Ki Lie

Propafenone versus disopyramide for maintenance of sinus rhythm after electrical cardioversion of chronic atrial fibrillation: A randomized, double-blind study

SummarySafety and efficacy of propafenone and disopyramide for long-term maintenance of sinus rhythm after electrical cardioversion was studied in 56 patients with chronic altrial fibrillation (median arrhythmia duration, 5 months). After cardioversion, patients were randomly assigned to receive double-blind propafenone 300 mg tid (25 patients) or disopyramide 250 mg tid (31 patients). Downward dose adjustment was allowed in case of intolerable side effects. The endpoints were arrhythmia recurrence; and side effects not amenable to dose reduction. For patients randomized to propafenone (mean dose, 878±65 mg/day), 66% [95% confidence interval [(CI) 46–85%] and 55% (95% CI, 34–76%) remained in sinus rhythm at 3 and 6 months, respectively (Kaplan-Meier method). Similar figures were found with disopyramide (mean dose, 704±81 mg/day): 71% (95% CI, 54–87%) and 67% (95% CI, 50–84%) at 3 and 6 months, respectively (p=NS). In the patients with a relapse of atrial fibrillation, the ventricular rate while still using the prophylactic agents did not increase significantly compared with precardioversion. However, one patient on disopyramide had an excessively high relapse heart rate (170 vs. 100 beats/min). Side effects were more frequent on disopyramide. Side effects necessitating drug discontinuation occurred in 12 patients: 4 patients (16%) on propafenone and 8 (26%) on disopyramide. Severe adverse effects occurred in two patients, who developed heart failure while on disopyramide. There were no proarrhythmic events or deaths. Thus, propafenone and disopyramide are equally effective for maintaining sinus rhythm after cardioversion of atrial fibrillation. Propafenone is, however, better tolerated than disopyramide, which may cause heart failure.

Heart rate variability in patients with mild to moderate heart failure: Effects of neurohormonal modulation by digoxin and ibopamine

OBJECTIVES: This study assessed the effects of digoxin and ibopamine on variables of heart rate variability in relation to neurohormonal activation. BACKGROUND: Analysis of heart rate variability can be used to study the autonomic dysfunction that characterizes chronic heart failure. In the Dutch Ibopamine Multicenter Trial, patients with heart failure were found to have increased neurohormonal activation with placebo therapy but not with digoxin and ibopamine therapy. METHODS: We studied 59 patients with mild to moderate heart failure (mean [+/- SEM] age 60 +/- 1 years, mean ejection fraction 0.30 +/- 0.01). Patients were randomized to double-blind treatment with digoxin (0.25 mg [n = 22]), ibopamine (100 mg three times a day [n = 19]) or placebo (n = 18); background therapy consisted of furosemide (up to 80 mg). RESULTS: After 3 months, plasma norepinephrine levels had increased with placebo, whereas they decreased with digoxin (+31 vs. -60 pg/ml, respectively, p 50 ms (pNN50) increased (+ 1.7 +/- 0.9%, p < 0.01), along with absolute and normalized high frequency power (+ 40 +/- 33 ms2, p < 0.05 and + 2.4 +/- 1.7%, p < 0.01, respectively). These changes were observed during daytime hours only and were most pronounced in patients with the most impaired baseline heart rate variability. With ibopamine, nonsignificant trends similar to the changes with digoxin were observed. CONCLUSIONS: In patients with early stages of heart failure, digoxin may prevent a progressive deterioration in heart rate variability, whereas ibopamine does not show statistically significant effects. The changes in heart rate variability with digoxin parallel an observed decrease in neurohormonal activation. Digoxin apparently enhances cardiac vagal tone in the setting of neuroendocrine activation.

FLECAINIDE VERSUS QUINIDINE IN THE PREVENTION OF PAROXYSMS OF ATRIAL-FIBRILLATION

We compared the efficacy of flecainide versus quinidine in preventing paroxysms of atrial fibrillation in a randomized open crossover study. Twenty-six patients with weekly attacks of atrial fibrillation during the last 3 months, objectified by 24-h holter monitoring or 12-lead electrocardiogram (ECG) were treated for a period of 3 months with flecainide 100 mg b.i.d. or quinidine 500 mg b.i.d. Efficacy was assessed by 24-h holter monitoring and a questionnaire at the end of each month. Dosage was adjusted to flecainide 100 mg t.i.d. or quinidine 500 mg t.i.d. if patients still had symptomatic paroxysms of atrial fibrillation according to a questionnaire or on holter monitoring. In 46% of the patients, flecainide 100 mg b.i.d. caused total abolition of supraventricular tachycardia; after dose adjustment it caused 50% total abolition. For quinidine, the figures are 16% (p less than 0.05) and 32% (NS), respectively. Side effects occurred with flecainide only after dose adjustment (23%), but on quinidine they occurred before (8%) and after dose adjustment (20%). We conclude that flecainide suppresses paroxysms of atrial fibrillation significantly more often as compared with quinidine in the lower dosage regimen. Optimal treatment dosage of flecainide is 100 mg b.i.d. After quinidine dose adjustment, the difference in efficacy is no longer significant. However, side effects necessitating discontinuation of quinidine developed in 20% of the patients as compared to none in patients treated with flecainide 100 mg b.i.d.

Dose-finding study of imidapril, a novel angiotensin converting enzyme inhibitor, in patients with stable chronic heart failure

Objective: To study the haemodynamic profile and tolerability of imidapril, a new long-acting ACE inhibitor, and to investigate the effect of inhibition of circulating ACE on blood pressure in patients with stable chronic heart failure. Methods:Twenty-four patients with stable, chronic heart failure (New York Heart Association (NYHA) functional Class II–III) were randomised to receive either 2.5 mg or 5 mg imidapril. Other vasodilators were withheld for ≥ 5 half-lives. Blood pressure and ACE activity were carefully monitored for 24 h after dosing. Results:Both 2.5 mg and 5 mg imidapril decreased systolic blood pressure, while diastolic blood pressure fell only after 5 mg imidapril. The two doses produced a significant and similar inhibition of circulating (serum) ACE. No serious adverse effects were observed, although symptomatic hypotension occurred in 1 patient (5 mg). The decrease in blood pressure was not related to baseline ACE activity, serum sodium or serum creatinine concentration. Conclusions:Imidapril significantly lowered systolic blood pressure and was well tolerated. The difference in the first dose response to the two doses with respect to diastolic blood pressure suggests that this haemodynamic effect of ACE-inhibition is not related to inhibition of circulating ACE.

Effect of ibopamine on ventricular remodeling after experimental myocardial infarction: a comparison with captopril.

Remodeling after myocardial infarction (MI) is influenced not only by hemodynamic but possibly by neurohumoral factors as well. Ibopamine is an orally active dopamine agonist (DA) with both hemodynamic and neurohumoral properties in humans. The latter property prevails in rats. To study the dose-dependent effect of ibopamine on myocardial remodeling and compare it with the effect of captopril, we randomized rats with (n = 27) or without (n = 27) experimental MI to captopril (25 mg/kg/day), low-dose ibopamine (10 mg/kg/day), high-dose ibopamine (30 mg/kg/day), or no treatment. After 8-week treatment, hearts were isolated and left ventricular (LV) function, LV cavity volume, and infarct size (IS) were evaluated. Both ibopamine and captopril significantly reduced plasma norepinephrine (NE) levels in rats with MI. In untreated but not in treated infarcted rats, LV function was significantly reduced as compared with that of controls. IS was reduced in all three active treatment groups as compared with untreated rats. LV cavity volume was significantly increased in untreated rats with MI as compared with controls. This dilatation was attenuated by both ibopamine and captopril. Ibopamine, comparable to captopril, administered early after coronary ligation reduced IS and subsequent ventricular dilatation, resulting in preservation of cardiac function in this rat model. This observation suggests a major role for neurohumoral activation in the process of remodeling.

Alterations in the Prognosis of Chronic Heart Failure: An Overview of the Major Mortality Trials

Treatment of chronic heart failure (CHF) remains a major medical problem. Although in the last decades the benefits of several therapies in different patient populations with left ventricular dysfunction have been established, morbidity and mortality of CHF patients are high. Consequently, in the last decade improvement of survival has become the primary therapeutic endpoint in CHF studies, and the evaluation of the influence of (new) drugs on mortality has become crucial. In the present article an overview of the large mortality trials is given, and the shifts and alterations in the drug treatment strategy of CHF are discussed.

NEUROHUMORAL AND HEMODYNAMIC-EFFECTS OF IBOPAMINE IN A RAT MODEL OF CHRONIC MYOCARDIAL-INFARCTION AND HEART-FAILURE

SummaryThere is increasing evidence that both neurohumoral and hemodynamic factors play a role in disease progression in chronic heart failure (CHF). To examine the influence of the oral dopamine agonist ibopamine on these factors, we studied 20 rats with chronic myocardial infarction and CHF, and compared them with 20 normal rats. After 6 weeks, rats were randomly divided between control treatment (50%) or ibopamine (50%) for 3 weeks. At the end of the study, plasma and tissue neurohumoral parameters, as well as hemodynamics, were determined. In infarcted rats, the elevated plasma norepinephrine (PNE) levels were reduced by ibopamine (251±19 vs. 138±32 pg/ml; p<0.05). Other plasma neurohormones measured (epinephrine, renin, aldosterone, and angiotensin converting enzyme [ACE]) were not significantly increased in rats with myocardial infarction and were not affected by ibopamine. Cardiac (tissue) ACE was increased in infarcted rats (12.1±1.9 U/l/min) and was significantly lowered by ibopamine (9.6±1.0 U/l/min; p<0.05); renal ACE was unaffected. Blood pressure and heart rate were similar in the two groups and were not influenced by ibopamine treatment. In conclusion, in chronic myocardial infarction and CHF in rats, ibopamine reduces the elevated levels of PNE and cardiac ACE. Further research will be needed to determine whether this effect may lead to a favorable influence on disease progression in CHF.

ELECTROPHYSIOLOGIC AND PHARMACOKINETIC PROFILE OF THE NEW ANTIARRHYTHMIC DRUG TYB-3823 IN HUMANS

In an open-label study, electrophysiology and pharmacokinetics of TYB-3823, a new antiarrhythmic compound, were investigated. Sixteen patients underwent an electrophysiologic study before and after intravenous (i.v.) administration of TYB-3823. Two patients each received the following increasing doses: 0.2, 0.4, 0.8, and 1 mg/kg. Eight patients received 1.2-mg/kg. TYB-3823 concentrations followed a biexponential decrease with a terminal half-life (t1/2) of 3.88 ± 0.87 h. Clearance was 47.2 ± 18.5 L/h, and volume of distribution was 250 ± 77 L. Dose-dependent pharmacokinetics were evident. Significant effects of TYB-3823 were apparent at doses ≥0.8 mg/kg (n = 12), including increase in the AH and HV interval from 92 ± 17 to 105 ± 19 ms (p < 0.002) and 47 ± 7 to 60 ± 12 ms (p < 0.005), respectively. QRS duration was prolonged from 100 ± 16 to 126 ± 22 ms (p < 0.001), accompanied by an increase of the corrected QT interval from 425 ± 28 to 465 ± 37 ms (p < 0.002). The corrected JT interval remained unchanged, however, refractoriness did not change, but monophasic action potential duration (APD) tended to decrease. TYB-3823 appeared effective against reinduction of all arrhythmias observed during the control study [atrial fibrillation, atrioventricular (AV) nodal tachycardias]. TYB-3823 depresses conduction velocity significantly without prolonging refractoriness. Therefore, TYB-3823 may be classified as a class 1C antiarrhythmic. On the basis of the present results, additional class 1B activity cannot be excluded. TYB-3823 has antiarrhythmic properties, appears to be devoid of proarrhythmic effects, and is well tolerated.

RENAL AND SYSTEMIC HEMODYNAMIC-EFFECTS OF IBOPAMINE IN PATIENTS WITH MILD-TO-MODERATE CONGESTIVE-HEART-FAILURE

Summary To study the hemodynamic and renal effects of the orally (p. o.) active dopamine (DA) agonist ibopamine, we examined 10 patients with mild to moderate congestive heart failure (CHF). who were stable while treated with digoxin and diuretics. All patients were in New York Heart Association (NYHA) functional class II-III; their mean age was 63 years (range 51–79 years), and mean left ventricular ejection fraction (LVEF) was 28% (range 18–360%). The protocol consisted of a control study-day with measurements of renal characteristics including glomerular filtration rate (GFR). effective renal plasma How (ERPF), and filtration fraction (FF). One-week later, systemic and renal hemodynamics were measured simultaneously before and after patients received one 100-mg tablet of ibopamine. Ibopamine caused a slight but significant increase in both FRPF (from 288 ± 32 ml/min/1.73 m2 at baseline to 316 ± 32 ml/min/1.73 m2 after ibopamine) and GFR (from 77 ± 8 to 85 ± 8 ml/min/1.73 m2; both p < 0.05); FF was not affected (mean value 0.26 ± 0.02). Sodium excretion was not influenced by ibopamine. but diuresis increased significantly. Cardiac output (CO) increased significantly (from 4.0 ± 0.4 L/min at baseline to a maximum of 5.0 L/min after ibopamine, p < 0.05). mainly due to decreased systemic vascular resistance (SVR). Heart rate (HR) and blood pressure (BP) were unchanged throughout the studies. The percentage of contribution of CO to renal blood flow (RBF) was not significantly affected by ibopamine. In conclusion, ibopamine causes a slight but significant increase in both ERPF and GFR and a significant increase in diuresis, but no increase in sodium excretion in patients with mild to moderate CHF. In addition, the drug increases CO and decreases SVR to a similar extent. Therefore, the renal effects of ibopamine with equal pre- and postglomerular vasodilation, appear to be primarily due to its systemic hemodynamic effects.

ELECTROPHYSIOLOGICAL PROPERTIES OF ISRADIPINE (PN200-110) IN HUMANS

Isradipine (PN 200–110) is a new dihydropyridine calcium-entry blocker with powerful vasodilating properties. Therapeutic concentrations do not affect myocardial contractility. However, in vitro studies have demonstrated at higher concentrations negative chronotropic action with only minor dromotropic influence. For this reason we studied the effect of intravenous isradipine (0.3 μg/kg/min during 30 min) on sinus node and atrioventricular (AV) nodal function in 25 patients. Nine of these patients had normal sinus node function (group I), nine patients were treated with a β blocker (group II), and seven patients had a sick sinus syndrome (group III). Mean supine arterial blood pressure decreased in all groups; however, in group I not significantly. Spontaneous sinus cycle length decreased significantly in all groups. In none of the patients effective refractory periods of atrium or ventricle were depressed. QRS duration was not significantly affected in any of the groups. There was only a slight, but significant, prolongation of the QTc of maximal 4% (except in group III). We concluded that isradipine has no depressant effect on sinus and AV nodal function in humans, not even in the presence of β blockade or impaired sinus node function.