Pimobendan

Pimobendan is available in the United States as a licensed oral formulation for dogs in chewable tablet form. At this time, the drug has not been labeled for use in cats.

Pimobendan (Vetmedin, bi-vetmedica.com) is an oral inodilator with a number of secondary effects. The drug exerts positive inotropic effects mainly through sensitization of the cardiac contractile apparatus to intracellular calcium. Overall, pimobendan enhances systolic function by improving the efficiency of cardiac contraction.

Pimobendan is also a phosphodiesterase (PDE)-III inhibitor, resulting in arterial and venous dilation and leading to reduction in both cardiac preload and afterload. In addition, the drug has demonstrated vasodilatory properties that are endothelium-mediated and may involve inhibition of PDE-V. This mechanism of vasodilation may be beneficial in the treatment of pulmonary hypertension (PH).

Clinical Overview

Although pimobendan is not available as an IV preparation, the oral preparation is rapidly absorbed with peak effects in 2 to 4 hours. Generic formulations have not been clinically evaluated and should be avoided. In addition, reformulation (suspensions) should be avoided since the product in solution is known to have limited stability.

In dogs, pimobendan has proven clinical efficacy for the treatment of congestive heart failure (CHF) from chronic valvular disease (CVD) or from dilated cardiomyopathy (DCM).^1,2 The recommended canine dose is 0.25 to 0.3 mg/kg q12h. In later stages of heart failure or when clinical signs become refractory (stage D, Table 1), the dose frequency is increased to q8h.

In cats, there are no published studies to date on the pharmacokinetics and pharmacodynamics of pimobendan, but studies have reported off-label doses for treating feline heart failure similar to those used for dogs.^3-6  

Table 1. Modified ACVIM Heart Failure Classification Scheme

Indications

Dogs

Pimobendan can prolong survival and reduce clinical signs in dogs with CHF secondary to both CVD and DCM.^1,2 According to the 2010 ACVIM consensus statement, pimobendan should be considered a foundation of multimodal therapy in stages C and D of canine heart failure (past or present signs) caused by CVD.⁷

Emerging indications: Some emerging indications are under investigation in prospective clinical trials, but to date no data prove their efficacy. Other uses represent rescue indications, including pimobendan combined with other therapy for symptomatic heart failure refractory to conventional medical strategies (Table 1).

Off-label rescue indications: Pimobendan, commonly recommended in the emergency treatment of CHF caused by CVD and DCM, is rapidly absorbed with peak effects in 2 to 4 hours, making it valuable in initial stabilization and for chronic treatment. In addition, the drug can treat both right- and left-sided heart failure associated with various underlying causes.

Pimobendan is used as a rescue agent on a case-by-case basis when conventional therapy is failing and/or when (on echocardiogram) the underlying cardiac disease is characterized by ventricular systolic dysfunction or myocardial failure (eg, tricuspid valve dysplasia).

Pimobendan may also have a role when treating PH, particularly when combined with pure PDE-V inhibitors (eg, sildenafil). The combination of pimobendan and PDE-V inhibitors might be superior for PH treatment than either agent alone. This may be especially relevant in clinical right-sided heart failure when the echocardiogram suggests right ventricular myocardial failure or the PH is related to advanced CVD.^8,9

Investigated indications not currently recommended: ACVIM stage B2 heart disease is characterized by cardiac remodeling (eg, cardio­megaly) in the absence of current or historical signs of heart failure.

To date, no medication has been definitively proven to delay the onset of heart failure in stage B2 CVD and DCM (Table 1); however, angiotensin-converting enzyme inhibitors (ACE-I) may be effective in some subpopulations.^10–12 Prospective placebo-controlled clinical trials in dogs with stage B2 CVD and DCM are currently investigating pimobendan’s efficacy.

Potential indications not currently recommended: Although there is potential benefit of β-blockers in cases of myocardial systolic dysfunction caused by CVD and DCM, their use may be difficult because of the relative risk for decompensation, particularly in patients with advanced disease (stages C and D, Table 1). Whether this relative risk may be minimized or eliminated by the combination of a b-blocker with pimobendan requires further study.

Cats

There are no proven indications for the use of pimobendan in cats at this time.

Right lateral radiograph showing feline active congestive heart failure (stage C) [A] and feline stable congestive heart failure (stage C) [B]

Off-label indications: Feline heart disease leading to CHF is predominantly characterized by diastolic dysfunction. Chronic oral treatment emphasizes control of clinical signs associated with volume overload

(eg, furosemide with/without an ACE-I), arterial thromboembolism prophylaxis (eg, clopidogrel with/without aspirin), and medications that may improve ventricular relaxation (eg, diltiazem or a b-blocker).

However, a number of feline heart diseases are characterized by echocardiographic evidence of systolic ventricular dysfunction. These include many forms of unclassified cardiomyopathy (UCM), DCM, and arrhythmogenic right ventricular cardiomyopathy (ARVC). Cats with CHF caused by systolic failure have poor long-term prognosis with a reported median survival of 13 days with conventional therapy.¹³

Pimobendan has been used as a rescue agent in cats and appears to be well tolerated.^3,5,6 However, there may be rationale for its use in CHF caused by all cardiomyopathies, in part from pimobendan’s secondary ancillary properties.⁴ However, its safety in cardiomyopathy characterized by obstruction to outflow (eg, hypertrophic obstructive cardiomyopathy) needs to be better established.^3-6

Reported Side Effects

• Poor appetite
• Lethargy
• Diarrhea
• Dyspnea
• Azotemia
• Weakness & ataxia
• Pleural effusion
• Syncope

Note: In the author’s experience, pimobendan is well-tolerated with minimal (if any) side effects.

Advantages

• Pimobendan is easy to use, requires no special monitoring beyond what is typically indicated, and is well-tolerated by dogs and cats.
• Pimobendan can be safely used with all conventional heart failure medications.
• Pimobendan can prolong survival and reduce clinical signs in dogs with CHF.
• Pimobendan should be considered a foundation of multimodal therapy in stages C and D of canine heart failure (see Table 1).

Disadvantages

• The chewable formulation may not be readily accepted by some pets.
• No IV preparation is available (although the oral preparation is rapidly absorbed).
• Reformulation (suspensions) should be avoided since the product in solution is known to have limited stability.

Contraindications The inodilator properties of pimobendan cause reductions in cardiac preload and afterload through balanced venous and arterial dilation, which are desirable hemodynamic effects in patients with symptomatic heart failure. In patients with CVD and DCM, systolic dysfunction is present in advanced stages (Table 2) and safe augmentation or support of inotropy is desirable.

The benefit of pimobendan in cases of diseases with preserved contractility (ie, hypertrophic cardiomyopathy) or pericardial or congenital disease is unknown. Relative contraindications to pimobendan include treatment of diseases characterized by obstruction to flow such as subaortic stenosis, pulmonic stenosis, and systolic anterior motion of the mitral valve as well as early CVD (Tables 1 and 2).¹⁴

Table 2. Summary of Possible Indications for Pimobendan Use

* Based on echocardiographic diagnosis † Used in combination with other appropriate treatment § Systemic blood pressure should be monitored after therapy initiation (4–6 hours after first dose) and pimobendan should be discontinued if patient becomes hypotensive

ARVC = arrhythmogenic right ventricular cardiomyopathy, CVD = chronic valvular disease, DCM = dilated cardiomyopathy, HCM = hypertrophic cardiomyopathy, HOCM = hypertrophic obstructive cardiomyopathy, PH = pulmonary hypertension  

Economic Impact

Pimobendan is relatively expensive compared with generic furosemide and ACE-Is, but given its beneficial effects on mortality and morbidity in dogs with CHF caused by CVD and DCM, the cost is in favor of pimobendan. Plus, although pimobendan is more expensive than generic heart failure medication, it is still reasonably priced compared with the cost of other nongeneric veterinary medications.

Dr. Gordon is a consultant with Boehringer Ingelheim Vetmedica and has received support for and investigated in corporate-sponsored clinical trials, including as lead investigator.