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Keywords:

  • Canine;
  • Mitral regurgitation;
  • Mortality;
  • Therapy

Abstract

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgments
  8. References

Background

Myxomatous mitral valve disease (MMVD) is an important cause of morbidity and mortality in dogs.

Objectives

To compare, throughout the period of follow-up of dogs that had not yet reached the primary endpoint, the longitudinal effects of pimobendan versus benazepril hydrochloride treatment on quality-of-life (QoL) variables, concomitant congestive heart failure (CHF) treatment, and other outcome variables in dogs suffering from CHF secondary to MMVD.

Animals

A total of 260 dogs in CHF because of MMVD.

Methods

A prospective single-blinded study with dogs randomized to receive pimobendan (0.4–0.6 mg/kg/day) or benazepril hydrochloride (0.25–1.0 mg/kg/day). Differences in outcome variables and time to intensification of CHF treatment were compared.

Results

A total of 124 dogs were randomized to pimobendan and 128 to benazepril. No difference was found between groups in QoL variables during the trial. Time from inclusion to 1st intensification of CHF treatment was longer in the pimobendan group (pimobendan 98 days, IQR 30–276 days versus benazepril 59 days, IQR 11–121 days; P = .0005). Postinclusion, dogs in the pimobendan group had smaller heart size based on VHS score (P = .013) and left ventricular diastolic (P = .035) and systolic (P = .0044) dimensions, higher body temperature (P = .030), serum sodium (P = .0027), and total protein (P = .0003) concentrations, and packed cell volume (P = .030). Incidence of arrhythmias was similar in treatment groups.

Conclusions and Clinical Importance

Pimobendan versus benazepril resulted in similar QoL during the study, but conferred increased time before intensification of CHF treatment. Pimobendan treatment resulted in smaller heart size, higher body temperature, and less retention of free water.

Abbreviations
ACE-I

angiotensin-converting enzyme inhibitor

ACVIM

American College of Veterinary Internal Medicine

AF

atrial fibrillation

AUC

area under curve

BPM

beats per minute

BW

body weight

CHF

congestive heart failure

FS

fractional shortening

HF

heart failure

IQR

interquartile range

K

potassium

LA/Ao

left atrial to aortic root ratio

LVIDd inc

percentage increase in LVIDd from expected values

LVIDd

left ventricular internal diameter in diastole

LVIDs inc

percentage increase in LVIDs from expected values

LVIDs

left ventricular internal diameter in systole

MMVD

myxomatous mitral valve disease

Na

sodium

NYHA

New York Heart Association

PCV

packed cell volume

PE

pulmonary edema

QoL

quality of life

SVPC

supraventricular premature complex

TPC

total protein concentration

VHS

vertebral heart scale

VPC

ventricular premature complex

Myxomatous mitral valve disease (MMVD) is common and continues to be an important cause of morbidity and mortality in older small breed dogs.[1-3] We and others have demonstrated that treatment can prolong the survival of dogs with congestive heart failure (CHF) secondary to this condition.[4, 5] The ideal treatment should both lengthen life and allow the dog to enjoy a good quality of life (QoL). Quality of life and survival will be closely linked in veterinary patients where owners are more likely to opt for the euthanasia of their pet when they consider the pet's QoL to be intolerable. When asked, the majority of owners indicate that they would prioritize QoL of their pet over its survival time.[6] Clinicians will modify medication to optimize the QoL of the patients they are treating.

There are problems in attempting to compare QoL between groups. Quality of life and clinical heart failure scores are inherently subjective. The ability of survival studies to demonstrate differences between groups of patients is further impaired by different rates of dropout in treatment groups.[7-10] If a dog has reached the primary endpoint of a study, or has been withdrawn for other reasons, and continuation in the study is no longer possible, it can no longer contribute data to longitudinal analyses. This results in missing data, and studies have differed in how they deal with this problem. Many studies use the approach of either “last observation carried forward” or “worst observation carried forward,” but this approach tends to make the treatment with the higher dropout rate appear worse.

Heart disease and heart failure are known to lead to changes in clinical, laboratory, radiographic, and echocardiographic variables. Monitoring these variables in dogs undergoing treatment for heart failure is a common practice and recommended in the ACVIM consensus statement.[11] The comparative effects of angiotensin-converting enzyme inhibitors (ACEI) and pimobendan on some of these variables have not been described, and for others they have only been described for periods of 6 months or less.[9, 10]

We previously have reported results from the QUEST study showing that pimobendan treatment was associated with improved survival when compared with benazepril treatment.[5] However, we have not reported the results with respect to the secondary outcome variables of QoL or described comparisons between groups for the clinical data acquired longitudinally. The aims of this study were to compare the longitudinal effects of pimobendan treatment on QoL indices, concomitant treatment, and clinical, laboratory, echocardiographic, and radiographic variables with those of a positive control (benazepril hydrochloride) in dogs diagnosed with CHF secondary to MMVD.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgments
  8. References

We previously have described in detail the materials and methods of this study.[5] Pertinent details are repeated here.

Dogs

Client-owned dogs were recruited at 28 centers in Europe, Canada, and Australia. The study terminated on 31 October 2006.

Enrollment Criteria

Inclusion Criteria

Dogs were eligible for inclusion in the study provided the owner had given informed consent. To be eligible for inclusion at the time of the 1st examination, the dog must have been >5 years of age, weighed between 5 and 20 kg, had a characteristic heart murmur of moderate to high intensity with maximal intensity over the mitral area, had echocardiographic evidence of advanced MMVD defined as characteristic valvular lesions of the mitral valve apparatus (leaflet thickening, valve prolapse), demonstrated mitral regurgitation on color Doppler echocardiography, had echocardiographic evidence of moderate to severe left atrial, left ventricular enlargement, or both (ie, left atrial to aortic root [LA/Ao] ratio >1.5[12] and left ventricular internal diameter in diastole [LVIDd] values above normal reference range[13]), and demonstrated current or prior radiographic evidence of pulmonary edema and cardiomegaly (ie, vertebral heart scale [VHS] >10.5).[14] Clinical signs of decompensated CHF must have been present at the time of the 1st examination or have previously been resolved with treatment (that must have included furosemide) that was still being administered and in the opinion of the attending clinician necessary to prevent the return of clinical signs.

Exclusion Criteria

Dogs were excluded from the study if they had a clinically relevant cardiac disease (congenital or acquired) other than mitral regurgitation secondary to MMVD, had another relevant systemic disease, or had evidence of other clinically relevant organ dysfunction.

Study Design

Randomization and Allocation

This was a prospective multicenter, single-blinded, positive-controlled study.

Investigators, study monitors, and the sponsor remained blinded for the duration of the study. Unblinding occurred only after completion of the study and data entry.

Blinding

In each center, the blinding of the investigator was ensured by the use of a dispenser. At inclusion and before each visit, the owner was instructed to discuss test treatments with the dispenser only. Drugs were dispensed by the dispenser in opaque boxes to prevent inadvertent disclosure of the treatment group to the investigator.

Test Treatments

The pimobendan group received pimobendan1 PO at a dosage of 0.4–0.6 mg/kg/day. The calculated daily dose was divided into 2 and adjusted to a suitable number of 1.25 or 2.5 mg capsules. Owners were instructed to administer the drug in the morning and evening, approximately 12 hours apart, and approximately 1 hour before feeding.

The benazepril group received benazepril hydrochloride2 PO at a dosage of 0.25–0.5 mg/kg once a day. In keeping with the manufacturer's recommendations, at the discretion of the investigator, the benazepril dose could be doubled. This involved the investigator instructing the dispenser, “If the dog is receiving benazepril, please double the dose,” thus ensuring the investigator remained blinded as to treatment allocation of the case. The time of such a request was recorded and regarded as an intended intensification of treatment. The dosage was adjusted to a suitable number of 5 mg tablets.

Concomitant Treatments

Standard concomitant treatment for heart failure (such as diuretics and digoxin) was permitted throughout the trial with the following restrictions: open label use of pimobendan, benazepril, or any other ACE-I was precluded as was the use of phenylalkylamine calcium channel antagonists, xanthines, or angiotensin II receptor antagonists. In cases where dogs were already receiving an ACE-I or pimobendan treatment at inclusion, these drugs were discontinued immediately before allocation to either of the 2 test treatments. Dosages of concomitant treatments could be modified, if needed, throughout the study. The time and nature of any change in concomitant treatment were recorded.

Schedule of Events

Before inclusion, the case history of each dog was ascertained and any previous documentation of the case was reviewed (eg, radiographs, laboratory results). The dogs then underwent physical examination, electrocardiography (ECG), echocardiography, thoracic radiography, and routine hematology and blood biochemistry with a minimal database consisting of packed cell volume (PCV) and plasma total protein concentration (TPC), and serum creatinine, potassium, and sodium concentrations.

Scheduled reexaminations were at day 7, day 28, and 3 months after inclusion. Thereafter, the dogs were scheduled for reexamination every 3 months. On every visit, the following occurred: a case history was obtained including recording the type and dose of each medication the dog was receiving, a complete physical examination was performed, an ECG was recorded, and blood was taken to measure PCV, TPC, and serum creatinine, sodium, and potassium concentrations. Echocardiography and thoracic radiographic examinations were scheduled every 6 months after inclusion.

Clinical Evaluation

At inclusion, canine characteristics were recorded. The time since onset of clinical signs and the duration, type, and efficacy of any pretreatment were recorded. At each examination, body weight and rectal temperature were measured.

Quality of Life and Respiratory Variables

After history taking and clinical examination, the following variables were scored according to the system outlined in Table 1: appetite, demeanor, exercise tolerance, respiratory effort, coughing, and nocturnal dyspnea.

Table 1. Scoring protocol for clinical variables
VariableScoreClinical Correlate
  1. NYHA, New York Heart Association.

Exercise tolerance1 (Very good)Dog moved around with ease, was able to fully exercise
2 (Good)Dog moved around with ease, was not able to fully exercise; ability to run was reduced
3 (Moderate)Dog was less active than normal, moved around a few times per day, avoided long walks
4 (Poor)Dog was inactive and would only get up to eat, drink, or urinate
Demeanor1Alert, responsive
2Mildly depressed
3Moderately depressed
4Minimally responsive
5Unresponsive
Appetite1Increased
2Normal
3Decreased (2/3 normal)
4Markedly decreased (<2/3 normal)
Respiratory effort1Normal
2Mildly increased rate or effort
3Moderately labored
4Severe respiratory distress
Coughing1None
2Occasional (a few times a week)
3Frequent (a few times a day)
4Persistent (frequently during the day)
Nocturnal dyspnea1None
2Dog coughed from time to time during the night, but no other clinical signs of dyspnea or restlessness were present
3Dog coughed consistently; increased respiratory effort or restlessness during the night
Pulmonary edema1None
2Mild interstitial opacity
3Moderate interstitial opacity
4Alveolar pattern, severe consolidation
Modified NYHA heart failure score[16]IAsymptomatic dogs with murmur, but no cardiac enlargement
IIAsymptomatic dogs with murmur and cardiac enlargement, but no pulmonary edema or congestion
IIISlightly or moderately symptomatic dogs (dyspnea), increased heart rate and disappearance of sinus arrhythmia) with murmurs, cardiac enlargement, and interstitial pulmonary edema
IVSeverely symptomatic dogs with murmurs, cardiac enlargement, and alveolar pulmonary edema
Heart Rate and ECG

The resting heart rate was measured during the physical examination. A 3-minute ECG recording was performed with the dogs lying in right lateral recumbency. Each dog's cardiac rhythm was classified as showing sinus rhythm, extrasystoles (ventricular or supraventricular or both), or atrial fibrillation (AF).

Echocardiography

Echocardiography was used to confirm the diagnosis of MMVD before inclusion and, thereafter to monitor disease progression. The following measurements were recorded: the LA/Ao ratio obtained from the right parasternal short axis 2-dimensional (2D) view as previously described.[12] The LVIDd and left ventricular internal diameter in systole (LVIDs) were measured from the M-mode echocardiogram, which was obtained from the right parasternal short-axis 2D view.[15] M-mode values were used to derive the percent increase in LVIDd (LVIDd inc) and LVIDs (LVIDs inc) as follows: % increase = [100 × (observed dimension − expected normal dimension)/expected normal dimension] and the fractional shortening (FS). Expected normal dimensions based on body weight (BW) were calculated as previously described.[13]

Thoracic Radiography

Thoracic radiography was used to confirm the presence of cardiomegaly and pulmonary edema, to exclude concurrent disease at inclusion into the study, and to measure cardiac dimensions. Right lateral and dorsoventral projections were used to evaluate the thorax. Cardiomegaly was assessed with the VHS method[14] and pulmonary edema if present was scored (Table 1).

Heart Failure Score

The modified New York Heart Association (NYHA) score was used to score the severity of heart failure (Table 1).[16]

Endpoints

Dogs were considered to have reached the primary endpoint of the QUEST trial only when one of the following occurred: sudden cardiac death, euthanasia as a consequence of the cardiac disease, or treatment failure leading to the clinician withdrawing the dog from the trial.[5] Dogs were censored if they died or were euthanized because of noncardiac causes, were lost to follow-up, or were alive and had not reached the primary endpoint at the termination of the study.

Time from randomization to the 1st increase in dose of any treatment or the introduction of any permitted additional concomitant treatment (as outlined above) after enrollment in the study was considered as a secondary endpoint and referred to as intensification of CHF treatment. For this secondary endpoint, dogs in which no intensification of their treatment had occurred during the study were censored, which included dogs that had reached the primary endpoint without undergoing any intensification of their treatment.

Outcome Measure

The primary outcome measure of the QUEST trial was the time from randomization to withdrawal because of death or euthanasia owing to cardiac causes or treatment failure.

Secondary outcome measures included values of QoL, clinical, radiographic, echocardiographic, and laboratory variables measured over the duration of the study and time from randomization to any increase in dose of any treatment, or the introduction of any permitted additional concomitant treatment (as outlined above) after enrollment in the study.

Statistical Methods

For every dog for which any of the QoL, clinical, radiographic, echocardiographic, and laboratory variables was measured on ≥1 occasions after baseline assessment, a curve was constructed by plotting each data point on a graph with the unit of measurement on the vertical axis and time on the horizontal axis. The area under the curve averaged for the number of days between the 1st and last observation was calculated thus giving an average value for the variable that incorporated all of the observations made and was independent of the duration of time the dog remained in the study.[17] These derived variables were used as summary measures of the values of the variable over the time in study for each dog. These values then were compared between treatment groups using the Wilcoxon rank sum test.[17]

The proportions of dogs in each treatment group experiencing modifications in the dose, or addition of the drugs furosemide, spironolactone, or digoxin, or in which the investigator expressed an intention to increase the benazepril dosage, at the time of the 1st intensification of treatment, were compared using the Fisher's exact test. Furthermore, the proportion of dogs in each treatment group receiving spironolactone and the proportion of dogs in each treatment group receiving digoxin at each scheduled visit were compared using the Fisher's exact test.

A log-rank test with right censoring was used to determine whether a significant difference existed between the 2 treatment groups for the variable “time from randomization to the first increase in dosage of any treatment, or the introduction of any permitted additional concomitant treatment after enrollment in the study.” The Kaplan–Meier method was used to estimate the median time to this secondary endpoint for each treatment group and plot time to event curves. In addition, univariate and multivariate Cox proportional hazards analyses with right censoring were performed to determine whether there was a significant difference between treatment groups. The hazard ratio with 95% confidence intervals was calculated.

For all analyses, a P value <.05 was considered significant. All analyses were 2-tailed. Median values and interquartile (IQR) ranges are reported. All statistical analyses were performed by an independent statistician3 using a commercially available software program.4

Results

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgments
  8. References

The study population (Table 2), event rate, and effect of baseline variables and treatment on the time to composite primary endpoint have been described previously.[5] Pertinent details are repeated below.

Table 2. Summary of baseline characteristics in the 2 treatment groups (frequencies or medians [IQR])
VariablePimobendan (N = 124)Benazepril (N = 128)P Value
  1. IQR, interquartile range; M, male; F, female; MC, male castrated; FN, neutered female; bpm, beats per minute; HF, heart failure; VHS, vertebral heart scale; PE, pulmonary edema; LVIDs, left ventricular internal diameter in systole; LVIDs inc, percentage increase in left ventricular internal diameter in systole from expected values; LVIDd, left ventricular internal diameter in diastole; LVIDd inc, percentage increase in left ventricular internal diameter in diastole from expected values; FS, fractional shortening; LA/Ao, left atrial to aortic root ratio; K, potassium; Na, sodium; PCV, packed cell volume; TPC, total protein concentration.

Canine characteristics
Age (years)10.0 (8.0–11.0)10.0 (8.0–12.0).06
Sex (M/F/MC/FN)59/14/24/2757/24/13/34.08
Cavalier (yes/no) (%)34/90 (27/73%)48/80 (38/62%).09
Treatment
Furosemide dose (mg/kg/day)4.7 (3.4–6.7)4.4 (3.0–6.4).18
Digoxin (yes/no)16/10827/101.10
Spironolactone (yes/no)21/10324/104.74
Quality of life and respiratory variables
Appetite2.0 (2.0–3.0)2.0 (2.0–3.0).95
Demeanor1.0 (1.0–2.0)1.0 (1.0–2.0).61
Exercise tolerance2.0 (2.0–3.0)2.0 (2.0–3.0).62
Respiratory effort2.0 (1.2–3.0)2.0 (1.0–3.0).84
Cough3.0 (2.0–3.0)3.0 (2.0–3.0).32
Nocturnal coughing2.0 (1.0–3.0)2.0 (1.0–3.0).74
Physical examination
Rectal temperature (°C)38.5 (38.2–38.9)38.5 (38.2–38.9).42
Heart rate (bpm)144 (126–162)148 (128–165).54
Body weight (kg)9.0 (6.9–11.4)9.5 (7.6–11.7).18
HF score3.0 (3.0–3.0)3.0 (3.0–3.0).97
Diagnostic imaging
VHS score12.5 (11.5–13.0)12.5 (12.0–13.5).15
PE score2.5 (1.0–5.0)3.0 (1.0–5.0).65
LVIDs inc (%)19.7 (4.0–37.0)24.5 (10.7–43.4).08
LVIDd inc (%)42.9 (30.0–57.6)45.5 (33.8–58.6).40
FS (%)45 (41–50)44 (39–48).09
LA/Ao2.4 (2.0–2.7)2.3 (2.0–2.7).61
Laboratory variables
Na (mmol/L)148 (145–151)148 (146–150).65
K (mmol/L)4.4 (3.9–4.9)4.3 (3.9–4.8).53
PCV (%)45.2 (42–51)46.0 (41–50).39
Creatinine (mg/dL)1.0 (0.8–1.1)1.0 (0.8–1.2).38
TPC (g/dL)6.5 (6.0–7.0)6.4 (6.0–7.0).72

Two hundred and sixty dogs were recruited; 8 dogs were excluded from further analysis after termination of the trial, but before unblinding. Of the 252 dogs analyzed (116 males, 38 females, 37 neutered males, and 61 neutered females), the most commonly recruited breed was the CKCS (n = 82). One hundred and twenty-four dogs were randomized to the pimobendan group and 128 dogs to the benazepril group. One hundred and ninety dogs (75%) reached the primary endpoint; 62 dogs (25%) were censored. No dogs were lost to follow-up.

Effect of Treatment over Time (AUC adjusted for days in study) and Incidence of Arrhythmias

The results of the comparisons of QoL, clinical, laboratory, radiographic, and echocardiographic variables between groups over time are illustrated in Table 3. The following variables were significantly higher in the dogs receiving pimobendan: rectal temperature, serum sodium concentration, PCV, and TPC. The following variables were significantly lower in the dogs receiving pimobendan: VHS, LVIDs inc, and LVIDd inc (also LVIDd and LVIDs). There was no difference in incidence of new arrhythmias between the treatment groups (Table 4).

Table 3. Median AUC adjusted for days in study and IQR for dogs treated with pimobendan and dogs treated with benazepril
 VariableTreatmentNMedianIQRP Value Wilcoxon
  1. AUC, area under curve; IQR, interquartile range; bpm, beats per minute; HF, heart failure; VHS, vertebral heart scale; PE, pulmonary edema; LVIDs, left ventricular internal diameter in systole; LVIDs inc, percentage increase in LVIDs from expected values; LVIDd, left ventricular internal diameter in diastole; LVIDd inc, percentage increase in LVIDd from expected values; FS, fractional shortening; LA/Ao, left atrial to aortic root ratio; K, potassium; Na, sodium; PCV, packed cell volume; TPC, total protein concentration.

Quality of life and respiratory variables (see Table 1 for levels)AppetitePimobendan1182.01.9–2.1.12
Benazepril1242.02.0–2.30
CoughPimobendan1182.31.6–2.9.71
Benazepril1242.31.9–2.8
DemeanorPimobendan1181.21.0–1.5.86
Benazepril1241.21.0–1.5
Exercise tolerancePimobendan1182.01.6–2.4.73
Benazepril1242.01.6–2.4
Nocturnal dyspneaPimobendan1181.41.0–2.0.54
Benazepril1241.41.0–2.0
Respiratory effortPimobendan1181.51.1–2.0.47
Benazepril1241.71.2–2.0
Furosemide doseFurosemide dose (mg/kg/day)Pimobendan1174.83.4–6.6.69
Benazepril1215.13.7–6.8
Physical examinationRectal temperature (°C)Pimobendan11838.638.3–38.8.029
Benazepril12438.538.2–38.7
Heart rate (bpm)Pimobendan118137.6128.1–151.8.32
Benazepril124140.9128.6–156.8
Body weight (kg)Pimobendan1189.07.1–11.3.29
Benazepril1249.47.6–11.6
HF scorePimobendan1182.52.0–3.0.44
Benazepril1242.52.1–3.0
Diagnostic imagingVHS scorePimobendan 6912.411.5–13.0.013
Benazepril 4912.911.9–13.8
Severity of PE (scores 1–5)Pimobendan 692.01.5–2.5.81
Benazepril 492.01.5–2.5
LVIDs inc (%)Pimobendan 6715.2−0.6–24.7.0044
Benazepril 4924.314.6–39.0
LVIDd inc (%)Pimobendan 6736.328.4–50.9.035
Benazepril 4946.533.0–61.1
FS (%)Pimobendan 6946.542.5–48.8.11
Benazepril 4944.540.3–48.4
LA/AOPimobendan 692.21.9–2.6.83
Benazepril 492.32.0–2.6
Laboratory variablesNa (%)Pimobendan117148.7146.2–150.7.0027
Benazepril120147.0144.7–149.5
K (mmol/L)Pimobendan1174.33.9–4.7.92
Benazepril1204.33.9–4.8
PCV (%)Pimobendan11746.842.8–50.9.030
Benazepril12045.540.5–49.3
Creatinine (mg/dL)Pimobendan1171.10.9–1.287.58
Benazepril1201.10.907–1.4
TPC (g/dL)Pimobendan1176.76.4–7.2.0003
Benazepril1196.56.0–6.9
Table 4. Number and proportions of new arrhythmias by treatment groups over time in 252 dogs treated with pimobendan or benazepril
Time (months)Total Dogs Remaining in StudyTotal Dogs with New Onset Arrhythmia, n (%)P Value for ComparisonDogs with New Onset SVPC, n (%)Dogs with New Onset VPC, n (%)Dogs with New Onset AF, n (%)
PimobendanBenazeprilPimobendanBenazeprilPimobendanBenazeprilPimobendanBenazeprilPimobendanBenazepril
  1. AF, atrial fibrillation; SVPC, supraventricular premature complex; VPC, ventricular premature complex.

  2. The P value represents a comparison of the proportions of dogs in each treatment group with a new onset of an arrhythmia at each time point.

11081117 (6.5)14 (12.6).264 (3.7)8 (7.2)3 (2.8)5 (4.5)0 (0)1 (0.9)
3 94 7512 (12.8)6 (8.0).457 (7.4)3 (4.0)3 (3.2)2 (2.7)2 (2.1)1 (1.3)
6 70 509 (12.9)13 (26.0).097 (10.0)7 (14.0)2 (2.9)2 (4.0)0 (0)4 (8.0)
9 52 346 (11.5)3 (8.8)1.004 (7.7)2 (5.9)2 (3.8)0 (0)0 (0)1 (2.9)
12 37 256 (16.2)5 (20.0).743 (8.1)4 (16.0)3 (8.1)1 (4.0)0 (0)0 (0)
15 25 194 (16.0)2 (10.5).683 (12.0)1 (5.3)0 (0)1 (5.3)1 (4.0)0 (0)
18 16 170 (0)0 (0)1.000 (0)0 (0)0 (0)0 (0)0 (0)0 (0)

Effect of Treatment Group on Concurrent Treatment

The proportions of dogs and the nature of the change in treatment required at the time of modification that were first deemed as necessary were no different in the 2 treatment groups (Table 5). Only 6 dogs (4 dogs in the benazepril group and 2 in the pimobendan group) had an intended intensification of heart failure treatment consisting only of a desire to increase the benazepril dosage. Intensifications in all other dogs for which the investigator expressed a desire to increase the benazepril dosage consisted of a change in at least 1 additional drug. A significantly greater proportion of dogs received spironolactone treatment in the benazepril group at 28 days, 3 months, and 6 months and a significantly greater proportion of dogs received digoxin treatment in the benazepril group at 3 months (Table 6).

Table 5. Number and proportion of all dogs in the 2 treatment groups that underwent intensification of heart failure treatment and the number and proportion of those dogs that underwent a change, that experienced the 4 most common changes. Notice that dogs could experience an intensification of heart failure treatment consisting of more than one change
 Pimobendan (%)Benazepril (%)P Value
  1. a

    A desire to increase the ACE-inhibitor dose, without any other changes to the medication, occurred in 4 dogs in the benazepril group and 2 dogs in the pimobendan group.

Change in treatment83/124 (67)89/128 (70).69
Nature of 1st treatment change
Increased furosemide dose71/83 (86)77/89 (87)1.0
Added spironolactone43/83 (52)55/89 (62).21
Indicated desire to increase ACE-inhibitor dosea20/83 (24)31/89 (35).14
Added digoxin16/83 (19)23/89 (26).36
Table 6. Total number of dogs in each treatment group remaining in the study, and number and proportion of dogs in each treatment group receiving spironolactone, digoxin, or both over time in 252 dogs
Time of ExaminationDogs Remaining in StudyDogs Receiving SpironolactoneDogs Receiving Digoxin
PimobendanBenazeprilPimobendan, n (%)Benazepril, n (%)P Value for ComparisonPimobendan, n (%)Benazepril, n (%)P Value for Comparison
  1. The P values represent a comparison of the proportions of dogs in each treatment group receiving spironolactone, digoxin, or both at each time point.

Day 112412821 (16.9)26 (20.3).5219 (15.3)28 (21.9).20
Day 711912420 (16.8)33 (26.6).08717 (14.3)32 (25.8).037
Day 2810811521 (19.4)39 (33.9).01617 (15.7)33 (28.7).025
3 months 95 8126 (27.4)37 (45.7).01815 (15.8)25 (30.9).020
6 months 72 4821 (29.2)28 (58.3).002313 (18.1)17 (35.4).052
9 months 52 3419 (36.5)16 (47.1).3711 (21.2)8 (23.5).80
12 months 39 2516 (41.0)12 (48.0).6112 (30.8)8 (32.0)1.0
15 months 27 1912 (44.4)10 (52.6).778 (29.6)4 (21.1).72
18 months 19 179 (47.4)10 (58.8).536 (31.6)4 (23.5).72

Of the 252 dogs included in the study, there was an intensification of heart failure treatment in 172 dogs (83 dogs in the pimobendan group and 89 in the benazepril group), whereas 80 dogs (41 dogs in the pimobendan group and 39 in the benazepril group) were censored in the statistical analyses. The proportions of censored dogs in the 2 treatment groups were not significantly different (P = .69), whereas the time in the study to censoring was significantly longer in the pimobendan group compared with the benazepril group (median, 123 days; IQR, 19.5–372 days versus median, 39 days; IQR, 26–92 days; P = .038). Dogs receiving pimobendan had a significantly longer time period (median, 98 days; IQR, 30–276 days) before experiencing any intensification in their treatment compared with those receiving benazepril (59 days; IQR, 11–121 days; Fig 1; P = .0005). This significant difference persisted (P = .014) if the desire to increase benazepril dosage was not considered as an intensification of heart failure treatment. Dogs receiving benazepril were 1.69 times more likely to undergo intensification of their treatment first (hazard ratio, 1.69; 95%, CI, 1.24–2.29; P = .0008) in the univariate analysis. This difference persisted after adjusting for all baseline variables in the multivariate Cox proportional hazard analysis.

image

Figure 1. Kaplan–Meier plot of percentage dogs with no intensification of heart failure therapy as a function of time in 124 dogs treated with pimobendan and in 128 dogs treated with benazepril. Dogs receiving pimobendan had a significantly longer time period (median, 98 days; IQR, 30–276 days) before experiencing any intensification in their treatment compared to those receiving benazepril (median, 59 days; IQR, 11–121 days; P = 0.0005).

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Discussion

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgments
  8. References

The current report shows that in dogs receiving concurrent heart failure treatment, pimobendan when compared with benazepril treatment results in a similar QoL for the duration of the period of treatment, but increases the time period before it is necessary to intensify treatment, which, in turn, leads to a lower proportion of dogs receiving additional heart failure drugs. Furthermore, dogs receiving pimobendan had smaller heart size and higher body temperature, serum sodium concentration, TPC, and PCV by comparison to dogs receiving benazepril.

Quality of life is defined in people as a reflection of the way a person's mental and physical well-being is evident in their everyday life.[18] One of the main ways in which heart failure and its treatment affects QoL is through its impact on people's ability to perform their normal daily activities.[19] In some studies, QoL is considered the most important outcome in symptomatic people with heart failure even surpassing quantity of life.[20] Comparatively little work has evaluated the assessment of QoL in veterinary cardiac patients or addressed the importance of preservation of QoL in the face of terminal disease. A recent study demonstrated that owners of dogs with heart disease place a high value on preservation of QoL and, in fact, most of these owners valued preservation of QoL over survival.[6]

The area under the curve approach used in this report is, in this setting, a novel method to deal with missing data and variable periods of follow-up. This technique has been used previously for the analysis of longitudinal data in veterinary studies.[21] The summary statistic (area under the curve) was used to compare QoL and other indices between treatment groups. This technique has the advantage that data from every visit of every dog for which longitudinal measurements are available can be included and yet it reduces the values of the variable over multiple observations to a single index. It does not require comparisons between groups at multiple time points (repeated measures analysis), a technique with statistical limitations.[17] Finally, it does not require the carrying forward of any data for dogs that have already reached the primary endpoint, a technique which may bias the outcome when there is an unequal rate of removal from the study.[22]

In studies in which determination of the effect of a drug on QoL is a primary aim, it is necessary to maintain background treatment at a constant level to identify differences between groups as a consequence of the drug being studied.[23] In long-term studies, it is not ethically acceptable to deny modification in background treatment to patients, particularly those that are doing poorly. It has been argued that intensification of treatment represents evidence of a patient's condition worsening.[24] Recognition of this fact has been employed in developing a composite index of a patient's overall experience in heart failure trials in humans referred to as the “Patient Journey.”[24, 25] This index was used in the COMET trial and patients in whom treatment was intensified were considered to score 1 rank worse than those in whom intensification was not required.[25]

We examined the necessity for intensification of concurrent treatment in patients in the QUEST study by looking at the time to intensification of treatment and the frequency of use of common concurrent medications. We presumed that the reason an investigator decided to increase the dosage of one or more of the baseline therapies or to add another agent was because he or she believed the dog would benefit from the change because of a deterioration in the condition of the dog or the owner being concerned that their pet was failing to achieve an adequate QoL on their current treatment regimen.

Thus, although the average values for QoL variables were found to be similar in the 2 treatment groups over the duration of the study, dogs in the benazepril group required intensification of treatment earlier to maintain their QoL. The intensification of heart failure treatment could consist of more than 1 change in the medication. Among several possible changes in medication in this study, the investigators had the opportunity to indicate that an increase in benazepril dosage was desired, and this was considered an intensification of the treatment. Because dogs in the pimobendan group could not receive this intensification of treatment, this potentially could be a confounder in this study. However, only 6 dogs (4 in the benazepril and 2 in the pimobendan group) had an intended increase in benazepril dosage as the only intensification. All other dogs had a change (intensification) in more than 1 drug. Furthermore, the significant difference in time to intensification persisted after having ignored a desire to increase benazepril dosage as an intensification of heart failure treatment. The similarity of QoL in the 2 groups is therefore probably a consequence of investigators being at liberty to modify medication to maintain an acceptable QoL for their patients. As we have already shown, the administration of pimobendan was associated with a prolongation of survival[5] and this analysis suggests that dogs receiving pimobendan have a longer life of a similar quality. We also can conclude that this prolongation of survival was achieved without the need for more intensive treatment. In fact, it appears that dogs in the benazepril group required alteration of their treatment sooner and more frequent administration of other medications (eg, spironolactone, digoxin) to maintain the same QoL. We consider this finding clinically relevant because one of the goals of treating any condition (and especially CHF) in view of maintaining a good QoL is to do so with the fewest number of different drugs necessary. Polypharmacy has the potential to decrease owner compliance, increases the risk of accidental dosage errors and omission of drug administration by the owner, and increases the total cost of treatment.

In addition to the QoL indices, we also compared clinical, radiographic, echocardiographic, and laboratory variables between the groups of dogs in our study using the area under the curve statistic. We found that 7 variables differed significantly between the pimobendan and benazepril groups over the duration of the study. One was rectal temperature, 3 were indicators of heart size (VHS, LVIDs inc, and LVIDd inc) and 3 were blood constituents (TPC, PCV, and serum sodium concentration). Rectal temperature previously has been shown in Doberman Pinschers with heart failure secondary to dilated cardiomyopathy to be an independent predictor of outcome.[26] In human heart failure patients, low body temperature at time of hospital admission[27] and decreasing body temperature over time[28] both are predictors of poor outcome. The median values of rectal temperature were within the normal reference range for dogs in both treatment groups with a difference of 0.1°C. Although this difference between treatment groups was statistically significant (P = .030), it is too small a change to be of clinical value in monitoring individual patients. It has been speculated that lower body temperature may be a result of lower cardiac output,[26] and the small difference between our treatment groups may have been because of improved perfusion in the pimobendan group.

Differences in heart size between groups of dogs treated with pimobendan and dogs receiving an ACE-I have been demonstrated previously.[9, 29] Several mechanisms could be responsible for changes in heart size. The reduction in vascular resistance and enhancement of cardiac contractility achieved with an inodilator may allow the heart to contract down to a smaller end-systolic diameter and maintain an adequate stroke volume with a lower end-diastolic diameter. A larger ventricular diameter will be directly associated with an increase in systolic wall stress and worse secondary mitral regurgitation, and may therefore be associated with worse outcome.[30, 31]

Three of the variables that differed significantly between groups were blood constituents: TPC, PCV, and serum sodium concentration. Over the period of time that dogs spent in the study, the median values for these variables differed by only a relatively small amount and neither group had a median value outside the reference range, but median values were consistently lower in the benazepril group (1.6 mmol/L lower sodium concentration, 1.2% lower PCV, and 0.2 g/dL lower TPC; P = .0027, P = .0299, and P = .0003, respectively). Although these differences between treatment groups were statistically significant, they are too small to be of clinical value in monitoring individual patients. These differences, however, are unlikely to be caused by hemoconcentration in the pimobendan group because the furosemide dosage and serum creatinine concentrations were similar in the treatment groups. Hyponatraemia,[32] hypoalbuminemia[33] and anemia[34] all have been shown to be independent predictors of poor outcome in human heart failure patients, although this has not been demonstrated in veterinary patients.

There are multiple factors that can lead to alterations in PCV and TPC in heart failure, including hemodilution, malnutrition, and chronic inflammation.[33, 34] In the absence of unmeasured osmoles (eg, glucose), the most likely reason for a decrease in serum sodium concentration is an excess of free water retention (or failure of free water clearance), which occurs either in the presence of sodium depletion or in isolation.[35] The combination of higher serum sodium concentration, plasma proteins, and PCV in dogs receiving pimobendan suggests that there may be decreased free water retention or improved free water excretion associated with the administration of this agent in comparison with the administration of benazepril. Increasing serum sodium concentrations have been shown to indicate a more favorable prognosis in hospitalized human heart failure patients.[36, 37] To our knowledge, ours is the 1st veterinary study showing differences in PCV, TPC, and serum sodium concentrations arising from differences in the administration of standard heart failure therapies.

Our electrocardiographic findings suggest that the pimobendan and benazepril groups had a similar frequency of onset of new arrhythmias. This finding indicates that neither treatment was associated with an increased likelihood of development of arrhythmia in dogs with advanced MMVD.

Limitations

As with the original report,[5] the principal limitation is the single-blinded nature of the study. Owners were aware of the medication used on their pets, whereas the investigators were not. The risk with a single-blinded design is that the unblinded party (the owner) may influence the outcome based on some preconceived or acquired sense that one treatment may be superior to the other. QoL variables are inherently subjective and so it is possible that this design may affect these variables more than objective variables.

The area under the curve statistic uses 1 value for the variable measured over multiple time points. However, the time points were not equally distributed in time. Thus, variations in values in the first 30 days could have more influence on the summary statistic than later observations.

The method of acquiring the QoL data used in this study has not been analyzed with respect to validity, reliability, and responsiveness as a metric tool. The use of the FETCH questionnaire[38] may have enabled the detection of more subtle differences between treatment groups. However, this particular instrument was not available at the time the QUEST study was designed and has yet to be fully evaluated in the setting of a large clinical trial.

Conclusions

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgments
  8. References

Pimobendan plus conventional treatment compared with benazepril plus conventional treatment resulted in similar QoL during the study, but conferred an increased time before intensification of heart failure treatment was deemed necessary, leading to a lower proportion of dogs receiving additional treatments at certain time points. Pimobendan treatment also was associated with a smaller heart size, higher body temperature, and less tendency to retain free water, as indicated by certain laboratory variables. There was no difference in arrhythmia incidence between treatment groups.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgments
  8. References

The investigators are grateful to Boehringer Ingelheim Animal Health GmbH for funding the study, and we thank the small animal hospitals involved and the schools of veterinary medicine for their efforts and support enabling successful completion of the study. We also thank all canine owners for their excellent cooperation and willingness to contribute with their dogs.

Conflict of Interest Declarations: The study was funded by Boehringer Ingelheim Animal Health GmbH. The sponsor granted the investigators the right to publish the results, regardless of outcome. Olaf Jöns is an employee of Boehringer Ingelheim Animal Health GmbH. All other authors have received funding from Boehringer Ingelheim within the last 5 years for some or all of the following activities: research, travel, speaking fees, consultancy fees, and preparation of educational materials.

Footnotes
  1. 1

    Vetmedin; Boehringer Ingelheim Vetmedica, Ingelheim, Germany

  2. 2

    Fortekor; Novartis Animal Health, Basel, Switzerland

  3. 3

    Dr Martin Vanselow; Biometrie & Statistik, Hannover, Germany

  4. 4

    SAS Version 8.2; SAS Institute Inc., Cary, NC

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  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgments
  8. References
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