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An Urban Experience
J. Haggstrom1
1Swedish University of Agriculural Sciences, Department of Clinical Sciences, Uppsala, Sweden
J. Häggström
Professor, DVM, PhD, DECVIM-CA (Cardiology)
Department of Clinical Sciences, Faculty of Veterinary Medicine and Animal Science
Swedish University of Agricultural Sciences, Uppsala, Sweden
Pimobendan and levosimendan are drugs that possess both inotropic and vasodilating properties. They are therefore referred to as inodilators. These drug acts to less degree by inhibiting cAMP-phospodiesterase III (similar to milrinone and amrinone), and to greater degree by increasing the calcium sensitivity of cardiac myofibrils with a proportional increase in ATPase activity. This means that myocardial contractility is enhanced without increase of myocardial oxygen consumption as occurs with sympathomimetics and pure phosphodiesterase inhibitors. Moreover, a marked reduction of pulmonary capillary wedge pressure, an increase in cardiac output, stroke volume, left ventricular systolic pressure gradient (dp/dt) and renal blood flow in a dose-dependent manner were demonstrated in various experimental models of impaired myocardial function in dogs, while heart rate, systolic and diastolic blood pressures and myocardial oxygen consumption were virtually unaffected.
Clinical use of pimobendan
Chronic oral administration of pimobendan is currently approved for veterinary use in dogs with CHF caused by DCM or myxomatous mitral valve disease (MMVD). Two studies showed increased survival in Dobermans with CHF due to DCM in pimobendan treated dogs
as compared to conventional therapy, though one of the studies failed to show a similar effect in Cocker Spaniels with CHF due to DCM. Because of these results and because of the pathophysiology of DCM it is not controversial to treat these dogs with a positive inotrope. However, the place for a positive inotrope in managing heart failure caused by MMVD and mitral regurgitation (MR) has been more controversial. Systolic
dysfunction, although present in more progressed
cases, is less apparent in the typical dogs with primary MR, and a positive inotropic drug has the potential to increase the MR and promote valvular lesions. These effects of pimobendan were described in a population experimental dogs with minimal MR. However,
clinical studies of pimobendan involving dogs with decompensated MR report of unchanged or decreased cardiac size, decreased pulmonary transit time, and decreased biomarker concentrations, findings which are not compatible with increased MR. The different results between these studies could reflect that the effects
of pimobendan are dependent on stage of disease. Inodilator therapy is probably not effective in dogs with minimal or mild MMVD, but the hemodynamic situation is different once secondary changes to heart size develop. This combined effect of preload and afterload reduction, together with positive inotropic support, could result in
a reduction of cardiac size and filling pressures in dogs with asymptomatic MMVD with cardiomegaly.
Studies in dogs with pre-clinical heart disease
To investigate the effect of pimobendan in this setting
a total of 360 dogs with cardiomegaly secondary to MMVD, but no signs of CHF were randomly allocated to pimobendan or placebo, making it the largest prospective, blinded survival study so far undertaken
in canine cardiology. Dogs were followed at regular visits from inclusion until they developed CHF. The
main result of this trial was that the median time to the primary endpoint was 1228 days (95% CI 856 – NA)
in the pimobendan group and 766 days (95% CI 667- 875) in the placebo group (P = 0.0038). Hazard ratio for the pimobendan group was 0.64 (95% CI: 0.47–0.87) compared to the placebo group. The benefit persisted after adjustment for other variables. Adverse events were not different between treatment groups. Dogs in the pimobendan group lived longer (P = 0.012). The trial concluded that administration of pimobendan to dogs with MMVD and echocardiographic and radiographic evidence of cardiomegaly results in the prolongation
of the preclinical period and is safe and well tolerated. Prolongation of the preclinical period by approximately 15 months represents a substantial clinical benefit.
MMVD is not the only condition characterized by increased preload. The results from a placebo-controlled, parallel group multicenter study, the PROTECT Study, were published in 2012. Seventy-six client-owned Dobermans were recruited at 10 centers in the UK and North America. The composite primary endpoint was defined as either onset of CHF or sudden death. Time
to death from all causes was a secondary endpoint. Pimobendan administered to Dobermans with pre-clinical DCM prolonged the time to the onset of CHF or sudden

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