The positive inotropic and vasodilatory drug pimobendan has become part of the standard of care for management of dogs with CHF and is approved by the US FDA Center for Veterinary Medicine for use in dogs with CHF secondary to dilated cardiomyopathy and chronic mitral valve disease.1–7 Short-term use of positive inotropic agents can also aid in resolution of pulmonary edema and CHF of any etiology in humans because of the ability of these agents to promote improved myocardial relaxation, sarcoplasmic reticulum function, blood flow, and venous capacitance.8–10 Short-term and long-term use of positive inotropic agents in patients with diastolic heart failure is less well accepted. One large post hoc analysis revealed improved survival time in humans administered digoxin, an inotropic agent with a number of additional neuroendocrine-modulating properties.11 Additionally, pimobendan administration to dogs with tachycardia-induced cardiomyopathy resulted in improved cardiac function during diastole.12 There is controversy regarding the use of positive inotropes in cats with CHF; however, the use of pimobendan has been reported with positive results on a limited basis.13–15
Hypertrophic cardiomyopathy and HOCM represent 2 of the most common underlying causes of CHF in cats.16,17 Hypertrophic cardiomyopathy and HOCM are primarily characterized by ventricular hypertrophy, dysfunction during diastole, and elevation of left ventricular end-diastolic pressure and left atrial pressure. The pathological elevation of left ventricular end-diastolic pressure and left atrial pressure translates into elevated pulmonary venous pressures and, in the case of CHF, generation of a combination of pulmonary edema and pleural, pericardial, and abdominal effusions. Additional consequences of HCM and HOCM include arrhythmias, sudden death, and thromboembolic disease. One current recommendation for treatment of CHF in cats includes the use of diuretics, angiotensin-converting enzyme inhibitors, and antiplatelet drugs.18
Some cats with HCM have concurrent LVOT obstruction and are thus classified as having HOCM. Obstruction of the LVOT in cats may be secondary to a single cause or a combination of causes. These include dynamic processes such as cranial motion of the mitral valve during systole, asymmetric septal hypertrophy, or a combination of both. Additionally, fixed obstructions (eg, subaortic stenosis) have been identified in cats. Use of positive inotropic agents and afterload reduction is contraindicated in the face of a fixed obstruction of the outflow tract; therefore, pimobendan is not recommended in these patients.18 Obstruction of the LVOT and its diagnosis may be variable in terms of its presence and severity from day to day because it is dependent on a variety of physiologic factors such as adrenergic tone and blood volume.18 Although pimobendan may be considered contraindicated in patients with severe dynamic obstruction, no information exists to suggest whether the other proposed benefits of pimobendan may outweigh the risks in these patients. As such, treatment of cats with HOCM may be variable depending on the attending clinician and severity of obstruction.
Pimobendan is a positive inotrope and also has other pharmacological actions that include vasodilatory and antiplatelet properties.19–22 The pharmacological action of pimobendan is a result of inhibition of phosphodiesterase-3 and calcium sensitization of cardiomyocytes.23 Despite these actions, the use of pimobendan in cats with CHF has not gained widespread acceptance and is considered by some to be contraindicated in cats with HCM or HOCM. Investigators of recent studies13–15 have described the therapeutic effect and tolerability of pimobendan in cats with CHF and highlighted its safety as well as its suggested benefits.
We hypothesized that the addition of pimobendan to traditional CHF treatment would provide a benefit in survival time for HCM-affected cats with CHF and HOCM-affected cats with CHF. The purpose of the study reported here was to identify cats treated with a regimen that included pimobendan as well as age-, sex-, and disease-matched control cats treated with a regimen that did not include pimobendan to assess potential benefits in survival time gained with pimobendan treatment and characterize adverse drug effects that may have resulted from a standard dosage regimen of pimobendan.
Materials and Methods
A retrospective case-control study was performed. Medical records of North Carolina State University Veterinary Teaching Hospital from July 2003 to January 2013 were searched to identify cats with HCM and CHF or HOCM and CHF.
Hypertrophic cardiomyopathy was diagnosed during evaluation of an echocardiogram obtained by a board-certified veterinary cardiologist or a resident in a cardiology training program who was working under the direct supervision of a board-certified veterinary cardiologist. Diagnostic criteria for HCM or HOCM included a thickened (≥ 6 mm; measured during diastole) ventricular septum or left ventricular posterior wall in the absence of hyperthyroidism, systemic hypertension, or aortic stenosis.24 In addition to these criteria, HOCM was diagnosed by the presence of dynamic LVOT obstruction evident as an increased LVOT velocity (> 2 m/s) with cranial motion of the mitral valve during systole. Diagnosis of CHF was made by confirming the presence of pulmonary edema or pleural, pericardial, or peritoneal effusions with ≥ 1 imaging technique (eg, thoracic radiography, thoracic ultrasonography, or echocardiography) and was determined by the attending clinician to be cardiac in origin and treatable with furosemide. Cats with fixed LVOT obstruction were excluded from the study.
Pharmacy records for all cats on the initial day of CHF diagnosis were reviewed. All cats evaluated were under the primary care of a board-certified veterinary cardiologist or resident in a cardiology training program. Inclusion criteria for case cats were pimobendan treatment that began within 48 hours after CHF diagnosis and fractional shortening ≥ 30% at time of CHF diagnosis. Case cats must have received at least 2 doses of pimobendan prior to death or end of the study and had to have received pimobendan from the time of inclusion until death or end of the study. Controls (cats in CHF treated without the use of pimobendan) were identified and matched to case cats on the basis of sex, age (within 24 months), body weight (within 1 kg [2.2 lb]), and manifestation of CHF (pulmonary edema or pleural, pericardial, or abdominal effusion). Investigators were not aware of the medical information for the case cats (other than for the criteria used for matching) during the matching process. Cats that never received pimobendan as part of the treatment regimen and had fractional shortening ≥ 30% at time of CHF diagnosis were considered for inclusion as controls. Cats were excluded from the control group if they had received pimobendan at any time.
Records of all case and control cats were reviewed, and the following information was obtained: signalment (date of birth, sex, and breed); body weight; systolic arterial blood pressure at time of CHF diagnosis; rectal temperature, SUN concentration, and serum creatinine concentration prior to treatment; cause of CHF (HCM vs HOCM); function assessment during systole prior to treatment (fractional shortening and cardiologist comments about results of echocardiography); evidence of left atrial thrombi on echocardiogram prior to treatment; 2-D left atrium-to-aortic root ratio obtained from the right parasternal short-axis imaging plane; radiography reports that included the manifestation of CHF (pulmonary edema and pleural, pericardial, or abdominal effusion); pharmaceutical treatment including drug and dosing frequency; presence of arrhythmias before and during the course of treatment; presence of thromboembolic disease before or after treatment for CHF; and outcome (including date and cause of death if known). Cats were excluded if any data were incomplete or unavailable. Careful attention was given to adverse effects that were mentioned, specifically including vomiting, diarrhea, hair loss, and hysteria.
The LVOT velocity was examined in cats with HOCM (n = 10) to compare severity of obstruction between groups at the time of CHF diagnosis. The velocity was recorded from the echocardiography report for these 10 cats. Reports for repeated echocardiography on these 10 cats were reviewed, when available, throughout the course of treatment, and subsequent LVOT velocities were also recorded.
Cause of death was defined as cardiac or noncardiac. A cardiac cause of death was defined as any of the following scenarios: death or euthanasia following respiratory distress, sudden loss of use of ≥ 1 limb, sudden death, and euthanasia because of worsening clinical signs or quality of life attributable to CHF, cardiogenic shock, or arterial thromboembolism. Investigators telephoned owners of cats that did not have a date of death at the end of the study in May 2013 to verify that the cats were still alive.
A commercially available statistical programa was used to evaluate differences between case and control cats. Significance was set at α = 0.05. Differences at the time of diagnosis were evaluated for body weight, age, systolic arterial blood pressure, rectal temperature, SUN concentration, creatinine concentration, presence of arterial thromboembolism, left atrial thrombi, left atrium-to-aortic root ratio, total daily dose of furosemide, presence of atrial fibrillation, and presence of ventricular or other supraventricular arrhythmias. Comparisons for age and body weight were used to verify the success of the matching process. Differences at the time of study end (last evaluation of patient prior to death or at end of study in May 2013) were evaluated for total daily dose of furosemide, presence of left atrial thrombi, presence of arterial thromboembolism, atrial fibrillation, and ventricular or other supraventricular arrhythmias. Differences in the number of case and control cats receiving angiotensin-converting enzyme inhibitors, β-adrenergic receptor antagonists, and anticoagulants were evaluated. Dichotomous variables were entered into a contingency table, and a McNemar test was used to detect differences between the case and control cats. Continuous data were reported as median and IQR. For normally distributed data, a paired t test was used to detect differences between case and control cats for each continuous variable. For data that were not normally distributed, a nonparametric test (Wilcoxon matched-pairs signed rank test) was used to detect differences between case and control cats.
The LVOT velocity was compared between the case cats with HOCM and control cats with HOCM by means of the Wilcoxon matched-pairs signed rank test.
Complications were tabulated for all cats at time of CHF diagnosis and throughout the study period. These results were tabulated to identify cats entering the study with left atrial thrombi, arterial thromboembolism, and various arrhythmias within each group.
Survival time analysis was performed by creating Kaplan-Meier survival curves for the case and control cats. The curves were compared by means of the Mantel-Cox log rank test. Median survival time for the case and control groups and median survival time ratio, hazard ratio, and respective 95% confidence intervals were reported. Case cats that were still alive at time of analysis were censored as the last date known to be alive.
Results
Record evaluation yielded 164 potential cats for inclusion in the study. Of those, 27 cats met all entrance criteria for case cats, had a complete data set for evaluation, and had matching control cats.
Of the 27 case cats, 21 were castrated males and 6 were spayed females. There were 23 mixed-breed cats, 1 Maine Coon, 1 Siamese, 1 Himalayan, and 1 Sphinx. Median body weight was 5.1 kg (11.2 lb), with a range of 2.5 to 8.3 kg (5.5 to 18.3 lb). Median age at diagnosis with CHF was 9.0 years (range, 3.1 to 16.5 years). Hypertrophic obstructive cardiomyopathy was diagnosed in 5 cats (4 males and 1 female [all mixed-breed cats]), and HCM was diagnosed in the remaining 22 cats (17 males and 5 females [18 mixed-breed cats and 4 purebred cats]). Congestive heart failure manifested as pulmonary edema in 12 cats; in the remaining 15 cats, there was > 1 manifestation of CHF. Case cats received a minimum of 1.25 mg (0.15 mg/kg/d [0.068 mg/lb/d) and maximum of 3.75 mg (1.0 mg/kg/d [0.45 mg/lb/d]) of pimobendan daily, with the median, 25th percentile, and 75th percentile dose of 2.5 mg/d (divided between 2 or 3 doses). The median, 25th, and 75th percentile doses represented 0.49, 0.40, and 0.67 mg/kg/d (0.22, 0.18, and 0.30 mg/lb/d), respectively. All cats, except for 3, received pimobendan twice daily; those 3 cats received pimobendan 3 times daily. Of the 27 case cats, 16 died during the study period; all met the described criteria for a cardiac cause of death. The remaining 11 cats were verified as alive on the last date of the study via telephone communication with the owners; these case cats were censored in the survival analysis by use of this date.
The 27 control cats comprised 21 castrated males and 6 spayed females. There were 24 mixed-breed cats, 1 Maine Coon, 1 Manx, and 1 Siamese. Median body weight was 5.3 kg (11.7 lb), with a range of 3.7 to 8.9 kg (8.1 to 19.6 lb). Median age at diagnosis with CHF was 8.8 years (range, 3.0 to 18.0 years). Hypertrophic obstructive cardiomyopathy was diagnosed in 5 control cats (4 males and 1 female [all mixed-breed cats]), and HCM was diagnosed in the remaining 22 (17 males and 5 females [19 mixed-breed cats and 3 purebred cats]). Congestive heart failure manifested as pulmonary edema in 14 cats; in the remaining 13 cats, there was > 1 manifestation of CHF. Of the 27 control cats, 26 died during the study period; all met the described criteria for a cardiac cause of death. The remaining cat was alive on the last date of the study, as verified by telephone communication with the owner. Thus, this control cat was censored in the survival analysis by use of this date.
Date of study entrance ranged from 2003 to 2013. Although there may have been slight temporal variability between the time of collection for case and control cats, at least one-third of the cats in both groups were treated concurrently during the interval from 2007 to 2011.
Pharmacological treatment was recorded for each case and control cat (Table 1). All cats received furosemide.
Drugs administered to cats with CHF secondary to HCM or HOCM treated with a regimen that included (case cats) and that did not include (control cats) pimobendan.
| Drug | Case (n = 27) | Control (n = 27) |
|---|---|---|
| Pimobendan | 27 | 0 |
| Furosemide | 27 | 27 |
| Enalapril | 21 | 24 |
| Benazepril | 2 | 0 |
| Atenolol | 3 | 9 |
| Clopidogrel | 13 | 4 |
| Aspirin | 1 | 4 |
| Dalteparin | 5 | 7 |
| Clopidogrel and dalteparin | 3 | 2 |
| Clopidogrel and aspirin | 1 | 0 |
| Aspirin and dalteparin | 2 | 2 |
No significant differences were detected between groups for additional medications administered, such as angiotensin-converting enzyme inhibitors (P = 1.0), β-adrenergic receptor antagonists (P = 0.11), and anticoagulants (P = 0.11). Complications during the study period were tabulated for each group (Table 2).
Complications at the time of CHF diagnosis or that developed subsequently in cats with CHF secondary to HCM or HOCM treated with a regimen that included (case cats) and that did not include (control cats) pimobendan.
| Case (n = 27) | Control (n = 27) | |||
|---|---|---|---|---|
| Complication | At CHF diagnosis | Developed subsequently | At CHF diagnosis | Developed subsequently |
| Arterial thromboembolism | 2 | 5 | 2 | 3 |
| Left atrial thrombi | 5 | 0 | 0 | 0 |
| Ventricular ectopy | 3 | 2 | 6 | 4 |
| Supraventricular ectopy | 2 | 2 | 2 | 2 |
| Atrial fibrillation | 3 | 4 | 0 | 1 |
| Atrioventricular block | 1 | 1 | 0 | 0 |
No significant differences were detected for any variables at the start or completion of the study. Significant differences were not found at the time of CHF diagnosis for body weight (P = 0.44), age (P = 0.41), systolic arterial blood pressure (P = 0.57), rectal temperature (P = 0.15), SUN concentration (P = 0.32), creatinine concentration (P = 0.28), presence of arterial thromboembolism (P = 0.62), left atrium-to-aortic root ratio (P = 0.15), fractional shortening (P = 0.87), total daily dose of furosemide (P = 0.49), presence of ventricular arrhythmia (P = 0.51), atrial fibrillation (P = 0.25), atrioventricular block (P = 1.0), other supraventricular arrhythmias (P = 0.62), and left atrial thrombi (P = 0.07; Figure 1). Significant differences were not found at the time of study completion for total daily dose of furosemide (P = 0.84), presence of arterial thromboembolism (P = 0.72), ventricular arrhythmias (P = 0.68), atrioventricular block (P = 1.0), atrial fibrillation (P = 0.37), and other supraventricular arrhythmias (P = 0.62).
Box-and-whisker plots of the daily dose of furosemide (A), left atrium-to-aortic root ratio (B), serum creatinine concentration (C), and fractional shortening (D) at the time of CHF diagnosis in cats with CHF secondary to HCM or HOCM treated with a regimen that included (case cats; n = 27) and that did not include (control cats; 27) pimobendan. There were no significant (P > 0.05) differences between case and control cats for any of the variables. For each plot, the box represents the IQR, the horizontal line in each box represents the median, and the whiskers represent the minimum and maximum values.
Citation: Journal of the American Veterinary Medical Association 245, 5; 10.2460/javma.245.5.534
Median LVOT velocity for case cats with HOCM was 2.5 m/s (IQR, 2.25 to 3.85 m/s) and for control cats with HOCM was 3.0 m/s (IQR, 2.75 to 5.2 m/s); these values did not differ significantly (P = 0.27) between the groups. There were 3 case cats and 2 control cats that had LVOT velocity within anticipated limits during subsequent echocardiographic examinations, which may have indicated disease progression or the possible transient nature of dynamic LVOT obstruction.
Three case cats had atrial fibrillation at the time of CHF diagnosis, whereas none of the control cats had atrial fibrillation at the time of CHF diagnosis. Throughout the course of the study, 1 additional case cat and 1 control cat developed atrial fibrillation. Additionally, 5 of 27 case cats had evidence of left atrial thrombi at the time of CHF diagnosis, whereas none of the control cats had evidence of left atrial thrombi at the time of CHF diagnosis. Despite this finding, no additional case or control cats developed left atrial thrombi during the course of the study. No additional adverse effects were reported.
Analysis of the Kaplan-Meier survival curves revealed a significant (P = 0.024) survival time benefit for the cats receiving pimobendan (Figure 2). The median survival time of case cats was 626 days, whereas median survival time for control cats was 103 days. The median survival time ratio was 6.1:1 (95% confidence interval, 5.5 to 6.6). The hazards ratio was 0.49 (95% confidence interval, 0.27 to 0.91).
Kaplan-Meier survival curves for cats with CHF treated with a regimen that included (case cats; gray line) and that did not include (control cats; black line) pimobendan. The 2 curves differ significantly (P = 0.024) indicating a survival benefit in the pimobendan group.
Citation: Journal of the American Veterinary Medical Association 245, 5; 10.2460/javma.245.5.534
Discussion
Addition of pimobendan to standard treatment regimens for cats with CHF secondary to HCM or HOCM appeared to confer a clear benefit in survival time in the retrospective case-control study reported here. Furthermore, pimobendan was tolerated well by cats with CHF secondary to HCM and HOCM, and no additional adverse effects were noted in case versus control cats enrolled in the study. To the authors’ knowledge, this was the first study in which investigators used a control group in the evaluation of cats that received pimobendan as a component of treatment for CHF. Pimobendan is widely used for CHF secondary to dilated cardiomyopathy and mitral valve degeneration in dogs.1–7 A pharmacokinetic study25 of pimobendan in cats revealed a longer half-life after administration, compared with the half-life after administration to dogs, which supports twice-daily administration, as was used for most of the cats in the present study. Although pimobendan is not licensed for use in cats, previous studies13–15 have identified that there may be a positive effect on contractility, cardiac output, and survival time in cats with CHF secondary to various causes, including cats with dysfunction during systole. The investigation of pimobendan in cats with dysfunction during systole was not a specific objective of the present study and was the reason that cats with a fractional shortening < 30% were excluded.
Although results of the present case-control study do not offer the same quality of evidence for therapeutic benefit as results of a prospective randomized clinical trial, the case-control design offers the strongest evidence of a treatment effect available from a retrospective study.26,27 Limitations of this study included the fact that not all of the cats were receiving treatment at the same time, and although one-third of the case and control cats were treated within the same calendar year, control cats were more often treated during the early years of the study period, compared with the years when case cats were treated. The use of historical controls confers some risk that changes in treatment strategies over time could lead to substantial differences between treatment groups. The authors attempted to ensure appropriate matching of cats and provide evidence that there was no appreciable difference between the groups, except for the addition of pimobendan to the treatment regimen. Importantly, the 27 case cats were appropriately matched with the control cats, and the number of cats was adequate for detection of significant differences between groups. Additionally, no significant difference was identified between groups for any variable that would indicate more severe disease (eg, left atrial size, rhythm disturbances, and renal dysfunction) in the case or control cats.
Another limitation was the factors that dictated whether cats received pimobendan. It is possible that some clinicians chose to use pimobendan because of disease severity. Although we did not detect a significant difference in disease severity between groups, this possible bias must be considered.
A final concern was the small number of cats that met our inclusion criteria for HOCM. These few cats, although matched in the control group, had a dynamic obstruction, some of which was normalized during subsequent echocardiographic examinations. Given this information, no firm conclusions on the use of pimobendan in cats with HOCM can be made from results of the present study. In fact, if anything, cats receiving pimobendan treatment may have had more advanced disease than those in the control group, as determined on the basis of absolute values for left atrium-to-aortic root ratio and left atrial thrombi, which thereby supports the conclusion that pimobendan appeared to confer a clear benefit in survival time for cats with CHF secondary to HCM and, possibly, HOCM.
The use of pimobendan in cats with CHF secondary to HCM and some cats with HOCM was tolerated well and associated with a significant increase in median survival time. Analysis of results of the present study would suggest that pimobendan treatment is warranted in cats with CHF secondary to HCM. Further evaluation of the role of pimobendan in cats with HOCM is needed to reach firm conclusions regarding this subset of cats. Prospective placebo-controlled studies are warranted to further investigate these findings.
Prism, version 5.0, Graphpad Software Inc, La Jolla, Calif.
ABBREVIATIONS
| CHF | Congestive heart failure |
| HCM | Hypertrophic cardiomyopathy |
| HOCM | Hypertrophic obstructive cardiomyopathy |
| IQR | Interquartile range |
| LVOT | Left ventricular outflow tract |
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