Introduction

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-phosphodiesterase Ill (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 Cocke r 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% Cl: 856–N/A) in the pimobendan group and 766 days (95% Cl: 667–875) in the placebo group (p=0.0038). Hazard ratio for the pimobendan group was 0.64 (95% Cl: 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 death (718 days, IQR 441–1152 days versus the placebo group 441 days, IQR 151–641 days, p=0.0088) and increased survival time (623 days, IQR 491–1531 days versus the placebo group 466 days, IQR 236–710 days, p=0.034). Furthermore, pimobendan conferred a reduction cardiac size, a reduction that appeared to be primary effector for the increased preclinical period and survival.

Studies in Dogs with Clinical Heart Disease

To study the effect of pimobendan on survival in dogs with CHF secondary to MMVD the QUEST study was undertaken. The aim of the study was to compare the time taken to reach the primary endpoint for dogs receiving either pimobendan or benazepril in conjunction with other therapy. The primary endpoint was a composite of spontaneous cardiac death, euthanasia for cardiac reasons or withdrawal from the study due to treatment failure. On the basis of a power calculation informed by previous studies, 260 dogs were recruited to the study, recruitment took place at 28 centers in Europe, Canada, and Australia. Dogs were included if they had demonstrated evidence of CHF. After enrolment to the study they were randomised to receive either pimobendan plus standard therapy or benazepril plus standard therapy. They were then re-evaluated at regular intervals and followed until they reached the study endpoint, were censored from the study for other reasons, or the study was concluded (whichever occurred first). Dogs receiving pimobendan plus standard therapy had a longer survival time compared to those receiving benazepril plus standard therapy.

Analysis of longitudinal QUEST trial data showed that pimobendan results in a similar quality of life for the duration of the period of treatment. However, results showed that pimobendan therapy reduced heart size (VHS, LVIDs Inc and LVIDd Inc) and resulted in a higher body temperature, sodium concentration, total protein and packed cell volume by comparison with benazepril. The latter 3 variables indicate less retention of free water. Furthermore, the necessity for intensification of concurrent therapy in patients in the QUEST study was evaluated by looking at the time to intensification of therapy and the frequency of use of commonly used concurrent medications. Thus, although the average values for QoL variables were similar in the two treatment groups over the duration of the study, dogs in the benazepril group required intensification of treatment earlier to maintain their QoL. The similarity of QoL in the two groups is therefore probably a consequence of investigators being at liberty to modify concurrent medication to maintain an acceptable QoL for their patients. Thus, the results showed that the benazepril group required alteration of their therapy sooner and more frequent administration of other medications (spironolactone and digoxin) to maintain the same quality of life as dogs receiving pimobendan.

Conclusions

Clinical trials concerning pimobendan performed in dogs suggests that treatment effect and adverse side reactions depends on dose, type of underlying cardiac disease, stage of disease, and differences between species cannot be ruled out. To disregard from these differences is to oversimplify. Currently, there is convincing evidence that pimobendan prolong the pre-clinical period and extend survival times in dogs with MMVD or Dobermann Pinschers with DCM. Furthermore, pimobendan improves some quality of life variables in dogs with CHF due to DCM or MMVD, and increases survival in dogs with CHF due to MMVD.

References

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