3 Aug 2015
David Mills
Job Title
Cats with heart failure have historically been poorly served by published evidence on effective therapies.
Cats with heart failure are poorly served by published evidence regarding the most effective therapy. Until recently only a single conference abstract from 2003, as yet unpublished, detailed a prospective comparative study on different therapeutic agent effects1.
However, this may be changing. In recent years, attention has been paid to pimobendan following its successful use and strong evidence base in dogs; novel therapies such as the heart rate modifier ivabradine, have been investigated, and the recent emergence of a cat-specific angiotensin-II receptor blocker agent (ARB) – telmisartan – opens up the possibility of studies into its use in cats with heart disease.
Pimobendan is a phosphodiesterase-III inhibitor (PDE-III), classed as an inodilator due to its dual action positive inotropic and vasodilatory effects. However, it is a wide-acting drug with several additional actions2,3. Its inotropic effects are mainly mediated by calcium sensitisation (and, to a lesser extent, PDE-III inhibition) in the myocardium, and vasodilatory effects by PDE-III inhibition in vascular smooth muscle cells, mainly in arteries and arterioles, that reduces cardiac after load.
Crucially, it increases cardiac output without a concurrent increase in myocardial oxygen demand and, despite effects on calcium cycling, is non-arrhythmogenic. It additionally acts as a positive lusitrope, increasing the rate of relaxation of the myocardium following contraction, thereby allowing a greater diastolic filling time. The inotropy, vasodilation and lusitropy underpin its profound positive effect on cardiac output.
It also displays anti-cytokine effects, especially on NFκB, which is raised in congestive heart failure (CHF) and thought to significantly contribute to cardiac cachexia. It shows anti-thrombotic effects, inhibiting platelet aggregation, and anti-endotoxin effects2.
The use of pimobendan in dogs with CHF due to mitral valve disease and dilated cardiomyopathy has been shown to offer marked improvements in survival time and quality of life, and studies into its use (in conjunction with furosemide) represent some of the most robust evidence available in the whole of veterinary medicine (for example, the QUEST study)4,5.
However, its use in cats was thought to be generally contraindicated due to the different nature of their heart disease.
The majority of CHF cases in cats is due to cardiomyopathy, with hypertrophic cardiomyopathy (HCM) by far the most common, representing around 60% to 80% of cases6.
CHF due to HCM has been classically characterised as primarily due to diastolic failure, with a combination of insufficient diastolic volume (due to mural hypertrophy) and diastolic filling time (due to tachycardia from sympathetic upregulation) to maintain adequate cardiac output. Because of this, it was unclear pimobendan would benefit this disease process.
It was feared in HCM cases it may lead to end-systolic luminal obliteration, and in cats with hypertrophic outflow tract obstruction (HOCM) its use would worsen the condition – either by ejecting blood with greater force through a hypertrophy-narrowed outflow tract, or exacerbate anterior motion of the mitral valve, thereby impeding outflow2.
While its use in feline dilated cardiomyopathy (DCM) and, possibly, restrictive cardiomyopathy may have been justifiable on the grounds that this represents a systolic failure, HCM/HOCM cats were considered unsuitable targets by many.
However, this was not universal, especially following studies that showed cats with HCM also suffer from systolic dysfunction7. Further, it was thought the lusitropic effect of pimobendan could improve HCM diastolic function.
Work has now provided evidence for the beneficial use of pimobendan in cats with HCM, DCM and, to a lesser extent, HOCM. A retrospective case-control study by Reina-Doreste et al showed a significant survival benefit for cats with CHF due to HCM and HOCM treated with pimobendan versus those not given pimobendan8. Cats, mostly mixed domestic breed, were divided into either a pimobendan (n=27, receiving median dose 0.25mg/kg q12h) or non-pimobendan (n=27) group, with all cats receiving concurrent furosemide, most also receiving an angiotensin-converting enzyme (ACE) inhibitor, and a small number a beta-blocker.
No differences existed between groups on severity of echocardiographic findings, arrhythmia presence, thromboembolism incidence or furosemide dosage.
The pimobendan group showed a significantly greater median survival time (MST) of 626 days compared to 103 days for the non-pimobendan group (p=0.024) and there was no influence of type of cardiomyopathy (HCM or HOCM), or other medications being administered, on survival.
The authors concluded the study gave strong evidence for the use of pimobendan in cats with CHF due to HCM, and limited evidence for its use where HOCM is present (only five HOCM cats were present in both groups).
Although the small study numbers and retrospective nature inevitably weakens the study, the use of case controls and the size of the benefit seen means it provides a robust evidential basis for the use of pimobendan in cats with CHF due to HCM, and, to a lesser extent, HOCM.
Indeed, it is the only study to date that has shown a benefit of the addition of a particular therapeutic agent to the standard CHF treatment (ACE inhibitor, furosemide with or without beta-blocker) in cats.
Interestingly, the MST for non-pimobendan cats is similar to that reported in the abstract by Fox for furosemide alone, suggesting “standard” treatment (furosemide, ACE inhibitor with or without beta-blocker) offers no benefit above furosemide alone1.
The study builds on earlier work on pimobendan use in cats. MacGregor et al assessed safety and tolerability of its use in a retrospective study of 170 cats with CHF due to various causes: HCM (68; 40%), unclassified cardiomyopathy (UCM; 63; 37%), DCM (27; 16%) mitral valve disease (seven; 4%) and a small number of other cardiac disorders9.
Cats were given a median dosage of 0.24mg/kg q12h. The MST for all cats was 151 days, but this included all cardiac conditions – UCM and DCM in particular showed significantly reduced MSTs reported compared to HCM10. A significant improvement in echocardiographic variables was seen in cats with systolic dysfunction present (73%). There were few adverse effects, with gastrointestinal upset the most common.
Two studies have assessed the use of pimobendan in cats with systolic dysfunction. A retrospective study by Hambrook et al looked at 32 cats with CHF due to DCM given either pimobendan at median dose 0.26mg/kg q12h (n=16) or no pimobendan (n=16) in addition to other treatments (furosemide, an ACE inhibitor and taurine given to all cats)11.
It found a significant improvement in MST with the pimobendan group at 49 days compared with the non-pimobendan group at 12 days (p=0.045). No adverse effects were noted with pimobendan. No assessment of effect on echocardiographic variables was undertaken.
Gordon et al retrospectively assessed 27 cats with CHF due to systolic dysfunction from a variety of causes (UCM = 14, DCM = eight, arrhythmogenic right ventricular cardiomyopathy = four, congenital heart disease = three, HCM = one) given pimobendan at mean dosage of 0.26mg/kg q12h alongside other medications (all receiving furosemide, most cats receiving ACE inhibitors, some beta-blockers and various other medications)12.
The MST for all cats was 167 days, which was similar to that reported by MacGregor et al. Interestingly, no significant change in echocardiographic variables of systolic function was noted, though this may be due to the large percentage of UCM cats that are notoriously hard to diagnose accurately.
One cat with HOCM showed significant hypotension following pimobendan administration – which led the authors to urge caution in its use in these cats – but otherwise it was well tolerated.
The pharmacokinetics of oral administration of pimobendan have been studied3. Following a single oral dose of 0.28mg/kg in 10 cats at various time points, maximal plasma concentrations was found to be four times greater, and elimination half life three times longer, than seen in dogs. In dogs and people, pimobendan is rapidly metabolised, but effects of active metabolites last for more than eight hours following administration.
These results open the possibility of dosing cats with pimobendan q24h, though pharmacodynamics studies would be required to confirm this. Nevertheless, in patients difficult to tablet this may significantly improve compliance – this is the dosing strategy the author employs (1.25mg/cat q24h PO).
Pimobendan use in cats with CHF due to various causes is supported by the most robust evidence available for any agent (in addition to furosemide). It is especially applicable to cats with HCM and DCM, and possibly other CHF causes; the absence of systolic dysfunction does not seem to limit its usefulness.
Use in HOCM is controversial. While it does not appear absolutely contraindicated, accurate echocardiographic assessment of severity of outflow tract obstruction would be advisable. The author uses pimobendan in cats with CHF due to all causes (1.25mg/kg/cat q24, alongside furosemide) except those with severe HOCM.
Ivabradine is a novel negative chronotropic agent, inhibiting the funny current at the sinoatrial pacemaker node leading to a decrease in heart rate, and increases in left ventricular diastolic filling times and end-diastolic volumes13.
It is proposed ivabradine by its novel action improves diastolic function without the undesirable negative effects of beta-blockers, that is, significant depression of systolic dysfunction and increasing sympathetic sensitivity by upregulation of myocardial adrenoreceptors. However, no clinical studies into its use have been published. It remains an interesting possibility for future treatment of HCM as a sole or adjunctive agent.
Although they have not shown superiority to ACE inhibitors19, theoretically, by blocking receptors, they can modify the effects of angiotensin “escape” seen with chronic ACE inhibitor therapy via alternative angiotensin-II production in tissue and chymase pathways, which can return angiotensin-II levels to pretreatment levels very quickly (within a month).
Moreover, they may help prevent the deleterious effects of angiotensin-II production in areas that ACE inhibitors can struggle to penetrate, such as the myocardium. Licensing and release of a feline-specific ARB – telmisartan – for chronic kidney disease management – opens the possibility of the use of this agent in feline CHF. No studies exist, but it is a tantalising prospect for future study.
