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Toxicity in Doberman Pinchers with Ventricular Arrhythmias Treated with Amiodarone (1996–2005)

Authors


Corresponding author: Marc S. Kraus, DVM, Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853; e-mail: msk16@cornell.edu.

Abstract

Background: Asymptomatic Doberman Pinschers with dilated cardiomyopathy (DCM) often die suddenly owing to ventricular tachycardia that degenerates into ventricular fibrillation. A safe and effective antiarrhythmic drug treatment is needed. This will require a large, well-controlled, prospective study.

Hypothesis: Amiodarone toxicity is common in Dobermans with occult DCM and ventricular tachyarrhythmias refractory to antiarrhythmia therapy. Infrequent monitoring of hepatic function is inadequate. Frequent monitoring may be useful to determine dogs in which the dosage should be decreased or the drug withdrawn.

Methods: Medical records from the University of Georgia and Cornell University were searched for Doberman Pinschers diagnosed with preclinical DCM that received amiodarone for severe ventricular arrhythmias refractory to other antiarrhythmic agents. Echocardiographic data, Holter recording data, hepatic enzyme serum activity, and serum amiodarone concentrations were recorded. The presence of clinical signs of toxicity was recorded. Serum amiodarone concentrations were obtained in some dogs.

Results: Reversible toxicity was identified in 10 of 22 (45%) dogs.

Conclusion and Clinical Importance: Adverse effects from amiodarone were common and were, in part, dosage related. Patients should be monitored for signs of toxicity and liver enzyme activity should be measured at least monthly.

Dilated cardiomyopathy (DCM) in Doberman Pinschers is characterized by a slowly progressive presymptomatic phase during which ventricular premature contractions (VPC) occur along with progressive left ventricular dysfunction and, usually, progressively more severe ventricular tachyarrhythmias.1–9 The outcome in cardiomyopathic patients usually is either sudden death or congestive heart failure (CHF).

Markers for cardiomyopathy in overtly healthy dogs include VPC, echocardiographic abnormalities indicating left ventricular systolic dysfunction, or both. Holter recording often is required to detect the early appearance of VPC because their numbers are few.3,4,8–10 If and when to initiate antiarrhythmic treatment and the most effective drug regimen are unknown. Doberman Pinschers that experience rapid, sustained ventricular tachycardia (VT), often accompanied by syncope, presyncope, or rear limb weakness commonly die suddenly.4,8 Sudden death also has been reported in dogs with a signal-averaged ECG consistent with ventricular late potentials.10 Antiarrhythmic therapy is warranted in such dogs.

We prescribed amiodarone to Doberman Pinschers with severe ventricular tacyarrhythmias that were refractory to other therapy. Early in our experience with amiodarone we noticed evidence of hepatic toxicity and data collection then was initiated. The purpose of this retrospective study was to report the observed adverse effects of amiodarone in Doberman Pinschers with VT and without CHF.

Materials and Methods

This retrospective study consisted of Doberman Pinschers seen at the University of Georgia or Cornell University between 1996 and 2005 and diagnosed with preclinical (occult) DCM that received amiodarone therapy for severe ventricular tachyarrhythmias refractory to other antiarrhythmic agents. Severe ventricular tachyarrhythmia was defined either as rapid (>200 beats/min [bpm]) VT, >6,000 VPCs per 24 hours of Holter recording with couplets and triplets of VPC but no VT or syncope with subsequent documentation of many VPC (presumed VT) by a routine ECG recording. Refractory ventricular tachyarrhythmia was defined as the identification of VT in dogs being treated with mexiletine, tocainide, or procainamide alone or in combination with atenolol, carvedilol, or sotalol.

DCM was defined as a left ventricular internal dimension at end-diastole (LVIDd) > 49 mm, left ventricular internal dimension at systole, (LVIDs) > 39 mm, fractional shortening (FS) < 26%, and E-point to septal separation (EPSS) > 9 mm. Each patient studied had echocardiographic confirmation of DCM, Holter recording documentation of VT by Holter recording (n = 19) or routine ECG (n = 3), and none had developed CHF or had been treated with cardiac drugs before initial examination at the University of Georgia or Cornell University.

For dogs that met the inclusion criteria, records were searched for evidence of general toxicity and hepatotoxicity. Hepatotoxicity was defined as increases in serum alanine transferase (ALT) and alkaline phosphatase (AP) activities. When present in the medical record, serum amiodarone concentrations were recorded. These serum samples were assayed by a commercial laboratory.

Tabulated data included overt signs of gastrointestinal upset (eg, lethargy, vomiting, diarrhea, anorexia), liver enzyme (ALT and AP) activities, cardiac drug dosages and schedules, and time to toxicity, if any. Holter recording data and selected echocardiographic parameters measured at the time amiodarone therapy was initiated were tabulated. Abdominal ultrasound examinations for evaluation of the liver were performed in a subset of dogs.

Statistical Analysis

The significance of association between increased liver enzyme activities or overt toxicity and the combinations of treatments was evaluated by a 2-tailed Fisher exact test. Two sets of comparisons were performed. The 1st compared all dogs that received 200 mg of amiodarone and mexiletine (n = 15) to those that received these drugs plus pimobendan (n = 7) or carvedilol (n = 11). The 2nd compared all 21 dogs that received amiodarone at either 200 or 400 mg daily and either tocainide or mexiletine to 11 dogs that also received mexiletine plus carvedilol (n = 4) or mexiletine, carvedilol, and pimobendan (n = 7). The level of significance was set at P < .05.

Results

Twenty-two Doberman Pinschers with occult DCM were identified that received amiodarone therapy for severe ventricular tachyarrhythmias refractory to other antiarrhythmic agents.

All dogs studied were middle aged or older. The mean (±SD, range) age of the 22 study dogs at the time of initiation of amiodarone treatment was 7.58 (±1.46, 6–11) years. There were 13 male and 9 female dogs.

At the time amiodarone was initiated, the mean (±SD, range) FS was 19.7 (±2.01, 17–23) percent. The mean LVIDs was 44.8 (±3.26, 40–50) mm and the mean LVIDd was 55.7 (±2.40, 52–60) mm. The mean EPSS was 12.6 (±1.69, 10–15) mm.

Baseline Hepatic Enzyme Activities

Serum AP and ALT activities were measured in 19 of 22 dogs at the time amiodarone therapy was initiated. Baseline hepatic enzyme activities were not measured in 3 dogs. Among the 19 dogs, the liver enzyme activities were within the reference ranges (AP < 123 U/L, ALT < 110 U/L) in 16 of 19 (84%) dogs. Serum AP and ALT activities in 1 dog were 145 and 184 U/L, respectively, the ALT activity was increased at 118 U/L in 1 dog, and at 208 U/L in another. The latter dog had a recent history of increased (up to 600 U/L) serum ALT activity. Ultrasound examination of the liver either was not performed (n = 17) or was normal (n = 5) in 3 dogs with increased liver enzyme activity and in 2 additional dogs.

Treatment of Myocardial Failure

At the time amiodarone therapy was initiated, drugs used to treat myocardial failure were already being administered to each dog. These drugs were enalaprila (n = 16) or benazeprilb (n = 6), carvedilolc (n = 11), spironolactoned (n = 12), and pimobendane (n = 3). Pimobendan (n = 4) or digoxinf (n = 3) subsequently were prescribed when left ventricular contractility was <19%. Furosemide precluded enrollment in the study, and none of the dogs were receiving it at the time amiodarone therapy was initiated. Two dogs were subsequently treated with furosemide.g

Antiarrhythmic Therapy

Before the onset of amiodarone administration each of 17 dogs had 1 or >1 episode of VT with heart rate > 200 bpm confirmed by Holter recordings. Three dogs experienced syncope and subsequent routine ECG contained many VPC including triplets and couplets (presumed rapid, sustained VT). Two dogs had not only multiple couplets or triplets of VPC, but also >8,000 VPC per 24 hours of Holter recording.

Amiodarone treatment was initiated when severe ventricular tachyarrhythmia persisted or relapsed after 1–3 different antiarrhythmic drug regimens were attempted and did not control the arrhythmia adequately based on the clinician's judgment. Antiarrhythmic drugs that the 22 dogs had receivied before amiodaroneh included mexiletinei (n = 19), tocainidej (n =10), atenololk (n =2), quinadinel (n = 2), procainamidem (n = 2), carvedilol (n = 11), and sotaloln (n = 1). At the time amiodarone treatment was initiated, concurrent antiarrhythmic drug treatment included 1 or more of the following: mexiletine (n = 19), tocainide (n = 3), procainamide (n = 1), carvedilol (n = 11), and sotalol (n = 1). All dogs receiving amiodarone continued to receive either tocainide (n = 3) or mexiletine (n = 19). Eleven of the 19 dogs administered mexiletine also were receiving carvedilol. In 3 dogs, after amiodarone treatment was initiated, tocainide (n = 1) or mexiletine (n = 2) was tapered over a 2-week period and then discontinued. Ventricular tachyarrhythmia worsened in each dog within 2 weeks. The total numbers of VPCs approximately doubled and episodes of VT were more frequent in each dog. Tocainide or mexiletine then were reinstituted.

Amiodarone Dosages

Oral amiodarone treatment consisted of a 1 week (n = 17) or 2 week (n = 5) loading schedule followed by a once daily maintenance schedule (Table 1). One dog was given 400 mg twice daily for 5 days and then amiodarone was permanently discontinued because of toxicity. Therefore, all observations reported are based on 22 dogs that underwent a loading regimen and 21 dogs that underwent a maintenance regimen of amiodarone. The 400 mg maintenance dosage range was 9.0–12.1 mg/kg. The 200 mg maintenance dosage range was 4.3–6.3 mg/kg.

Table 1.   Amiodarone dosage regimens and selected drugs coadministered to 22 Doberman Pinschers with occult dilated cardiomyopathy.
No. of DogsLoading DosesMaintenance DosesToxicitya,bLEMTCP
  • a

    During maintenance therapy except for the 1st row.

  • b

    b Anorexia, vomiting, and diarrhea.

  • c

    c One dog without overt signs of toxicity, 1 of which receiving C and P.

  • d

    d Three dogs without overt signs of toxicity, 2 of which receiving C and P.

  • LE, liver enzymes and the number of dogs with increased liver enzymes; M, mexiletine and the number of dogs administered mexiletine; T, tocainide and the number of dogs administered tocainide; C, carvedilol and the number of dogs administered carvedilol; P, pimobendan and the number of dogs administered pimobendan.

1400 mg q12h, 1 weekDiscontinued110100
4400 mg q12h, 1 week400 mg q24h444000
2400 mg q12h, 1 week then 300 mg q12 h, 1 week400 mg q24h220200
3400 mg q12h, 1 week then 400 mg q24h, 1 week200 mg q24h12c3010
12400 mg q12 h, 1 week200 mg q24h25d120107

Amiodarone Serum Concentrations

The recommended serum amiodarone concentration in humans is approximately 1.0–2.5 μg/mL.11,12 Serum amiodarone concentrations were measuredo in 9 of 22 (41%) dogs from 1 to 12 weeks after drug initiation. In 1 dog, amiodarone (dosage of 400 mg twice daily for 1 week, 300 mg twice daily for 1 week, and then 400 mg once daily) serum concentrations at approximately 1, 2, 3, and 12 weeks of treatment were 3.7, 2.7, 1.7, and 1.8 μg/mL, respectively. In another dog, amiodarone (400 mg twice daily for 1 week, 300 mg twice daily for 1 week, and then 400 mg once daily) serum concentrations at 1, 2, and 3 weeks were 3.2, 2.5, and 2.0 μg/mL, respectively. In a 3rd dog, amiodarone (400 mg twice daily for 1 week and then 200 mg once daily) serum concentrations at approximately 1, 6, and 12 weeks were 1.1, 2.0, 1.5 μg/mL. In 6 dogs that received amiodarone at 400 mg twice daily for 1 week and then 200 mg once daily, serum concentrations (1 in each dog) at 3–12 weeks of treatment were 1.5, 1.8, 1.9, 1.9, 2.0, and 2.1 μg/mL, respectively.

Outcome

Ten of 22 (45%) dogs developed anorexia (n = 10) and vomiting (n = 8). Three (14%) dogs developed toxicity during the loading schedule and 9 of 21 (43%) dogs developed similar signs during the maintenance treatment schedule. Two dogs developed toxicity during both loading and maintenance treatment. Toxicity occurred during maintenance therapy in 9 dogs at an average of approximately 15.5 weeks (range, 1–32 weeks) and a median of 16 weeks.

Toxicity during the Loading Regimen

Three dogs developed toxic signs comprised of anorexia (n = 3), vomiting (n = 3), and diarrhea (n = 1) on day 6 or 7 of amiodarone administration (400 mg twice daily). Serum amiodarone concentrations and liver enzyme activity were measured within 3 days of signs of toxicity in 2 of these dogs. The amiodarone concentrations were 3.7 and 3.2 μg/mL. Hepatic enzyme activities were increased (ALT = 1,128 U/L, AP = 325 U/L and ALT = 841 U/L, AP = 593 U/L). In each case, the loading schedule was stopped when gastrointestinal signs were reported, amiodarone was withheld until anorexia and vomiting resolved, and then amiodarone administration was resumed in 2 of the 3 dogs and discontinued in 1 of the 3 dogs. A maintenance dosage of 200 mg once daily was administered to 1 of the 3 dogs, but progressively increasing hepatic enzyme activities with reduced appetite occurred and the dosage was reduced to 200 mg every other day. Hepatic enzyme activity continued to increase and after 2 additional weeks the dosage was reduced to 100 mg every other day. Hepatic enzyme activity did not decrease and amiodarone was withdrawn after approximately 8 weeks of treatment. Liver enzyme activities then gradually decreased over an 8-week period and returned to normal.

A maintenance schedule of 400 mg once daily was initiated after resolution of overt toxicity that occurred during the loading schedule in the 3rd dog. Hepatic enzyme activities gradually decreased and after 6–8 weeks the AP was 89 U/L and the ALT was 103 U/L. Clinical signs of toxicity reappeared in this dog after approximately 6 months and amiodarone was discontinued.

Toxicity during Maintenance Treatment

Signs of toxicity developed in 9 of 21 (43%) dogs, including all 3 dogs that had increased baseline serum ALT activity. Toxicity occurred in all 6 dogs that were being treated at a dosage of 400 mg once daily and in 3 of 15 dogs (20%) treated at a dosage of 200 mg once daily. Amiodarone either was discontinued (n = 7) or the dosage reduced to 200 mg once daily (n = 2) because of anorexia, vomiting, or hepatotoxicity that occurred after approximately 1, 8, 12, 12, 16, 17, 18, 24, and 32 weeks of treatment. Serum amiodarone concentrations (1.8, 2.0, 2.0 μg/mL) were obtained within 2–5 days of the onset of anorexia and vomiting in 3 of 9 dogs.

Increased Liver Enzyme Activity and Signs of Toxicity

Amiodarone toxicity in 10 dogs consisted of anorexia (n = 10) and vomiting (n = 8), and diarrhea (n = 2). Increases in hepatic enzyme activities were detected in each dog. Toxicity occurred from approximately 6 days to 8 months after initiation of amiodarone treatment. Overt signs of toxicity improved (n = 1) or resolved (n = 9) in 10 dogs associated with the discontinuation of amiodarone treatment (n = 9) or reduced dosage (n = 1) to 200 mg once daily.

Increases in hepatic enzyme activity were tabulated. The mean and median values calculated from the highest ALT activities for each dog were 1,048 and 670 U/L, respectively (range, 427–2,306). The mean and median of the highest AP activities for each dog were 679 and 397 U/L, respectively (range, 265–1,075). Total bilirubin concentrations were measured in 7 dogs and were increased in 5. The mean and median values were 2.2 and 2.2 mg/dL (range, 1.8–2.7 mg/dL). Icterus was not observed in any dog.

Among the 12 dogs that did not experience overt toxicity, hepatic enzyme activities were measured at 1–3-month intervals. Enzyme activities remained within the reference range in 9 dogs. Increased AP activity (178 U/L) was detected in 1 dog and increased ALT activity (highest values, 117, 126, 139 U/L) was detected in 3 dogs on at least 1 occasion.

Statistical analysis indicated a significant association between overt toxicity and increased liver enzyme activities and the administration of a maintenance amiodarone dosage of 400 mg once daily compared with 200 mg once daily. Among the dogs receiving a maintenance dosage of 200 mg once daily, neither overt toxicity (P= .03) nor increased liver enzyme activities (P= .02) were more likely in dogs receiving carvedilol or carvedilol plus pimobendan. Among 21 dogs receiving maintenance dosages of amiodarone of either 400 or 200 mg and tocainide or mexiletine, the coadministration of pimobendan, carvedilol, or both was not associated with increased incidence of overt toxicity or increased liver enzyme activity.

Discussion

Cardiomyopathy is common in Doberman Pinschers and sudden death is the outcome in at least 30% of affected dogs.4,5 Only dogs with severe ventricular tachyarrhythmia nonresponsive to antiarrhythmic drugs that then were treated with amiodarone were included in this study. These dogs were studied because of an observation of toxicity that was characterized by lethargy, anorexia, vomiting, diarrhea, and hepatotoxicity associated with amiodarone administration. Sustained VT, collapse, or near collapse with subsequent documentation of many VPC (presumed sustained VT), couplets and triplets of VPC with >6,000–8,000 VPC per 24 hours, and ventricular late potentials on a signal-averaged ECG are among the markers that we believe are indications for antiarrhythmic drug therapy.4,10

The treatment of ventricular tachyarrhythmia is controversial owing to lack of demonstrated efficacy, proarrhythmia risk, and adverse effects of antiarrhythmic drugs.11–15 In the present study, commonly prescribed antiarrhythmic drugs were used, most often mexiletine, tocainide, and carvedilol. Most dogs in this study were being treated with a combination of mexiletine and carvedilol along with amiodarone when toxicity occurred. The use of 3 drugs for arrhythmia control might be considered unusual. However, β-blockers may be of benefit in patients with DCM.16–18 Carvedilol was initiated in some of the study dogs before the development of arrhythmia severe enough to warrant antiarrhythmic therapy and it was continued throughout the amiodarone treatment regimen.

In humans, carvedilol has been shown to exert a favorable influence on disease progression beyond antiarrhythmic action.16–18 It should be noted, however, that these studies involved patients with CHF. We are aware of no reports evaluating the influence of carvedilol on disease progression of occult or preclinical DCM in either humans or Doberman Pinschers. The only class of drug that has been demonstrated to improve outcome in Doberman Pinschers with occult DCM is angiotensin-converting enzyme inhibitors.p

Amiodarone was prescribed only if drug-refractory, severe arrhythmia persisted. Amiodarone is a unique wide spectrum antiarrhythmic agent with predominant Class III activity, but also potent Class I activity and ancillary Class II and Class IV activity.19–25 The efficacy of arrhythmia suppression by amiodarone in humans generally is thought to exceed that of other antiarrhythmic compounds.11,23–25 Results of some, but not all, studies in humans suggest a marginally favorable influence on arrhythmic death,21,22 including some patients with nonischemic DCM.24–26 Amiodarone's marginal potential for mortality reduction in humans is balanced against its slow onset to action and adverse effects which include hepatic toxicity,20,24,25,27–29 thyroid dysfunction, gastrointestinal disturbances, pulmonary fibrosis, and blood dyscrasias.11,30–32 Many of the adverse reactions to amiodarone were dosage related. However, low dosages of amiodarone also have been associated with toxicity in humans.30,31 Three dogs treated with relatively low dosages (200 mg once daily) developed toxicity.

The pharmacokinetics of amiodarone differ from most other cardiac drugs.11,19–25 The onset of action after oral administration in humans is delayed and a loading dosage schedule is recommended for therapeutic concentrations to be achieved in <3 weeks. In the present study, toxicity was encountered in 3 dogs during the loading schedule and was accompanied by relatively high serum amiodarone concentrations (3.7 and 2.7 μg/mL at 1 and 2 weeks of treatment in 1 dog and 3.2 and 2.5 μg/mL at 1 and 2 weeks in another dog).

A correlation between antiarrhythmic effects and serum concentrations of the drug has not been clearly demonstrated, but there is a direct relationship between serum concentration and oral dosage.12 Myocardial concentrations correlate poorly with serum concentrations and the former are more important for antiarrhythmic effects.12 The recommended serum drug concentration in humans, although not well defined, may be between 1.0 and 2.5 μg/mL because higher concentrations are associated with increased toxicity.11,12,26–28 Serum concentrations were within the reference range in all of 9 dogs during maintenance treatment, including 3 of 9 (33%) that exhibited clinical toxicity nonetheless.

There is a favorable interaction between amiodarone and β-blockers.33 The antiarrhythmic efficacy of amiodarone generally is increased in humans by the coadministration of β-blocking drugs, including carvedilol.34,35 There may be favorable electrophysiologic effects from the combination of amiodarone and mexiletine, although amiodarone may interfere with clearance of mexiletine and the serum concentration of the latter may increase.35 Mexiletine can cause anorexia, vomiting, and increased liver enzyme activities.36 These adverse effects might be more likely if blood concentrations of mexiletine are increased by concomitant amiodarone administration.

Toxicity that we attributed to amiodarone administration was common, occurring in approximately 45% of the dogs. Overt signs of toxicity, such as vomiting and anorexia, usually resolved within a few days of stopping the drug. Typically, increased hepatic enzyme activities gradually decreased and enzyme activities usually were normal within 3 months. Amiodarone at a maintenance dosage of 200 mg q24h was tolerated in 12 of 15 (80%) dogs. Hepatotoxicity was a consistent outcome when a maintenance dosage of 400 mg was administered. In Doberman Pinschers with occult DCM, hepatic enzyme activities must be monitored frequently even in the absence of clinical signs of toxicity. During maintenance amiodarone treatment, it was our experience that monitoring serum hepatic enzyme activities at 3-month intervals was not frequent enough to detect hepatic toxicity.

In this study, we chose to use the Fisher exact test because of the relatively few numbers of observations per cell. The χ2 test would not be stable if small numbers were used. The influence, if any, of coadministered tocainide or mexiletine on amiodarone toxicity in this study could not be evaluated because all dogs were receiving these drugs. Coadministration of pimobendan or carvedilol or both was not associated with increased incidence of clinical toxicity or increased liver enzyme activities. Coadministered β-adrenergic blocking drugs, including carvedilol, are recommended in humans with CHF.33,34 Among the dogs in this study, mexiletine or tocainide was withdrawn from the treatment regimen in 3 dogs receiving amiodarone. The severity of the arrhythmia in each dog, as assessed by Holter recording, worsened within 2 weeks.

The decision to administer antiarrhythmic drugs should be limited to patients with a high risk of sudden arrhythmic death, as in the dogs in this study. The efficacy of an antiarrhythmic drug or drugs along with potential for toxicity must be considered. There is no proof of a favorable influence on sudden arrhythmic death for amiodarone in dogs.

Pimobendan has the potential to aggravate ventricular tahcyarrhythmias.37 Its use should be restricted to patients with overt or impending CHF. In addition, careful monitoring of the heart rhythm is recommended when pimobendan is administered to Doberman Pinschers with DCM.

The influence of amiodarone, if any, on survival times, sudden death incidence or frequency or severity of ventricular tachyarrhythmia could not be evaluated not only because of the small numbers of patients studied, but also because there was not a comparable group that did not receive amiodarone.

This study was not prospective and all data were not collected on all dogs at regular intervals, such as serum concentration of amiodarone, hepatic enzyme activities, and asking owners to monitor for signs of toxicity such as anorexia and gastrointestinal disturbances. Coadministered drugs were not controlled with respect to their use or dosage. There were no control groups to provide evidence of the extent to which any of these clinical signs or laboratory signs would have otherwise occurred in such a cohort or the extent to which these signs would have occurred in dogs receiving the other antiarrhythmic drugs in the absence of amiodarone.

Conclusions

Because of the incidence of toxicity in our patients, we advise caution when considering the administration of amiodarone to Doberman Pinschers with preclinical left ventricular systolic dysfunction receiving other antiarrhythmics, particularly mexiletine. Signs of toxicity were common and consisted primarily of vomiting, anorexia, and increased hepatic enzyme activities. Hepatic enzyme activities should be measured before starting amiodarone, after 5 days if a loading schedule is used, and at least once monthly during maintenance treatment. Although few dogs were treated, a maintenance dosage of 200 mg q24h usually was tolerated but 400 mg q24h was consistently associated with toxicity. Whether the high incidence of hepatotoxicity encountered is breed specific is uncertain. However, we have encountered amiodarone hepatotoxicity in a Labrador Retriever, 3 Boxer dogs, and a Golden Retriever.

Footnotes

aVasotec, Merck and Co Inc, West Point, PA

bLotensin, Novartis Pharmaceutical Corp, East Hanover, NJ

cCoreg, SmithKline Beecham, Pittsburgh, PA

dAldactone, G.D. Searle and Co, Chicago, IL

eVetmedin, Boehringer Manheim Therapeutics, Gaithersburg, MD

fLanoxin, Glaxo Wellcome Inc, Research Triangle Park, NC

gLasix, Hoechst Marion Roussel, Kansas City, MO

hCordarone, Wyeth-Ayerst Labs., Philadelphia, PA

iMexitil, Boehringer Mannheim Therapeutics

jTonocard, Merck and Co Inc

kTenormin, Zeneca Pharmaceuticals, Wilmington, DE

lQuinaglute, Berlex Labsoratories, Wayne, NJ

mProcan SR, Parke-Davis, Morris Plains, NJ

nBetapace, Berlex Laboratories

oLaboratory Corporation of America, Burlington, NC

pO'Grady MR, Horne R, Gordon SG. Does angiotensin converting enzyme inhibitor therapy delay the onset of congestive heart failure or sudden death in Doberman pinschers with occult dilated cardiomyopathy? J Vet Intern Med 1998;12:199 (abstract)

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