Koonlawee Nademanee

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.

Control of refractory life-threatening ventricular tachyarrhythmias by amiodarone☆

Abstract The antiarrhythmic effects and dose-response relationship of amiodarone hydrochloride, 600 to 1200 mg daily, were studied in 22 patients with recurrent life-threatening symptomatic ventricular tachyarrhythmias refractory to two or more conventional antiarrhythmic agents. In all patients the presence of the arrhythmia was confirmed on ECG and/or 24-hour Holter readings. In 10 one or more episodes of cardiac arrest had been documented by ECG. Two patients died prior to initiation or stabilization of therapy; the goal of therapy was attained in all but one patient. Amiodarone abolished all complex premature ventricular contractions (PVCs) and paroxysmal or sustained episodes of ventricular tachycardia (VT) in all 19 remaining patients; In the 15 in whom predrug and serial 24-hour Holter recordings could be obtained and analyzed, the total PVC counts were reduced 90% to 98% by amiodarone. After a mean follow-up of 12 months on chronic amiodarone therapy, there have been no recurrences of VT or ventricular fibrillation and sustained antiarrhythmic response has been confirmed by Holter recordings. One patient died suddenly at home despite complete suppression of PVCs. Amiodarone prolonged the PR (+16.7%; P c (+22.7%; P

Electrophysiologic and antiarrhythmic effects of sotalol in patients with life-threatening ventricular tachyarrhythmias.

Sotalol is a unique beta-blocker that lengthens cardiac repolarization and effective refractory period (ERP). Its efficacy after intravenous (1.5 mg/kg) and oral (160 to 480 mg bid) administration was therefore evaluated in 37 patients with refractory recurrent ventricular tachycardia/fibrillation (VT/VF). Thirty-five patients, 33 with inducible VT/VF, underwent electrophysiologic testing. Intravenous sotalol lengthened the ERP in the atrium (+24.6%, p less than .01), atrioventricular node (+24.9%, p less than .01), and ventricle (+14.9%, p less than .01). It also significantly lengthened sinus node recovery time, corrected QT interval (QTc), and the AH interval, but not the HV interval. Sotalol prevented reinduction of VT/VF in 15 patients (45.5%). Twenty-five of the 33 patients (15 with positive results of electrophysiologic tests; 10 with negative results) were given oral sotalol. The drug was ineffective in seven (26.9%) and aggravated arrhythmia in one (3.8%). In four patients sotalol was withdrawn because of side effects; arrhythmias recurred late in two (7.7%). Eleven patients (42.3%) have continued on oral sotalol over a mean follow-up period of 9.2 +/- 8.6 months. Sotalol reduced (n = 21) total premature ventricular complex (PVC) count on the Holter electrocardiogram by 73% (p less than .01), paired PVCs by 89% (p less than .01), and beats of ventricular tachycardia by 95% (p less than .01). In 52% (n = 11), total reduction in PVCs was at least 85%, and incidence of paired and tachycardiac beats was reduced at least 90% (group A). In the remainder (n = 10), PVC suppression was not significant (group B). Group A included nine patients with nonreinducible VT/VF and two in whom it was reinducible; in group B, eight of 10 patients had reinducible VT/VF. The difference between the two groups (Fisher exact test) was significant (p less than .01). The prevention of reinduction of VT/VF by intravenous sotalol and suppression of spontaneously occurring arrhythmias by the oral drug were both predictive of long-term drug efficacy. Sotalol is a significant advance in the short- and long-term management of life-threatening ventricular tachyarrhythmias.

Pharmacokinetic significance of serum reverse T3 levels during amiodarone treatment: a potential method for monitoring chronic drug therapy.

We studied the antiarrhythmic effects of amiodarone, 600-1400 mg/day, in 18 patients with refractory arrhythmias, and related the drug efficacy and side effects to serum levels of T4, reverse T3 (rT3) and the QTc interval. In the 11 patients with ventricular arrhythmias, premature complexes were reduced by 90-98%, and complex ectopy and runs of ventricular tachycardia were abolished; in the seven patients with paroxysmal atrial flutter, there were no recurrences on stable drug therapy. The QTc lengthened by 11.6% (p < 0.01), T4 increased by 31.6-63.3% (p < 0.001) and rT3 increased by 82.9-176.8% (p < 0.001) as a function of dose and duration of amiodaronetherapy. A close correlation was found between rT3 (normal up to 50 ng/dl) and drug efficacy and some of the drug side effects; arrhythmia suppressionoccurred at levels of 55-100 ng/dl, and some of the known side effects at levels of 100-110 ng/dl. When amiodarone was stopped in nine patients, the changes in QTc, T4 and rT3 regressed toward normal and arrhythmia recurred in eight 2-20 weeks (mean 7.4 weeks) and when rT3 levels fell below 55 ng/dl; arrhythmia resuppression was achieved 3-28 days (mean 11 days) after resumption of amiodarone therapy. The indirect therapeutic half-life of amiodarone in seven patients, computed from the semilogarithmic plots of plasma rT3 after cessation of amiodarone therapy, ranged from 25 to 55 days (mean 35days). The data suggest that rT3 levels may be useful in monitoring the efficacy and certain side effects of amiodarone.

Fractionated endocardial electrograms are associated with slow conduction in humans: evidence from pace-mapping.

Fractionated ventricular electrograms recorded during catheter mapping may arise from areas of asynchronous depolarization associated with slow conduction, the substrate for reentrant ventricular tachycardia, but can also be a nonspecific abnormality or even artifact. To determine whether fractionated sinus rhythm electrograms are associated with slow conduction in humans, the results of endocardial catheter mapping and pacing at 133 endocardial sites in 13 patients were analyzed. Eleven patients had sustained monomorphic ventricular tachycardia and two patients had old myocardial infarction without ventricular tachycardia. Functional evidence of slow conduction at the recording site was assessed by pacing at that site and measuring the interval between the stimulus artifact (S) and the onset of the QRS complex in the 12 lead electrocardiogram (ECG). During pacing at 89 of 90 sites without fractionated sinus rhythm electrograms, the S-QRS interval was less than 40 ms, a value consistent with rapid propagation of the stimulated wave front away from the pacing site. During pacing at 21 (49%) of 43 sites with fractionated sinus rhythm electrograms, the S-QRS interval was greater than 40 ms (range 40 to 140), consistent with slow conduction at the pacing site (p less than 0.001 versus nonfractionated sites). In 9 of the 11 patients with ventricular tachycardia analysis of the paced QRS configuration, electrograms during induced ventricular tachycardia or programmed stimulation during tachycardia suggested that a site with a long S-QRS interval during pacing was located at or near a ventricular tachycardia circuit. Therefore, fractionated sinus rhythm electrograms are often associated with slow conduction, which may be the substrate for reentrant ventricular tachycardia.(ABSTRACT TRUNCATED AT 250 WORDS)

Amiodarone and thyroid function: clinical implications during antiarrhythmic therapy.

Amiodarone, an iodinated benzofuran derivative, has electrophysiologic effects on cardiac muscle akin to those of hypothyroidism. It is possible that the drug exerts its salutary effect, at least in part, by selectively inhibiting the action of triiodothyronine (T3) on the myocardium. The drug produces complex changes in thyroid hormones, with significant elevations in thyroxine (T4) and reverse T3 (rT3), with minor decreases in T3, and with minor and transient increases in thyroid-stimulating hormone, but without effect on thyroid-binding globulin. These changes may interfere with the biochemical evaluation of thyroid function. Rarely, hypothyroidism or hyperthyroidism may develop during the course of amiodarone therapy, a complication caused by the iodine contained in the drug rather than by the direct pharmacologic actions of the compound. The incidence of altered thyroid function induced is likely to vary with populations susceptible to iodine-induced goiter. Under the action of amiodarone, serum rT3 levels increase as a function of dose and duration of therapy and therefore provide a basis for judging the magnitude of in vivo drug cumulation. It was found that therapeutic efficacy was usually predictable on the basis of the attainment of a defined range of serum values, established by a correlation of rT3 levels with therapeutic responses both during loading and maintenance phases as well as after withdrawal of treatment of steady-state drug effects. Serious adverse effects occurred nearly always in association with four- to fivefold increases of rT3 above baseline values, and disappeared when such levels fell as a result of dosage reduction or after temporary drug discontinuation. The data suggest that the determination of serum rT3 levels during amiodarone therapy provides a simple and reliable technique for monitoring the drugs antiarrhythmic efficacy and toxicity, thereby enhancing its clinical utility. The use of rT3 levels may permit the development of a safe but optimal therapeutic regimen for the control of a wide spectrum of refractory atrial and ventricular tachyarrhythmias. The use of this technique, however, presupposes the allowance that must be made for variations in the methods for the serum assay of rT3 and of the systemic conditions in which the rT3 levels fluctuate relative to severity of the illness.

Electrophysiologic and hemodynamic effects of slow-channel blocking drugs

T HE last decade has witnessed an intense clinical and experimental investigation of the pharmacologic properties and the therapeutic applications of the class of drugs which now have come to be known as “calcium antagonists, ” “slow-channel inhibitors”, or “calcium influx blockers.“i-3 Although the prototype agent of such compounds, verapamil, has been known since 1 962,4 it is only recently that the concept of the selective slow-channel inhibition has been clearly delineated and has gained widespread recognition.5,6 Such an appreciation has followed closely in the wake of numerous developments which have provided a rational basis for the use of slow-channel inhibitors in a very large and increasing number of cardiocirculatory disorders.‘x7 An important advance was made when it was found that the inward depolarizing current in heart muscle had two components, one having fast kinetics and the other slow, each capable of being blocked selectively by specific antagonists.8-‘0 It was aIso found that certain fibers in the normal heart were dependent almost exclusively on slow-channel potentials.” For example, the selective inhibition of such potentials in the middle of the AV node provided a highly effective and predictable method for terminating reentrant paroxysmal supraventricular tachycardias which utilize anterograde conduction through the AV node as part of the re-entrant circuit.‘2,13 Although not all slow-channel antagonists block AV conduction in this manner, the selective inhibition of the slow-channel in cardiac muscle in general has become the main basis for identifying slow-channel inhibitors.236,‘4 The fact that the transport of calcium through the slowchannel during an action potential is responsible for excitation-contraction coupling in heart muscle, a major consequence of the inhibition of this process is a reduction in myocardial contractility, most clearly evident15*16 in isolated cardiac muscle. However, if such a negative inotropic propensity of this class of agents were not modulated favorably by their associated extracardiac effects, it is unlikely that they could be employed “safely” in clinical therapeutics. It so happens that slow-channel blocking compounds also inhibit calcium movements in smooth muscle;‘7*‘8 in so doing they reduce contraction thereby producing vasodilatation in the peripheral vessels and in the coronary circulation.4”7”9-2’ The peripheral vasodilator effect is of particular significance insofar as it may reflexly increase heart rate, AV conduction, and myocardial contractility while improving ventricular performance indirectly by reducing ventricular afterload. In this atricle, the electrophysiologic and hemodynamic effects of slow-channel blockade are discussed relative to the overall pharmacologic properties of the most significant compounds (Fig. 1). Since the precise delineation of their cardiocirculatory and electrophysiologic actions in intact animals and man is critically dependent on their fundamental effects on isolated cardiac and smooth muscle cells, the role of the slow channel in excitation-contraction coupling in these tissues will first be discussed in brief.

Amiodarone and Thyroid Function

Amiodarone blocks the action of thyroid hormone by the inhibition of 5-deiodinase which reduces production of T3 in peripheral tissues and possibly by blocking nuclear binding of T3. Since the drug inhibits peripheral conversion of T4 to T3, many patients taking amiodarone have abnormal thyroid function studies (increased T4 and rT3; decreased T3) despite being euthyroid. Treatment of patients with amiodarone generates an iodine excess, which contributes greatly to the significant incidence of altered thyroid status in this population. The diagnosis of hyperthyroidism and hypothyroidism can be difficult. However, using the overall clinical picture and the tolerance limits of hormone levels determined for patients remaining euthyroid on amiodarone therapy, the accurate diagnosis of clinically significant thyroid dysfunction can almost always be made. To screen for thyroid disease, thyroid function should be assessed before initiating therapy, semiannually during therapy or whenever clinical features of thyroid dysfunction occur. Subclinical hypothyroidism as denoted by modest increases in TSH levels do not require treatment or the discontinuation of amiodarone therapy. An appreciation of the mechanism of the interaction between amiodarone and thyroid hormone metabolism allows the clinician to recognize thyroid dysfunction at an early stage and initiate appropriate therapy, thereby minimizing the morbidity associated with forms of amiodarone toxicity.

Resetting of ventricular tachycardia: Implications for localizing the area of slow conduction

Analysis of local endocardial electrograms recorded during reentrant ventricular tachycardia does not provide direct information as to the participation of the recording site in the tachycardia circuit. To determine if programmed electrical stimulation at the recording site can assist in localizing areas of slow conduction that are participating in the tachycardia circuit, seven patients with sustained monomorphic ventricular tachycardia were studied. The cardiac cycle was scanned with single stimuli delivered during ventricular tachycardia at multiple endocardial sites. In four patients, an endocardial site was identified at which stimuli advanced the tachycardia with marked conduction delay and without alteration of the ventricular activation sequence, as indicated by a lack of change in the configuration of the QRS complex and endocardial electrograms distant from the stimulation site. This finding was seen only during stimulation at sites displaying abnormal electrograms and is consistent with premature depolarization of an area of slow conduction within the tachycardia focus by stimuli delivered at or near that area. Attempted endocardial catheter ablation at or adjacent to these sites in three patients was followed by persistent noninducibility of ventricular tachycardia in one patient, marked modification of the configuration and cycle length of inducible tachycardia in one patient and transient noninducibility of tachycardia in one patient. Programmed electrical stimulation during ventricular tachycardia at sites with abnormal electrograms may provide information about the proximity of the stimulation site to the tachycardia circuit.

Amiodarone, thyroid hormone indexes, and altered thyroid function: Long-term serial effects in patients with cardiac arrhythmias

Amiodarone, a drug that has electrophysiologic actions resembling those of hypothyroidism, increases serum levels of T4 and reverse T3 (rT3) and decreases T3. The drugs long-term effects on thyroid function are poorly defined. Serial thyroid hormone indexes in 76 patients given amiodarone for 6 to 32 months (mean +/- standard deviation 16 +/- 7) for arrhythmias were determined serially. Over this period, 68 patients (89%) remained euthyroid; hypothyroidism developed in 6 (8%) and hyperthyroidism developed in 2 (3%). In patients who remained euthyroid, thyroid hormone alterations attained steady-state values at 3 months: T4 increased 42% (p less than 0.01), rT3 increased 172% (p less than 0.01) and T3 decreased 16% (p less than 0.05), without significant effect on thyroid stimulating hormone. For the euthyroid patients, the 90% tolerance limits (95% confidence) over the follow-up period for T4 was 5 to 19 micrograms/dl (normal 4 to 12), for T3 36 to 163 ng/dl (normal 60 to 160), for rT3 22 to 131 ng/dl (normal 15 to 50) and for thyroid stimulating hormone 0 to 14 microU/ml (normal 1 to 6). The changes in hormone indexes in hyperthyroid or hypothyroid patients were unrelated to the cumulative dose or duration of drug therapy. The most reliable diagnostic indexes for amiodarone-induced altered thyroid state were: thyroid stimulating hormone level over 20 microU for hypothyroidism and T4 over 20 ng/dl or high T3 over 200 ng/dl for hyperthyroidism. All levels were within the 90% tolerance limits derived for these hormones from patients remaining euthyroid on amiodarone long-term.(ABSTRACT TRUNCATED AT 250 WORDS)