Whats New with Pimobendan? Current Research and Treatment
Recommendations
Whats New with Pimobendan?Current Research and Treatment
RecommendationsAgnieszka Kent, DVM, MS, DACVIM (Cardiology)Upstate
Veterinary Specialties CE Lecture SeriesSeptember
OutlinePharmacology and PharmacokineticsPimobendan use in
dilated cardiomyopathyPimobendan use in myxomatous valvular
degenerationEPIC trialPimobendan use in catsSummary
If you have a questionplease ask!
PimobendanINODILATORCalcium sensitizer Increased affinity of
troponin C binding sites for calciumPositive inotropyDoes not
increase intracellular calcium like digoxinNot associated with an
increase in myocardial O2 consumptionPhosphodiesterase III
inhibitorDecreased break down of cAMPBalanced
vasodilationContributes to positive inotropyInhibitor of platelet
aggregation in some species
Pimobendan versus DigoxinDigoxinClassic positive inotropeNa+/K+
ATPase antagonistIncreased intracellular CalciumIncreased risk for
arrhythmiasPimobendanNo increase in intracellular calciumNo
significant increase in risk for arrhythmia formation
Lake-Bakaar GA, et al. Journal of Veterinary Cardiology (2015)
17, 120e128
This study showed no increase in incidence of arrhythmias after
two weeks of administration of pimobendan when compared to a
placebo based on Holter monitoring before and after treatment.
5
Pimobendan and RAASFurosemide is known to stimulate
RAASPimobendan does not stimulate the renin-angiotensin-aldosterone
systemVasodilatory effect mediated by positive inotropic
effectsPimobendan does not prevent RAAS activationIdeally always
accompany chronic furosemide therapy with RAAS suppressive therapy
ACE inhibitor (benazepril, enalapril)If giving solely pimobendan
RAAS suppression not necessary
Sayer, et al. Acute effect of pimobendan and furosemide on the
circulating renin-angiotensin-aldosterone system in healthy dogs. J
Vet Intern Med 2009;23:1003-1006
Pharmacokinetics in DogsSingle oral 0.25 mg/kg dose peak
levelsParent compound: 2h; active metabolite: 3hFood decreased
bioavailability of aqueous solutionEffect of food on chewable
tablets is unknownProtein binding >90% of parent compound and
active metaboliteEliminated in the feces (biliary excretion)Plasma
concentrations (Cmax)Parent compound: 3.09 ng/mL; active
metabolite: 3.66 ng/mLTerminal elimination half livesParent
compound: 0.5 h; active metabolite: 2 h
In dogs it is converted in the liver to UDCG-212 which is a more
potent inhibitor of PDE III7
Pharmacokinetics in CatsPharmacokinetics of oral pimobendan in
healthy catsJournal of Veterinary Cardiology (2012) 14, 489e496;
Andrew S. Hanzlicek, MS, DVM, Ronette Gehring, BVSc, MMedVet,
MRCVS, Butch KuKanich, PhD, DVM, Kate S. KuKanich, PhD, DVM,
Michele Borgarelli, PhD, DVM, Nicole Smee, DVM, Emily E. Olson,
DVM, Marco Margiocco, MS, DVMSingle oral dose 0.28 +/- 0.04
mg/kgPlasma concentration (Cmax): 34.5 +/- 6.59 ng/mL ~10 x higher
than in dogsElimination half life (T1/2) 1.3 +/- 0.2 h~3 x longer
than dogsRapidly absorbed after a lag time of 0.3 hOne cat vomited
10 min after administration, much lower Cmax (3 ng/mL)Infrequent
side effects in 2 cats: 2 cats ptyalism, 1 cat vomited
Pimobendan in Canine Clinical DiseaseDilated
CardiomyopathyPrimary myocardial disease resulting in systolic
dysfunction and eccentric hypertrophy of one or both
ventriclesSecondary DCM phenotype from nutritional deficiencies,
endocrinopathy, toxins, myocarditisDoberman pinscher, Great Dane,
Irish Wolf Hound, Cocker Spaniel (taurine), juvenile DCM of
Portugese Water DogMyxomatous (degenerative) valve
diseaseDeposition of mucopolysaccharides primarily in the spongiosa
layerDistortion of the valve leaflets, nodular changes, thickening
and lengthening of the chordae tendineae all resulting in valve
incompetence and regurgitationSmall breed dogs
Dilated CardiomyopathyOccult phaseAsymptomatic but progressive
diseaseMyocardial changesArrhythmiasVentricularEnds with the first
clinical signOvert clinical phaseSymptoms appearExercise
intolerance, weakness, syncope, signs of CHF, sudden
deathArrhythmiasVentricular premature complexes, ventricular
tachycardia, atrial fibrillation
~40% of Dobermans experience sudden death as first clinical
sign10
Dilated Cardiomyopathy
Occult DCM and PimobendanEfficacy of Pimobendan in the
Prevention of Congestive Heart failure or Sudden Death in Doberman
Pinschers with Preclinical Dilated Cardiomyopathy (The PROTECT
Study)J Vet Intern Med 2012;26:13371349; N.J. Summerfield, A.
Boswood, M.R. OGrady, S.G. Gordon, J. Dukes-McEwan, M.A. Oyama, S.
Smith, M. Patteson, A.T. French, G.J. Culshaw, L. Braz-Ruivo, A.
Estrada, M.L. OSullivan, J. Loureiro, R. Willis, and P.
WatsonDobermans 4-9 years old
Body weight (kg) up to:LVIDs
(mm)2538.83039.53540.24040.94541.65042.3
PROTECTRandomized, blinded, placebo-controlled, parallel group,
multicenter studyPrimary endpoint: CHF or sudden cardiac death76
dogs; 39 dogs: pimobendan, 37 dogs: placebo58% (44 dogs) reached
primary endpointPlacebo: 25 dogs (17 CHF, 8 SCD); pimobendan 19
dogs (12 CHF, 7 SCD)Median time to primary endpoint significantly
longer in pimobendan groupPimobendan: 693 days; placebo: 441
days
13
DCM and Congestive Heart Failure
DCM with Congestive Heart failureA Double-Blind, Randomized,
Placebo-Controlled Study of Pimobendan in Dogs with Dilated
CardiomyopathyJ Vet Intern Med 2002;16:255261; Virginia Luis
Fuentes, Brendan Corcoran, Anne French, Karsten E. Schober, Rainer
Kleemann, and Claus JustusDoberman pinschers and Cocker
SpanielsPimobendan or placebo to dogs with DCM already receiving
triple therapyFurosemide, enalapril, and digoxinEffect on heart
failure class (NYHA)Addition of pimobendan associated with
significant improvement in heart failure class, regardless of
breedDobermans had significantly longer survival, not the case for
Cockers
MST50 days329 days
DPs: MST 50 days in placebo group versus 329 days in pimobendan
group. However, CS tend to have a better prognosis and survival
anyway and it is possible that this study was not of high enough
power to show benefit or side effect of pimobendan. 15
DCM with Congestive Heart FailureEffect of Pimobendan on Case
Fatality Rate in Doberman Pinschers with Congestive Heart Failure
Caused by Dilated CardiomyopathyJ Vet Intern Med 2008;22:897904;
M.R. OGrady, S.L. Minors, M.L. OSullivan, and R. HorneProspective
randomized, double-blind, placebo-controlledPrimary end-point:
treatment failure; secondary: quality of life (QoL)Dogs received
pimobendan (8) or placebo (8) AND furosemide, benazeprilMedian time
to primary endpointPimobendan: 130.5 days, placebo: 14 days.QoL
analysis could not be performedToo few placebo dogs remained over
time
Treatment failure, including death (due to progressive chf,
sudden death, or euthanized for refractory CHF), or refractory
pulmonary edema (>/= furosemide >5 mg/kg q 8h. LVIDd and
LVIDs were higher in placebo group. 16
Myxomatous mitral valve degeneration (MMVD)
MMVD with Congestive Heart FailurePimobendan has been shown to
have short term benefit in dogs with CHF1 Lower heart rateImproves
pulmonary transit timeDecreases left atrial sizeDecreases systolic
and diastolic internal dimensions and volumesIncreased ejection
fraction1Hggstrm J, et al. Short-term hemodynamic and
neuroendocrine effects of pimobendan and benazepril in dogs with
myxomatous mitral valve disease and congestive heart failure. JVIM
2013;27:1452-1462
Over a period of 7 days.18
The QUEST study Hggstrm J, et alPimobendan267 days to reach the
primary end-pointBenazepril 140 days to reach the primary
end-pointPimobendan plus conventional therapy prolongs time to
sudden death, euthanasia for cardiac reasons, or treatment failure
in dogs with CHF caused by MMVD compared with benazepril plus
conventional therapyNo benazepril + pimobendan groupBenazepril
dose: 0.25-1.0 mg/kg/dMedian dose 0.38 mg/kg/dSingle blinded
study
252 dogs randomized, pimo 124 dogs, benazepril 128 dogs, all
small dogs; 190 dogs reached primary end point, cardiac death,
euthanized for CHF, treatment failure 19
QUEST Longitudinal Analysis Hggstrm J, et al
Variables significantly higher in the pimobendan groupRectal
temperatureSerum sodiumPCVTotal protein concentration
Pimobendan increased time to intensification of treatmentNo
difference in quality of lifeNo difference in arrhythmia
frequency
Variables significantly lower in the pimobendan groupVertebral
heart sizeLVIDs increase, LVIDsLVIDd increase, LVIDd
No difference in quality of life variables. Time to
intensification of treatment, pimo 98 days, benaz 59 days20
Preclinical MMVD and Pimobendan12 Beagles with mild MMVD, low
murmur grade (I-II/VI) and no cardiomegaly and no decrease in
systolic functionPimobendan 0.25 mg/kg BID or benazepril 0.25 mg/kg
SIDEuthanized after 512 daysHigher indices of systolic
functionLower GFRHigher increases in heart murmur gradeThicker
anterior mitral leaflets by echocardiography and some dogs had
abnormal proliferative lesions on atrial surface and markedly
echoic and irregular chordae tendineae with worsening of mitral
regurgitant jetHistopathology revealed more severe myxomatous
lesionsStudy supported by Novartis Animal Health
Increase in MV glycosaminoglycans, characterized by multifocal
accumulation of GAG in the valvular spongiosa. Acute focal
hemorrhages in connective tissue beneath the endocardium in 2 dogs.
Pimo group showed moderate or slight endocardial sclerosis of the
left papillary muscles mainly at insertion of the CT with local
myocardial infiltration.21
Canyoncrestcavalierspaniels.com
Pimobendan?YESNO
Evaluating Pimobendan in Cardiomegaly (EPIC) TrialEvaluating the
outcome of small breed dogs with preclinical myxomatous mitral
valve disease and cardiomegaly with administration of pimobendan
(stage B2)Inclusion criteriaVery specific inclusion criteria to
define cardiomegaly2D LA/Ao ratio >1.61 LVIDDN 1.72 VHS
>10.53 4.6 kg 15 kg> 6 years old III/VI heart
murmurEchocardiographic lesions consistent with myxomatous mitral
valve disease1Hansson K, et al. Left atrial to aortic root indices
using two-dimensional and m-mode echocardiography in Cavalier King
Charles spaniels with and without left atrial enlargement. Vet Rad
US 2002;43(6):568-575)2Cornell CC, et al. Allometric scaling of
m-mode cardiac measurements in normal adult dogs. J Vet Intern Med
2004;18:311-3213Buchanan JW, Bucheler J. Vertebral scale system to
measure canine heart size in radiographs. J Am Vet Med Assoc
1995;206:194-199
Classification of degenerative valve disease Stage AHigh risk
for developing heart disease but currently have no heart
diseaseStage BHave structural heart disease but no clinical signs
of CHFB1 Asymptomatic but no cardiac remodeling on radiographs or
echocardiogramB2 Asymptomatic with hemodynamically significant
valve regurgitation with radiographic or echocardiographic
left-heart enlargementStage CPast or current clinical signs of
CHFStage DEnd-stage disease with clinical signs of CHF that are
refractory to standard therapy'JVIM 2009 Consensus statement.
Guidelines for the diagnosis and treatment of canine chronic
valvular heart disease
Evaluating Pimobendan in Cardiomegaly (EPIC) TrialEvaluating the
outcome of small breed dogs with preclinical myxomatous mitral
valve disease and cardiomegaly with administration of pimobendan
(stage B2)Inclusion criteriaVery specific inclusion criteria to
define cardiomegaly2D LA/Ao ratio >1.61 LVIDDN 1.72 VHS
>10.53 4.6 kg 15 kg> 6 years old III/VI heart
murmurEchocardiographic lesions consistent with myxomatous mitral
valve disease1Hansson K, et al. Left atrial to aortic root indices
using two-dimensional and m-mode echocardiography in Cavalier King
Charles spaniels with and without left atrial enlargement. Vet Rad
US 2002;43(6):568-575)2Cornell CC, et al. Allometric scaling of
m-mode cardiac measurements in normal adult dogs. J Vet Intern Med
2004;18:311-3213Buchanan JW, Bucheler J. Vertebral scale system to
measure canine heart size in radiographs. J Am Vet Med Assoc
1995;206:194-199
Measuring the vertebral heart size (VHS)
Appropriate image Minimal rotationCostochondral junctions
alignedLine 1: Carina to apexPlace this line over the vertebrae
starting at cranial aspect of T4Measure to nearest 0.1
vertebraeLine 2: Perpendicular to first line at widest pointMeasure
same as for #2Sum up the two measurementsVHS: 5.7 + 6.2 =
11.95.76.212NormalMean + SD = 9.7 + 0.5Mean + 2 SD will encompass
96% of the population
Cats 7.5 + 0.3 26
Echocardiogram Measurements
LVIDd
LA:AO
EPIC Trial DesignAt inclusion of the studyPhysical
examinationBlood pressureThoracic radiographsCBC,
biochemistryEchocardiogramRechecks performed every 4 months with a
physical examinationEvery 8 months thoracic radiographs were
performedAlso rechecked if the patient had an event
EPIC Trial Exclusion CriteriaCongestive heart
failureSupraventricular or ventricular arrhythmias that required
treatmentOther structural heart diseaseOther significant systemic
diseasesModerate to severe pulmonary hypertensionRA:RV gradient
>65 mmHg based on tricuspid regurgitation
velocitiesDiureticsBeta-blockers, antiarrhythmic therapy
EPIC TrialPrimary endpointsCongestive heart failureClinical
signsPhysical examinationThoracic radiographsDeathEnd-point
committee confirmed diagnosis of CHFNeeded at least 2 on committee
to agree
EPIC Trial DesignRecruitment time 2 years, 8 monthsInterim
analysis planned at 3.5 years but was slightly prolongedTotal
duration 4.5 yearsDose 0.49 mg/kg/d (0.44-0.53) divided to twice
dailyGroups were equally dividedPlacebo group had fatter dogs (not
significant effect on outcome)~45% Cavalier King Charles
Spaniels
EPIC Trial ResultsTotal of 360 dogs162/354 dogs reached primary
end-point79 dogs still alive at end of studyKaplan meierPimobendan
median 1228 dPlacebo median 766 daysOverall 46% risk reduction
EPIC ResultsOther things effect outcomeBigger LA/AoHigher
LVIDdNHigher fractional shortening had worse outcomeDecreased
appetiteMultivariate analysis without echocardiogram dataHigher HR
worse outcomeHigher BP worse outcome
EPIC ResultsHow could pimobendan have such a positive effect?Not
clearPossibilitiesVasodilation Decreasing the size of the mitral
annulus thereby decreasing the severity of MRHas been shown to
decrease the size of the left ventricle (LVIDd and LVIDs)Hggstrm J,
et al J Vet Intern Med 2013;27:1452-1462; Kanno N, et al J Vet Med
Sci 69(4):373-377How will these patients do once they develop
congestive heart failure?Pimobendan is no longer a novel drugDoes
it matter?
Pimobendan?
Maybe
Pimobendan and CatsMost common heart disease is hypertrophic
cardiomyopathy Myocardial diseaseDefect of the sarcomereConcentric
hypertrophy of the left ventricleDisease of diastolic dysfunctionNo
prospective clinical trials evaluating use of pimobendan in cats
with hypertrophic cardiomyopathy or other heart diseases
Pimobendan and CatsMacGregor JM, et al. Use of pimobendan in 170
cats (2006-2010). J Vet Cardiol. 2011;13:251-260164 cats had
congestive heart failureMedian dose: 0.24 mg/kg q 12hWell
tolerated; 5 cats (3%) had potential side effectsTreatment
discontinued in one catHCM (40%), UCM (37%), DCM (16%), mitral
valve disease (4%), other2 cats had systolic anterior motion of the
mitral valve2 cats had dynamic left ventricular outflow tract
obstruction73% had systolic dysfunctionNo progressive hypertrophy
in HCM catsMedian survival time 151 days for cats with congestive
heart failure
Pimobendan in CatsReina-Doreste Y, et al. Case-control study of
the effects of pimobendan on survival time in cats with
hypertrophic cardiomyopathy and congestive heart failure. JAVMA
2014; 245(5):534-539Retrospective study27 cats with pimobendan and
27 cats no pimobendanMedian dose 0.49 mg/kg/dMedian survival
timesPimo: 626 dNo pimo: 103 d
Clear limitations: retrospective study. Not the same level of
evidence as a prospective placebo controlled study. Could have been
biases in case selection for cats receiving pimo. Case versus
controls were not at same time, control cats were from earlier
years than case cats. May have been differences in how cats are
treated overall. 38
In general pimobendan is contraindicated in cats with HOCMCan
worsen dynamic left ventricular outflow tract obstruction Positive
inotropyVasodilationVery small number of HOCM cats5 HOCM cats in
each groupPrevious study reported 1 HOCM cat developed severe
hypotension after pimobendan (Gordon SG, et al. JAVMA, 2012)
Hypertrophic cardiomyopathy
Hypertrophic obstructive cardiomyopathy
41
Pimobendan in cats with systolic dysfunctionCats with
non-taurine responsive dilated cardiomyopathy Hambrook LE, Bennett
PF. J Small An Prac, 2012All cats had clinical signs attributable
to DCM Congestive heart failure and/or arterial thromboembolismPimo
(16 cats) MST: 49 d (1->502)Larger left atriaNo pimo (16 cats)
MST: 12 d (1-244)9/16 also received digoxin
Gordon SG, et al. J Am Vet Med Assoc
2012;241:89-94Retrospective27 cats, all had ventricular systolic
dysfunctionUCM, DCM, ARVC, congenital, HCM with regional
hypokinesisDose 0.26 mg/kg q 12hPimobendan was well toleratedMedian
survival time 167 daysSame group reported an abstract (ECVIM
2008)Appeared to improve clinical signs
Take Home PointsPimobendan is recommended in occult phase of
dilated cardiomyopathy that is diagnosed by an
echocardiogramPimobendan is recommended in dogs with both DCM and
myxomatous valve degeneration and congestive heart failureNot every
dog with a heart murmur should receive pimobendanNot every dog with
a heart murmur who is coughing should receive pimobendanCough
should be evaluated with thoracic radiographsPimobendan is
recommended to dogs with myxomatous valve disease that meet
specific criteria for left-sided cardiomegaly Based on radiographs
and an echocardiogram (ideally)
Take Home PointsThere may be a place for pimobendan in cats with
echocardiographic evidence of ventricular systolic dysfunction and
congestive heart failureParticularly if hypotensiveAvoidance of
pimobendan administration to cats with dynamic left ventricular
outflow tract obstruction/systolic anterior motion of the mitral
valve is still recommendedFurther studies evaluating the use of
pimobendan in cats with hypertrophic cardiomyopathy and
hypertrophic obstructive cardiomyopathy are needed
Thank you! Questions?
