J Vet Intern Med 2002;16:255–261

A Double-Blind, Randomized, Placebo-Controlled Study of Pimobendan in Dogs with Dilated Cardiomyopathy Virginia Luis Fuentes, Brendan Corcoran, Anne French, Karsten E. Schober, Rainer Kleemann, and Claus Justus A double-blind, randomized, placebo-controlled study was conducted to examine the effect on heart failure class and survival of pimobendan, an oral calcium-sensitizing inodilator, in dogs with dilated cardiomyopathy (DCM). Pimobendan (0.3–0.6 mg/kg body weight/d) or placebo was administered to English Cocker Spaniels (CSs; n ⫽ 10) and Doberman Pinschers (DPs; n ⫽ 10) that had DCM in addition to background therapy of furosemide, enalapril, and digoxin. Addition of pimobendan to standard triple therapy was associated with a significant improvement in heart failure class, regardless of breed (P ⬍ .02, Mann-Whitney rank sum test). Overall, 8 of 10 animals in the pimobendan-treated group, and 1 of 10 animals in the placebo group improved their heart failure status by at least 1 modified New York Heart Association functional class after initial stabilization (P ⫽ .005, Fisher’s exact test). Pimobendan had no significant effect on survival in the CSs (P ⫽ 0.77, log-rank test), but DPs treated with pimobendan had significantly longer survival times compared with placebo (P ⬍ .02, log-rank test), with a median survival time of 329 days in the pimobendan group compared with 50 days in the placebo group, and a hazard ratio of 3.4 (95% confidence interval 1.4– 39.8). Pimobendan resulted in significant improvement in heart failure class when added to standard therapy in this group of dogs with DCM, and may have contributed to improved survival in DPs. Key words: Calcium-sensitizing agent; Congestive cardiac failure; Doberman Pinscher; English Cocker Spaniel; Heart; Inodilator.

P

imobendan is a benzimidazole-pyridazinone inodilator. Pimobendan causes venodilation and arteriodilation via inhibition of phosphodiesterase (PDE) III, and has positive inotropic effects as a result of both PDE III inhibition (like amrinone and milrinone) and from a calcium-sensitizing effect.1–3 Calcium sensitizers affect the interaction of calcium with the troponin C complex,3,4 and increase the extent of contraction for a given cytosolic concentration of calcium. The effect of increased preload, whereby increased stretch of the myofilaments results in increased shortening, may operate via a similar mechanism.5 This inotropic mechanism seems to have advantages, because myocardial energy expenditure is lower than with positive inotropic agents operating via cyclic adenosine monophosphate (cAMP).6–9 In skinned myofiber preparations, the rate of adenosine triphosphatase activity per unit force generated is unchanged with addition of pimobendan, despite an increase in active tension.10 In studies of human patients, myocardial oxygen consumption actually may be reduced with administration of pimobendan.11 Pimobendan also has favorable effects on left ventricular relaxation and end-diastolic pressure-volume relations.12–15 The positive inotropic effect of pimobendan in dogs has From the Department of Veterinary Clinical Studies, Royal Dick School of Veterinary Studies, Summerhall, Edinburgh, UK (Luis Fuentes, Corcoran, French, Schober); and Boehringer Ingelheim, Vetmedica GmbH, Ingelheim am Rhein, Germany (Kleemann, Justus). Dr Luis Fuentes is presently affiliated with The Ohio State Veterinary Teaching Hospital, Columbus, OH. Data from this study were presented as an abstract at the British Small Animal Veterinary Association Congress in Birmingham, UK, in 1998. Reprint requests: Virginia Luis Fuentes, MA, VetMB, PhD, CertVR, DVC, Dipl ACVIM (Cardiology), The Ohio State Veterinary Teaching Hospital, 601 Vernon Tharp Street, Columbus, OH 43210; e-mail: [email protected]. Submitted April 5, 2001; Revised September 4, 2001; Accepted December 18, 2001. Copyright 䉷 2002 by the American College of Veterinary Internal Medicine 0891-6640/02/1603-0007/$3.00/0

been demonstrated in a number of studies,9,13,16–19 including in dogs with myocardial failure, wherein the effect of traditional positive inotropic agents is often blunted.14 The calcium-sensitizing effect of pimobendan may predominate over the PDE III effect in chronic heart failure, because down-regulation of the cAMP signaling transduction pathway occurs not only by down-regulation of beta-adrenergic receptors, but also by increases in the inhibitory subunit of the G-protein complex20 and activation of ␤-adrenergic receptor kinase,21 thus diminishing the effect of PDE III inhibition.22,23 Pimobendan’s vasodilatory effects occur as a result of PDE III inhibition, and result in both venodilation and arteriodilation.18,24,25 Studies in dogs after IV administration, and in human heart failure patients after PO administration, demonstrate a reduction in filling pressures and systemic vascular resistance.13,14,18,26–31 Studies of pimobendan in human heart failure patients have shown an improvement in exercise tolerance and peak rate of oxygen consumption,26,27,32–35 in contrast with the inconsistent influence of PDE inhibitors on exercise duration.36,37 Most studies have also shown improvement in quality of life.32,33,38 Results have been favorable in human clinical trials comparing treatment with pimobendan and angiotensin-converting enzyme (ACE) inhibitors,26,34,39 and additional benefits were seen when pimobendan was added to background therapy of diuretics, ACE inhibitors, digoxin, and carvedilol.40 This double-blind, placebo-controlled trial was undertaken to examine the effects of pimobendan in dogs with naturally occurring dilated cardiomyopathy (DCM). Because differences in the clinical course of DCM have been noted among affected breeds,41 the interpretation of any response to drug therapy is complex when multiple breeds are involved. Two specific breeds were recruited for this study: Doberman Pinschers (DPs) and English Cocker Spaniels (CSs), reflecting 2 breeds with a contrasting clinical course. DPs have a very poor prognosis, with the majority of dogs surviving less than 6 months after diagnosis.42,43 The prog-

256

Luis Fuentes et al

Table 1. Modified New York Heart Association (NYHA) scoring system used to assess functional severity of heart failure. NYHA Class 1 2

3

4

Clinical Signs Evidence of cardiac disease, but no clinical signs or exercise intolerance. Evidence of cardiac disease, but no clinical signs except at exercise. Moderate activity causes fatigue, dyspnea, or both. Cardiac disease associated with clinical signs such as coughing or dyspnea, but comfortable at rest. Cardiac disease associated with severe congestive heart failure, such that the animal is exhibiting clinical signs at rest, with little or no capacity for exercise.

nosis is better in CSs, with some dogs surviving for more than 4 years after diagnosis.44,45 The aim of this clinical trial was to evaluate the efficacy and influence of pimobendan on long-term survival in dogs with DCM, when used in combination with background therapy of furosemide, enalapril, and digoxin.

Materials and Methods The study conformed to the Use of Animals (Scientific Procedures) Act 1986, and informed consent was obtained from each owner.

Subjects DPs (n ⫽ 10) and CSs (n ⫽ 10) presented with congestive heart failure resulting from DCM to the Small Animal Clinic, Royal (Dick) School of Veterinary Studies, were recruited for the study. All dogs were currently in modified New York Heart Association (NYHA) class 3 or 4 (Table 1), or had been in modified NYHA class 3 or 4 within the 2 weeks before presentation. Inclusion criteria included echocardiographic confirmation of a dilated, hypocontractile left ventricle in the absence of marked valvular disease or congenital heart defects, and radiographic evidence of pulmonary edema. In 3 of the CSs, subjective thickening of the mitral valve leaflets was noted, but all had an increased left ventricular end-systolic volume index, consistent with myocardial failure.46,47 The gender distribution in the pimobendan and placebo groups was similar, with 1 neutered female in both groups of CSs, and 2 neutered females and 3 males (or neutered males) in each DP group. Median age was 6 years (3–9 years) in the CS placebo group and 9 years (3– 14 years) in the pimobendan-treated group. Median age was 10 years (8–10 years) in the DP placebo group and 9 years (6–9 years) in the pimobendan-treated DPs. At the start of therapy, all CSs were in sinus rhythm, and 1 DP in the pimobendan group was in atrial fibrillation, compared with 3 of the placebo-treated DPs. The median NYHA class was 3.0 (3.0–4.0) in the placebo group, and 3.5 (2.0–4.0) in the pimobendan group.

Concurrent Therapy Prior therapy with diuretics or ACE inhibitors was not an exclusion criterion. On entry to the study, all dogs were treated PO with furosemide, enalapril,a and digoxin,b and any additional drugs were withdrawn for at least 10 days. Furosemide was given to effect (2–9 mg/ kg/d PO in divided doses), enalapril was given at 0.5 mg/kg PO q12– 24h, and serum digoxin concentration was confirmed to be in the therapeutic range of 0.6–1.9 ng/mL before commencement of study drug administration. Mean doses of furosemide, enalapril, and digoxin were not significantly different for placebo- versus pimobendan-treated dogs (Table 2). DPs and CSs were randomized separately to receive either pimobendan (0.3–0.6 mg/kg/d PO) or placebo in addition to standard triple therapy, according to a double-blind protocol. The randomization was carried out off-site in blocks of 10 for each breed, by means of proprietary software,c with the identity of the capsules (whether containing pimobendan or placebo) unknown to anyone attending the dogs. No dog received any oral drugs during the study period apart from furosemide, enalapril, digoxin, and either pimobendan or placebo. One CS in the placebo group received topical ear preparations intermittently throughout the study period.

Study Design The clinical condition of each subject was evaluated at baseline and at 3-week intervals for the DPs, and at 6-week intervals for the CSs. In addition to information on the patient response provided by the owner, a complete physical examination, 6-lead ECG, thoracic radiographs, and echocardiogram were obtained at each reevaluation. The major study variables were modified NYHA class and survival time. Survival times were calculated as the period from the initiation of pimobendan or placebo treatment until death of the animal, withdrawal from the study, or the end of the 4-year study period (whichever was soonest). Withdrawal from the study was evaluated as a fatality even though survival time may have been longer. Noncardiac causes of death and euthanasia for intractable heart failure were also treated as uncensored data.

Statistical Analysis Results are reported as the mean ⫾ standard deviation (SD), 95% confidence intervals of the mean (95% CI), or the median value and range. A Fisher’s exact test was used to assess the response to pimobendan or placebo as binary data (improved/not improved) after addition to treatment with conventional therapy. An improvement was indicated by attainment of a lower modified NYHA class at any point during the study period with respect to the NYHA class achieved after stabilization with conventional therapy. For the comparison of survival times, Kaplan-Meier curves were constructed and log-rank tests were used to compare survival curves, with the hazard ratio expressed as 95% CIs. The significance level was set at P ⬍ .05. All statistical analyses were carried out with proprietary statistical software programs.d,e

Results Clinical Efficacy After initiation of standard triple therapy, both groups improved to a median NYHA class of 2.0 (range in placebo

Table 2. Drug doses at start of trial therapy. Group English Cocker Spaniel Placebo English Cocker Spaniel pimobendan Doberman Pinscher placebo Doberman Pinscher pimobendan

Digoxin (mg/kg/d) 0.011 0.012 0.008 0.009

⫾ ⫾ ⫾ ⫾

0.002 0.003 0.003 0.002

Furosemide (mg/kg/d) 4.0 4.0 5.7 2.9

⫾ ⫾ ⫾ ⫾

2.0 1.8 2.4 1.1

Enalapril (mg/kg/d) 0.62 0.59 0.81 0.68

⫾ ⫾ ⫾ ⫾

0.29 0.23 0.29 0.27

Pimobendan in Canine DCM

257

failure class during treatment with pimobendan compared with placebo (P ⬍ .02). Only 1 of 10 dogs receiving placebo showed further improvement after stabilization with conventional therapy, whereas 8 of 10 of the dogs receiving pimobendan showed further improvement at some point during the study period (P ⫽ .005, Fisher’s exact test). Two dogs developed diabetes mellitus during the course of the study: a CS in the placebo group, and a DP in the pimobendan group. One CS in the placebo group had 2 episodes of witnessed syncope.

Survival

Fig 1. Modified New York Heart Association (NYHA) heart failure class is shown in 10 dogs treated with pimobendan (A) and 10 dogs treated with placebo (B) in addition to treatment with furosemide, enalapril, and digoxin (triple). The graphs show heart failure class on 1st presentation (initial), after stabilization with conventional treatment (triple), and then the lowest heart failure class achieved during the study period (triple ⫹ pimobendan/triple ⫹ placebo). The majority of dogs in both treatment groups improved with conventional therapy, but only 1 of 10 of the dogs in the placebo-treated group showed further improvement after initial stabilization. In the pimobendan group, 8 of 10 dogs showed improvement with the addition of pimobendan to standard therapy (P ⬍ .005, Fisher’s exact test).

group, 2.0–4.0; range in pimobendan group, 2.0–3.0; Fig 1). The median value for the lowest NYHA class attained at any point during the study period was 2.0 (1.0–4.0) for the placebo group, and 1.0 (1.0–2.0) for the pimobendantreated group. No statistical difference was found between placebo and pimobendan groups for the NYHA class at initial presentation or after conventional therapy, but a Mann-Whitney rank sum test showed a significant improvement in heart

CSs. Four CSs died during the follow-up period. Three of these animals were euthanized for noncardiac diseases. One dog in the placebo group was euthanized with gastrointestinal disease, and 2 dogs were euthanized in the pimobendan group (1 with a nasal tumor, and 1 with fecal incontinence). One animal in the pimobendan group died suddenly within 1 month of diagnosis. All other CSs were still alive at the end of the study period, although 1 dog from the placebo group was withdrawn from the study with diabetes mellitus. Median survival according to KaplanMeier analysis (including all-cause mortality and study withdrawals) was 537 days (range, 61–1,428 days) in the placebo group and 1,037 days (range, 51–1,127 days) in the pimobendan group (P ⫽ .77; Fig 2A). DPs. All DPs died during the study period. Six dogs died suddenly (3 dogs in each group), and 2 dogs were euthanized with intractable cardiac failure (placebo group). One dog in the pimobendan group developed immune-mediated hemolytic anemia that was treated with corticosteroids, and subsequently developed pancreatitis. Signs of congestive failure recurred with fluid therapy, and her death was not observed, so that it was not clear which of the conditions was primarily responsible for her death. The pimobendantreated DP that developed diabetes mellitus was withdrawn from the study after 329 days. The pimobendan treatment was stopped, although he continued with the standard therapy, and was euthanized for congestive failure 2 months later. A log-rank test comparing the survival curves showed significant differences between the placebo- and pimobendan-treated DPs (P ⬍ .02; Fig 2B). The median survival time for pimobendan-treated DPs was 329 days (range, 42– 393 days), and the median survival time in the placebo group was 50 days (range, 13–196 days), with a hazard ratio of 3.4 (95% CI 1.4–39.8).

Discussion This study examined the effects of pimobendan on dogs with DCM when added to background therapy of furosemide, enalapril, and digoxin. In both breeds, the addition of pimobendan to a standard treatment protocol was associated with a significant improvement in functional heart failure class. Overall, 8 of 10 animals in the pimobendantreated group improved their modified NYHA-class status during the study period, compared with 1 of 10 animals in the placebo group. Therefore, pimobendan therapy seemed to confer additional benefit over the background therapy of furosemide, enalapril, and digoxin. Although the ages in

258

Luis Fuentes et al

Fig 2. Survival curves for English Cocker Spaniels (A) and Doberman Pinschers (B). No significant difference was found in survival between the placebo- and pimobendan-treated English Cocker Spaniels, with both groups having relatively long survival times. A significant difference was found in the survival curves between the 2 Doberman Pinscher groups, with the pimobendan group having longer survival times (P ⬍ .02, log-rank test).

the 2 DP groups were similar, a nonsignificant trend towards a younger age was found in the CS placebo group compared with the CS pimobendan group. Younger age at diagnosis has been associated with a poorer prognosis in canine DCM, and may have been a factor in the poorer response in the CS placebo group compared with the CS pimobendan group.48 At the end of the 4-year study period, 6 of 10 CSs were still alive, and 3 of 10 CSs had died of noncardiac disease, thus confirming previous observations that CSs with DCM have the potential for long survival times. The lack of obvious benefit on survival times does not exclude the possibility of a potential adverse effect of pimobendan in CSs, although the study did not have adequate power to assess this possibility. From the results of this study, any trial undertaking the effect of therapy on the survival of CSs with DCM clearly would have to be of much longer duration and include larger numbers of dogs. Although it had been suspected that survival times might be above average in the CS group compared with historical controls, the magnitude

of the survival times and the incidence of noncardiac deaths had not been anticipated. Although DPs are known to have poor survival times after development of congestive signs,43,49 a significant improvement in survival was found for pimobendan-treated animals, with a median survival of 50 days in the placebo group compared with 329 days in the pimobendan group (P ⬍ .02, log-rank test). This finding contrasts with the prevailing attitude to use of positive inotropic agents in the treatment of chronic heart failure in human patients, where a number of trials have revealed adverse effects on survival despite short-term hemodynamic benefits.37,50–52 Even where short-term quality of life is markedly improved, any increase in mortality is considered unacceptable in the treatment of human heart failure.52,53 However, the appropriate use of positive inotropic agents in human patients is an area of controversy, especially because differences may occur in outcome according to dose and whether treatment is short-term, intermittent, or long-term.54–57 The cause of the increased mortality seen with long-term use of some positive inotropes in human patients is unknown, but may be related to increased cytosolic calcium concentrations, because increased calcium concentrations predispose to arrhythmia, and may increase the likelihood of sudden death. Additional problems associated with positive inotropes include increased myocardial energy expenditure, although this is less true of PDE inhibitors, where the arteriodilating effects may reduce myocardial workload sufficiently to offset increased energy consumption from increased contractility.58 Pimobendan was shown to increase survival in cardiomyopathic Syrian hamsters.59 In human patients, studies have shown reduced numbers of hospitalizations or adverse events with pimobendan compared with placebo,31,32,60 although no studies have been published of human heart failure patients where survival has been a primary endpoint. A number of studies that used 24-hour Holter monitoring failed to demonstrate any proarrhythmic tendencies.31,34,60 The Pimobendan in Congestive Heart Failure (PICO) trial of 317 patients followed over 6 months was not designed as a survival study, but showed a nonsignificant trend toward increased mortality in the low-dose group of pimobendan-treated patients.35 However, the number of sudden cardiac deaths in the high-dose pimobendan group of the PICO study was identical to that of the placebo group. In a recent study of patients with nonischemic DCM who were unable to tolerate beta-adrenergic antagonists, pimobendan had no adverse effect on survival over 2 years when added to standard therapy. In this human study, patients treated with pimobendan in addition to standard therapy had lower requirements for additional medications for worsening heart failure, compared with patients receiving standard therapy and placebo.60 Differences may occur in outcome between cardiomyopathic patients of ischemic and nonischemic origin, with a more favorable response to pimobendan in the latter.35,60 Nevertheless, in the absence of any specifically designed survival trials, whether the effect of pimobendan on mortality in human heart failure patients differs from that of other positive inotropic agents is unclear. The addition of pimobendan to conventional therapy in DPs in our study resulted in a survival advantage, although

Pimobendan in Canine DCM

the true magnitude of the effect is difficult to assess with the uneven number of dogs with atrial fibrillation in the 2 groups. The effect on survival in CSs was unclear, because their survival times in general were so long. The possibility of a contributory effect to the sudden death of the CS in the pimobendan group cannot be ruled out, although no trend was found toward increased sudden death in the DPs. The effect of positive inotropic agents on survival in dogs with naturally occurring heart failure has not been critically evaluated, and the validity of extrapolating from human survival trials remains unknown. Despite ominous longterm effects in human heart failure patients with ischemic disease, clinical trials of milrinone appeared very promising in the treatment of heart failure in dogs,61–64 although the studies were never extended to long-term, placebo-controlled trials. Factors possibly were operating that may have adversely influenced survival in the DP placebo group, contributing to the differences in survival. The DP placebo group included an increased number of dogs with atrial fibrillation (3 of 5 dogs, versus 1 of 5 dogs in the pimobendan group). Atrial fibrillation has been shown to be associated with poor survival times in DPs with DCM, with a median survival time of only 2.9 weeks in 1 study.43 In view of this, it would have been preferable to have a separate randomization schedule for dogs with atrial fibrillation, because the survival times would be expected to be shorter. The randomization unfortunately resulted in an uneven distribution of atrial fibrillation cases, which may have unduly affected the outcome. The trend toward a higher furosemide dose in the DP placebo group may reflect this. However, the sample size was too small to allow a subanalysis of the DPs without the atrial fibrillation cases. Nevertheless, the dog with atrial fibrillation in the pimobendan group survived for 265 days, despite having ascites and pleural effusion on initial presentation. The combination of atrial fibrillation and biventricular failure was associated with a particularly poor prognosis in the study by Calvert et al,43 with such dogs having a median survival time of only 2.0 weeks and a range of ⬍1–13 weeks, yet this DP survived for 37 weeks. With only 1 DP with atrial fibrillation in the pimobendan group, knowing if this was a chance effect or related to the pimobendan treatment is difficult. One of the pimobendantreated DPs subsequently developed atrial fibrillation after being withdrawn from the study (and thus withdrawn from pimobendan treatment, although continuing with standard treatment) and 1 of the placebo-treated CSs developed atrial fibrillation during the course of treatment. Although some of the benefit seen in the pimobendantreated DP most likely was associated with sustained improvement in hemodynamic function, other factors also may have played a role. By improving hemodynamic function, pimobendan may have resulted in an indirect reduction in neurohormonal activation. Several studies have shown a reduction in neurohormonal activation, with reductions in plasma norepinephrine levels,28,60 atrial and brain natriuretic hormones,60 and endothelin-1 levels.40 Also, effects are apparent on proinflammatory cytokines, with reductions reported in tumor necrosis factor ␣ and interleukin (IL)-1b65 and IL-6.40 Whenever euthanized animals are not censored in sur-

259

vival studies, the influence of timing of euthanasia must be considered. Two of the placebo-treated DPs were euthanized at the request of the owners after developing intractable congestive cardiac failure that did not respond to increasing the dosage of diuretics. Two of the pimobendantreated dogs also developed congestive heart failure during the study period, but this was after developing anemia and pancreatitis in 1 dog, and after withdrawal of pimobendan after development of diabetes mellitus in the other. The latter dog’s survival time was assessed up to the point of withdrawal from the study, although he survived a further 2 months on standard triple therapy without pimobendan before developing a recurrence of congestive signs. In both cases, development of congestive heart failure was more than 350 days after entering the study. No attempt was made to record 24-hour ambulatory ECGs, or to stratify the risk of fatal arrhythmia. Three sudden deaths occurred in each DP treatment group, and 1 sudden death occurred in the pimobendan-treated CS group, all of which were assumed to be cardiac.66,67 Although adverse effects on survival were not apparent in this study, ambulatory ECG recordings would be important in identifying the risk of proarrhythmia associated with pimobendan, and should be considered in a larger study. Diet was not standardized during the study, although supplementation with taurine and carnitine has been shown to be helpful in American Cocker Spaniels with DCM.68 Serum or whole blood taurine concentrations were not measured in any of the dogs in this study, although the authors have previously failed to identify low serum taurine concentrations in any CSs with DCM (unpublished observations). Blood pressure was not routinely recorded during this study, although hypotension is a potential risk with severe DCM, use of ACE inhibitors, and with the vasodilating effects of pimobendan. Hypotension, if present, did not appear to result in clinical signs. Although the sample size in this study was small, the results suggest that pimobendan may be a useful treatment for dogs with congestive heart failure associated with DCM. Pimobendan resulted in improvement in functional heart failure class, and was associated with reduced mortality in the DPs presenting with congestive heart failure in this study. These results suggest that undertaking a larger study with a longer duration of follow-up would be worthwhile, to evaluate the effect of pimobendan in a broader range of dogs with DCM.

Footnotes Enalapril Cardiovet, Intervet Ltd, Milton Keynes, Bucks, UK Lanoxin, Greenford, Middlesex, UK c SAS, SAS Institute Inc, Cary, NC, USA d SigmaStat 2.0, Jandel Scientific, San Rafael, CA, USA e Prism, Version 3.0, GraphPad Software, Inc, San Diego, CA, USA a

b

Acknowledgments Funding and pimobendan and placebo were provided by Boehringer Ingelheim Vetmedica GmbH, Ingelheim am

260

Luis Fuentes et al

Rhein, Germany. KDS was supported by a grant from the German Academic Exchange Service (DAAD), Bonn, Germany.

References 1. Fitton A, Brogden RN. Pimobendan. A review of its pharmacology and therapeutic potential in congestive heart failure. Drugs Aging 1994;4:417–441. 2. Mathew L, Katz SD. Calcium sensitising agents in heart failure. Drugs Aging 1998;12:191–204. 3. Holubarsch C. New inotropic concepts: Rationale for and differences between calcium sensitizers and phosphodiesterase inhibitors. Cardiology 1997;88(Suppl 2):12–20. 4. Solaro RJ, Fujino K, Sperelakis N. The positive inotropic effect of pimobendan involves stereospecific increases in the calcium sensitivity of cardiac myofilaments. J Cardiovasc Pharmacol 1989; 14(Suppl 2):S7–S12. 5. Fuchs F, Wang YP. Sarcomere length versus interfilament spacing as determinants of cardiac myofilament Ca2⫹ sensitivity and Ca2⫹ binding. J Mol Cell Cardiol 1996;28:1375–1383. 6. Hasenfuss G, Holubarsch C, Just H, et al. Energetic aspects of inotropic interventions in rat myocardium. Basic Res Cardiol 1987; 82(Suppl 2):251–259. 7. Holubarsch CH, Hasenfuss G, Just H, et al. Modulation of myothermal economy of isometric force generation by positive inotropic interventions in the guinea pig myocardium. Cardioscience 1990; 1:33–41. 8. Holubarsch C, Hasenfuss G, Just H, et al. Influence of the positive inotropic substance pimobendan (UD-CG 115 BS) on contractile economy of guinea pig papillary muscles. J Cardiovasc Pharmacol 1989;14(Suppl 2):S13–S17. 9. Goto Y, Hata K. Mechanoenergetic effect of pimobendan in failing dog hearts. Heart Vessels 1997;12(Suppl):103–105. 10. Fujino K, Sperelakis N, Solaro RJ. Sensitization of dog and guinea pig heart myofilaments to Ca2⫹ activation and the inotropic effect of pimobendan: Comparison with milrinone. Circ Res 1988;63: 911–922. 11. Hasenfuss G, Holubarsch C, Heiss HW, et al. Influence of the calcium-sensitizer UDCG-115 on hemodynamics and myocardial energetics in patients with idiopathic dilated cardiomyopathy. Comparison with nitroprusside. Basic Res Cardiol 1989;84(Suppl 1):225–233. 12. Remme WJ, Wiesfeld AC, Look MP, et al. Hemodynamic effects of intravenous pimobendan in patients with left ventricular dysfunction. J Cardiovasc Pharmacol 1989;14(Suppl 2):S41–S44. 13. Asanoi H, Ishizaka S, Kameyama T, et al. Disparate inotropic and lusitropic responses to pimobendan in conscious dogs with tachycardia-induced heart failure. J Cardiovasc Pharmacol 1994;23:268– 274. 14. Ohte N, Cheng CP, Suzuki M, et al. The cardiac effects of pimobendan (but not amrinone) are preserved at rest and during exercise in conscious dogs with pacing-induced heart failure. J Pharmacol Exp Ther 1997;282:23–31. 15. Ishiki R, Ishihara T, Izawa H, et al. Acute effects of a single low oral dose of pimobendan on left ventricular systolic and diastolic function in patients with congestive heart failure. J Cardiovasc Pharmacol 2000;35:897–905. 16. Ichihara K, Abiko Y. The effect of pimobendan on myocardial mechanical function and metabolism in dogs: Comparison with dobutamine. J Pharm Pharmacol 1991;43:583–588. 17. Hata K, Goto Y, Futaki S, et al. Mechanoenergetic effects of pimobendan in canine left ventricles. Comparison with dobutamine. Circulation 1992;86:1291–1301. 18. Meel JC, Diederen W. Hemodynamic profile of the cardiotonic agent pimobendan. J Cardiovasc Pharmacol 1989;14(Suppl 2):S1–S6. 19. Pouleur H, Hanet C, Schroder E, et al. Effects of pimobendan (UD-CG 115 BS) on left ventricular inotropic state in conscious dogs

and in patients with heart failure. J Cardiovasc Pharmacol 1989; 14(Suppl 2):S18–S22. 20. Bohm M, Flesch M, Schnabel P. Role of G-proteins in altered beta-adrenergic responsiveness in the failing and hypertrophied myocardium. Basic Res Cardiol 1996;91(Suppl 2):47–51. 21. Akhter SA, Eckhart AD, Rockman HA, et al. In vivo inhibition of elevated myocardial beta-adrenergic receptor kinase activity in hybrid transgenic mice restores normal beta-adrenergic signaling and function. Circulation 1999;100:648–653. 22. Sato N, Asai K, Okumura S, et al. Mechanisms of desensitization to a PDE inhibitor (milrinone) in conscious dogs with heart failure. Am J Physiol 1999;276:H1699-H1705. 23. Ravens U, Himmel HM, Fluss M, et al. Phosphodiesterase inhibition and Ca2⫹ sensitization. Mol Cell Biochem 1996;157:245–249. 24. Verdouw PD, Hartog JM, Duncker DJ, et al. Cardiovascular profile of pimobendan, a benzimidazole-pyridazinone derivative with vasodilating and inotropic properties. Eur J Pharmacol 1986;126:21– 30. 25. Fujimoto S, Matsuda T. Effects of pimobendan, a cardiotonic and vasodilating agent with phosphodiesterase inhibiting properties, on isolated arteries and veins of rats. J Pharmacol Exp Ther 1990;252: 1304–1311. 26. Erlemeier HH, Kupper W, Bleifeld W. Comparison of hormonal and haemodynamic changes after long-term oral therapy with pimobendan or enalapril—A double-blind randomized study. Eur Heart J 1991;12:889–899. 27. Katz SD, Kubo SH, Jessup M, et al. A multicenter, randomized, double-blind, placebo-controlled trial of pimobendan, a new cardiotonic and vasodilator agent, in patients with severe congestive heart failure. Am Heart J 1992;123:95–103. 28. Renard M, Walter M, Liebens I, et al. Pimobendane (UD-CG 115 BS) in chronic congestive heart failure. Short-term and one-month effects of a new inotropic vasodilating agent. Chest 1988;93:1159– 1164. 29. Hagemeijer F, Brand HJ, Mechelen R. Hemodynamic effects of pimobendan given orally in congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 1989;63: 571–576. 30. Hagemeijer F, Roth W, Brand HJ. Correlations between the cardiovascular effects of pimobendan and plasma concentrations of the parent compound and of its major active metabolite, UD-CG 212 CL, in patients with congestive heart failure. J Cardiovasc Pharmacol 1989; 14(Suppl 2):S57–S64. 31. Walter M, Liebens I, Goethals H, et al. Pimobendane (UD-CG 115 BS) in the treatment of severe congestive heart failure. An acute haemodynamic cross-over and double-blind study with two different doses. Br J Clin Pharmacol 1988;25:323–329. 32. Kubo SH, Gollub S, Bourge R, et al. Beneficial effects of pimobendan on exercise tolerance and quality of life in patients with heart failure. Results of a multicenter trial. The Pimobendan Multicenter Research Group. Circulation 1992;85:942–949. 33. Sasayama S, Asanoi H, Kihara Y, et al. Clinical effects of longterm administration of pimobendan in patients with moderate congestive heart failure. Heart Vessels 1994;9:113–120. 34. Remme WJ, Krayenbuhl HP, Baumann G, et al. Long-term efficacy and safety of pimobendan in moderate heart failure. A doubleblind parallel 6-month comparison with enalapril. The PimobendanEnalapril Study Group. Eur Heart J 1994;15:947–956. 35. Lubsen J, Just H, Hjalmarsson AC, et al. Effect of pimobendan on exercise capacity in patients with heart failure: Main results from the Pimobendan in Congestive Heart Failure (PICO) trial. Heart 1996; 76:223–231. 36. Massie B, Bourassa M, DiBianco R, et al. Long-term oral administration of amrinone for congestive heart failure: Lack of efficacy in a multicenter controlled trial. Circulation 1985;71:963–971. 37. Uretsky BF, Jessup M, Konstam MA, et al. Multicenter trial of oral enoximone in patients with moderate to moderately severe con-

Pimobendan in Canine DCM gestive heart failure. Lack of benefit compared with placebo. Enoximone Multicenter Trial Group. Circulation 1990; 82:774–780. 38. Kato K. Clinical efficacy and safety of pimobendan in treatment of heart failure—Experience in Japan. Cardiology 1997;88(Suppl 2): 28–36. 39. Hauf GF, Grom E, Jahnchen E, et al. Acute and long-term hemodynamic effects of pimobendan (UD-CG 115 BS) in comparison with captopril. J Cardiovasc Pharmacol 1989;14(Suppl 2):S49–S56. 40. Yoshikawa T, Baba A, Suzuki M, et al. Effectiveness of carvedilol alone versus carvedilol ⫹ pimobendan for severe congestive heart failure. For the Keio Interhospital Cardiology Study (KICS) Group. Am J Cardiol 2000;85:1495–1497. 41. Sisson D, Thomas WP. Myocardial diseases. In: Ettinger SJ, Feldman EC, eds. Textbook of Veterinary Internal Medicine. Diseases of the Dog and Cat. Philadelphia, PA: WB Saunders; 1995:995–1033 42. Calvert CA, Chapman WC, Toal RC. Congestive cardiomyopathy in Doberman Pinscher dogs. J Am Vet Med Assoc 1982;181: 598–602. 43. Calvert CA, Pickus CW, Jacobs GJ, et al. Signalment, survival, and prognostic factors in Doberman Pinschers with end-stage cardiomyopathy. J Vet Intern Med 1997;11:323–326. 44. Thomas RE. Congestive cardiac failure in young Cocker Spaniels (a form of cardiomyopathy?): Details of eight cases. J Small Anim Pract 1987;28:265–279. 45. Staaden RV. Cardiomyopathy of English Cocker Spaniels. J Am Vet Med Assoc 1981;178:1289–1292. 46. Kittleson MD, Eyster GE, Knowlen GG, et al. Myocardial function in small dogs with chronic mitral regurgitation and severe congestive heart failure. J Am Vet Med Assoc 1984;184:455–459. 47. Borow KM, Green LH, Mann T, et al. End-systolic volume as a predictor of postoperative left ventricular performance in volume overload from valvular regurgitation. Am J Med 1980;68:655–663. 48. Tidholm A, Svensson H, Sylven C. Survival and prognostic factors in 189 dogs with dilated cardiomyopathy. J Am Anim Hosp Assoc 1997;33:364–368. 49. Calvert CA. Effect of medical therapy on survival of patients with dilated cardiomyopathy. Vet Clin North Am Small Anim Pract 1991;21:919–930. 50. Packer M, Carver JR, Rodeheffer RJ, et al. Effect of oral milrinone on mortality in severe chronic heart failure. For the PROMISE Study Research Group. N Engl J Med 1991;325:1468–1475. 51. Cowley AJ, Skene AM. Treatment of severe heart failure: Quantity or quality of life? A trial of enoximone. Br Heart J 1994;72: 226–230. 52. Cohn JN, Goldstein SO, Greenberg BH, et al. A dose-dependent increase in mortality with vesnarinone among patients with severe heart failure. Vesnarinone Trial Investigators. N Engl J Med 1998;339: 1810–1816. 53. Ewy GA. Inotropic infusions for chronic congestive heart fail-

261

ure: Medical miracles or misguided medicinals? J Am Coll Cardiol 1999;33:572–575. 54. Packer M. The development of positive inotropic agents for chronic heart failure: How have we gone astray? J Am Coll Cardiol 1993;22:119A–126A. 55. Asanoi H, Inoue H. Positive inotropic agents: A double-edged sword for chronic heart failure. Intern Med 1996;35:63–64. 56. Sasayama S. Inotropic agents in the treatment of heart failure: Despair or hope? Cardiovasc Drugs Ther 1997;10:703–709. 57. Silver MA. Intermittent inotropes for advanced heart failure: Inquiring minds want to know. Am Heart J 1999;138:191–192. 58. Takaoka H, Takeuchi M, Odake M, et al. Comparison of the effects on arterial-ventricular coupling between phosphodiesterase inhibitor and dobutamine in the diseased human heart. J Am Coll Cardiol 1993;22:598–606. 59. van Meel JC, Mauz AB, Wienen W, et al. Pimobendan increases survival of cardiomyopathic hamsters. J Cardiovasc Pharmacol 1989; 13:508–509. 60. Sasaki T, Kubo T, Komamura K, Nishikimi T. Effects of longterm treatment with pimobendan on neurohumoral factors in patients with non-ischemic chronic moderate heart failure. J Cardiol 1999;33: 317–325. 61. Keister DM, Kittleson MD, Bonagura JD, et al. Milrinone: A clinical trial in 29 dogs with moderate to severe congestive heart failure. J Vet Intern Med 1990;4:79–86. 62. Kittleson MD, Johnson LE, Pion PD. The acute hemodynamic effects of milrinone in dogs with severe idiopathic myocardial failure. J Vet Intern Med 1987;1:121–127. 63. Kittleson MD. The efficacy and safety of milrinone for treating heart failure in dogs. Vet Clin North Am Small Anim Pract 1991;21: 905–918. 64. Kittleson MD, Pipers FS, Knauer KW, et al. Echocardiographic and clinical effects of milrinone in dogs with myocardial failure. Am J Vet Res 1985;46:1659–1664. 65. Iwasaki A, Matsumori A, Yamada T, et al. Pimobendan inhibits the production of proinflammatory cytokines and gene expression of inducible nitric oxide synthase in a murine model of viral myocarditis. J Am Coll Cardiol 1999;33:1400–1407. 66. Calvert CA, Jacobs G, Pickus CW. Bradycardia-associated episodic weakness, syncope, and aborted sudden death in cardiomyopathic Doberman Pinschers. J Vet Intern Med 1996;10:88–93. 67. Calvert CA, Hall G, Jacobs G, Pickus C. Clinical and pathologic findings in Doberman Pinschers with occult cardiomyopathy that died suddenly or developed congestive heart failure: 54 cases (1984–1991). J Am Vet Med Assoc 1997;210:505–511. 68. Kittleson MD, Keene B, Pion PD, et al. Results of the multicenter spaniel trial (MUST): Taurine- and carnitine-responsive dilated cardiomyopathy in American Cocker Spaniels with decreased plasma taurine concentration. J Vet Intern Med 1997;11:204–211.