Bramah N. Singh

Amiodarone in Patients with Congestive Heart Failure and Asymptomatic Ventricular Arrhythmia

BACKGROUND Asymptomatic ventricular arrhythmias in patients with congestive heart failure are associated with increased rates of overall mortality and sudden death. Amiodarone is now used widely to prevent ventricular tachycardia and fibrillation. We conducted a trial to determine whether amiodarone can reduce overall mortality in patients with congestive heart failure and asymptomatic ventricular arrhythmias. METHODS We used a double-blind, placebo-controlled protocol in which 674 patients with symptoms of congestive heart failure, cardiac enlargement, 10 or more premature ventricular contractions per hour, and a left ventricular ejection fraction of 40 percent or less were randomly assigned to receive amiodarone (336 patients) or placebo (338 patients). The primary end point was overall mortality, and the median follow-up was 45 months (range, 0 to 54). RESULTS There was no significant difference in overall mortality between the two treatment groups (P = 0.6). The two-year actuarial survival rate was 69.4 percent (95 percent confidence interval, 64.2 to 74.6) for the patients in the amiodarone group and 70.8 percent (95 percent confidence interval, 65.7 to 75.9) for those in the placebo group. At two years, the rate of sudden death was 15 percent in the amiodarone group and 19 percent in the placebo group (P = 0.43). There was a trend toward a reduction in overall mortality among the patients with nonischemic cardiomyopathy who received amiodarone (P = 0.07). Amiodarone was significantly more effective in suppressing ventricular arrhythmias and increased the left ventricular ejection fraction by 42 percent at two years. CONCLUSIONS Although amiodarone was effective in suppressing ventricular arrhythmias and improving ventricular function, it did not reduce the incidence of sudden death or prolong survival among patients with heart failure, except for a trend toward reduced mortality among those with nonischemic cardiomyopathy.

Rhythm control versus rate control for atrial fibrillation and heart failure.

BACKGROUND It is common practice to restore and maintain sinus rhythm in patients with atrial fibrillation and heart failure. This approach is based in part on data indicating that atrial fibrillation is a predictor of death in patients with heart failure and suggesting that the suppression of atrial fibrillation may favorably affect the outcome. However, the benefits and risks of this approach have not been adequately studied. METHODS We conducted a multicenter, randomized trial comparing the maintenance of sinus rhythm (rhythm control) with control of the ventricular rate (rate control) in patients with a left ventricular ejection fraction of 35% or less, symptoms of congestive heart failure, and a history of atrial fibrillation. The primary outcome was the time to death from cardiovascular causes. RESULTS A total of 1376 patients were enrolled (682 in the rhythm-control group and 694 in the rate-control group) and were followed for a mean of 37 months. Of these patients, 182 (27%) in the rhythm-control group died from cardiovascular causes, as compared with 175 (25%) in the rate-control group (hazard ratio in the rhythm-control group, 1.06; 95% confidence interval, 0.86 to 1.30; P=0.59 by the log-rank test). Secondary outcomes were similar in the two groups, including death from any cause (32% in the rhythm-control group and 33% in the rate-control group), stroke (3% and 4%, respectively), worsening heart failure (28% and 31%), and the composite of death from cardiovascular causes, stroke, or worsening heart failure (43% and 46%). There were also no significant differences favoring either strategy in any predefined subgroup. CONCLUSIONS In patients with atrial fibrillation and congestive heart failure, a routine strategy of rhythm control does not reduce the rate of death from cardiovascular causes, as compared with a rate-control strategy. (ClinicalTrials.gov number, NCT00597077.)

Verapamil: A Review of its Pharmacological Properties and Therapeutic Use

SummarySynopsis: Verapamil is a novel antiarrhythmic and antianginal agent which, although introduced in 1962, has only recently gained prominence not only as a significant agent in cardiovascular therapeutics but also as a powerful tool to examine the nature of some of the biophysical phenomena at the membrane of cardiac and other excitable tissues. Verapamil is the prototype of those agents which selectively inhibit membrane transport of calcium, an action which accounts for the drug’s peripheral and coronary vasodilator properties, its effect on excitation-contraction coupling and hence its negative inotropic propensity, as well as its depressant effects on the sinus node and atrioventricular conduction. Its pharmacological effects are largely independent of the autonomic nervous system. The main therapeutic uses of the drug are in the management of atrial tachyarrhythmias, angina, and possibly hypertension. The overall experimental and clinical data suggest that verapamil will become an important and safe addition to existing drug regimens, especially as an agent of choice for the short-term treatment of most cases of paroxysmal supraventricular tachycardias. The initial experience in other arrhythmias, angina and hypertension, is also sufficiently encouraging to justify further detailed clinical trials to define its potential role in cardiovascular therapeutics. Pharmacodynamic Properties: Verapamil is a weak local anaesthetic; it does not depress the upstroke velocity of the cardiac action potential, nor does it prolong the action potential duration in heart muscle. It selectively depresses nodal tissues, presumably by an effect on the calcium-mediated slow response, an action distinct from that of all other antiarrhythmic agents. Pharmacokinetics: Preliminary pharmacokinetic studies reveal major discrepancies between the duration of the electrophysiological and haemodynamic effects of verapamil and the presence of unchanged drug in the plasma, raising the possibility of active metabolites. Plasma protein binding of verapamil approaches approximately 90%. Despite almost complete gastrointestinal absorption following oral administration, the overall bioavailability of the drug is about 10 to 22% reflecting substantial first pass hepatic metabolism which may account for the 8 to 10-fold greater oral compared with intravenous doses needed to produce comparable pharmacodynamic effects. Therapeutic Trials: The antiarrhythmic effects of verapamil are explained largely by its action on the atrioventricular node: intravenously administered verapamil (10mg in adults, 3.5 to 5mg in children) produces prompt reversion to sinus rhythm of 80 to 100% of cases with paroxysmal supraventricular tachycardias, especially those due to AV nodal re-entry. The drug has little effect on the anomalous pathways in the Wolff-Parkinson-White syndrome so that atrial fibrillation or flutter complicating this disorder are not affected by verapamil, in contrast to other cases of atrial fibrillation or flutter in which the ventricular response is consistently reduced in most cases and sinus rhythm restored in a few. The role of oral verapamil used alone or in combination with other agents in the prophylaxis of paroxysmal supraventricular tachycardias and in the maintenance of sinus rhythm following cardioversion of atrial fibrillation remains to be defined. Verapamil is of little value in the control of ventricular arrhythmias.Verapamil is also effective in angina pectoris in doses in excess of 120mg 3 times daily orally. At this dose schedule, its efficacy is comparable with that of 80mg 3 times daily of oral propranolol, although the latter produces a significant degree of bradycardia whereas verapamil does not. The mode of antianginal action of verapamil is therefore not understood, but unlike propranolol the drug has no effects on lung function. Experimental studies suggest that verapamil might reduce myocardial infarct size and preliminary clinical studies raise the possibility that the drug may be of value in the management of acute hypertensive crisis as well as of treatment of essential hypertension. Side-effects: Orally administered verapamil is extremely well tolerated and few side-effects have been encountered following intravenous administration of the drug, especially when it is given slowly. Transient hypotension and prolongation of AV conduction time or even AV dissociation may occasionally be seen. Haemodynamic effects in patients with cardiac disease include short-lived decreases in mean arterial pressure, first derivative of the left ventricular pressure, systemic resistance and a rise in left ventricular filling pressure, but with little change in stroke volume, cardiac index or heart rate. Rarely, severe hypotension, bradycardia, or asystole have been reported, most cases occurring in patients previously treated with β-adrenoceptor blocking drugs. Precautions: Prior digitalisation is not a contraindication to the use of intravenous or oral verapamil, except in the case of the sick sinus syndrome in which verapamil alone or in combination with other depressant drugs which influence automaticity or conduction may produce severe bradycardia or atrioventricular block. The drug is also contraindicated in unstable atrioventricular block, heart failure (especially that complicating acute myocardial infarction), cardiogenic shock or other hypotensive states. Side-effects resulting from verapamil may be reversed, at least in part, by atropine, isoprenaline, intravenous calcium or glucagon, with ventricular pacing being required occasionally.

Spontaneous Conversion and Maintenance of Sinus Rhythm by Amiodarone in Patients With Heart Failure and Atrial Fibrillation Observations from the Veterans Affairs Congestive Heart Failure Survival Trial of Antiarrhythmic Therapy (CHF-STAT)

BACKGROUND In a multicenter, double-blind, placebo-controlled study, the long-term effects of amiodarone on morbidity and mortality in patients with congestive heart failure (CHF) and atrial fibrillation (AF) were evaluated during a 4-year period. METHODS AND RESULTS Of 667 patients with CHF, 103 (15%) had AF at baseline. Of these, 51 were randomized to amiodarone and 52 to placebo. The group with sinus rhythm and the group in AF were comparable except for a higher proportion of AF in patients with nonischemic versus ischemic cardiomyopathy (41% versus 27%, P<0.005). The mean ventricular response (VR) during AF over 24 hours was reduced by amiodarone at 2 weeks (20%, P=0.001), at 6 months (18%, P=0.001), and at 12 months (16%, P=0.006). Maximal VR was reduced 22% (P=0.001) at 2 weeks, 19% (P=0.001) at 6 months, and 14% (P=0.001) at 12 months. Sixteen of 51 patients on amiodarone and 4 of 52 on placebo converted to sinus rhythm during the study (chi2=9.23, P=0.002). During follow-up, 11 of 268 patients in sinus rhythm on amiodarone at baseline and 22 of the 263 in sinus rhythm on placebo developed AF; the difference was significant (chi2=12.88, P=0.005). Analysis of total mortality during follow-up showed a significantly lower mortality rate (P=0. 04) in patients in AF at baseline who subsequently converted to sinus rhythm on amiodarone than in those who did not convert to sinus rhythm on the drug. CONCLUSIONS In patients with CHF, amiodarone has a significant potential to spontaneously convert patients in AF to sinus rhythm, with patients who convert having a lower mortality rate than those who do not. The drug prevented the development of new-onset AF and significantly reduced the VR in those with persistent AF.

Acute Hemodynamic and Clinical Effects of Levosimendan in Patients With Severe Heart Failure

BackgroundWe determined the short-term hemodynamic and clinical effects of levosimendan, a novel calcium-sensitizing agent, in patients with decompensated heart failure. Methods and ResultsOne hundred forty-six patients with New York Heart Association functional class III or IV heart failure (mean left ventricular ejection fraction 21±1%) who had a pulmonary capillary wedge pressure ≥15 mm Hg and a cardiac index ≤2.5 L · min−1 · m−2 were enrolled in a multicenter, double-blind, placebo-controlled study and randomized 2:1 to intravenous infusion of levosimendan or placebo. Drug infusions were uptitrated over 4 hours from an initial infusion rate of 0.1 &mgr;g · kg−1 · min−1 to a maximum rate of 0.4 &mgr;g · kg−1 · min−1 and maintained at the maximal tolerated infusion rate for an additional 2 hours. Levosimendan caused dose-dependent increases in stroke volume and cardiac index beginning with the lowest infusion rate and achieving maximal increases in stroke volume and cardiac index of 28% and 39%, respectively. Heart rate increased modestly (8%) at the maximal infusion rate and was not increased at the 2 lowest infusion rates. Levosimendan caused dose-dependent decreases in pulmonary capillary wedge, right atrial, pulmonary arterial, and mean arterial pressures. Levosimendan appeared to improve dyspnea and fatigue, as assessed by the patient and physician, and was not associated with a significant increase in adverse events. ConclusionsLevosimendan caused rapid dose-dependent improvement in hemodynamic function in patients with decompensated heart failure. These hemodynamic effects appeared to be accompanied by symptom improvement and were not associated with a significant increase in the number of adverse events. Levosimendan may be of value in the short-term management of patients with decompensated heart failure.

Ventricular rate control in chronic atrial fibrillation during daily activity and programmed exercise : A crossover open-label study of five drug regimens

OBJECTIVES We compared the effects of five pharmacologic regimens on the circadian rhythm and exercise-induced changes of ventricular rate (VR) in patients with chronic atrial fibrillation (CAF). BACKGROUND Systematic comparison of standardized drug regimens on 24 h VR control in CAF have not been reported. METHODS In 12 patients (11 male, 69+/-6 yr) with CAF, the effects on VR by 5 standardized daily regimens: 1) 0.25 mg digoxin, 2) 240 mg diltiazem-CD, 3) 50 mg atenolol, 4) 0.25 mg digoxin + 240 mg diltiazem-CD, and 5) 0.25 mg digoxin + 50 mg atenolol; were studied after 2 week treatment assigned in random order. The VR data were analyzed by ANOVA with repeated measures. The circadian phase differences were evaluated by cosinor analysis. RESULTS The 24-h mean (+/-SD) values of VR (bpm) were - digoxin: 78.9 +/- 16.3, diltiazem: 80.0+/-15.5, atenolol: 75.9+/-11.7, digoxin + diltiazem: 67.3+/-14.1 and digoxin + atenolol: 65.0+/-9.4. Circadian patterns were significant in each treatment group (p < 0.001). The VR on digoxin + atenolol was significantly lower than that on digoxin (p < 0.0001), diltiazem (p < 0.0002) and atenolol (p < 0.001). The time of peak VR on Holter was significantly delayed with regimens 3 and 5 which included atenolol (p < 0.03). During exercise, digoxin and digoxin + atenolol treatments resulted in the highest and lowest mean VR respectively. The exercise Time-VR plots of all groups were nearly parallel (p = ns). The exercise duration was similar in all treatment groups (p = ns). CONCLUSIONS This study indicates that digoxin and diltiazem, as single agents at the doses tested, are least effective for controlling ventricular rate in atrial fibrillation during daily activity. Digoxin + atenolol produced the most effective rate control reflecting a synergistic effect on the AV node. The data provides a basis for testing the effects of chronic suppression of diurnal fluctuations of VR on left atrial and ventricular function in CAF.

Prognostic significance of silent myocardial ischemia in patients with unstable angina

Silent myocardial ischemia is common in unstable angina, but its prognostic significance is unknown. Fifty-two (42 with subsequent angiography) of 81 patients prospectively evaluated for unstable angina had ambulatory electrocardiographic (Holter) recordings analyzed by compact analog technique after they had received medical treatment (3 of the 52 had unanalyzable recordings and were excluded). From 1,103 hours of recordings, 298 ischemic episodes were identified, only 9% associated with angina. By Ridit analysis a significant correlation was found between the cumulative duration of transient myocardial ischemia and the number of diseased coronary vessels and indexes of proximal stenosis. During a 3 to 6 month follow-up period, there was one death and one patient was lost to follow-up among 20 patients without transient ischemia; in the group of 11 patients with a cumulative duration of transient ischemia less than 60 minutes/24 h, 7 were alive and well, 2 required coronary bypass surgery, 1 had coronary angioplasty for recurrence of angina and 1 was lost to follow-up. In the group of 18 patients with ischemia duration greater than 60 minutes/24 h, only 1 developed a stable angina pattern; 12 required coronary surgery (n = 11) or angioplasty (n = 1) and 5 developed myocardial infarction (2 died, 2 needed surgery for postinfarction angina and 1 recovered). A favorable clinical outcome occurred in only 6% of patients in the group with ischemia duration greater than 60 minutes/24 h; this rate was significantly lower (p less than 0.001) than that (70%) for the group with ischemia duration less than 60 minutes/24 h or that (95%) for the group without ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Amiodarone: Historical development and pharmacologic profile

Although synthesized as a coronary dilator for use as an antianginal agent over 20 years ago, amiodarone hydrochloride has recently drawn much attention as a potent antiarrhythmic compound for the control of a variety of cardiac dysrhythmias. The rapidly expanding clinical and experimental data continue to emphasize the unusual electrophysiologic, pharmacologic, and especially pharmacokinetic properties of this benzofuran derivative. The compound is a potent coronary dilator and has minimal negative inotropic propensity of a direct nature while exhibiting a mild degree of noncompetitive sympathetic antagonism. Pharmacokinetically, it has a long elimination half-life with a correspondingly long and variable latency of onset of therapeutic effect. Electrophysiologically, the drug has the propensity to lengthen the action potential duration and hence the voltage-dependent effective refractory period in all cardiac tissues after long-term, rather than short-term, administration. It has little effect on depolarization, conduction velocity, or the slow response. The precise ionic mechanisms mediating its effects on repolarization are not known. Clinically, the electrophysiologic effects of the drug differ significantly when it is given by mouth over a longer period and when it is given intravenously, a difference that remains to be explained in terms of mechanism. These differences, however, account for the varying spectrum of the drugs action after single intravenous doses (when its antiarrhythmic effects are essentially explained by the drugs action on the atrioventricular node and possibly its antiadrenergic actions) in comparison to long-term oral administration, which predictably suppresses ectopic activity and lengthens the effective refractory period in all cardiac tissues. These features may account for the drugs remarkable efficacy in the control of supraventricular and ventricular tachyarrhythmias. The safe and rational therapeutic uses of amiodarone as an antiarrhythmic agent presuppose detailed understanding of its manifold pharmacodynamic and pharmacokinetic properties.

Therapeutic implications of slow-channel blockade in cardiocirculatory disorders

SUMMARY The inhibition of slow-channel activity in vascular smooth muscle and myocardium produces a wide range of beneficial effects in various cardiocirculatory disorders, such as arrhythmias, myocardial ischemic syndromes and hypertension. As in the case of β, B antagonists, slow-channel inhibitors constitute a heterogeneous group with a variable degree of selectivity for heart muscle, atrioventricular conduction, peripheral vessels and the coronary circulation. Their hemodynamic effect is the net result of a complex interplay of simultaneous changes in heart rate, preload, afterload, contractility and coronary blood flow. In animals, these agents reduce myocardial ischemic injury and may enhance collateral perfusion; in man, they have salutary effects in exertional angina in which they probably act by reducing cardiac work, an effect quantitatively not dissimilar to that produced by β antagonists. This approach thus provides an alternative mode of medical therapy for patients with exertional angina who do not tolerate d β blockers or in whom β blockers are contraindicated by the presence of bronchospasm or peripheral vascular disease. However, the major additional advantage that slow-channel antagonists unquestionably have over β blockers is the fact that they all are potent coronary vasodilators. In contrast,β antagonists constrict coronary vessels. For this reason, the advent of slow-channel inhibitors such as verapamil, nifedipine and diltiazem is a very timely landmark in relation to the wealth of data that have confirmed the belief that coronary vasospasm plays an important role not only in the pathogenesis of classic variant angina, but also in many patients with unprovoked angina, myocardial infarction or sudden death in the setting of diseased as well as normal coronary arteries. For a patient who has normal or relatively normal coronary vessels but who develops vasospastic angina, slow-channel inhibitors are likely to become the agents of choice and preliminary clinical experience is in line with these considerations. Similarly, patients who have exertional and vasospastic angina are more likely to derive greater behefits from slow-channel inhibitors than from β blockade, which may aggravate coronary spasm. Evidence also indicates that certain slow-channel antagonists may be useful in other cardiocirculatory disorders, such as acute pulmonary edema, acute hypertensive emergencies and obstructive cardiomyopathies. Such indications, if confirmed, will broaden the clinical usefulness of this class of compounds, whose introduction is likely to be a significant advance in cardiovascular therapeutics.

Long-Term Efficacy of Amiodarone for the Maintenance of Normal Sinus Rhythm in Patients With Refractory Atrial Fibrillation or Flutter

The purpose of this study was to examine the efficacy and safety of amiodarone to maintain sinus rhythm in patients with refractory atrial fibrillation or flutter. One hundred ten patients with atrial fibrillation or flutter, refractory to > or = 1 class I antiarrhythmic agents (mean +/- SD 2.5 +/- 1.5, median 2), were given low-dose amiodarone (mean maintenance dose 268 +/- 100 mg/day) to determine its efficacy to maintain normal sinus rhythm after chemical or electrical cardioversion. Fifty-three patients had chronic and 57 patients had paroxysmal atrial fibrillation or flutter. Mean age of the study population was 60 +/- 13 years, and the mean follow-up was 36 +/- 38 months (range 31 days to 137 months). Actuarial rates for maintenance of sinus rhythm were 0.87, 0.70, and 0.55 at 1, 3, and 5 years, respectively. Twenty-one patients (19%) with arrhythmia recurrence had an increase in amiodarone dose, and after a mean additional follow-up of 2.5 years, 86% remained in normal sinus rhythm. The only observed predictor of atrial fibrillation or flutter recurrence was paroxysmal arrhythmia (40% recurrence vs 9% in patients with chronic atrial fibrillation or flutter; p < 0.001). Actuarial rates for withdrawal because of adverse effects were 0.08, 0.22, and 0.30 at 1, 3, and 5 years, respectively. The most frequent adverse effects necessitating withdrawal were skin discoloration (4.5%), pulmonary fibrosis (3.6%; none fatal), and thyroid toxicity (2.7%). No deaths occurred during the study period. In conclusion, amiodarone sinus rhythm in patients with atrial fibrillation or flutter, with a relatively low incidence of adverse effects necessitating withdrawal.