Page 159 - Feline Cardiology

158 Section D: Cardiomyopathies

regular or sustained release preparation is prescribed, Neurohormonal Antagonists in
the drug name remains diltiazem hydrochloride, so the Asymptomatic HCM
clinician must be careful not to confuse the prepara-
tions when writing prescriptions. The nonsustained There is a logical rationale for early use of an ACE inhib-
release standard formulation (Diltiazem HCl, Cardizem) itor (e.g., enalapril, benazepril, ramipril), angiotensin
is typically dosed at 7.5 mg PO q 8 h and can be slightly receptor blocker (e.g., losartan, irbesartan), or aldoste-
up-titrated if needed. Owner compliance of administer- rone antagonist (e.g., spironolactone) for reduction of
ing q 8 h dosing frequency for the life of the cat is of left ventricular hypertrophy and fibrosis in HCM, since
concern. There is much higher bioavailability of stan- these pharmacologic agents have been shown to exert
dard diltiazem in cats (71%) compared to dogs (17%). antihypertrophic and antifibrotic effects in other cardiac
Cardiomyopathies a terminal half-life of 113 minutes (Johnson et al. 1996). et al. 2001; Linz et al. 2004; Zhu et al. 1997; Schmieder
diseases and in transgenic rodent models of HCM (Lim
Time to peak concentration postpill is 45 minutes, with
et al. 1996; Tsybouleva et al. 2004). Unfortunately, in
Cardizem CD is a sustained release formulation which
veterinary medicine, we are limited by a lack of clinical
is available as a 180 mg capsule that is filled with hun-
studies that confirm or deny benefit of treatment in
dreds of microspheres, and can be divided by a com-
pounding pharmacy to 45 mg doses placed in smaller
with the remaining choice of theoretical rationale,
gelatin capsules, to be administered as 45 mg PO q 24 hr many diseases such as HCM, so often clinicians are faced
or 10 mg/kg PO q 24 hr (Johnson et al. 1996). Cardizem extrapolations from other species, and clinical experi-
CD has half the bioavailability of the conventional ence. Cardiac effects of pharmacologic therapy may be
preparation. The time to peak concentration is 340 different in cats with spontaneously occurring HCM
minutes and terminal half-life is 410 minutes. compared to transgenic models of HCM in mice and
Pharmacodynamic effects on heart rate and PR interval rabbits, so data cannot be directly extrapolated from
were studied in healthy cats, and neither conventional laboratory studies to clinical feline medicine. Four
nor CD formulation reduced heart rate or prolonged studies have evaluated RAAS antagonists for treatment
PR interval, despite blood concentrations within the of asymptomatic cats with HCM (MacDonald et al.
therapeutic range defined in people. Dilacor XR is 2006b; MacDonald et al. 2008; Rush et al. 1998; Amberger
another sustained-release form of diltiazem, and it is et al. 1999). The first study was a randomized, placebo
supplied as 120 mg, 180 mg, and 240 mg capsules, con- controlled, double blinded, prospective design, which
taining 2, 3, or 4 60 mg sustained release tablets, respec- evaluated the effect of ramipril on LV mass quantified
tively, which are removed from the gelatin capsule and by cardiac MRI, diastolic function quantified by pulsed-
then broken in half and given at 30 mg PO q 24 hr. A wave tissue Doppler imaging, neurohormones (plasma
pharmacologic study of Dilacor XR in normal cats and aldosterone and BNP concentrations), and blood pres-
cats with HCM showed that 30 or 60 mg PO q 24 hr sure in 26 asymptomatic Maine coon cats with mild to
produced erratic blood levels of diltiazem; many cats severe familial HCM (MacDonald et al. 2006b). There
had higher than the recommended range of blood was no difference in LV mass, diastolic function, delayed
concentration for 12 hours, and less than recommended contrast enhancement assessment of myocardial fibro-
range at 18 and 24 hours postpill (Wall et al. 2005). sis, blood pressure, or neurohormones between the
Thirty-six percent of cats with HCM had adverse reac- placebo and ramipril treatment groups over 12 months
tions, consisting of decreased appetite, vomiting, leth- of therapy. Approximately 60–70% of cats treated with
argy, weight loss, and diarrhea. Therefore, sustained- ramipril had elevated plasma aldosterone concentration,
release diltiazem is no longer recommended (and may demonstrating the phenomenon of ACE escape that is
even be considered as relatively contraindicated due to also seen in people and dogs treated with ACE inhibi-
these limitations) in cats. tors. It is likely that persistent elevations of plasma aldo-
There are only two small but important studies sterone in the face of low plasma ACE activity may have
evaluating diltiazem in asymptomatic cats with HCM, been due to alternative tissue-dependent pathways of
with disparate results as described above (see Drug ATI conversion to ATII, mainly chymase. In contradic-
selection for treating asymptomatic HCM in cats, tion to the first study, two small, uncontrolled or retro-
above). Therefore, given the possibility of adverse spective studies reported that ACE inhibitors reduced LV
effects (sustained-release diltiazem) versus q 8h dosing hypertrophy assessed by echocardiography (Rush et al.
schedule (regular diltiazem), and lack of demonstrated 1998; Amberger et al. 1999). The first of the two studies
superiority over atenolol, calcium channel blockers was a randomized, open-label prospective clinical study
have largely been replaced by atenolol in feline of benazepril in 28 cats with HCM (Amberger et al.
cardiology. 1999). All cats were treated with a background (stan-