Journal of Veterinary Cardiology, Vol. 1, No. 1, May 1999
The effect of benazepril on survival times and clinical signs of dogs with congestive heart failure: Results of a multicenter, prospective, randomized, double-blinded, placebo-controlled, long-term clinical trial The BENCH (BENazepril in Canine Heart disease) Study Group*
Objective - To test the efficacy and tolerability of long-term administration of the angiotensin converting enzyme inhibitor, benazepril, in dogs with heart failure. Methods - The study was a prospective, randomized, double-blind, placebo-controlled clinical trial involving 16 centers in France, Italy, Switzerland and UK. A total of 162 dogs with class I1 and I11 (ISACHC classification) heart failure caused by chronic valvular disease (CVD) or dilated cardiomyopathy (DCM) were enrolled. Benazepril (minimum dosage, 0.25 mg/kg) or placebo were administered orally once daily for up to 34 months, either alone or as add-on therapy to “standard therapy” i.e. diuretics and/or digoxin and/or anti-arrhythmic drugs. Results - The mean survival time (to death or withdrawal from the study due to worsening of heart failure) was 2.7 times longer in the benazepril treated group (428 days) as compared with the placebo group (158 days). Differences reached statistical significance (pO.l, Chi-square or t-test) in the two groups (Table 1). The frequency of occurrence of clinical signs of heart failure (ascites, cough, dyspnea, dysrhythmias, exercise intolerance, pulmonary edema, syncope) was similar (p>O.I) in the tw o groups (data n o t shown). A wide range of breeds (36 in total, with predominantly poodles, crossbreeds, spaniels, dachshunds, boxers and fox terrier), body weights (5-73 kg) and ages (2-15 years) of dogs were included in the trial. The commonest etiology of heart failure was CVD (affecting 77% of cases) which occurred mainly in older dogs (mean age 12 years) of smaller breeds (mean body weight 11 kg). A total of 23 % of cases were DCM, which affected mainly younger dogs (mean age 8 years) of larger breeds (mean body weight 41 kg). At the time when the test drug was introduced, 67% of dogs presented in ISACHC class I1 heart failure and 33% in ISACHC class 111. Clinical signs had been present for a mean of 8 months with a large range (0 to 72 months in the benazepril and O to 60 months in the placebo group). Cardiac arrhythmia's were common (50% of cases: 38% supraventricular and 12% ventricular), notably in cases of D C M (86% of cases). The biochemical results indicate that renal and hepatic disturbances were frequent, presumably secondary to the primary heart failure. Hypokalemia (< 4 mmol/l) was detected in 43% of cases (45% in the benazepril and 30% in the placebo group).
Drug treatmentpre-trial (Table 1 ) At day 0,drugs affecting the cardiovascular system had been already been prescribed in 70% of dogs (Table 1). The previous use of diuretics, digoxin, anti-arrhythmic and vasodilator drugs (including ACE inhibitors) was equally balanced in the 2 treatment groups. Prior administration of an ACE inhibitor had no significant effect on the primary (heart failure) endpoint (p>0.3).
Drug treatment during the trial The mean dosage of benazepril administered at day 0 was 0.33 mg/kg (range 0.25 to 0.5 mg/kg). The dose was doubled during the study to a dosage of 0.5 - 1.0 mg/kg once daily in a total of 33% of dogs in the benazepril group and 39% of dogs in the placebo group. The mean final dose of benazepril administered was 0.45 mg/kg (range 0.23 - 1.0 mg/kg). Benazepril or placebo were always administered once a day. The mean duration the test treatments were administered was 161 days (range 1 to 1009) in the benazepril group and 127 days (range 2 to 834) in the placebo group. A total of 10 dogs (11%) in the benazepril group and 6 dogs (8%) in the placebo group received the test treatment as a monotherapy throughout their follow-up. The frequency of use and dosages of concomitant drugs were similar (p>O.l) in the two groups (data
Journal of Veterinary Cardiology, Vol. 1, No. 1, May 1999
Table 1
- Baseline characteristics of dogs included in the trial Placebo group (n=75)
Benazepril group (n=87)
Parameter
(% > normal range) a
Mean f SEM
Mean f SEM (% > normal range)"
10.5f 0.3 16.9f 1.6
11.O f 0.3 19.4 k 2.0
Age (yr) Body weight (kg) Male sex Duration of HF signs (months) Class of HF (ISACHC) Class II Class 111 Etiology of HF Chronic valvular disease (CVD) Dilated cardiomyopathy(DCM) Plasma biochemicalparameters Urea (mmol/l) Creatinine (umol/l) ALT (UI/I) ALP (UI/I) Na (mmol/l) K (rnmol/l) Previous treatments administered Vasodilatorsb(including ACEI) Diureticsc Digoxin Anti-arrhythmicsd
No. (%)
60 (69)
No. (%)
56 (75) 6.7 k 1.5
8.4 f 1.6 61 (70) 26 (30)
47 (63) 28 (37)
70 (80) 17 (20)
55 (73) 20 (27)
11.6f 0.7 (57) 82.0 k 3.7 (14) 109 f 14.5 (57) 215 f 47.4 (41) 148 f 0.56 (7) . . 4.2 k 0.07 (3.5)
11.6 f 0.6 (62) 83.0 4.1(14) 85.0 f 8.6 (53) 127 f 20.1 (49) 148 f 0.54 (11) 4.3 k 0.07 ( 3 )
*
,
I
59 (68) 37 (42) 41 (47) 17 (20) 3 (3)
55 (73) 33 (44) 46 (61) 19 (25) 4 (5)
HF = heart failure, ACE I =ACE inhibitor = the percentage of cases presenting with a value exceeding the normal range for dogs = isosobide dinitrate (E), enalapril (20), visnadine (17), lisinopril (5),prazosin (2), captopril (I), hydralazine (I), rnolsidomine(1) and trinitrine (1) = furosernide (81), spironolactone-aldactazine (4),bumetanide (I), Lespedesa capitata (1) = diltiazem (3), amiodarone (2), propranolol (I), disopyramide (1)
a
-
Table 2 Survival analysis of dogs reaching the "heart failure endpoint" (death or withdrawal from the study due to worsening of heart failure) in the trial. Survival times and survival rates were determined by the Kaplan-Meier procedure, risk ratios and p-values by the multivariate Cox proportional hazards model. Treatment group
No at day 0
Survival rate
Survival time (mean f SEM)
% (no at risk)
Risk ratio
p-value
0.5 year
I year
1.5 year
428 f 52 158f 17
59%(22) 40% (15)
49%(12) 20% (6)
43%(7) 20% (4)
0.56
0.019
436 f 57 151 f 2 0
63% (20) 34% (10)
51 % (10) 20% (5)
42% (5) 20% (4)
0.51
0.015
394 f I23 164 f 29
46% (3) 54% (5)
46% (2) 22% (1)
46% (2) 0% (0)
0.8
0.66
434 f 60 152f 19
64%(17) 42% (10)
51 % ( l o ) 29% (5)
42%(5) 29% (3)
0.54
0.045
417 f 99 150 f 27
47% (6) 37% (5)
47% (2) 7% (1)
47% (2) 7% (1)
06
0 22
All dogs
Benazepril Placebo
87 75 CVD _ _
Benazepril Placebo
70 55 DCM
Benazepril Placebo
17 20 ISACHC class II
Benazepril Placebo
61 47 ISACHC class 111
BenazepriI Placebo
26 28
CVD = chronic valvular disease, DCM = dilated cardiornyopathy
11
The BENCH Study Group Figure 1 - Kaplan-Meier ( l a ) and Cox proportional hazards nodel (Ib) plots of survival rate versus time of dogs with ieart disease receiving benazepril or placebo The deined endpoint, denoted the “heart failure (HF) endpoint”, was death or withdrawal of the dog from the study due to worsening of heart failure Data are from all 162 dogs in the ,tudy (CVD and DCM, ISACHC class II and Ill). Benazepril educed the risk of reaching the endpoint b y 44% p=O 019 )
Figure 2 - Kaplan-Meier plots of survival rate of dogs receiving benazepril or placebo. The “heart failure (HF)” zndpoint was death or withdrawal of the dog from the Study due to worsening of heart failure. For 125 dogs with zhronic valvular disease (CVD) shown in Fig 2a, benazepril ,educed the risk of reaching the endpoint b y 49% :p=0.015). For 37 dogs with dilated cardiomyopathy :DCM), shown in Fig 2b, differences did not reach statistical significance (p=0.66).
Figure l a
Figure 2a
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Figure 1b
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not shown). Diuretics were used in 140 dogs (86%), digoxin in 57 dogs (35%) and other anti-arrhythmic drugs in 11dogs (7%).
Efficacy - survival time (Table 2) The mean survival time in all dogs after initiation of the test treatment was 2.7 times longer with benazepril (428 days) as compared to standard therapy alone (158 days). Survival rates after one year of the test treatment were 49% with benazepril as compared to 20% with standard therapy alone (Fig 1, Table 2). The risk ratio was 0.56, which means that the risk of reaching the heart failure endpoint was reduced with benazepril by 44%. Differences reached statistical significance (p
