Tocainide kinetics in congestive heart failure.

Our subjects were 20 patients with life-threatening or symptomatic ventricular arrhythmias refractory to standard oral antiarrhythmic drugs but responsive to intravenous lidocaine. After evaluation of arrhythmias and treatment with intravenous lidocaine, oral tocainide dosage regimens were based on age, weight, and clinical status. During initial tocainide treatment, six plasma tocainide concentrations were recorded within a single dosing interval in 17 of 20 patients, by which standard kinetic parameters were calculated. Eventual trough steady-state tocainide plasma concentrations were predicted from the derived patient-specific kinetic parameters. Mean daily tocainide dose was 1800 mg (1200 to 2400). Mean daily tocainide doses (milligram per kilogram) did not differ significantly among responders and nonresponders or among patients with or without congestive heart failure. Mean peak and trough plasma concentrations 48 hr after initiation of therapy were 9.8 and 7.5 mcg/ml. Tocainide plasma concentrations did not correlate with responders and nonresponders or identify patients who were developing adverse reactions to tocainide. There were no significant differences in any of the calculated kinetic parameters as a function of response to tocainide or the presence of congestive heart failure, but there was a trend toward smaller volumes of distribution and higher average plasma concentrations at steady state in patients with congestive heart failure. There were no significant kinetic differences among patients with and without congestive heart failure, but a trend toward higher plasma concentrations in patients with congestive heart failure and the small number of patients suggests that further data collection is necessary before dosage recommendations can be made.

Long-term follow-up of patients with echocardiographically detected mitral anular calcium and comparison with age- and sex-matched control subjects.

One hundred seven patients with echocardiographically documented mitral anular calcium (MAC) and 107 age- and sex-matched control subjects without MAC were studied and followed for a mean of 4.4 +/- 2.4 (standard deviation) years. Fourteen (7%) patients were lost to follow-up. Compared with the control group, patients with MAC had higher frequency of precordial murmurs (p less than 0.0001), cardiomegaly (p less than 0.0001), left atrial enlargement (p less than 0.0001), and rhythm and conduction disturbances (p less than 0.0001). During the follow-up, patients with MAC had higher incidence of valve replacement (p less than 0.0025), permanent pacemaker implantation (p less than 0.0025), congestive heart failure (p less than 0.0001), thromboembolic cerebrovascular event (p less than 0.01), sudden death (p less than 0.001) and total cardiac death (p less than 0.0001). However, the frequencies of myocardial infarction, coronary artery bypass surgery and angioplasty, endocarditis or noncardiac death were not significantly different between patients with MAC and the control subjects. Thus, patients with MAC have higher frequencies of precordial murmurs, cardiomegaly, left atrial and ventricular enlargement, rhythm and conduction disturbances. They more frequently undergo valve replacement and permanent pacemaker implantation, develop congestive heart failure and die of cardiac causes than age- and sex-matched control subjects.

Clinical and echocardiographic characteristics of patients with mitral anular calcification. Comparison with age- and sex-matched control subjects.

The clinical and echocardiographic features of 104 patients (53 women and 51 men) with mitral anular calcification (MAC) were compared with those of 121 age- and sex-matched control subjects (62 women and 59 men) without MAC. The incidence of coronary artery disease, rheumatic heart disease, systemic hypertension, and diabetes mellitus was similar in both groups. Patients with MAC had a greater incidence of cardiomegaly (p less than 0.001), cardiac conduction defects (p less than 0.001), and aortic outflow tract murmurs (p less than 0.005) than did control patients. Patients with MAC and without aortic root calcification had a higher incidence (p less than 0.001) of conduction defects than did patients with aortic root calcification without MAC. Control patients with and without aortic root calcification had a similar incidence of conduction defects. A higher incidence of atrioventricular block (p less than 0.025) and bundle branch block or left anterior hemiblock or intraventricular conduction defect (p less than 0.05) was present in anterior MAC than in posterior MAC. In conclusion, patients with MAC have a higher incidence of cardiomegaly, cardiac conduction defects, and aortic outflow tract murmurs than a control group.

Efficacy and tolerance of high-dose intravenous amiodarone for recurrent, refractory ventricular tachycardia.

High-dose intravenous amiodarone was given to 35 patients with recurrent life-threatening ventricular tachycardia (VT) refractory to conventional antiarrhythmic agents. Intravenous amiodarone was given as a 5 mg/kg dose over 30 minutes followed by 20 to 30 mg/kg/day as a constant infusion for 5 days. Twenty-two (63%) patients responded to intravenous amiodarone. All 22 responders received oral amiodarone. Thirteen (59%) continue to receive oral amiodarone after an average follow-up of 19 months, 4 (18%) had sudden cardiac death on oral amiodarone, 2 (9%) died while receiving amiodarone, secondary to left ventricular failure, and 3 (14%) discontinued amiodarone because of side effects. Of the 13 (37%) nonresponders, 10 died in the hospital while receiving intravenous amiodarone, secondary to lethal arrhythmia. Three nonresponders were discharged from the hospital; 2 with automatic cardioverter/defibrillators and 1 receiving a combination of antiarrhythmic agents. Serious adverse events occurred in 13 (37%) patients during intravenous amiodarone therapy. These included hypotension in 8 patients, symptomatic bradycardia in 4 patients and sinus arrest with bradycardia and hypotension in 1 patient. Minor side effects occurred in 23 (66%) patients. In conclusion, high dose intravenous amiodarone is effective in most patients with recurrent, sustained VT but is associated with an unacceptably high incidence of serious adverse events. The optimal dose and duration of intravenous amiodarone for patients with recurrent, refractory sustained VT remain unknown.

Dressler's syndrome complicating radiofrequency ablation of an accessory atrioventricular pathway.

Radiofrequency energy is being used frequently in catheter ablation of accessory pathways. This case reports a patient who underwent radiofrequency ablation that was complicated by the development of Dressler's syndrome.

Loss of efficacy during long-term cifenline therapy: development of antiarrhythmic resistance?

OBJECTIVE: To describe the possible development of antiarrhythmic resistance to cifenline, an investigational Class I agent. METHODS: Forty patients with chronic ventricular premature depolarizations (VPDs) underwent dose-ranging studies with cifenline, an investigational Class I antiarrhythmic agent. Patients had a minimum of 30 VPDs/h detected by ambulatory electrocardiographic (ECG) monitoring over a 48-hour baseline placebo lead-in period. Twenty-two patients (55 percent) who initially responded received long-term cifenline therapy. Ambulatory ECG monitoring over 24 hours was repeated during active cifenline therapy at three-month intervals and during placebo reintroduction at six-month intervals. RESULTS: After an average follow-up of 28 months, VPD frequency during cifenline therapy was similar to that during initial baseline placebo therapy in 8 of the 22 patients (36 percent) who initially responded. Placebo reintroduction following cifenline failure showed a VPD frequency similar to that with active therapy. All patients had further cifenline dosage increases without success. Plasma cifenline concentrations increased in all patients and were in the high therapeutic range. All 8 patients were switched to other Class I antiarrhythmic agents with successful VPD suppression during treatment with the first alternative drug. CONCLUSIONS: We conclude that antiarrhythmic resistance occurred with cifenline in these patients as (1) initial efficacy was established for a minimum of two years, (2) VPD frequency was similar during cifenline therapy and placebo reintroduction, (3) cifenline therapy failure continued despite further dosage titration, and (4) alternative Class I antiarrhythmic therapy was successful in all patients. Repeat intermittent ambulatory ECG monitoring is necessary not only to assess the continued need for antiarrhythmic drug therapy, but also to establish continued long-term efficacy.

Efficacy and safety of clonazepam in refractory neurally mediated syncope.

Neurally mediated syncope is a complex syndrome that is often difficult to manage using currently available treatment strategies. The efficacy and safety of clonazepam was evaluated in 35 patients with refractory neurally mediated syncope. All patients had syncope (n = 33) or disabling presyncope (n = 2) and a positive head-up tilt table test (HUTT) despite treatment with one or more of the following therapies: beta-blocker, high-salt diet, fludrocortisone, elastic compression stockings, and disopyramide. Clonazepam was initiated at 0.5 mg/day and titrated in 0.25-0.5 mg/day increments for symptom control. Early (first 8 weeks) symptomatic response was achieved in 31 of 35 (89%) patients. Early HUTT reverted to negative in 29 of 35 (83%) patients. Two patients discontinued clonazepam during early follow-up due to side effects. Thirty-three patients received long-term clonazepam therapy. Twenty-five patients had late HUTT with 21 remaining negative. Of the eight patients who did not have late HUTT, one patient discontinued clonazepam prior to HUTT due to side effects. Seven patients refused late HUTT. All seven patients achieved symptomatic control on clonazepam with two requiring dose titration. Of the 21 patients with a negative late HUTT, 18 achieved symptomatic control with two of these patients requiring dose titration. Two patients who had only partial symptom control despite dose titration achieved total symptomatic control with the addition of disopyramide and beta-blockers. Two patients with a negative late HUTT discontinued clonazepam due to side effects. One patient had been symptomatically controlled while the other had recurrent symptoms with dose limiting side effects occurring after clonazepam dose titration. In the 4 patients with a positive late HUTT, 2 patients were symptomatically controlled, 1 patients required combination therapy with a beta-blocker to achieve symptomatic control, and 1 patient discontinued therapy due to side effects. Overall, 29 of 35 (83%) patients continue to receive clonazepam with symptom control. Based on intention-to-treat HUTT results, 21 of 35 (60%) patients were responders. Four patients required clonazepam dose titration and three required combination therapy with clonazepam plus disopyramide and/or a beta-blocker to achieve control. Clonazepam was discontinued in 6 patients, 5 for side effects and 1 following a transient ischemic attack. Clonazepam appears to be an effective therapeutic alternative in patients with refractory neurally mediated syncope. Based on our preliminary findings, a placebo controlled evaluation of clonazepam in neurally mediated syncope is warranted.