy adjustment in case of worsening. Pimobendan treated dogs completed the study in higher numbers (68%) than Ramipril-treated dogs (43%), and Pimobendan-treated dogs also had a significantly lower adverse HF-outcome (18%) than Ramipril-treated dogs (48%, p= 0.046 calculated as an odds ratio). Tolerance, i.e., drug-related sideeffects, of Pimobendan was low and comparable to Ramipril, as it had been in comparison to Benazepril in the studies above.
All 3 studies did not reveal any tendency to increased tachyarrhythmias or heart rate elevation, although ECGs had only been measured over max. 5 minutes, rather than by Holter electrocardiography for convincing proof of the absence of arrhythmogenesis of this drug.
General Remarks and Conclusions
The new inodilator or calcium-sensitiser drug Pimobendan has shown convincing evidence of good tolerability, safety and clinical efficacy in randomised, blinded multicenter clinical trials; it proved statistically superior to the ACE-inhibitors Benazepril and Ramipril when analysing clinical parameters, and prolonged survival significantly. The drug showed these desired effects in both of the most common canine cardiac diseases dilated cardiomyopathy and mitral regurgitation due to chronic valvular disease, in moderate to severe stages of congestive heart failure. It appears therefore that this new drug represents a new pillar in the heart failure therapy of dogs. What remains to be tested are its safety and efficacy when applied in less severe stages of heart failure, convincing evidence of non-arrhythmogenesis, and elucidation of its influence on pathologic remodeling of the heart during these diseases.
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