Introduction

Positive inotropic agents increase the force of ventricular contraction mediated through a suppression of phosphodiesterase activity (amrinone, milrinone, pimobendan, levosimendan), act as sympathicomimetic (dopamine, dobutamine) or increase the calcium sensitivity of the contractile proteins (pimobendan, levosimendan). The phosphodiesterase inhibitors also have arterial vasodilating properties to a varying degree. Positive inotropes are currently well established in treatment of acute heart failure precipitated by a hypocontractile failing heart both in dogs and in people. For instance, intravenous infusion of dobutamine has been used for years to manage dogs with acute heart failure caused by dilated cardiomyopathy (DCM). In people, intravenous infusion of levosimendan is frequently used in severe congestive heart failure. Mainly because of cost, the latter therapy is usually not used in dogs. Regardless of which type of intravenous infusion administered, there has been a problem to find oral alternatives for chronic therapy once the infusion therapy is stopped.

Chronic Oral Use

Unfortunately, chronic oral use of positive inotropic agents has been more controversial. In dogs, chronic oral administration of milrinone showed very promising results in clinical studies. Indeed, the increase in contractility observed with amrinone and milrinone (and possibly with levosimendan and pimobendan too) seems to be species dependent, with maximum effect detected in dogs and cats compared to humans and rat. Indeed, milrinone was shown to improve symptomatology and quality of life variables in a study comprising 117 dogs with DCM with congestive heart failure (CHF), but the drug did not influence survival. However, the development of oral formulation of milrinone therapy came to a halt after the results of a large clinical trial, the PROMISE study, in people with severe hypocontractile heart failure was published in the early 1990s. This study showed an increased risk of sudden death in patients in the milrinone treated group.

The next generation positive inotropic drugs were pimobendan and levosimendan; these possess both inotropic and vasodilating properties. These drug acts to a lesser degree by inhibiting cAMP-phosphodiesterase 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; heart rate, systolic and diastolic blood pressures and myocardial oxygen consumption were virtually unaffected.

Chronic oral administration of pimobendan is currently approved for veterinary use in dogs with CHF caused by DCM or myxomatous mitral valve disease (MMVD). Clinical studies concerning pimobendan showed improved quality of life variables in dogs with DCM. Furthermore, one study showed increased survival in Dobermans with CHF due to DCM in pimobendan treated dogs as compared to conventional therapy, though the study 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 (hypocontractile heart failure) and the generally poor prognosis in this disease, it is not controversial to treat these dogs with a positive inotrope.

Use in MMVD

However, the place for a positive inotrope in managing heart failure caused by MMVD has been more controversial. Systolic dysfunction, although present in more progressed cases, is less apparent in typical dogs with primary mitral regurgitation; also a positive inotropic drug has the potential to increase mitral regurgitation and promote valvular lesions as a consequence of increased systolic pressure gradient over the mitral valve. These effects of pimobendan were recently described in a population of experimental dogs with minimal mitral regurgitation. However, clinical studies of pimobendan involving dogs with decompensated mitral regurgitation report unchanged or decreased cardiac size, decreased pulmonary transit time (a measurement of overall cardiac pump function), and decreased atrial natriuretic peptide concentrations, findings which are not compatible with increased mitral regurgitation. The different results between these studies could reflect that the effects of pimobendan are dependent on stage of disease.

Veterinary clinical studies concerning pimobendan in dogs with CHF attributable to MMVD have shown improved quality of life variables (when compared to placebo) and a reduced risk for adverse events (death, recurrent CHF or additional veterinary visits etc.) when compared to a positive control (ramipril). To study the effect of pimobendan on survival in dogs with CHF secondary to MMVD, the recently completed QUEST (Quality of life and Extension of Survival Time) study was untaken. The aim of the study was to compare the time taken to reach the primary end point for dogs receiving either pimobendan or benazepril in conjunction with other therapy. The primary end point 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 making it the largest prospective, blinded survival study so far undertaken in canine cardiology. Recruitment took place at 28 centres in Europe, Canada, and Australia. Dogs were of small and medium breeds and were only included in the study if they had, at some point, demonstrated convincing radiographic evidence of left-sided congestive heart failure. 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). No dogs were lost to follow up. Three quarters of all the dogs enrolled reached the primary end point. Throughout the study the investigators undertaking the examinations of patients were blinded to the treatment that the patient was receiving. Dogs receiving pimobendan plus standard therapy had a longer survival time compared to those receiving benazepril plus standard therapy. The benefit of pimobendan persisted after adjusting for all baseline variables. Several other baseline variables were shown to influence survival time. Most of these were direct or indirect indicators of disease severity. The incidence of potential adverse effects was comparable between the two groups, indicating that pimobendan was equally well tolerated.

The QUEST study offers the most compelling evidence to date demonstrating the beneficial effect of pimobendan when compared to benazepril for extending survival in dogs with CHF due to MMVD when used in conjunction with other standard therapy. Because ACE-inhibitors, when administered as adjunct therapy to other heart failure therapy (i.e., diuretic), have been shown to increase survival times in dogs with CHF due to MMVD, it can be assumed that pimobendan would also increase survival times when compared to a placebo. The study included an extensive analysis of covariates. It demonstrated that the benefit of pimobendan persisted after adjusting for multiple historical, clinical and therapeutic covariates. However, further studies are required to address the impact of combined pimobendan and ACEI therapy and to address the importance of pimobendan in large breed dogs with CHF secondary to MMVD

Conclusions

Clinical trials concerning positive inotropic drugs performed in people and in dogs suggests that treatment effect and adverse side reactions depends on type of inotropic agent, type of underlying cardiac disease, stage of disease; differences between species cannot be ruled out. To disregard these differences is to oversimplify. Currently, there is convincing evidence that pimobendan improves quality of life variables in dogs with CHF due to DCM or MMVD. Furthermore, pimobendan increases survival in dogs with CHF due to MMVD, and presumably also in dogs with DCM (variable results in different breeds).

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