ANGIOLOGY The Journal
of Vascular Diseases
Comparative Effects of Digoxin and Xamoterol on Arrhythmias in Patients with Mild to Moderate Heart Failure Werner Klein, M.D., F.I.C.A. Bernd Eber, M.D., F.A.C.A. and Brigitte Rotman, M.D.
GRAZ, AUSTRIA
Abstract The prognosis of heart failure patients is poor and as many as half of the deaths are sudden and thereby presumably attributable to arrhythmias. In the present study the effect of traditional therapy of mild heart failure with digoxin on arrhythmias was compared with the effect of xamoterol, a cardioselective 1 partial agonist, which has in addition beta-blocking properties at higher beta levels of sympathetic tone. Fifteen patients (NYHA class II-III) were included in the study. After a two-week baseline period they were randomized to digoxin or xamoterol for four weeks followed by a two-week washout and another four weeks of crossover therapy. Heart rate, blood pressure, and the number of complex ventricular premature beats remained essentially unchanged with digoxin. With xamoterol heart rate increased from 86 to 93 (ns) but was significantly higher during the night in comparison with digoxin. The number of ventricular premature beats decreased from 186 ± 317 to 110 ± 137 and increased to 130 ± 175 after treatment. The number of runs decreased from 11 ± 35 to 2.7 ± 5 and increased to 5.6 ± 9 after therapy. In conclusion, no significant effect of digoxin or xamoterol on ventricular arrhythmias was found. However, xamoterol showed a tendency to reduce simple and complex ventricular arrhythmias in patients with mild to moderate heart failure.
From the Department of Internal Medicine, Cardiology Division, University of Graz, Graz, Austria Presented at the 37th Annual Meeting, American College of Angiology, Atlanta, Georgia, October 1990
281
Downloaded from ang.sagepub.com at NORTH DAKOTA STATE UNIV LIB on June 4, 2015
282 Introduction Heart failure is
increasingly common form of cardiovascular death owing in part to improvements in the outcome of patients with ischemic heart disease, which is its most common etiology. The prognosis of heart failure patients is poor and as many as half of the deaths are sudden and thus presumably attributable to arrhythmias.’ There is increasing evidence that the prognosis in patients following a myocardial infarction is strongly related to the extent of left ventricular dysfunction2-4 and not to the degree of ongoing ischemia.’ The degree of left ventricular dysfunction is likely to be an important etiologic factor in the development of ventricular arrhythmias in these patients. It is unclear, however, whether traditional approaches to the treatment of mild heart failure, such as digoxin, may not only fail to improve prognosis but may even worsen prognosis in patients with left ventricular dysfunction following myocardial infarction. 6,7 There is increasing evidence that beta blockers will evidently increase survival after myocardial infarction, but the individual subgroups who benefit most are less well documented.’ The improved rate of survival in moderately severe heart failure is probably related, however, to an improvement in left ventricular function.5 Yet, conventional beta blockers do not invariably improve left ventricular function and thus necessarily act an
via other mechanisms in cases of mild failure. In order to activate beta-receptor modulation, a new medication with xamoterol was introduced.9 It represents a cardioselective beta, partial agonist, with only 45 070 of the intrinsic activity of isoprenaline. Xamoterol will improve left ventricular function both at rest and at exercise, with additional beta-blocking properties at high levels of sympathetic tone. 10-12 Long-term studies in heart failure have shown that only few adverse events attricutable to xamoterol were reported during three month efficacy studies in more than 600 patients and that the laboratory safety profile over one year treatment was good.l3 Xamoterol is, therefore, particularly suitable for patients with poor left ventricular function with or without continuous evidence of active ischemia. Xamoterol tends to reduce noradrenaline levels at rest.’4 Thus, it not only modifies the effects of increased levels of sympathetic tone through the betal receptor but may also reduce basal levels of sympathetic
activity. In the present study of patients with mild to moderate heart failure due to myocardial infarction, the effects of digoxin and xamoterol on ventricular arrhythmias and heart rate were
compared. Materials and Methods
Patients Patients were selected from those presenting with symptoms of mild to moderate cardiac failure (NYHA class II-III) as a consequence of myocardial infarction. They were either untreated, with regard to cardioactive medication, or receiving regular therapy with digitalis or digitalis plus diuretic.
Downloaded from ang.sagepub.com at NORTH DAKOTA STATE UNIV LIB on June 4, 2015
283
FIG. 1. Trial design. P = placebo, AEM ambulatory electrocardio=
graphic monitoring.
Excluded were premenopausal women; patients more than seventy-five years old; patients with symptoms or history of asthma; patients with supraventricular tachycardia including sinus rhythm exceeding 120 beats/minute, ventricular tachycardia, R-on-T beats, aortic stenosis, or hypertrophic obstructive cardiomyopathy; patients with serious renal, hemopoietic, hepatic, or endocrine disorders; and patients receiving concomitant therapy with beta blockers, vasodilators, or antiarrhythmics. Altogether, 15 patients (10 men, 5 women) were included into the study; their mean age
was
Design
fifty-eight
years.
of the study
This was a double-blind, within-patient comparison of digoxin and xamoterol. After two-week baseline single-blind running period, patients were randomized to digoxin or xamoterol for four weeks, followed by a two-week washout period and another four weeks a
of
crossover
treatment
(Figure 1).
Dosage Oral doses of digoxin (0.125 mg) and xamoterol (200 mg) were given twice daily. Placebo tablets were given twice daily during the run-in and washout periods. Assessments The following assessments were done at the end of the run-in period, the first treatment period of four weeks, the washout period, and the second treatment period: heart rate, blood pressure, effort tolerance, functional capacity, adverse symptoms, ambulatory Holter monitoring, hematology, biochemistry, and plasma xamoterol and digoxin concentrations.
Statistics
Digoxin and xamoterol were compared by an analysis of variance with respect to heart rate, blood pressure, exercise tolerance, and Holter data at two, six, eight and twelve weeks. Significance
was
assessed
by
an
F test.
Downloaded from ang.sagepub.com at NORTH DAKOTA STATE UNIV LIB on June 4, 2015
284 Results All
patients completed the study. Functional assessment was essentially unchanged throughout the study. Plasma concentrations of xamoterol (range 3.7-200 ng/mL) and digoxin (range 0.3-1.48 ng/mL) reflected the randomization schedule. There were no changes of clinical relevance in routine safety tests of blood and urine. Ambulatory ECG data The mean number of ventricular premature beats (VPBs) before digoxin was 85.3, the number of couplets and salves was together 4.4. With digoxin, the mean number of VPBs increased to 133.8 (ns), and the numbers of couplets and salves remained with 4.0
unchanged.
FIG. 2. Mean heart rate over 24 hours during digoxin and xamoterol medication, as well as in the placebo period.
In the xamoterol patients, the number of ectopic beats during placebo was 187.5, and the number of couplets and salvos was 11.0 before treatment. Xamoterol reduced the number of ectopic beats to 110.4, and the number of couplets and salvos to 2.7, which was also not significant. At the end of the last placebo period, the number of ectopic beats increased again to 129.6 and the number of couplets to 5.6. None of the tapes showed periods of S-A block, A-V block, asystole, or ventricular flutter or fibrillation. Heart rate and blood pressure remained unchanged with digoxin, and heart rate increased with xamoterol from 86 to 93 beats per minute (bpm) (ns). Blood pressure did not change with xamoterol either. In Figure 2 the mean heart rates over the twenty-four hour period are depicted. During the fourteen hours of wakefulness, the heart rate did not differ among
Downloaded from ang.sagepub.com at NORTH DAKOTA STATE UNIV LIB on June 4, 2015
285 the xamoterol, the digoxin, and the placebo groups. However, during the eight hours of sleep, the heart rate was significantly higher in the xamoterol-treated group (p
of Vascular Diseases
Comparative Effects of Digoxin and Xamoterol on Arrhythmias in Patients with Mild to Moderate Heart Failure Werner Klein, M.D., F.I.C.A. Bernd Eber, M.D., F.A.C.A. and Brigitte Rotman, M.D.
GRAZ, AUSTRIA
Abstract The prognosis of heart failure patients is poor and as many as half of the deaths are sudden and thereby presumably attributable to arrhythmias. In the present study the effect of traditional therapy of mild heart failure with digoxin on arrhythmias was compared with the effect of xamoterol, a cardioselective 1 partial agonist, which has in addition beta-blocking properties at higher beta levels of sympathetic tone. Fifteen patients (NYHA class II-III) were included in the study. After a two-week baseline period they were randomized to digoxin or xamoterol for four weeks followed by a two-week washout and another four weeks of crossover therapy. Heart rate, blood pressure, and the number of complex ventricular premature beats remained essentially unchanged with digoxin. With xamoterol heart rate increased from 86 to 93 (ns) but was significantly higher during the night in comparison with digoxin. The number of ventricular premature beats decreased from 186 ± 317 to 110 ± 137 and increased to 130 ± 175 after treatment. The number of runs decreased from 11 ± 35 to 2.7 ± 5 and increased to 5.6 ± 9 after therapy. In conclusion, no significant effect of digoxin or xamoterol on ventricular arrhythmias was found. However, xamoterol showed a tendency to reduce simple and complex ventricular arrhythmias in patients with mild to moderate heart failure.
From the Department of Internal Medicine, Cardiology Division, University of Graz, Graz, Austria Presented at the 37th Annual Meeting, American College of Angiology, Atlanta, Georgia, October 1990
281
Downloaded from ang.sagepub.com at NORTH DAKOTA STATE UNIV LIB on June 4, 2015
282 Introduction Heart failure is
increasingly common form of cardiovascular death owing in part to improvements in the outcome of patients with ischemic heart disease, which is its most common etiology. The prognosis of heart failure patients is poor and as many as half of the deaths are sudden and thus presumably attributable to arrhythmias.’ There is increasing evidence that the prognosis in patients following a myocardial infarction is strongly related to the extent of left ventricular dysfunction2-4 and not to the degree of ongoing ischemia.’ The degree of left ventricular dysfunction is likely to be an important etiologic factor in the development of ventricular arrhythmias in these patients. It is unclear, however, whether traditional approaches to the treatment of mild heart failure, such as digoxin, may not only fail to improve prognosis but may even worsen prognosis in patients with left ventricular dysfunction following myocardial infarction. 6,7 There is increasing evidence that beta blockers will evidently increase survival after myocardial infarction, but the individual subgroups who benefit most are less well documented.’ The improved rate of survival in moderately severe heart failure is probably related, however, to an improvement in left ventricular function.5 Yet, conventional beta blockers do not invariably improve left ventricular function and thus necessarily act an
via other mechanisms in cases of mild failure. In order to activate beta-receptor modulation, a new medication with xamoterol was introduced.9 It represents a cardioselective beta, partial agonist, with only 45 070 of the intrinsic activity of isoprenaline. Xamoterol will improve left ventricular function both at rest and at exercise, with additional beta-blocking properties at high levels of sympathetic tone. 10-12 Long-term studies in heart failure have shown that only few adverse events attricutable to xamoterol were reported during three month efficacy studies in more than 600 patients and that the laboratory safety profile over one year treatment was good.l3 Xamoterol is, therefore, particularly suitable for patients with poor left ventricular function with or without continuous evidence of active ischemia. Xamoterol tends to reduce noradrenaline levels at rest.’4 Thus, it not only modifies the effects of increased levels of sympathetic tone through the betal receptor but may also reduce basal levels of sympathetic
activity. In the present study of patients with mild to moderate heart failure due to myocardial infarction, the effects of digoxin and xamoterol on ventricular arrhythmias and heart rate were
compared. Materials and Methods
Patients Patients were selected from those presenting with symptoms of mild to moderate cardiac failure (NYHA class II-III) as a consequence of myocardial infarction. They were either untreated, with regard to cardioactive medication, or receiving regular therapy with digitalis or digitalis plus diuretic.
Downloaded from ang.sagepub.com at NORTH DAKOTA STATE UNIV LIB on June 4, 2015
283
FIG. 1. Trial design. P = placebo, AEM ambulatory electrocardio=
graphic monitoring.
Excluded were premenopausal women; patients more than seventy-five years old; patients with symptoms or history of asthma; patients with supraventricular tachycardia including sinus rhythm exceeding 120 beats/minute, ventricular tachycardia, R-on-T beats, aortic stenosis, or hypertrophic obstructive cardiomyopathy; patients with serious renal, hemopoietic, hepatic, or endocrine disorders; and patients receiving concomitant therapy with beta blockers, vasodilators, or antiarrhythmics. Altogether, 15 patients (10 men, 5 women) were included into the study; their mean age
was
Design
fifty-eight
years.
of the study
This was a double-blind, within-patient comparison of digoxin and xamoterol. After two-week baseline single-blind running period, patients were randomized to digoxin or xamoterol for four weeks, followed by a two-week washout period and another four weeks a
of
crossover
treatment
(Figure 1).
Dosage Oral doses of digoxin (0.125 mg) and xamoterol (200 mg) were given twice daily. Placebo tablets were given twice daily during the run-in and washout periods. Assessments The following assessments were done at the end of the run-in period, the first treatment period of four weeks, the washout period, and the second treatment period: heart rate, blood pressure, effort tolerance, functional capacity, adverse symptoms, ambulatory Holter monitoring, hematology, biochemistry, and plasma xamoterol and digoxin concentrations.
Statistics
Digoxin and xamoterol were compared by an analysis of variance with respect to heart rate, blood pressure, exercise tolerance, and Holter data at two, six, eight and twelve weeks. Significance
was
assessed
by
an
F test.
Downloaded from ang.sagepub.com at NORTH DAKOTA STATE UNIV LIB on June 4, 2015
284 Results All
patients completed the study. Functional assessment was essentially unchanged throughout the study. Plasma concentrations of xamoterol (range 3.7-200 ng/mL) and digoxin (range 0.3-1.48 ng/mL) reflected the randomization schedule. There were no changes of clinical relevance in routine safety tests of blood and urine. Ambulatory ECG data The mean number of ventricular premature beats (VPBs) before digoxin was 85.3, the number of couplets and salves was together 4.4. With digoxin, the mean number of VPBs increased to 133.8 (ns), and the numbers of couplets and salves remained with 4.0
unchanged.
FIG. 2. Mean heart rate over 24 hours during digoxin and xamoterol medication, as well as in the placebo period.
In the xamoterol patients, the number of ectopic beats during placebo was 187.5, and the number of couplets and salvos was 11.0 before treatment. Xamoterol reduced the number of ectopic beats to 110.4, and the number of couplets and salvos to 2.7, which was also not significant. At the end of the last placebo period, the number of ectopic beats increased again to 129.6 and the number of couplets to 5.6. None of the tapes showed periods of S-A block, A-V block, asystole, or ventricular flutter or fibrillation. Heart rate and blood pressure remained unchanged with digoxin, and heart rate increased with xamoterol from 86 to 93 beats per minute (bpm) (ns). Blood pressure did not change with xamoterol either. In Figure 2 the mean heart rates over the twenty-four hour period are depicted. During the fourteen hours of wakefulness, the heart rate did not differ among
Downloaded from ang.sagepub.com at NORTH DAKOTA STATE UNIV LIB on June 4, 2015
285 the xamoterol, the digoxin, and the placebo groups. However, during the eight hours of sleep, the heart rate was significantly higher in the xamoterol-treated group (p
