Evaluation of Extended-Release Diltiazem Once Daily for Cats With Hypertrophic Cardiomyopathy

Part One of Study

In the first part of the study, 13 privately owned cats were utilized. Ten cats were clinically normal, and three had HCM. The 10 normal cats were owned by house officers (interns and residents) at the University of Georgia, and the three cats with HCM were client owned. All owners were informed of the nature of diltiazem and its potential adverse effects, and all consented for their cats to enter the study. The minimum database for these 13 cats included a physical examination, complete blood count, serum biochemical profile, total thyroxine level, urinalysis, indirect blood pressure measurement, and a complete echocardiographic and color-flow Doppler ultrasound examination.

All 13 cats were given sustained-release diltiazem^d at 60 mg PO once daily for 7 consecutive days. On day 7, serum samples were obtained via jugular catheter at 6, 12, 18, and 24 hours postdiltiazem. Diltiazem was withdrawn for 60 days, and then five (normal cats) of the 13 cats were given 30-mg diltiazem^d PO once daily for 7 consecutive days. On day 7, serum samples were obtained via jugular catheter at 6, 12, 18, and 24 hours postdiltiazem. All serum samples collected for diltiazem concentration assay were immediately frozen at −70°C in appropriately labeled vials. All samples were analyzed together during a 6-hour period.

Serum diltiazem concentrations were determined by gas chromatography performed by a laboratory specializing in drug assays.^e The lower limit for the detection of drug in the assay was 5 ng/mL. Feline serum was fortified with a reference standard of diltiazem and assayed to confirm measurement of a true concentration. This was performed on the same day as the sample assays. The reference range for serum diltiazem in humans in this laboratory was 50 to 200 ng/mL.^9–11 This reference range is applied to all diltiazem formulations and to all times in a dosing interval.

Following the serum diltiazem assays, one-way analysis of variance was used to determine whether serum concentrations at 6, 12, 18, and 24 hours produced by the 30-mg dosage were significantly (P<0.05) different from those produced by 60 mg. Pearson’s correlation coefficient was used to determine if there was an association between serum diltiazem concentrations at 6, 12, 18, and 24 hours or between dosage in body weight (mg/kg) following either the 30-mg or 60-mg doses. Fisher’s least significant difference test was used to determine if serum diltiazem concentrations were related to time postdiltiazem administration.^f

Part Two of Study

The second part of the study retrospectively assessed adverse clinical signs associated with once-daily PO administration of 60-mg extended-release diltiazem^d in 25 cats with HCM. The 25 client-owned cats were diagnosed with HCM by the University of Georgia’s cardiology service in the previous 5 years and were receiving 60 mg PO once daily of extended-release diltiazem as a monotherapy. To be included in the study, all noncardiac evaluations at initial presentation had to be normal, including a physical examination, a complete blood count, serum biochemical profile, thyroxine assay, infectious disease panel (i.e., feline infectious peritonitis, feline immunodeficiency virus, feline leukemia, and toxoplasmosis), urinalysis, and chest and abdominal radiographs or an abdominal ultrasound. Any cat with HCM with an incomplete database was excluded from the study. Also, any cat with HCM that either initially had, or later developed, additional medical problems (e.g., hyperthyroidism, renal failure, neoplasia, and neurological problems), and any cat receiving additional medications were also excluded from the study.

For the three cats with HCM in part one of the study and the 25 cats with HCM in part two of the study, HCM was diagnosed on echocardiography. Echocardiographic findings consistent with HCM included segmental or diffuse septal and left ventricular posterior (free) wall end-diastolic thicknesses >6 mm (n=28), decreased septal and free wall diastolic thinning, mitral valve regurgitation caused by systolic anterior (cranial) motion of the anterior (cranial) mitral valve leaflet, midsystolic partial closure of the aortic valve, increased (>2 meters per second) left ventricular outflow tract velocity, and increased subendocardial hyperechogenicity. In addition to increased septal and wall thickness, each cat had at least one additional echocardiographic abnormality.

The presence or absence of adverse effects associated with diltiazem was determined for each cat by review of the medical record. The record was searched for comments pertaining to possible adverse effects ascertained during any and all follow-up examinations. In addition, telephone interviews were conducted with 21 of the 25 owners. Four owners could not be located. Any weight loss was documented in the medical record and/or by the owner. Identification of lethargy, decreased appetite, vomiting, and diarrhea was noted in the record and/or reported by the owner.

Part One of Study

The 13 cats ranged from 1 to 13 years of age (mean 6.4, median 5.0) and weighed 3.6 to 7.3 kg (mean 4.6, median 4.1). The cats included seven spayed females, one intact male, and five castrated males. Multiple echocardiographic parameters consistent with HCM were present in three cats. With administration of 60-mg diltiazem, the mean (± standard deviation [SD], range) dose administered to the 13 cats was 12.01 (± 3.84, 8.27 to 16.85) mg/kg PO. The subsequent 30-mg diltiazem administered to five cats was equivalent to dosages of 5.78, 7.11, 7.73, 7.04, and 7.04 mg/kg PO.

Based on serum diltiazem assays, some cats given 60-mg diltiazem had serum diltiazem values within the recommended range (50 to 200 ng/mL) for humans at 6 (n=1), 12 (n=2), 18 (n=5), and 24 (n=8) hours [Figure 1]. Other cats had serum diltiazem concentrations higher than the recommended range for humans at 6 (n=12), 12 (n=11), 18 (n=7), and 24 (n=4) hours. Two cats had serum concentrations below the recommended human range at 18 (n=1) and 24 hours (n=1). The 60-mg dose resulted in mean (± SD, range) serum concentrations of 787 (±488, 71 to 1500), 583 (±394, 100 to 1640), 286 (±180, 35 to 650), and 196 (±232, 5 to 920) ng/mL at 6, 12, 18, and 24 hours, respectively [Figure 2]. One cat experienced a decrease in appetite with the 60-mg dosage. No known cardiac toxicities occurred, but follow-up electrocardiograms were not performed on any of the cats.

During the 30-mg diltiazem dosage period, the five owners reported that the tablets were difficult to cut or break in half. Following 30 mg of diltiazem, serum diltiazem concentrations were greater than the recommended human range at 6 hours (n=1) and 12 hours (n=3) and less than the recommended human range at 18 (n=1) and 24 (n=4) hours [Figure 3]. The 30-mg dosage resulted in mean serum diltiazem concentrations of 448 (±370, 20 to 800), 445 (±157, 84 to 680), 117 (±65, 47 to 200), and 43 (±24, 20 to 88) ng/mL at 6, 12, 18, and 24 hours, respectively [Figure 4]. Mean serum diltiazem concentrations in the five cats were above the recommended human range at 6 and 12 hours, within the recommended range at 18 hours, and below the recommended range at 24 hours. Adverse effects were not detected in any of the five cats.

Serum concentrations following both the 30-mg and 60-mg doses were erratic. There was no statistical difference (P=0.99) between serum concentrations at 6, 12, 18, and 24 hours following the 30 mg of diltiazem versus 60 mg. Furthermore, there was no correlation (P=0.99) between dosages in body weight (mg/kg) and serum concentrations at 6, 12, 18, and 24 hours for either 30 mg or 60 mg of diltiazem. For the five cats initially administered 60 mg of diltiazem and then later given 30 mg, there was no correlation (P=0.99) between serum concentrations produced by 60 mg versus 30 mg [Figure 5]. There were some significant correlations between times postdiltiazem administration and serum concentrations. Following the 60-mg dosage, serum diltiazem concentrations were significantly higher at 6 versus 18 hours (P=0.001), at 6 versus 24 hours (P<0.001), at 12 versus 18 hours (P=0.02), and at 12 versus 24 hours (P=0.003). Following the 30-mg dosage, serum diltiazem concentrations were significantly higher at 6 versus 18 hours (P<0.001), at 6 versus 24 hours (P<0.001), at 12 versus 18 hours (P<0.001), at 12 versus 24 hours, and at 18 versus 24 hours (P=0.01).

Part Two of Study

In the second part of the study, at least nine (36%) of the 25 cats experienced adverse reactions that were attributed to diltiazem. Signs resolved in seven cats when the drug was withdrawn. Adverse clinical signs included decreased appetite (n=7), vomiting (n=4), lethargy (n=4), weight loss (n=3), and diarrhea (n=3). Vomiting and/or anorexia developed within 1 to 7 days in five cats. In two cats, the diltiazem was continued at 60 mg once daily despite mild, intermittent gastrointestinal signs. Weight loss and a subtle decrease in appetite were observed at or after 6 months of treatment in four of the nine cats. The owners did not appreciate the decreased appetite until after the drug was discontinued, and then the appetite appeared to improve. In these four cats, diltiazem was electively discontinued because of perceived side effects, and it was replaced by atenolol (n=3) or discontinued arbitrarily by the owner (n=1).

The mean (± SD, range) weight of the nine cats that experienced adverse effects was 6.3 (±1.67, 3.9 to 9.0) kg. The mean weight of 16 cats that did not experience adverse effects was 5.38 (±1.35, 3.4 to 9.0) kg. There was no statistical correlation (P=0.99) between body weight and the occurrence of adverse effects. Among 16 cats that did not experience overt adverse reactions to 60 mg of extended-release diltiazem, the mean (± SD, range) time of follow-up was 24.1 (±16.17, 2.5 to 60) months. The mean (± SD, range) duration of treatment until adverse effects were observed in the nine cats was 1.19 (±1.83, <0.25 to 6) months.