Pimobendan for Congestive Heart Failure

Pimobendan seems to be a potent inhibitor of platelet aggregation, analecta that may be mediated by inhibition of platelet thromboxane A production [36,37].

Veterinary pimobendan studies

Although there are still few published reports, there have been a number of studies in dogs examining the use of pimobendan in dilated cardiomyopathy and chronic mitral valve disease. 

Short-term studies

Early open-label trials included a dose-ranging study in 45 dogs with chronic mitral valve disease or dilated cardiomyopathy. Pimobendan was started at 0.2 mg/kg/d and was increased up to 0.4 or 0.6 mg/kg/d in two divided doses until improvement was observed [38]. This dose was maintained for a further 2 weeks until the final examination. The authorsconcluded that 0.4 to 0.6 mg/kg/d seemed to be an effective dose in dogswith heart failure. Another open-label study compared the effects of pimobendan versus digoxin over 4 weeks in 109 dogs with congestive heart failure [39]. The NYHA score was significantly better in the pimobendan group than in the digoxin group after 4 weeks. One of the most comprehensive randomized, blind, controlled studies todate of pimobendan in canine congestive heart failure was the PiTCH study[40,41]. Dogs were recruited with NYHA class III or IV heart failure caused by dilated cardiomyopathy (n = 81) or chronic mitral valve disease, with105 dogs enrolled in total. Dogs were randomized to receive pimobendanand placebo, pimobendan and benazepril, or placebo and benazepril for a28-day period. A greater proportion of dogs failed to finish the initial study period because of lack of efficacy or death in the benazepril group (34%)compared with the pimobendan group (11%) or the combined group (9%).The low numbers of mitral insufficiency cases in the PiTCH trialprompted initiation of further trials in this subset of patients. One suchtrial compared the use of pimobendan with the ACE inhibitor ramipril indogs with myxomatous mitral valve disease over a 6-month period [42,43].Dogs showing signs of modified NYHA class II to III heart failure were randomized to pimobendan or ramipril in a single-blind fashion (owners were aware of the drug identity). Of 44 dogs recruited, there were  significantly fewer adverse outcomes in the pimobendan group comparedwith ramipril group (odds ratio = 5.03, 95% CI: 1.12–22.6).

Long-term studies

The PiTCH study also had a long-term arm, with an option to continuewith the medication after the 28-day initial study period. The pimobendan and combination groups continued with pimobendan and benazepril,whereas the benazepril-only group continued with benazepril and placebo.Additional medications could be added at the clinician’s discretion. Median survival time in the placebo group was 42 days compared with 217 days in the pimobendan group [41].It should be recognized that the above studies represent preliminary and as yet unpublished data. A small, double-blind, randomized, placebo-controlled study of dilated cardiomyopathy in Doberman Pinschers and English Cocker Spaniels reported use of pimobendan as an add-on therapy to background treatment with furosemide, enalapril, and digoxin [44]. An improvement in NYHA heart failure classification was seen in 8 of 10 dog sreceiving pimobendan compared with 1 of 10 of the dogs in the placebo group (

P

 = 0.005). Median survival was improved in the Doberman Pinschers in this study, from 50 days in the placebo group to 329 days in the pimobendan-treated group (hazard ratio = 3.4, 95% CI: 1.4–39.8).Similar benefits for Doberman Pinschers with dilated cardiomyopathy were shown in another randomized placebo-controlled study [45]. Doberman Pinschers with congestive heart failure caused by dilated cardio myopathyand receiving ACE inhibitors and diuretics (n = 15) were randomized to placebo or pimobendan. Quality-of-life scores were significantly better in the  pimobendan group, and mean survival times were 128, 29 days in thepimobendan group compared with 63

 14 days in the placebo group.

Recommendations for use of pimobendan

In Europe, pimobendan is available as 1.25-, 2.5-, and 5- g capsules. The recommended dose rate in dogs is 0.1 to 0.3 mg/kg administered every 12hours and given at least an hour before food. Dosing is usually started at the low end of the dose range. Pimobendan can be combined with diuretics ,ACE inhibitors, or digoxin. The positive inotropic effects may be reduced when given in conjunction with calcium channel antagonists or-adrenergicantagonists.

Future directions

Pimobendan is a highly interesting compound that is showing much promise in the treatment of canine congestive heart failure. Its calcium-sensitizing effect distinguishes it from other commercially available positive inotropes and may be responsible for its comparative lack of adverse effects compared with inotropic agents that rely on increasing cytosolic calcium levels. An alternative viewpoint is that PDE III inhibition is not uniformly harmful in all patient populations and that despite the findings of the PROMISE trial [27], it may be beneficial in dogs with nonischemic

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congestive heart failure. In fact, pimobendan has continued to be licensed for human use in Japan since 1994, and US investigators have re-examinedpimobendan in recent times as a means of facilitating tolerance of-adrenergic antagonists in human patients with severe heart failure [46].The combination of carvedilol and pimobendan was safe and seemed to result in favorable neurohormonal effects [46]. An additional possible use for pimobendan is in treating pulmonary hypertension [47].Trials are currently underway to elucidate the role of pimobendan in the treatment of chronic mitral valve disease. Early use of pimobendan tended to be focused on cases with systolic dysfunction, because it was thought that these patients would obtain the most benefit from a positive inotrope. New evidence is suggesting that pimobendan may relieve clinical signs even when systolic function is not impaired, and it is likely that the the rapeutic mechanisms are more complex than originally thought. The role of pimo-bendan’s effects on neurohormones and cytokines also requires further study. No work has been done on the effects of pimobendan in dogs with naturally occurring acute heart failure, and there are only anecdotal reports of its use in cats. Pimobendan’s antithrombotic effects may be particularly helpful in the latter species.

Summary

Pimobendan is a new inodilator compound available in many countries for use in canine heart failure. It combines calcium-sensitizing effects with PDE III inhibition, resulting in positive inotropic effects and veno- andarteriodilation. Because there is downregulation of the myocardial adren-ergic signal transduction pathway in the failing heart, the calcium-sensitizing effects may assume greater importance in patients with heart failure. Clinical studies in human patients have shown sustained improvement in hemodynamics and exercise tolerance, with favorable neurohormonal effects. One study showed a nonsignificant trend toward increased mortality [20], but proarrhythmic effects have not been observed. Studies in naturally occurring canine heart failure suggest that pimobendan’s effects are at least comparable to those of ACE inhibitors, if not superior. Pimobendan is likely toplay an increasing role in the future in the treatment of canine heart disease

67 german [Acute and long-term effects of pimobendan (UD-CG 115) in NYHA II and III heart failure. Results of a randomized multicenter double-blind study]

[Article in German]

I Assmann 1, P Kassel, H G Duck, H Fiehring, P Morgan, P K Schmidt, T HöfsG Nehmiz

• PMID: 1792811

Abstract

The effects of pimobendan (UD-CG 115) on hemodynamics and exercise capacity after acute (single dose) and chronic (6 month) oral treatment, as well as acute treatment after 6 months were investigated in 67 patients with chronic heart failure of NYHA classes II or III, which had persisted in spite of treatment with diuretics and digitalis. 

They were treated with pimobendan (2.5 mg bid or 5 mg) or placebo in a randomized, double-blind multicenter trial. With a single administration before and after 6 months’ treatment there was-compared to placebo-a significant fall in pulmonary capillary pressure (PCP) at rest (R) and during exercise (E) of 7% to 24%. Right atrial pressure (R) and pulmonary arterial pressure (PAP) (R, E) decreased after pimobendan on day 1; cardiac index (E) increased significantly. All other parameters were not influenced. After chronic therapy, PCP (E), PAP (E), LV stroke work index (E), and pulmonary resistance (R and E) values were significantly lowered by pimobendan when compared to day 1. 

Exercise duration was prolonged after 6 months by 83 s and 47 s after 5 and 10 mg/day, resp., compared to the placebo group (group difference not significant). Subjective wellbeing was improved in all three groups (no group difference). 

Clinical symptoms were not altered; six patients (two in each group) died suddenly. Another nine patients discontinued the trial prematurely because of poor efficacy or adverse events (no group difference). Overall, pimobendan was well-tolerated and had favorable effects on both acute and chronic hemodynamics and on exercise capacity. There was no evidence of any tolerance development.