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Retrospective evaluation of the safety and tolerability of pimobendan in cats with obstructive vs nonobstructive cardiomyopathy

Abstract Background Pimobendan is frequently used off‐label for treatments of cats with congestive heart failure (CHF). Concern exists regarding the safety of pimobendan in cats with outflow tract obstruction (OTO). Objectives In cats treated with pimobendan, incidence of adverse effects will not differ between cats with OTO vs cats with nonobstructive cardiomyopathy. Animals Two‐hundred sixty cats with CHF (57 with OTO, 203 with nonobstructive disease). Methods Retrospective medical record review. Groups were compared using 2‐sample t‐tests, Wilcoxon rank‐sum tests, and Fisher exact tests. Results Compared to cats with nonobstructive cardiomyopathy, cats with OTO were younger (8.9 [interquartile range (IQR) 6.6] vs 10.8 [6.3] years, P = .0036), more likely to have a heart murmur (51/57 [90%] vs 76/203 [37.8%] cats, P < .0001), more likely to manifest CHF as pulmonary edema (53/57 [83%] vs 144/203 [70.9%] cats, P = .0004), and less likely to have pleural effusion (19/57 [33%] vs 122/203 [60.1%] cats, P = .0005). Adverse effects suspected to be related to pimobendan administration occurred in 12/260 cats (4.6%), including 11/203 cats (5.4%) with nonobstructive cardiomyopathy and 1/57 cat (2%) with OTO (P = .7). Pimobendan was discontinued due to adverse effects in 4/260 cats (1.5%), 3 with nonobstructive disease and 1 with OTO (P = 1.0). Acute adverse hemodynamic effects after pimobendan administration were not detected in any cats. Conclusions and Clinical Importance Pimobendan is well tolerated in cats with cardiomyopathy and CHF, regardless of the presence of OTO.

vasodilator (phosphodiesterase-III inhibitor), has become the standard of care for dogs with advanced heart disease. This drug confers survival benefit in dogs with congestive heart failure (CHF) secondary to dilated cardiomyopathy (DCM) 1,2 and degenerative mitral valve disease (DMVD), 3 as well as benefit in delaying onset of CHF in dogs with preclinical DCM 4 and advanced preclinical DMVD. 5 No consensus exists about off-label use of pimobendan in cats with CHF. 6 The most common cause of CHF in cats is hypertrophic cardiomyopathy (HCM), a disease of primarily diastolic dysfunction for which positive inotrope treatment might appear counterintuitive. 6,7 In cats with hypertrophic obstructive cardiomyopathy (HOCM), pimobendan could be contraindicated because increased contractility could worsen the degree of dynamic left ventricular (LV) outflow tract obstruction (OTO). 8,9 However, biventricular longitudinal systolic dysfunction is a feature of HCM in cats, 10,11 suggesting that positive inotropy could confer therapeutic benefit.
Other potential ancillary benefits of using pimobendan in cats with HCM include positive lusitropy, improved left atrial (LA) function, balanced vasodilation, increased renal blood flow, and adjunctive anticytokine and antiplatelet effects. 12,13 Published literature regarding safety and efficacy of pimobendan in cats is relatively sparse, particularly in the subpopulation of cats with OTO. Based on several retrospective studies of cats with CHF and LV systolic dysfunction, pimobendan is well tolerated. 12,14,15 A total of 229 cats were evaluated across these studies, including 4 cats with HOCM, none of which had adverse effects of pimobendan. A single cat with multiple congenital cardiac defects (including an OTO) developed hypotension after receiving pimobendan, which resolved with discontinuation of the drug. 12 More recently, a retrospective case-control study of 54 cats with CHF and normal systolic function included 5 cats with HOCM, which received pimobendan, none of which had adverse effects. 16 A subsequent prospective placebo-controlled study of pimobendan in 82 cats with CHF included 27 cats with HOCM, none of which had adverse effects of pimobendan. 17 In a laboratory setting involving 13 research colony cats with familial HCM or HOCM, a single oral dose of pimobendan does not increase LV outflow velocity or likelihood of LV OTO compared to placebo, 13 challenging the specific concern that pimobendan worsens OTO in cats with HOCM.
Based on published evidence and clinical experience, some veterinary cardiologists currently administer pimobendan to cats as part of routine treatment of CHF regardless of the presence of OTO. Other cardiologists remain concerned about the safety of pimobendan in cats with OTO, particularly given the small total number of cats with HOCM receiving pimobendan in published studies. The purpose of the present study was to describe safety and tolerability of pimobendan administered to cats with cardiomyopathy and CHF, and particularly to compare results between cats with obstructive vs nonobstructive disease. We hypothesized that pimobendan would be well tolerated in cats with CHF, with no difference in incidence of adverse effects between cats with and without OTO.  Manifestation of CHF was recorded as presence or absence of pulmonary edema, pleural effusion, pericardial effusion, and ascites. Individual cats could have more than 1 manifestation of CHF; in these cases, cats were counted in each category of manifestation.
Cardiac disease diagnosis was based on echocardiographic findings as described by the ACVIM Consensus Panel. 6 Hypertrophic cardiomyopathy phenotype was defined by diastolic LV wall thickness > 6 mm.
Hypertrophic cardiomyopathy phenotype in the presence of concurrent hyperthyroidism or systemic hypertension (systolic blood pressure > 180 mmHg) was classified as "HCM phenotype with hyperthyroidism" or "HCM phenotype with hypertension," respectively; cats with both hyperthyroidism and hypertension were placed in the former (hyperthyroidism) category. Restrictive cardiomyopathy (RCM) was characterized by severe LA or biatrial dilation with evidence of LV diastolic dysfunction but normal LV wall thickness (< 6 mm). Dilated cardiomyopathy was characterized by LV dilation and systolic dysfunction. Acquired cardiomyopathies not conforming to these categories were classified as cardiomyopathy of nonspecific phenotype. Echocardiographic measurements of LV size, wall thickness, and fractional shortening were recorded from right parasternal short-axis M-mode views at the level of the chordae tendineae; LA to aorta ratio was recorded from 2-dimensional right parasternal short-axis views of the heart base using the Swedish method 18 ; and LV outflow tract velocity was measured from left apical views optimized for the LV outflow tract and aorta. 19 In cats with acquired heart disease, dynamic LV OTO was defined as the presence of turbulent flow on color Doppler in the LV outflow tract and a late-peaking continuous wave Doppler velocity > 1.9 m/s, with or without systolic anterior motion of the mitral valve. 13,20 Cats with dynamic midventricular LV obstruction were also classified as having OTO. 21   Medical records and owner communication logs were examined for evidence of adverse events noted by owners after prescription of pimobendan, including (but not limited to) hyporexia/anorexia, vomiting, diarrhea, lethargy, weakness, or unusual agitation; and for hypotension and new or worsening arrhythmias detected at follow-up examinations. 5,9 These events were considered to be potential adverse effects related to pimobendan administration if they occurred within 45 days initial pimobendan administration and resolved with discontinuation of pimobendan. Adverse events were considered unrelated to pimobendan if the clinical signs coincided with either a relapse of CHF, addition of a different medication, or diet change; or if the clinical signs self-resolved with no change in pimobendan dose.
If pimobendan was discontinued, date and reason for pimobendan discontinuation were recorded.
Long-term follow-up information included date and cause of death for cats that died during the study period, and date of last follow-up for cats alive at the end of the study period. Death was classified as cardiac for cats who died or were euthanized for worsening CHF or ATE, and for cats who died suddenly at home with no other obvious noncardiac cause.

| Statistical analysis
Statistical analysis was performed using commercially available software (SAS, version 9.4, Cary, NC; R software, version 3.6.2, R Foundation for Statistical Computing, Vienna, Austria). Normality of data was assessed using the Shapiro-Wilk test. Continuous data are presented as mean ± SD for normally distributed data and as median(interquartile range, IQR) for nonnormally distributed data. Comparisons of variables between groups were performed using 2-sample t-tests for continuous normally distributed data, Wilcoxon rank-sum tests for continuous nonnormally distributed data, and Chi-square or Fisher exact tests for categorical variables. Statistical significance was set at P < .05 for all analyses. Cox proportional hazards regression analysis was performed to assess variables that were associated with all-cause or cardiac survival. Variables approaching significance (P < .1) in univariable analysis were subsequently entered into stepwise multivariable logistic regression analysis, with significance of the final models set at P < .05.
Physical examination findings and manifestation of CHF for the study sample and by disease group (nonobstructive vs obstructive) are shown in Table 2. Murmurs were detected in a total of 127 cats and were localized as left parasternal (n = 80), left apical (9), right parasternal (9), and left basilar (2); 27 murmurs were not localized. Timing T A B L E 1 Cardiomyopathy phenotype in 260 cats with congestive heart failure treated with pimobendan, 57 of which had outflow tract obstruction (OTO) .58 Note: Data are presented as median (IQR) for continuous nonnormally distributed data, and as number (percent) for categorical variables. Significant differences between groups (P < .05) are denoted in bold with an asterisk (*). The number of cats with data included is noted for variables with incomplete data sets. Modified IRIS staging was performed by applying IRIS cutoff guidelines to single serum creatinine value at time of CHF diagnosis, with no substaging attempted. Abbreviation: IRIS, International Renal Interest Society.
was classified as systolic (n = 50) or not specified. Murmur intensity was graded as I/VI (n = 8), II/VI (42), III/VI (32), IV/VI (40), V/VI (2), or not recorded (3). One or more arrhythmias were diagnosed in 78 cats, characterized as ventricular ectopy (n = 48), atrial fibrillation (16), supraventricular ectopy (11), high-grade atrioventricular block (8), or atrial standstill (2). There were significant differences between nonobstructive and obstructive disease groups for cat age, presence of murmur, incidence of arrhythmia, and incidence of pulmonary edema or pleural effusion (see Table 2). When analysis was restricted to only primary HCM vs primary HOCM, the same patterns between groups were noted although the difference in incidence of pleural effusion was no longer statistically significant (P = .058).
Echocardiographic findings at time of CHF diagnosis are compared by disease groups in Table 3. Of cats diagnosed with dynamic LV OTO, 34/57 (60%) had systolic anterior motion of the mitral valve recorded. Mitral regurgitation was documented in a total of 194 cats (74.6%), graded as trace (n = 52), mild (118), moderate (22), and severe (2). Compared to cats with nonobstructive disease, cats with OTO had thicker LV walls, smaller LV lumen size, and higher fractional shortening (see Table 3). However, when restricting analysis to only cats with primary HCM vs HOCM, the only difference between groups was higher incidence of mitral regurgitation in the HOCM group (see Table 3).  to new or worsening azotemia. Neither incidence of furosemide dose decrease (P = .74) nor timing from CHF diagnosis (P = .84) differed between disease groups (see Table 4).   (7), coincided with a relapse of CHF and resolved with intensified treatment of CHF (6), was attributed to concurrent noncardiac disease (3), or had been reported before pimobendan prescription (2).

| Cardiac medication prescribing practices
Twelve cats (4.6%), including 11 (5.4%) cats with nonobstructive disease and 1 (2%) cat with obstructive disease, were reported to experience adverse effects considered to be potentially attributable to pimobendan based on patterns of timing and resolution. These adverse effects occurred a median of 10 days (range 1-40) after pimobendan initiation, and consisted of hyporexia/anorexia (7 cats, 1 of which was also lethargic and 2 of which also had vomiting), vomiting (6 cats, 2 of which also had hyporexia/anorexia), and subclinical hypotension (1 cat). Incidence of adverse effects did not differ between disease groups (P = .70).
Pimobendan was discontinued during the study period in 17 cats (6.5%), including 11/203 (5.4%) cats with nonobstructive disease and 6/57 (11%) cats with obstructive disease. Discontinuation of pimobendan occurred a median of 141 days after initiation of pimobendan (range 2-1078 days). There was no difference in incidence of discontinuation (P = 1.00) or time to discontinuation (P = .48) between disease groups. The most common reason for discontinuation of pimobendan was that the cat's CHF had resolved and the underlying structural heart disease had improved to the point where ongoing therapy for CHF was considered no longer necessary (n = 11). In all of these cases, diuretic therapy was also discontinued.
Pimobendan was discontinued due to adverse effects in a total of 4/260 cats (1.5%), including 3 cats with nonobstructive disease (1.5%) and 1 cat with obstructive disease (2%). There was no difference in incidence of pimobendan discontinuation due to adverse effects between groups (P = 1.00). with obstructive and nonobstructive heart disease, and no evidence to suggest a clinically relevant worsening of OTO with pimobendan.
Two cats in this study without previously recorded arrhythmias were diagnosed with ventricular ectopy after pimobendan administration. However, intermittent arrhythmias prior to pimobendan administration could certainly have been missed; diagnostic rhythm assessment was not standardized and Holter monitoring was not performed in any cats, making it difficult to rule out the possibility that ventricular ectopy predated pimobendan administration in these cases. 22 Pimobendan is not currently labeled for use in human heart disease in the United States based on a clinical trial suggesting increased death and a concern for proarrhythmic effects for pimobendan compared to placebo. 23  Results of this study suggest that pimobendan was safe and well tolerated in a large group of cats with CHF secondary to various underlying cardiac disease phenotypes, with no increased risk of adverse effects for cats with obstructive disease. Further long-term prospective studies will be needed to determine potential effects of pimobendan on quality of life and survival in cats with CHF.

ACKNOWLEDGMENTS
No funding was received for this study. The authors thank Lauren McKeen for assistance with statistical analysis.

CONFLICT OF INTEREST DECLARATION
Drs. Ward, Kussin, and Tropf have no relevant disclosures. Drs. DeFrancesco, Tou, and Keene have received consulting fees or honoraria from Boehringer Ingelheim Vetmedica, Inc. and CEVA Animal Health.

OFF-LABEL ANTIMICROBIAL DECLARATION
Authors declare no off-label use of antimicrobials.

INSTITUTIONAL ANIMAL CARE AND USE COMMITTEE (IACUC) OR OTHER APPROVAL DECLARATION
Authors declare no IACUC or other approval was needed.

HUMAN ETHICS APPROVAL DECLARATION
Authors declare human ethics approval was not needed for this study.