J Vet Intern Med 2002;16:80–88

Efficacy of Enalapril for Prevention of Congestive Heart Failure in Dogs with Myxomatous Valve Disease and Asymptomatic Mitral Regurgitation Clarence Kvart, Jens Ha¨ggstro¨m, Henrik Duelund Pedersen, Kerstin Hansson, Anders Eriksson, ˚ blad, Torkel Falk, Anna-Kaisa Ja¨rvinen, Anna Tidholm, Karina Bsenko, Erik Ahlgren, Mikael Ilves, Bjo¨rn A Ellen Bjerka˚s, Susanne Gundler, Peter Lord, Gudrun Wegeland, Eva Adolfsson, and Jens Corfitzen We evaluated the long-term effect of early angiotensin-converting enzyme (ACE) inhibition (enalapril maleate) as monotherapy to postpone or prevent congestive heart failure (CHF) in asymptomatic dogs with mitral regurgitation (MR) attributable to myxomatous valvular disease (MVD) in a prospective, randomized, double-blinded, placebo-controlled multicenter trial involving 14 centers in Scandinavia. Two hundred twenty-nine Cavalier King Charles (CKC) Spaniels with MR attributable to MVD but no signs of CHF were randomly allocated to treatment with enalapril 0.25–0.5 mg daily (n ⫽ 116) or to placebo groups (n ⫽ 113). Each dog was evaluated by physical examination, electrocardiography, and thoracic radiography at entry and every 12 months (⫾30 days). The number of dogs developing heart failure was similar in the treatment and placebo groups (n ⫽ 50 [43%] and n ⫽ 48 [42%], respectively; P ⫽ .99). The estimated means, adjusted for censored observations, for the period from initiation of therapy to heart failure were 1,150 ⫾ 50 days for dogs in the treatment group and 1,130 ⫾ 50 days for dogs in the placebo group (P ⫽ .85). When absence or presence of cardiomegaly at the entrance of the trial was considered, there were still no differences between the treatment and placebo groups (P ⫽ .98 and .51, respectively). Multivariate analysis showed that enalapril had no significant effect on the time from initiation of therapy to heart failure (P ⫽ .86). Long-term treatment with enalapril in asymptomatic dogs with MVD and MR did not delay the onset of heart failure regardless of whether or not cardiomegaly was present at initiation of the study. Key words: Angiotensin-converting enzyme inhibitor; Canine; Myxomatous mitral valve disease; Preventive cardiac therapy.

T

here is convincing evidence that suppression of the renin-angiotensin-aldosterone system (RAAS) with angiotensin-converting enzyme (ACE) inhibitors when added to other medical therapy improves clinical status and prolongs longevity in humans1,2 and in dogs with congestive heart failure (CHF).3–5 Previous studies concerning ACE inhibition in naturally occurring heart disease in dogs have involved symptomatic animals with or without concomitant From the Departments of Animal Physiology (Kvart, Ha¨ggstro¨m) and Clinical Radiology (Hansson, Lord), Faculty of Veterinary Medicine, Swedish University of Agricultural Sciences, Uppsala, Sweden; the Department of Anatomy and Physiology (Pedersen), Royal Veterinary and Agricultural University, Copenhagen, Denmark; the Department of Veterinary Clinical Studies, Faculty of Veterinary Medicine (Ja¨rvinen, Eriksson), University of Helsinki, Helsinki, Finland; the Department of Clinical Studies (Bjerka˚s), Norwegian School of Veterinary Science, Oslo, Norway; the Albano (Tidholm) and Bagarmossen (Gundler) Animal Hospitals, Stockholm, Sweden; the Sandviken Animal Hospital, Sandviken (Bsenko, Ahlgren); the Hau-Mau Animal Clinic, Helsinki, Finland (Ilves); the Bla˚ Stja¨rnan Animal Hospital, Gothenburg, Sweden (A˚blad); the Helsingborg Animal Hospital, ¨ rnsko¨ldsvik Animal Clinic, O ¨ rnHelsingborg, Sweden (Falk); the O sko¨ldsvik (Wegeland); the Stro¨msholms Animal Hospital, Kolba¨ck (Adolfsson); and the Middelfart Animal Clinic, Middelfart (Corfitzen). This study was initiated and planned by Henrik Duelund Pedersen, Clarence Kvart, and Jens Ha¨ggstro¨m during a Scandinavian Veterinary Cardiology meeting in 1993. Merck, Sharpe, and Dome (MSD) was approached with a protocol for the study and asked for support, which was approved in 1994. The study started in February 1995 and ended on July 1, 1999. Reprint requests: Clarence Kvart, DVM, PhD, DECVIM-CA (Cardiology), Department of Animal Physiology, Swedish University of Agricultural Sciences, P.O. Box 7045, 750 07 Uppsala, Sweden; e-mail: [email protected]. Submitted June 11, 2001; Accepted September 5, 2001. Copyright 䉷 2002 by the American College of Veterinary Internal Medicine 0891-6640/02/1601-0010/$3.00/0

therapy for CHF.3,4–8 These studies indicate that ACE inhibitors are effective in combination with other therapy, and ACE inhibitors are now widely used for medical therapy of CHF in dogs. However, no scientific investigation has hitherto shown that ACE inhibition prevents or delays the onset of clinical signs of CHF in asymptomatic dogs with cardiac disease, regardless of underlying diagnosis. The Scandinavian veterinary enalapril prevention trial was planned in 1994 because several reports indirectly indicated that early intervention with an ACE inhibitor might be beneficial in delaying the development of CHF in asymptomatic dogs and humans with heart disease.1,9,10 Enalapril had been shown to delay the onset of CHF and to decrease the hospitalization time when administered to human patients with asymptomatic left ventricular dysfunction.1 The RAAS came in focus as one of the most important neuroendocrine factors for the progression of CHF.11 An increased concentration of plasma renin and aldosterone was found in some asymptomatic dogs with myxomatous valvular disease (MVD), indicating an early activation of the RAAS.9 Moreover, tissue renin-angiotensin systems were suggested to be important for myocardial remodeling in various animal models of heart failure.10,12,13 The efficacy of ACE inhibitors for the treatment of CHF has been evaluated in a large number of experimental studies in dogs.11 However, experimentally induced heart disease and heart failure may not be equivalent to naturally occurring disease. It is well known that the 2 most common acquired heart diseases in dogs, MVD and dilated cardiomyopathy (DCM), both have asymptomatic phases that may precede the development of CHF for years.14,15 During this time, morphologic and endocrinologic changes ensue that may differ from those that develop during acute experiments. Clinical trials are therefore essential to prove beneficial effects of drugs in MVD and other common heart

Enalapril and Heart Failure

Table 1. Modified NYHA system for heart failure in dogs with myxomatous valvular disease (MVD). Class I—Asymptomatic dogs with murmur but no cardiac enlargement Class II—Asymptomatic dogs with murmur and cardiac enlargement but no pulmonary edema or congestion. Class III—Slightly or moderately symptomatic dogs (dyspnea), increased heart rate and disappearance of sinus arrhythmia) with murmurs, cardiac enlargement, and interstitial pulmonary edema. Class IV—Severely symptomatic dogs with murmurs, cardiac enlargement, and alveolar pulmonary edema. NYHA, New York Heart Association.

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Treatment Dogs in the weight range of 5 but less than 10 kg (at entrance to trial) received 2.5 mg enalapril or placebo, and dogs in the range 10– 15 kg received 5 mg enalapril or placebo. The tablets were administered PO once a day, and all dog owners were supplied with a daily log to record their drug administration. No other cardiac treatment was allowed while the dogs remained in the study.

Blinding The study was conducted double blinded, ie, neither the clinician examining the dog nor the dog owner/handler was aware of whether the dog received enalapril or placebo tablets.

Evaluation Schedule diseases in dogs. Also, results concerning therapy of CHF should not be regarded as applicable to the asymptomatic phases of heart disease. Earlier studies concerning Cavalier King Charles (CKC) Spaniels have shown a high prevalence of mitral regurgitation (MR) caused by MVD even in middle-aged animals.14 With a high prevalence and an early onset of MVD, this breed is well suited to study the pharmaceutical effects of ACE inhibition on naturally occurring MR. The objective of the present study was to test the longterm effect of ACE inhibition as monotherapy to postpone or prevent CHF in asymptomatic CKC Spaniels with MR caused by MVD. Results from this study have been presented earlier in abstracts at the American College of Veterinary Internal Medicine (ACVIM) forum in 1999 and 2000.16,17

Materials and Methods Animals Two hundred thirty-seven client-owned CKC Spaniels were enrolled at 14 different centers in Scandinavia (8 in Sweden, 3 in Finland, 2 in Denmark, and 1 in Norway). Eight dogs were not reexamined after the 1st visit, leaving 229 dogs to continue in the study. Enrolled dogs comprised patients at each animal hospital, referral cases from colleagues, and dogs recruited at dog shows and through screening programs. Consent was obtained from all owners involved with the study.

At entry and every 12 months (⫾30 days) until July 1, 1999, case history, clinical examination, thoracic radiography, and ECG examination were recorded for each dog. Two hundred thirteen dogs were enrolled during 1995, 23 during 1996, and 1 during 1997. All dogs remaining for examination during 1999 were examined before July 1, 1999, even if the interval from the last examination was shorter than 12 months. In addition to these scheduled visits, the dogs were examined as described above if they developed signs of CHF. When an individual dog entered CHF (modified NYHA III; see Table 1), the date was recorded, and the animal was considered to have reached end point and not examined further. If a dog was withdrawn for any other reason, time and cause were recorded. Date and cause of death were recorded for each dog that died during the study.

Clinical Evaluation A special evaluation form was used at all examination centers to allow the evaluation of dogs in a uniform manner. Thoracic radiographs in left lateral and ventrodorsal projections were made for all dogs. All radiographs were evaluated for signs of cardiomegaly and interstitial or alveolar pulmonary edema.19 The radiographic examinations were reviewed at annual evaluation meetings to ensure uniform film readings. At the completion of the trial, all radiographs were evaluated by a certified veterinary radiologist (KH), blinded to drug assignment and dog identity. If not confirmed on radiographs by signs of cardiomegaly, including left atrial enlargement and presence of interstitial or alveolar pulmonary edema, the proposed clinical diagnosis and date for CHF were rejected.

End Point

Exclusion Criteria

The end point was defined as the time when heart failure (class III; Table 1) was diagnosed. The diagnosis of heart failure was accepted only when the data from the case history and physical examination were accompanied by cardiomegaly, including left atrial enlargement and interstitial or alveolar pulmonary edema on thoracic radiographs. Information of special interest from dog owners was dyspnea, cough, nocturnal restlessness, and exercise intolerance. End point was also considered to be reached if the diagnosis of heart failure, ie, pulmonary edema and pulmonary congestion, was confirmed by postmortem examination in case of spontaneous death.

Dogs could not have received any other treatment for heart failure within 2 months before entering the trial. Dogs with signs of other systemic disease and dogs outside the weight range of 5–15 kg could not be enrolled in the study. Finally, dogs could not have clinical or radiological signs of CHF (functional class III or IV; see Table 1).

The outcome measure was the time from initiation of therapy with enalapril or placebo to withdrawal due to heart failure confirmed by clinical signs and thoracic radiographs or postmortem examination.

Randomization and Allocation

Statistical Analysis

At each clinic, the dogs were randomly assigned, in blocks of 8, to treatment or placebo groups.

The statistical analyses were performed with the JMP version 3.2a software package. Differences between treatment groups in case of

Enrollment Criteria Only CKC Spaniels afflicted with MR attributable to MVD in a modified New York Heart Association (NYHA) functional class I or II could be enrolled (see Table 1). Thus, all dogs included had a characteristic murmur.18 Some had enlargement of the left atrium and ventricle, but none had clinical or radiographic signs of cardiac failure.

Outcome Measure

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Table 2. Baseline characteristics in 229 dogs with myxomatous valvular disease (MVD). Variable

Enalapril

Placebo

P value

Number Gender (M/F) Age (years) Weight (kg) Cardiomegaly (Y/N) Murmur (L/M/H)

116 65/51 6.6 ⫾ 1.9 10.3 ⫾ 2.0 55/61 50/59/7

113 70/43 6.9 ⫾ 2.1 10.2 ⫾ 1.9 52/61 44/63/6

— .42 .28 .77 .89 .76

L, low intensity (grades 1 and 2); M, moderate intensity (grades 3 and 4); H, high-intensity murmurs (grades 5 and 6). categorical data were analyzed with Fisher’s exact test (two-tailed) or, in case of more than 2 levels, the chi-square test. The time from initiation of therapy to confirmed heart failure or censoring was analyzed with Student’s t-test for unpaired data. The effects of therapy, dose concentration of enalapril, cardiomegaly, age, gender, and heart murmur intensity at the time from initiation of therapy to heart failure were further analyzed with the log-rank (Kaplan-Meier) test, a nonparametric method that includes adjustments for censoring. In statistical analysis of time to end point data, observations for which the exact time to reach the end point is not known are referred to as censored. Censoring serves to reduce the number of remaining individuals on which the Kaplan-Meier (survival) plots are based. In this study, dogs were censored if they were withdrawn or if they had not developed heart failure at the end of the trial. The effects of age, presence of cardiomegaly, dose concentration of enalapril, gender, and therapy, at entry of trial, were further analyzed with the Cox Proportional Hazard Model. This method allows evaluation of several factors simultaneously while controlling for potential confounding factors. If not indicated otherwise, values are reported as mean ⫾ standard deviation. The minimal level of significance was set to P ⬍ .05.

Results Baseline Characteristics A total of 237 dogs were recruited to the study. However, only 229 (135 males and 94 females) were included in the analysis, as 8 dogs were not reexamined. The age at initiation of therapy was 6.7 ⫾ 2.0 years (range, 2–15 years). The mean body weight of the included dogs was 10.2 ⫾ 2.0 kg (range, 5–15 kg). The intensity of the auscultated heart murmur was graded low (grades 1 and 2) in 94 of the dogs, moderate (grades 3 and 4) in 122 of the dogs, and high in 13 dogs (grades 5 and 6). One hundred seven dogs had radiographic signs of cardiomegaly of varying degrees at entry. One hundred sixteen dogs were allocated to the treatment group and 113 to the placebo group. At baseline, the distributions of age, gender, body weight, heart murmur intensity, and cardiomegaly were similar in the treatment and placebo groups (Table 2). The average dose of enalapril given in the treatment group was 0.37 ⫾ 0.08 mg/kg, with 0.5 mg/kg as the maximal dose and 0.25 mg/kg as minimal dose given.

Overall Outcome Of the 229 dogs, 98 dogs (43%) developed heart failure by clinical criteria, confirmed by thoracic radiography (n ⫽ 91) or postmortem examination (n ⫽ 7). Sixty-seven (29%) dogs were withdrawn for different reasons, and 64 dogs (28%) did not reach CHF before the study was completed.

Effect of Therapy The number of dogs developing heart failure was similar in the treatment and placebo group (n ⫽ 50 [43%] and n ⫽ 48 [42%], respectively; P ⫽ .99). Likewise, the numbers of dogs withdrawn (n ⫽ 33 [28%] and n ⫽ 34 [30%]) or completing the study without CHF (n ⫽ 33 [28%] and n ⫽ 31 [27%]) were similar in the 2 groups (P ⫽ .89 and .88, respectively). Thus, 57% of the dogs in the treatment group and 56% of the dogs in the placebo group were censored. The mean number of days of censored observations was not significantly different between treatment and placebo groups (983 ⫾ 450 and 898 ⫾ 534 days, respectively; P ⫽ .32). Furthermore, there were no differences in the censoring pattern between the 2 groups with regard to time to censoring, initial age, gender, or stage of disease (initial cardiomegaly, heart murmur grade, or both). The mean time intervals from initiation of therapy to CHF were similar in dogs belonging to the treatment group and in dogs in the placebo group (743 ⫾ 421 and 816 ⫾ 406 days, respectively; P ⫽ .39). The estimated means adjusted for censored observations for the period from initiation of therapy to heart failure were 1,150 ⫾ 50 days for dogs in the treatment group and 1,130 ⫾ 50 days for dogs in the placebo group (P ⫽ .85, Fig 1a). The numbers of dogs remaining in the treatment and placebo groups were similar at 800 (63 and 63), 1,200 (36 and 40), and 1,400 (21 and 23) days (all P ⬎ .05). Dosage did not have any effect on the estimated means adjusted for censored observation for the period from initiation of therapy to heart failure, as dogs receiving a dosage between 0.38 and 0.5 mg/kg/d had a mean period comparable to those receiving a dosage between 0.25 and 0.38 mg/kg/d (1,110 ⫾ 60 and 1,170 ⫾ 80 days, respectively; Fig 1b). Furthermore, therapy had no effect on the time until CHF developed, when the material was divided in dogs with or without cardiomegaly at the entrance of the trial (P ⫽ .51 and .98, respectively; Fig 2a,b).

Effect of Cardiomegaly Dogs with initial cardiomegaly had a shorter estimated mean time to heart failure adjusted for censored observations (963 ⫾ 50 and 1,290 ⫾ 40 days, respectively; P ⬍ .001) with no difference between treatment and placebo groups (Fig 3).

Effect of Heart Murmur Intensity Dogs with an initial heart murmur of moderate intensity had markedly shorter time to heart failure than did dogs with low-intensity murmurs, as indicated by a shorter estimated mean time to heart failure adjusted for censored observations (1,020 ⫾ 50 and 1,330 ⫾ 40 days; P ⬍ .001) (Fig 4) with no difference between treatment and placebo groups. Dogs with high-intensity heart murmurs had an even shorter period before heart failure (759 ⫾ 179 days).

Effect of Gender Males had a tendency toward a more rapid progression of the disease than females, as indicated by a shorter estimated mean time to heart failure adjusted for censored ob-

Enalapril and Heart Failure

Fig 1. Percentage of all dogs in the study versus time. (a) The difference in number of days in the study between placebo- and enalapriltreated dogs was not significant (log-rank test P ⫽ .85). (b) In the treatment group, there was no difference in number of days between dogs receiving enalapril in the dose range 0.25–0.38 mg/kg and those in the dose range 0.38–0.5 mg/kg.

servations (1,090 ⫾ 40 and 1,230 ⫾ 60 days; P ⫽ .11, Fig 5).

Potential Adverse Reactions and Causes of Withdrawal In a total of 63 dogs, potential adverse reactions (not leading to withdrawal) were recorded (Table 3). The most common complaint was cough that disappeared after a variable period. Other common findings included eosinophilic granulomas in the pharynx and seizures. There was no statistically significant difference in the number of dogs with

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Fig 2. Percentage of dogs in the study versus time. The difference in number of days in the study between placebo- and enalapril-treated dogs was not significant even when the analysis was performed separately in 2 subsets of dogs, ie, (a) dogs with normal heart size (logrank test P ⫽ .51) or (b) in dogs with radiographic evidence of cardiomegaly at entry into the study (log-rank test P ⫽ .98).

recorded possible adverse reactions in the placebo group (n ⫽ 37) compared with the treatment group (n ⫽ 26) (P ⫽ .11). The most common cause for withdrawal was lack of owner compliance (Table 4). Other common causes included neoplastic disease, diagnostic error, and cervical disc disease. There was no significant difference in the number of dogs withdrawn because of lack of owner compliance between the treatment and placebo groups (P ⫽ .43).

Multivariate Analysis Multivariate analysis showed that age and cardiomegaly at entry had a significant effect on the time from initiation of therapy to heart failure (Table 5). Gender tended to in-

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Fig 3. Percentage of all dogs in the study versus time. The difference in number of days in the study between dogs with radiographic evidence of cardiomegaly at entry of the study and dogs with normal cardiac size was significant (log-rank test P ⬍ .001).

fluence the outcome, but therapy did not. Body weight did not influence the outcome and was therefore not included in the analyses.

Discussion The Scandinavian veterinary enalapril prevention trial is, so far, the largest and most comprehensive clinical trial completed studying the issue of whether ACE inhibition is

Fig 4. Percentage of all dogs in the study versus time. The difference in number of days in the study between dogs with low, medium, and high heart murmur intensity at entry into the study was significant (log-rank test P ⬍ .001).

Fig 5. Percentage of all dogs in the study versus time. The difference in number of days in the study between female and male dogs was not significant, although the males tended to have a more rapid progression of the disease (log-rank test P ⫽ .11).

effective to prevent CHF in asymptomatic dogs with MVD. It must be remembered that the preventive effect was not studied in the IMPROVE, COVE, LIVE, and BENCH trials.3–5,7 Two other studies published on monotherapy with benazepril over shorter periods had enrollment criteria, designs, and low number of animals not allowing conclusions regarding efficacy to asymptomatic dogs.6,8 The present Table 3. Potential adverse reactions (not leading to withdrawal) in 229 dogs with myxomatous valvular disease (MVD). Potential Adverse Reactions

Enalapril

Placebo

Cough (resolving) Eosinophilic granulomas, pharynx Epileptic seizures Dyspnea (intermittent) Back pain Fainting Increased appetite VPC Diarrhea Restlessness Anal bursitis Polyuria/polydipsia Leg pain Reduced appetite SVPC Weight loss Increased weight Mammary tumor Pseudopregnancy Deafness Otitis externa Seminoma Total

7 3 3 2 2 — 2 2 2 — — — 1 — — — 1 — — — 1 — 26

8 4 2 2 2 3 1 1 1 2 2 1 — 1 1 1 1 1 1 1 — 1 37

VPC, ventricular premature complexes; SVPC, supraventricular premature complexes.

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Table 4. Causes for withdrawal in 67 of 229 dogs with myxomatous mitral valve disease. Cause Owner compliance Neoplastic disease Diagnostic error Disc herniation Clinic compliance Owner died Dermatitis Other causes (1 case):

Total

Enalapril

Placebo

17 3 1 1 3 1 — Epilepsia Neurological crisis Otitis media Paralysis Peritonitis Urolithiasis Facial paralysis/vestibular syndrome

12 3 5 3 0 1 2 Cushing disease Lethargy Unverified congestive heart failure Hematuria Joint disease Chronic diarrhea Sudden death of unknown etiology Gastric ulceration 34

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degree of MR (when allowance was made for the effects of MVP).21 Furthermore, a longitudinal study involving 11 CKC Spaniels with moderate to severe MR attributable to MVD showed no signs of increased circulating RAAS activity during the development of decompensated heart failure.22 The authors speculated that this finding could have been caused by an increased activity of the atrial natriuretic peptide system. In contrast, dogs with decompensated DCM appear to have increased circulating activity of the RAAS.23,24 This finding and those in similar studies indicate that the stimuli for increased circulating RAAS activity in MVD may not be sufficient to override the concomitant activation of the inhibitory mechanisms, particularly the natriuretic peptides. On the local tissue level, studies have been published that may explain the lack of prophylactic effect of enalapril in this study. Recent autoradiographic studies indicate that in canine atrioventricular valves as opposed to rat valves, angiotensin II receptors and ACE are scant.25 This finding is at odds with the theory that local RAASs in the valves contribute to progressive valvular degeneration. In contrast, the canine myocardium has a comparably high concentration of angiotensin II receptors and ACE.26 Nevertheless, studies of experimental MR in dogs showed no effect of ramipril on myocardial remodeling and progressive ventricular dilatation.26 This lack of effect was probably attributed to an upregulation of angiotensin II receptors that occurred in response to decreased myocardial angiotensin II concen-

study was a prospective, randomized, double-blinded, placebo-controlled multicenter trial—a design considered to produce the highest grade of scientific evidence.20 The study comprised 229 dogs of 1 breed with 1 type of underlying cardiac disease, which resulted in almost equal characteristics of the treatment and placebo groups (Table 2). The advantage of using CKC Spaniels is that this breed is common in Scandinavian countries and has an onset of MVD at a relatively young age. As MVD is a slowly progressing disease,14 prevention therapy trials must be designed to account for this fact by a long-term consecutive study design. This trial was conducted over a 4.5-year period, and during such an extensive period, several other fatal diseases may develop that lead to withdrawal. Recruitment of young dogs is beneficial in that the risk of other diseases causing withdrawal is reduced. Nevertheless, this study failed to show any preventive effect of enalapril for developing CHF (Fig 1; Table 5). There are several studies concerning the RAAS published after the initiation of the Scandinavian veterinary enalapril prevention trial that may shed light on this result. The increased plasma concentration of renin and aldosterone found in some asymptomatic dogs with MVD9 was later found to be associated with the presence of mitral valve prolapse (MVP) rather than to MR per se.21 In a series of clinically healthy Dachshunds, a positive correlation was found between plasma renin activity and degree of MVP, whereas the plasma renin activity did not correlate with the

Table 5. Multivariate analysis (Cox Proportional Hazard Model) of time to heart failure by baseline, heart size, age, gender, and treatment in 229 Cavalier King Charles Spaniels with mitral regurgitation (MR) attributable to myxomatous valvular disease (MVD). Term Cardiomegaly (Yes/No) Initial age (Years) Gender (Female/Male) Therapy (Enalapril/Placebo) n ⫽ 229, ⫺LogLikelihood 440.5, P ⬍ .001

Est

SEM

P Value

RR

95% CI

0.84 0.15 ⫺0.20 ⫺0.02

.21 .05 .11 .10

⬍.001 ⬍.01 .06 .86

2.31 1.16 0.82 0.98

1.53–3.52 1.04–1.29 0.65–1.01 0.80–1.20

Est, estimate; SEM, standard error of the mean; RR, risk ratio.

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trations after ACE inhibition.26 An interesting finding was that, although left ventricular myocyte cell length was greater in the dogs with MR compared to the control dogs, it also tended (not dramatically) to be greater in dogs with MR that received ramipril than in dogs receiving placebo.26 Indeed, the finding in this study, ie, that enalapril did not prevent CHF regardless of whether the dogs had cardiomegaly or not at the time of initiation of therapy, speaks against the possibility that ACE inhibition prevents progression of dilatation. Accordingly, the practice of starting ACE inhibitor treatment in dogs with MVD as soon as cardiomegaly is evident, as is commonly recommended and used in clinical practice, is not supported by the present study. In this context, it is interesting that a 6-month study comparing enalapril with hydralazine in dogs with naturally occurring CHF (NYHA class III) caused by MVD showed that the enalapril group continued dilating their hearts, whereas the group on hydralazine did not.27 Possible explanations for this finding could be that hydralazine is a more potent vasodilator than enalapril28 and that the cardiotrophic effect of angiotensin II in the hydralazine group, in which the RAAS activity was markedly increased, helped prevent progression of cardiac dilatation. The present study indicates that initial heart size as estimated by thoracic radiographs and initial intensity of the heart murmur affected the time to develop CHF. Dogs with cardiomegaly at presentation developed CHF in less time, which is a natural finding, as they were in a more advanced stage of MVD and had more severe MR when entering the trial. Murmur intensity at entrance to the trial also had a dramatic effect on the prognosis (Fig 4). Dogs with murmurs of moderate intensity had a shorter estimated mean time to CHF than did dogs with low-intensity murmurs, and dogs with initial high-intensity murmurs had the shortest mean time to overt heart failure. This finding is in agreement with earlier studies in which the murmur intensity showed a marked correlation to the severity of MVD.18,29 Thus, dogs with initial high-intensity murmurs had a more advanced stage of MVD and MR with a shorter expected time to reach CHF than dogs with low-intensity murmurs. Male dogs tended to have a more rapid progression of the disease than female dogs (Cox Proportional Hazard Model [P ⫽ .06]), suggesting an 18% increase of risk for developing CHF (Table 5). This finding is expected, as a more rapid course for MVD has been found for male dogs in earlier studies,30–32 but the cause for this difference between the genders is unknown at present. In accordance with other studies involving ACE inhibitor therapy in dogs,3–5,7 this study also showed that adverse effects are few with this type of therapy, even with a 4.5year follow-up period. The treatment group was not different from the placebo group with regard to potential adverse reactions. Thus, it is unlikely that any of the potential adverse effects listed in the enalapril group in Tables 3 and 4 are actually caused by enalapril therapy. Compared to many large human multicenter trials, the number of included dogs in this study (229 dogs) may appear modest. A low number of included dogs may lead to a low power of the study. However, statistical power is determined not only by the number of observations but also by the interindividual variation. Many large human multi-

center trials are designed to give results valid for a wide variety of patients regarding age, lifestyle, detrimental factors such as smoking, genotype, and type of underlying disease. This is achieved by having wide inclusion criteria and, to get sufficient statistical power, a large number of patients. Also, the other large veterinary multicenter trials3–8 have had less strict inclusion criteria than the present study, in which we studied 229 dogs of 1 breed affected by 1 cardiac disease. It may be argued that MR and MVD may be different in CKC Spaniels than in other breeds. However, to our knowledge, this has never been shown, and it is our experience that the lesions are macro- and microscopically identical to those found in other breeds. The only known difference appears to be that CKC Spaniels develop the disease at a younger age than other breeds. Any trial aimed at studying the long-term effects of a drug in a naturally occurring disease in dogs is bound to have many censored observations. Data from censored patients are included in the statistical analysis only until the time they are removed from the study, even though the treatment may have been effective beyond that time. Statistically, large numbers of censored values decrease the number of subjects exposed (at risk) at later times, making the Kaplan-Meier estimates less reliable.33 At present, there is, to our knowledge, no recommendation of an acceptable level of censoring. The LIVE study had an overall rate of censored observations of 44% (52% in the enalapril group and 36% in the placebo group) over a maximal period of 17 months.5 The BENCH trial had an overall rate of censored observations of 53% (62% benazepril group and 53% placebo group) over a maximal study period of approximately 2 years.7 This study had a rate of censored values similar to the other 2 trials (57%), largely from having subjects withdrawn (29%) and lost to follow-up and from having the study end while many dogs had not yet developed heart failure (28%). In that context, it should be noted that the maximal study period in this trial was long, approximately 4.5 years, and that a similar number of dogs were censored in the placebo and treatment groups. The average dosage of enalapril in this study was 0.37 ⫾ 0.08 mg/kg (range, 0.25–0.5 mg/kg), which is the recommended dosage of enalapril. There was no difference in outcome between dogs receiving a dosage in the upper range (0.38–0.5 mg/kg) and the lower range (0.25–0.38 mg/ kg). In earlier studies investigating the effects of enalapril in naturally occurring heart disease, a dosage of ‘‘approximately 0.5 mg/kg’’ has been used.3–5,34 A certain range in dosage is unavoidable in any patient-based study, as there are only a few fixed tablet sizes to choose from. To reduce dosage variation and avoid over- or underdosage, the present trial involved dogs with a fixed weight range and 4 types of tablets: 2.5- and 5-mg enalapril tablets and macroscopically identical placebo tablets. Earlier studies have shown that a dosage of approximately 0.5 mg/kg leads to a maximum reduction of serum ACE activity of 75–85%, which in turn has effects on hemodynamics.3,27,35 Indeed, it is difficult to obtain 100% inhibition of ACE with the currently available ACE inhibitors, a finding that has been attributed to the presence of enzymatic systems other than ACE that can convert angiotensin I to angiotensin II.36,37 Although several general definitions of heart failure are

Enalapril and Heart Failure

available, it is not clear how it should be defined clinically in dogs. In the Scandinavian veterinary enalapril prevention trial, we used a special modification of the NYHA classification adapted to canine CHF (Table 1).38 This system is recommended for future trials, as it is based on the evaluation of clinical and radiological findings rather than ownerprovided data, which are often incomplete, leading to uncertain and variable classification. Clinical signs indicating CHF confirmed by the presence of cardiomegaly, including enlarged left atrium and interstitial or alveolar pulmonary edema on thoracic radiographs, were criteria for the diagnosis of heart failure in the present study. The study design of a long-term consecutive study in which each radiograph could be compared to previous ones facilitated evaluation and minimized the number of the false positives. However, the experience from this trial is that the false-negative rate is probably higher than the false-positive rate, as there were no cases in which the presence of radiographic signs of heart failure were not supported by the clinical data. On the contrary, there were a few dogs in this study that were reported to have clinical signs of heart failure, but the diagnosis could not be verified on the thoracic radiographs. These dogs were not regarded to have reached the end point. A warranted question is whether other ACE inhibitors would have generated results different from those obtained with enalapril in this study. As their pharmacokinetic properties are similar, we think it very unlikely that other available ACE inhibitors such as benazepril and ramipril would have different effects in trials similar to that described in this paper.35,39 Ramipril is considered to have a greater tissue penetration than the other 2 drugs. However, as ACE appears to be scant in canine atrioventricular valves and angiotensin II receptors and ramipril has been shown to have no effect on preventing volume-overload cardiac hypertrophy,26 it appears less likely that a higher tissue penetration would yield any major advantages in cases of MVD. In conclusion, long-term treatment with ACE inhibition in asymptomatic dogs with MVD does not delay the onset of CHF regardless of whether cardiomegaly is present at initiation of therapy or not. Basic mechanisms responsible for the valvular degeneration should be further studied to create a scientific basis for development of future efficient preventive therapy for MVD. MVD is a slowly progressing disease, and dogs may remain asymptomatic without any therapy for many years after the onset of heart murmurs. Research trials designed to evaluate ‘‘prophylactic’’ therapy for asymptomatic dogs with MVD must, accordingly, involve long-term treatment over several years rather than a few weeks or months.

Footnote a

JMP version 3.2 software package, SAS Institute Inc, Cary, NC

Acknowledgments The investigators are grateful to Merck Research Laboratories (later Merial Ltd) for supporting the study, and we

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thank the Small Animal hospitals involved (Albano Stockholm, Bagarmossen Stockholm, Bla˚ stja¨rnan Gothenburg, Helsingborg, Hau-Mau Helsinki, Mevet Helsinki, Middel¨ rnsko¨ldsvik) and the fart, Sandviken, Stro¨msholm, and O Schools of Veterinary Medicine in Copenhagen, Helsinki, Oslo, and Uppsala for their efforts and additional economical support enabling a successful completion of the study.

References 1. The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med 1992;327:725–727. 2. The CONSENSUS Trial Study Group. Effect of Enalapril on mortality in severe congestive heart failure. N Engl J Med 1987;316: 1429–1435. 3. The IMPROVE Study Group. Acute and short-term hemodynamic, echocardiographic, and clinical effects of enalapril maleate in dogs with naturally acquired heart failure: Results of the Invasive Multicenter Prospective veterinary evaluation of enalapril study. J Vet Intern Med 1995;9:234–242. 4. The COVE study group. Controlled clinical evaluation of enalapril in dogs with heart failure: Results of the cooperative veterinary enalapril study group. J Vet Intern Med 1995;9:243–252. 5. Ettinger SJ, Benitz AM, Ericsson GF, et al. Effects of enalapril maleate on survival of dogs with naturally acquired heart failure. The Long-Term Investigation of Veterinary Enalapril (LIVE) Study Group. J Am Vet Med Assoc 1998;213:1573–1577. 6. Kitagawa H, Wakamiya H, Kitoh K, et al. Efficacy of monotherapy with benazepril, an angiotensin converting enzyme inhibitor, in dogs with naturally acquired chronic mitral insufficiency. J Vet Med Sci 1997;59:513–520. 7. The BENCH (BENazepril in Canine Heart Disease) Study Group. 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. J Vet Cardiol 1999;1:7–18. 8. Kolm U, Kosztolich A. Therapie des herzinsuffizienten hundes mittels benazepril-HCL (Fortekor): Ergebnisse einer langzeitstudie: Klinischer Verlauf und elektrokardiographische kontrolle. Wien Tiera¨rztl Mschr 1999;86:289–300. 9. Pedersen HD, Koch J, Poulsen K, et al. Activation of the reninangiotensin system in dogs with asymptomatic and mildly symptomatic mitral valvular insufficiency. J Vet Intern Med 1995;9:328–333. 10. Brilla C, Maisch B. Regulation of the structural remodelling of the myocardium: From hypertrophy to heart failure. Eur Heart J 1994; 15:45–52. 11. Cleland S, Reid J. The renin-angiotensin system and the heart: A historical review. Heart 1996;76:7–12. 12. Lee M, Bohm M, Paul M, et al. Tissue renin-angiotensin systems: Their role in cardiovascular disease? Circulation 1993;87(Suppl 5):7–13. 13. Lindpaintner K, Wilhelm M, Jin T, et al. Tissue renin-angiotensin systems: Focus on the heart. J Hypertens 1987;5:33–38. 14. Ha¨ggstro¨m J. Chronic Valvular Disease in Cavalier King Charles Spaniels—Epidemiology, Inheritance and Pathophysiology. Uppsala, Sweden: Swedish University of Agricultural Sciences; 1996. Thesis. 15. Tidholm A. Canine idiopathic dilated cardiomyopathy—Epidemiology, Histopathology and Pathophysiology. Uppsala: Swedish University of Agricultural Sciences, 2000. Thesis. 16. Kvart C, Ha¨ggstro¨m J, Pedersen HD. ACE inhibition in asymptomatic MR dogs: Results from a 4 year prospective, double blind, placebo controlled, monotherapy trial. Proceedings of the 18th Annual ACVIM Forum. 2000:137–138 (abstract). 17. Kvart C, Ha¨ggstro¨m J. ACE inhibition and mitral valve disease.

88

Kvart et al

Proceedings of the 17th Annual ACVIM Forum. 1999:83–84 (abstract). 18. Ha¨ggstro¨m J, Hansson K, Kvart C. Heart sounds and murmurs: Changes related to severity of mitral regurgitation in Cavalier King Charles Spaniels. J Vet Intern Med 1995;9:75–83. 19. Suter PF, Lord PF. Thoracic Radiography, text atlas of thoracic diseases of the dog and cat. Wettswil, Switzerland: Selbstverlag PF Suter; 1984:24–43, 100–113, 480–497, 551–575. 20. Concato J, Shah N, Horwitz R. Randomized, controlled trials, observational studies, and the hierarchy of research designs. N Engl J Med 2000;342:1887–1892. 21. Pedersen HD, Olsen LH, Mow T, Christensen NT. Neuroendocrine changes in Dachshunds with mitral valve prolapse examined under different study conditions. Res Vet Sci 1999;66:11–17. 22. Ha¨ggstro¨m J, Hansson K, Kvart C, et al. Effects of naturally acquired decompensated mitral valve regurgitation on the renin-angiotensin-aldosterone system and atrial natriuretic peptide concentration in dogs. Am J Vet Res 1997;58:77–82. 23. Tidholm A, Ha¨ggstro¨m J, Hansson K. Effects of dilated cardiomyopathy on the renin-angiotensin-aldosterone system, atrial natriuretic peptide activity, and thyroid hormone concentrations in dogs. Am J Vet Res 2001;62:961–967. 24. Koch J, Pedersen HD, Jensen AL, et al. Activation of the reninangiotensin system in dogs with asymptomatic and symptomatic dilated cardiomyopathy. Res Vet Sci 1995;59:172–175. 25. Mow T, Pedersen HD. No expression of angiotensin II receptors and angiotensin-converting enzyme in myxomatous canine mitral valve leaflets. An autoradiographic study. J Vet Med Ser A 1999;46: 465–472. 26. Dell’italia L, Balcells E, Meng Q, et al. Volume-overload cardiac hypertrophy is unaffected by ACE inhibitor treatment in dogs. Am J Physiol 1997;273:H961–H970. 27. Ha¨ggstro¨m J, Hansson K, Karlberg B, et al. Effects of longterm treatment with enalapril or hydralazine on the renin-angiotensinaldosterone system and fluid balance in dogs with naturally acquired mitral valve regurgitation. Am J Vet Res 1996;57:1645–1652.

28. Kittleson M. Therapy of heart failure. In: Ettinger SJ, Feldman EC, ed. Textbook of Veterinary Internal Medicine, 5th ed. Philadelphia, PA: WB Saunders; 2000:718. 29. Pedersen HD, Ha¨ggstro¨m J, Falk T, et al. Auscultation in mild mitral regurgitation in dogs: Observer variation, effects of physical maneuvers, and agreement with color Doppler echocardiography and phonocardiography. J Vet Intern Med 1999;13:56–64. 30. Detweiler DK, Pattersson DF. The prevalence and types of cardiovascular disease in dogs. Ann N Y Acad Sci 1965;127:481–516. 31. Swenson L, Ha¨ggstro¨m J, Kvart J, et al. Relationship between parental cardiac status in Cavalier King Charles Spaniels and prevalence and severity of chronic valvular disease in offspring. J Am Vet Med Assoc 1996;208:2009–2012. 32. Olsen LH, Fredholm M, Pedersen HD. Epidemiology and inheritance of mitral valve prolapse in Dachshunds. J Vet Intern Med 1999;13:448–456. 33. Klein J, Moeschberger M. Censoring and truncation. In: Survival Analysis. New York, NY: Springer-Verlag; 1997:55–79. 34. Hamlin R, Benitz A, Erickson G, et al. Effects of Enalapril on exercise tolerance and longevity in dogs with heart failure produced by iatrogenic mitral regurgitation. J Vet Intern Med 1997;10:85–87. 35. Hamlin R, Nakayama T. Comparison of some pharmacokinetic parameters of 5 angiotensin-converting enzyme inhibitors in normal beagles. J Vet Intern Med 1998;12:93–95. 36. Miura S, Ideishi M, Sakai T, et al. Angiotensin II formation by an alternative pathway during exercise in humans. J Hypertens 1994; 12:1177–1181. 37. Balcells E, Meng Q, Hageman G, et al. Angiotensin II formation in dog heart is mediated by different pathways in vivo and in vitro. Am J Physiol 1996;271:H417–H421. 38. Ettinger SJ, Suter PF. Acquired valvular and endocardial heart disease. In: Canine Cardiology. Philadelphia, PA: WB Saunders; 1970: 324–325. 39. Fischler M, Follath F. Comparative aspects of ACE-inhibitors: What differences are relevant. Schweiz Med Wochenschr 1999;129: 1053–1060.

Laminin ␣2 (Merosin)-Deficient Muscular Dystrophy and Demyelinating Neuropathy in Two Cats.

lipid accumulation. Immunohistochemistry showed that laminin ␣2 chain was absent or reduced, while dystrophin and all the components of the dystrophin-associated glycoprotein complex were present and normal. One cat was examined in detail. Motor nerve conduction velocity (MNCV) was decreased, and ultrastructurally the peripheral nerves showed Schwann cell degeneration and demyelination. Brain imaging was not performed, but white matter changes were not apparent in the brain at necropsy. The disease in these cats is similar to primary or secondary merosin (laminin ␣2)-deficient congenital muscular dystrophy (CMD) in humans and to dystrophia muscularis in mice.

O’Brien DP, Johnson GC, Liu LA, Guo LT, Engvall E, Powell HC, and Shelton GD. J Neurol Sci 2001;189:37-43 We report laminin ␣2 (merosin) deficiency associated with muscular dystrophy and demyelinating neuropathy in two cats. The cats developed progressive muscle weakness, and atrophy. Either hypotonia or contractures resulted in recumbency, necessitating euthanasia. Muscle biopsies showed dystrophic changes including marked endomysial fibrosis, myofiber necrosis, variability of fiber size, and perimysial