Nicholas Z. Kerin

Nifedipine Therapy for Coronary-Artery Spasm: Experience in 127 Patients

We report clinical experience with the coronary vasodilator nifedipine in 127 patients with symptoms of myocardial ischemia associated with electrocardiographic or angiographic evidence, or both, of coronary-artery spasm. In the majority of patients conventional antianginal therapy including nitrates and beta-adrenergic blockers failed, and in one third of the patients at least one episode of ventricular tachycardia developed during an attack of angina. Nifedipine (40 to 160 mg every 24 hours) significantly reduced the mean weekly rate of anginal attacks from 16 to two (P less than 0.001). Similar marked reductions in the nitroglycerin requirement were noted. In 63 per cent of the patients complete control of anginal attacks was achieved, and in 87 per cent the frequency of angina was reduced by at least 50 per cent. Nifedipine was generally well tolerated, with only 5 per cent of the patients requiring termination of the drug because of intolerable side effects. This experience with nifedipine suggests that it is a highly effective drug for the treatment of coronary-artery spasm and variant angina.

Randomized withdrawal from nifedipine: placebo-controlled study in patients with coronary artery spasm.

A multicenter randomized double-blind withdrawal study was conducted to compare the efficacy of nifedipine to that of placebo in vasospastic angina. Following a 2-week single-blind nifedipine baseline period, during which nifedipine was maintained at prestudy levels, 38 patients, 19 taking placebo and 19 continuing nifedipine therapy, either completed a 4-week randomized phase or were prematurely withdrawn because of therapeutic failure. During the randomized phase, an increase in median anginal frequency (2.8 attacks/wk, p less than 0.003) and nitroglycerin usage (0.5 tablets/wk, p less than 0.03) occurred only in the placebo group. The randomized phase was prematurely terminated because of anginal exacerbation in 7 of 19 placebo patients (37%) (only 1 patient receiving nifedipine [p = 0.02] experienced anginal exacerbation). Double-blind therapy was judged effective in 16 patients (84%) receiving nifedipine and in 3 patients (16%) receiving placebo (p less than 0.001). Nifedipine was well tolerated. This study establishes the efficacy of nifedipine in the treatment of variant and validates previous clinical experience.

Concealed atrial bigeminy and trigeminy

Patterns indicative of concealed atrial extrasystoles were observed in two patients with frequent premature atrial depolarizations. In the first patient, the predominant pattern was such that most of the numbers (S) of sinus P waves between atrial extrasystoles satisfied the equation S = 3n-1, where n is any positive integer. This pattern is characteristic of concealed trigeminy. Over a sequence of 49 interectopic intervals, this patient vacillated between concealed atrial trigeminy and bigeminy. A second patient displayed a pattern characteristic of the even number variant of concealed bigeminy. The numbers of sinus P waves in consecutive interectopic intervals were predominantly even. These various patterns of concealed atrial extrasystoles closely resemble previously reported patterns of concealed ventricular extrasystoles.

Pharmacotherapy of Atrial Fibrillation: A Pathophysiological Perspective and Review

Atrial fibrillation (AF) is one of the most common arrhythmia encountered in clinical practice. Although AF is due to the structural and electrophysiological alterations in the atria, its sustainability is multifactorial, and the actual mechanisms are still not clear. Despite the recent advances in catheter ablation technology and techniques, pharmacotherapy still remains the first-line therapy for the management of AF. Current pharmacotherapy targets ion channel alterations that in fact represent only one aspect of the management of this complex arrhythmia. Successful pharmacological treatment of AF and restoration of sinus rhythm is limited and is in part due to its potential deleterious side effects. Newer agents having diverse mechanisms acting on the recently uncovered pathophysiological processes are on the horizon. These include atrial repolarization delaying agents, newer class III agents, Na+-Ca2+ channel blockers, stretch receptor blockers, IKACH blockers, gap junction modifiers, upstream therapies, and agents targeting ischemia-induced AF. Gene- and cell-specific therapies including ‘tailored nanopharmacy,’ newer rate control medications with minimal side effects and the emergence of novel drugs targeting multiple areas of AF arrhythmogenesis in tandem with electrical therapy may be the future direction in the management of AF.

Efficacy of low-dose amiodarone in the prevention of paroxysmal atrial fibrillation resistant to type IA antiarrhythmic drugs.

&NA; The efficacy and safety of low-dose amiodarone (Cordarone; Wyeth-Ayerst, Philadelphia, PA) was assessed in 62 symptomatic patients with paroxysmal atrial fibrillation who were resistant to at least two types of IA drugs. The beneficial response to this treatment was defined as a reduction in paroxysmal atrial fibrillation of greater than or equal to 50% within 1 month. Of the 42 patients (67.7%) who were responders, 39 (62.9%) were completely free of episodes. Intolerable side effects were seen in 12 patients (19.3%). Tolerable side effects were encountered by 73% of patients. Most of the adverse effects were transient and responded to a reduction in the dose. In conclusion, (1) low-dose amiodarone produces a beneficial response in the prevention of paroxysmal atrial fibrillation, and (2) low-dose amiodarone is well tolerated.

Hemodynamic effects of antiarrhythmic drugs.

T here has been no consistent and reliable profile of the hemodynamic effects of the available antiarrhythmic agents. The hemodynamic effects of these agents vary depending on the experimental model (isolated muscle, animal, human); dose (low, therapeutic, toxic); route of administration (intravenous, oral); duration of therapy (acute, chronic); concomitant medications (digitalis, beta-blockers, vasodilators); pharmacokinetics; clinical circumstance (normal volunteers, cardiac patients); autonomic tone (hyperadrenergic, catecholamine depleted); and the method of evaluation of hemodynamic effect (echocardiography, radionuclide angiography, invasive monitoring, strain gauge, etc). To complicate matters further, studies with similar design and intent have yielded internally or comparatively conflicting results. To treat patients safely and rationally, the clinician who uses antiarrhythmic agents must be aware of the potential hemodynamic consequences of therapy in various clinical settings. In this article, we outline the major hemodynamic effects of the clinically available Vaughan Williams class I and III antiarrhythmic drugs, with special emphasis on those agents with more profound effects or unique physiologic mechanisms.

Atrial fibrillation: focus on new therapeutic strategies: pharmacologic and nonpharmacologic approaches.

Atrial fibrillation (AF) is the most common of the supraventricular arrhythmias encountered in clinical practice. It is characterized by an asynchronous atrial movement to which ventricles respond chaotically. Many of the patients with paroxysmal or persistent AF develop permanent AF, and it is approximated that their combined prevalence exceeds 5 million in the United States. ‘‘The auricles pipe and the ventricles perforce must dance . . . a dance that sometimes leads to death.’’ In comparison with a healthy population, a significant increase in mortality rate has been described in patients suffering from AF with or without cardiovascular disease by Kannel et al. A healthy population has a 2% chance of developing chronic AF in the first 20 years of life, with the risk increasing dramatically with age, rising to over 10% in the elderly. AF occurs most frequently in association with heart disease, especially with congestive heart failure, rheumatic heart disease, and hypertensive and heart disease. (Table 1) Only 31% of patients develop AF without clinical apparent cardiovascular disease. The hemodynamic and myocardial consequences of AF can cause diverse symptoms including palpitations, dizziness, and decreased exercise capacity. This in time may lead to congestive heart failure. Persistent AF with fast ventricular response can lead to the development of atrial and ventricular decompensation (tachycardia-induced cardiomyopathy). In fact, AF is associated with a 1.2 to 5-fold increase in total and cardiovascular mortality.

Effect of multiple doses of oral isradipine on atrioventricular conduction in patients with first-degree atrioventricular block.

The purpose of this study was to investigate the effect of multiple doses of orally administered isradipine on atrioventricular nodal conduction in patients with first-degree atrioventricular block. Forty-eight patients with a P-R interval <0.22 seconds on a surface electrocardiogram (ECG) (first-degree atrioventricular block) with or without a bundle-branch block were randomized to one of four groups for 6 weeks of treatment with either placebo or 5.0 mg/d, 7.5 mg/d, or 10.0 mg/d isradipine. P-R interval prolongation was assessed at baseline and posttreatment using resting 12-lead ECGs and 24-hour Holter monitoring. The effect of isradipine on the following parameters were assessed: systolic and diastolic blood pressures, heart rate, respiration rate, oral temperature, and weight. Neither isradipine nor placebo treatment had a statistically significant treatment effect on the change from baseline in P-R interval, QRS duration, Q-T interval (uncorrected), or sinus heart rate at week 7 as measured by 12-lead ECG. All treatment groups, however, had small, statistically insignificant decreases from baseline in the mean P-R interval. The largest decrease (from 0.26 seconds at baseline to 0.22 seconds at week 7) was recorded for the 7.5 mg/d isradipine group, which also had the greatest posttreatment decreases in QRS duration, sinus heart rate, and systolic and diastolic blood pressures. The treatment groups did not differ significantly with respect to the change from baseline to study end in P-R interval prolongation or degree of atrioventricular block (as measured by 24-hour Holter monitoring), radial pulse rate, respiration rate, weight, or oral temperature. In this study, isradipine did not have a negative dromotropic effect on the atrioventricular node. The trend toward a posttreatment decrease in P-R interval suggests that isradipine may actually improve atrioventricular nodal conduction in patients with first-degree atrioventricular block and thus may be used safely in this population.

Is the Degree of Arrhythmia Suppression a Predictor of Survival

The effectiveness of an antiarrhythmic drug is judged by the degree of ventricular arrhythmia (VA) suppression. We evaluated the relationship between the degree of VA suppression and survival in a dose-adjusted trial of 110 symptomatic patients treated with amiodarone. Cohorts had leftventricular ejection fraction (LVEF) of 41 ± 18%, ventricular premature contractions (VPCs) of 445 ± 571 h, couplets (C) of 733 ± 149824 h and nonsustained (N) ventricular tachycardia (VT) of 65 ± 21724 h; these conditions were followed for 15 ± 11.5 months. Amiodarone was initiated with an oral loading of 670 + 111.7 mg per day for 10 days and continued on maintenance of 274.9 ± 102 mg per day. Survival rates of responders and nonresponders with VPCs <70%, 70–89%, >290%; C >90%; NVT (100%); and the response to all 3 criteria (suppression of VPCs >70%, C >90% and complete abolition of NVT) were not statistically significant. Survival rates as a function of LVEF <40% (51 patients) or >40% (59 patients), as well as responders or nonresponders to all three criteria, were not significant (p = NS). We conclude that, in patients treated with low-dose amiodarone, the degree of VA suppression of PVCs, C and NVT does not predict survival; the survival of patients with LVEF <40% improved irrespective of VA suppression; and criteria for VA suppression should be reassessed at lower levels of suppression for the improvement of the drug risk:benefit ratio. More improvement is not necessarily better.