Raphael F. Smith

Suppression of resistant ventricular arrhythmias by twice daily dosing with flecainide

Abstract Flecainide acetate is a new antiarrhythmic agent whose pharmacokinetics have suggested that effective therapy could be achieved with twice daily dosing. The antiarrhythmic and electrocardiographic effects of flecainide were evaluated in 11 patients with chronic ventricular ectopic beats. Nine patients had been resistant or intolerant to at least three antiarrhythmic agents and eight had recurrent nonsustained ventricular tachycardia. The antiarrhythmic efficacy of increasing doses of flecainide was determined by comparison with results during administration of a placebo 2 days before and 3 days after increasing doses of flecainide. All 11 patients had an antiarrhythmic response with a mean 97 percent (range 88 to 100) rate of suppression of ventricular ectopic beats and mean 100 percent rate of suppression of ventricular tachycardia with a mean daily dose of 410 mg (range 200 to 600) of flecainide. Effective therapy was accompanied by lengthening of the P-R (+ 29 percent), QRS (+ 27 percent) and Q-Tc (+ 11 percent) intervals. These changes were not associated with a deterioration in exercise tolerance or a reduction in ejection fraction (0.52 ± 0.08 with placebo, 0.53 ± 0.12 with flecainide) as assessed with two dimensional echocardiography. Increasing doses of flecainide were associated with progressive prolongation of the ventricular ectopic coupling interval before suppression of ventricular ectopic beats. During the placebo washout period after multiple oral doses, the terminal (postabsorptive) phase plasma half-life of flecainide was found to range from 13 to 27 hours (mean 20.3). The minimal effective plasma levels of flecainide (resulting in greater than 90 percent suppression of ventricular etopic beats) ranged from 245 to 980 ng/ml (mean 631). Adverse effects during the inpatient evaluation were limited to blurring of vision in three patients, which resolved with smaller but still effective doses. Suppression of ventricular ectopic beats at a mean rate of 95 percent continued during outpatient therapy. During a mean of 12 months of outpatient follow-up in nine patients, regularly scheduled evaluation of ambulatory arrhythmia frequency continued to document suppression of arrhythmia. Outpatient follow-up occurred monthly for the first 6 months and every 2nd month thereafter. In three patients it was necessary to administer flecainide every 8 hours because blurring of vision occurred at the time of peak plasma levels when the drug was administered every 12 hours. Flecainide was highly effective in suppressing ventricular arrhythmias when administered twice daily.

Antiarrhythmic efficacy, pharmacokinetics and safety of N-acetylprocainamide in human subjects: comparison with procainamide.

The antiarrhythmic efficacy and pharmacokinetics of N-acetylprocainamide (NAPA), the major metabolite of procainamide, were investigated in 23 patients with chronic, high frequency ventricular ectopic depolarizations. An extensive trial design incorporated the approaches of (1) generation of dose-response relations, (2) randomized crossover, and (3) prolonged electrocardiographic monitoring. Seven patients with reproducible suppression of arrhythmias (70 percent or greater reduction in frequency) were thus identified. The mean plasma concentration of acecainide associated with efficacy was 14.3 micrograms/ml (range 9.4 to 19.5) and with side effects (primarily gastrointestinal) was 22.5 micrograms/ml (10.6 to 37.9). The antiarrhythmic response to procainamide did not predict response to acecainide; this finding implies that estimates of the antiarrhythmic contribution of acecainide concentrations achieved during long-term procainamide therapy are unlikely to be meaningful in a given person. The mean half-life of elimination after a single 500 mg dose of acecainide was 7.5 hours; this had prolonged significantly (p < 0.05) to 10.3 hours after higher dosages. No variable examined (including acetylator phenotype) was found to be a predictor of responsiveness to acecainide. Outpatient therapy (2 to 20 months) was not associated with the development of antinculear antibodies or the lupus syndrome; one patients procainamide-induced arthritis resolved during therapy. Acecainide, unlike procainamide, is an agent whose pharmacokinetics allow long-term therapy on a practical schedule. It is effective in a subset of patients with ventricular arrhythmias yet appears much less likely to induce the lupus syndrome seen with the parent compound.

Suppression of chronic ventricular arrhythmias with propranolol.

The antiarrhythmic efficacy of propranolol was evaluated in 32 patients with chronic high frequency ventricular arrhythmias in a placebo-controlled protocol. After a placebo control period, propranolol was begun and the dosage increased sequentially until arrhythmia suppression was achieved, side effects appeared, or a maximum dosage of 960 mg/day was reached. Computerized analysis of ambulatory recordings was used to quantify the arrhythmias. Twenty-four patients had 70-100% arrhythmia suppression at plasma levels ranging from 12-1100 ng/ml (end of dosing interval). Eight patients in this group had frequent episodes of ventricular tachycardia that were totally suppressed at or below the dosage that produced ⩽70% suppression of ventricular ectopic depolarizations (VEDs). A biphasic dose-response curve was seen in five patients who responded with a decrease in arrhythmia frequency in the lower ranges of dosages but had increased frequency of ectopic rhythms as the dosage was increased above the optimal level. Only one-third of patients responded at dosages ⩽160 mg/day. However, with dosages of 200-640 mg/day, an additional 40% responded. Propranolol appears to control ventricular arrhythmias safely and effectively in many patients. The finding that the antiarrhythmic effect in many patients required plasma concentrations greater than those that produce substantial f-adrenergic blockade raises a question whether blockade of cardiac d receptors can directly account for all of the antiarrhythmic actions of propranolol.

Suppression of ventricular ectopic depolarizations by tocainide.

In a previous clinical study we demonstrated that tocainide is effective in the suppression of ventricular ectopic depolarizations (VEDs) after single oral doses. This information provided the basis for evaluating this drugs antiarrhythmic efficacy after multiple dose administration according to a loadingmaintenance regimen. Twelve patients with stable VEDs were given loading doses of tocainide (400-600 mg) with maintenance doses every 12 hours. Every 48 hours the dose was increased until either arrhythmia suppression to < 25%percnt; of VED frequency during placebo administration or side effects occurred. Computer analysis of 12-hr telemetric ECGs taken 24-36 hr after each dosage increment documented effective suppression (76-95%percnt;) in 8 of 12 patients. Those subjects demonstrating suppression were randomly assigned to a cross-over study of placebo or active drug at the dosage found effective in the dose-ranging phase. Dosages for the cross-over stage ranged from 400 to 1100 mg every 12 hours. Comparison of the two five-day periods documented suppression in these patients (mean ± SE = 83.3 ± 4%percnt;). No serious side effects or undue drug accumulation occurred during the study. The data indicate that tocainide can effectively suppress VEDs for 8-12 hours in many patients and that continuous suppression could be possible on an 8-12 hr dosage regimen.

Electrophysiologic Actions of High Plasma Concentrations of Propranolol in Human Subjects

The authors have previously shown that 40% of patients whose ventricular arrhythmias respond to propranolol require plasma concentrations in excess of those producing substantial beta-receptor blockade (greater than 150 ng/ml). However, the electrophysiologic actions of propranolol have only been examined in human beings after small intravenous doses achieving concentrations of less than 100 ng/ml. In this study, the electrophysiologic effects of a wider concentration range of propranolol was examined in nine patients. Using a series of loading and maintenance infusions, measurements were made at baseline, at low mean plasma propranolol concentrations (104 +/- 17 ng/ml) and at high concentrations (472 +/- 68 ng/ml). Significant (p less than 0.05) increases in AH interval and sinus cycle length were seen at low concentrations of propranolol, with no further prolongation at the high concentrations; these effects are typical of those produced by beta-blockade. However, progressive shortening of the endocardial monophasic action potential duration and QTc interval were seen over the entire concentration range tested (p less than 0.05). At high concentrations, there was significant (p less than 0.05) further shortening of both the QTc and monophasic action potential duration beyond that seen at low propranolol concentrations, along with a progressive increase in the ratio of the ventricular effective refractory period to monophasic action potential duration. No significant changes were seen in HV interval, QRS duration or ventricular effective refractory period. In summary, the concentration-response relations for atrioventricular conductivity and sinus node automaticity were flat above concentrations of 150 ng/ml.(ABSTRACT TRUNCATED AT 250 WORDS)

Tocainide therapy for refractory ventricular arrhythmias

Tocainide, a congener of lidocaine, was used to treat symptomatic ventricular arrhythmias in 19 patients resistant to or unable to tolerate conventional agents. In this highly selected group, 15 showed good initial responses to oral therapy. Ventricular tachycardia was suppressed to a greater extent than isolated ventricular ectopic depolarizations at any plasma concentration, and upward dose-ranging showed progressive suppression of both. Arrhythmia responsiveness to lidocaine was found to be an excellent predictor of tocainide response. Of the 15 responders, one died 24 hours after stopping therapy, three died while receiving tocainide, nine stopped because of adverse reactions (five allergic), and two continue on therapy at 1 and 4 years. We conclude that tocainide is an effective agent for the short-term suppression of ventricular arrhythmias, particularly ventricular tachycardia sensitive to lidocaine, but a high incidence of adverse effects limits its application to chronic therapy in many patients.

Correlation of Electrocardiographic Studies and Arteriographic Findings with Angina Pectoris

The relationships among angina pectoris, stress tests, and arteriography are complex. The majority of patients with angina pectoris can be adequately diagnosed by a careful history. Considerable attention to detail and repeated questioning is often necessary before the pain syndrome can be accurately classified. The resting electrocardiogram is of limited value in the diagnosis despite the fact that there is a high positive correlation between abnormal ST-T changes on the electrogram and significant obstructive lesions on coronary arteriograms. The value of the electrocardiogram is enhanced, and its specifiicity and sensitivity increased, when used in combination with exercise stress. The lowest error percentage is achieved by utilizing rate-standardized exercise tests and multiple leads with loads that produce heart rate responses of 80-90% of the expected maximum. Coronary arteriography gives the most specific anatomic information in patients with ischemic cardiac pain but will not directly disclose the cause of the pain. This fact assumes considerable importance when the pain has atypical features or when the patient is in the age group that has a high prevalence of coronary atherosclerosis. Similarly, the presence of past myocardial infarction is likely to be associated with obstructive disease, regardless of the cause of the patients current symptoms. The exact role of lipid and other metabolic abnormalities in producing coronary arteriographic changes in the absence of symptoms needs further clarification, although the available data suggest that marked elevations in lipid fractions are frequently associated with atherosclerotic change, regardless of symptoms. Finally, the data imply that the anatomic abnormalities and functional consequences of the coronary atherosclerotic process are more important predictors of the patients course than any specific symptomatic expression such as angina pectoris.

Right ventricular myocardial infarction in patients with chronic lung disease: possible role of right ventricular hypertrophy.

To determine the relation between right ventricular hypertrophy and right ventricular myocardial infarction in patients with chronic lung disease, the records of 28 patients with chronic lung disease, inferior myocardial infarction and significant coronary artery disease (group I) and 20 patients with right ventricular hypertrophy, chronic lung disease without inferior myocardial infarction or significant coronary artery disease (group II) were reviewed. Chronic lung disease was diagnosed by clinical criteria, chest radiographs and pulmonary function tests. All patients had postmortem examinations. Patients in group I were classified into two subgroups: group Ia (without right ventricular hypertrophy) and group Ib (with right ventricular hypertrophy). Right ventricular wall thickness was 3.3 mm ± 0.5 in group la, 6.0 mm ± 1.1 in group Ib and 8.8 mm ± 2.4 in group II (group Ia versus Ib, p Patients with right ventricular hypertrophy as a result of chronic lung disease are prone to right ventricular myocardial infarction in the setting of inferior myocardial infarction. Isolated right ventricular myocardial infarction may occur in patients with chronic lung disease, right ventricular hypertrophy and insignificant coronary artery disease. Both increased myocardial oxygen demand and a decreased supply may play a role in this relation.

Depolarization changes early in the course of myocardial infarction: Significance of changes in the terminal portion of the QRS complex

Studies of patients during variant angina have revealed that there are specific changes in the terminal part of the QRS complex that provide information regarding the location of the ischemia. Extending these studies to acute myocardial infarction, the electrocardiogram (ECG) obtained from 32 patients within 5 h of the onset of chest pain was analyzed to determine if similar inferences could be made. A preinfarction ECG was available from each patient for comparison and 30 patients underwent coronary arteriography within 3 weeks of the infarction. The 10 patients with anterior infarction had a decrease (p less than 0.05) in the S wave in leads V2 (0.80 +/- 0.50 mV) and V3 (0.65 +/- 0.43 mV). In 23 patients with inferior infarction an increase (p less than 0.05) in the R wave of lead III (0.47 +/- 0.35 mV), S wave of lead aVL (0.31 +/- 0.23 mV) and R wave of lead aVF (0.37 +/- 0.30 mV) occurred. A strong positive correlation between the R wave changes in leads III and aVF and the S wave in lead aVL (r = 0.94 and 0.91, respectively) suggests that the R and S wave changes in these leads are expressions of the same phenomenon and indicates that the terminal QRS complex is chiefly affected. Eight of 23 patients with inferior infarction and ST depression in the anterior precordial leads had a normal left anterior descending coronary artery. All had an increase in S wave amplitude in leads V2 and V3. Eight patients had inferior infarction, ST depression in anterior leads and severe lesions in the left anterior descending artery or anterior wall motion abnormalities.(ABSTRACT TRUNCATED AT 250 WORDS)

The QRS complex during transient myocardial ischemia: studies in patients with variant angina pectoris and in a canine preparation.

We made continuous electrocardiographic recordings on magnetic tape during 15 episodes of ischemia in five patients with variant angina to determine the characteristics of the QRS changes. Orthogonal leads were used and the electrocardiograms were analyzed visually and by digital computer. Changes were quantified by subtracting baseline electrocardiograms from those obtained during ischemia. Large changes in the QRS occurred during ischemia but the waveform quickly returned to baseline when the episode subsided. In all patients there was prolongation of the QRS duration and an increase in QRS voltage during the terminal 40 msec of the waveform in the lead(s) showing the most marked ST displacement. The increase in the terminal QRS could be represented by a vector directed toward the ischemic zone. In a given patient the amplitude of ST displacement varied between episodes, presumably because of variation in the intensity of ischemia, but the QRS changes were directionally similar in each episode. In two patients there was also a smaller change involving the initial 40 msec of the QRS that could be represented by a vector directed away from the ischemic zone. To determine the possible mechanism for the electrocardiographic changes, ischemic episodes of 120 to 150 sec were produced in seven dogs and electrocardiographic recording and analysis techniques similar to those used in patients were employed. Myocardial conduction velocity was measured in three directions in the ischemic zone and was correlated with simultaneous electrocardiographic recordings from the body surface. The electrocardiographic changes in the dog preparation were virtually identical to those in the patients and strongly correlated with a fall in myocardial conduction velocity. We conclude that the QRS changes during variant angina result from the altered excitation pattern produced by conduction delay in the ischemic zone. The probable cause for the increase in terminal QRS voltage is delayed (and uncancelled) activation of the ischemic zone.