Christophe W. Lombard, DACVIM (Cardiology), DECVIM-CA
Professor, Department of Clinical Veterinary Medicine, Vetsuisse Faculty, University of Berne
Pimobendan is a novel new cardiac pharmaceutical termed an inodilator as it possesses both positive inotropic and balanced peripheral vasodilatation properties. Unlike historical positive inotropes (e.g., digoxin, milrinone) that function by increasing intracellular calcium concentrations with increased energy/oxygen requirements being a direct consequence, pimobendan acts as a positive inotrope via enhancing the affinity of myocardial troponin C to existing intracellular calcium (Gwathmey et al 1987, Morgan 1991) The result is improved contractility without attendant increased myocardial oxygen or energy requirements (Bohm 1991). Peripherally, pimobendan is a phosphodiesterase III inhibitor resulting in balanced peripheral vasodilation through increased efflux of intracellular calcium from vascular smooth muscle (Meel and Dierden 1989, Verdouw et al, 1986). With balanced vasodilatation reducing cardiac work via reductions in preload and afterload, coupled with the economical increase in contractility, the dual action of pimobendan has a favourable hemodynamic effect without an adverse effect on myocardial energy consumption and thus does not further compromise the failing heart.
The result has been a reduction in the activity of the neurohormonal compensatory mechanisms (i.e., renin-angiotensin-aldosterone system [RAAS], sympathetic nervous system [SNS]) active in heart failure, evidenced by reductions in atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), norepinephrine, renin, and angiotensin II as demonstrated via studies done in people (Sasaki et al, 1999, Erlemeyer et al, 1991). Additional properties include improved reversal of desensitization of baroreceptors (Baumann et al 1989), lusitropy (Asanoi 1994), reduced platelet aggregation (Batisda 1986), and an antiinflammatory effect through cytokine reduction (Iwasaki 1999).
Canine Studies with Cardiomyopathy
Based on pimobendan's pharmacodynamic profile, it appears to be a pharmaceutical agent well suited for the treatment of heart failure due to cardiomyopathy as well as chronic valvular disease/mitral regurgitation. Studies in dogs with dilated cardiomyopathy have clearly demonstrated the improvements in quality and quantity of life when pimobendan was added to traditional (i.e., diuretic, ACEI, + digoxin) therapy (Luis Fuentes et al, 2002, O'Grady et al 2003) and supported by similar studies in people (the EPOCH study group 2002).
A summary of the soon to be published PiTCH study reads as follows: A multicenter randomized, positive-controlled double-blind trial compared pimobendan 0.4-0.6 mg/kg/day orally with benazepril 0.25-0.5 mg/kg/day or a combination of both drugs, with additional furosemide allowed as needed, in dogs with modified NYHA class III or IV heart failure over 28 days. In a follow-up voluntary long-term study phase, dogs were allowed to continue on pimobendan or placebo until study withdrawal, death or censoring. A total of 81 dogs with dilated cardiomyopathy were included. Eight different clinical parameters such as appetite, demeanour, exercise tolerance etc. as well as ECG's, radiographs and echocardiograms were evaluated. Pimobendan was well-tolerated, had a better overall efficacy (p<0.05) and fewer treatment failures than benazepril (8% versus 33 %, p<0.05) in the first 28 days (Lombard 2001). In the long-term study period, median survival was 249 days in the pimobendan group versus 34 days in the placebo group (p<0.05). Pimobendan therefore improved clinical signs with advanced heart failure, and improved long-term survival compared with placebo when added to standard treatment. So far, the mechanism of clinical improvements could not be elucidated and supported/buttressed by beneficial echocardiographic changes of the ventricular volumes or shortening fractions. Admittedly however, these echocardio-graphic measurements are fairly crude assessments of ventricular function, and more advanced methods such as Doppler-derived indicators of systolic and diastolic function or TDI-assessment of ventricular function are needed to document or illustrate the cardiac improvements by such graphical measurements.
Canine Studies with Chronic Valvular Disease/Mitral Regurgitation
The recently published VetSCOPE study (Lombard et al, 2006) documented similar beneficial of Pimobendan effects in dogs with congestive heart failure due to valvular regurgitation. Besides superior clinical improvements over Benazepril and smaller drop-out rates during the mandatory 56-day study period, Pimobendan caused a significant reduction of heart size assessed by the VHS-method (Buchanan and Bucheler 1995) and therefore showed beneficial effects of reverse remodeling, one of the important goals of modern therapy for congestive heart failure. In the optional long-term arm of the VetSCOPE study, Pimobendan again proved superior to Benazepril and caused significantly longer median survival times (415 vs. 128 days).