Seth J. Rials

Meta-analysis of the effectiveness of prophylactic drug therapy in preventing supraventricular arrhythmia early after coronary artery bypass grafting

Abstract There has been considerable interest in evaluating the usefulness of drug therapy in patients who undergo operative coronary revascularization procedures to prevent the development of supraventricular tachyarrhythmia after surgery.1,2 Much concern stems from the fact that postoperative atrial fibrillation prolongs hospitalization, thus increasing the cost of this already expensive and frequently used procedure.3 There is an attendant risk of severe complications of atrial fibrillation (most importantly stroke), which necessitates anticoagulation in a significant percentage of these patients.4 Furthermore, the medications used to convert atrial fibrillation to sinus rhythm and to prevent recurrence are not innocuous, and arguably may increase the risk of death during follow-up. 5 For all these reasons, it is worthwhile to investigate whether medication, administered either before or immediately after the procedure, may prevent atrial fibrillation and other supraventricular arrhythmias. Currently, the most frequently used medications for preventing the development of supraventricular tachyarrhythmia after surgery are β-adrenergic blocking agents and digitalis. Several studies have been undertaken to study their effectiveness.6–17 Unfortunately, no consensus opinion has been reached regarding their relative usefulness. In fact, there has been considerable inconsistency of results. Consequently, in most hospitals there is no uniform policy regarding their routine use. Much of the problem occurs because of the small number of patients in each study, and the relatively modest treatment effect in most of these. The technique of meta-analysis can often help to interpret this kind of diverse data.18 By combining the information obtainable from a number of small but well-done studies, it is possible to draw some conclusions about the relative magnitude of treatment effect. We reviewed 12 full-length reports in which digitalis or β-blocker therapy, or both, was compared with control therapy, combined the information and herein report the results.

Regression of Left Ventricular Hypertrophy With Captopril Restores Normal Ventricular Action Potential Duration, Dispersion of Refractoriness, and Vulnerability to Inducible Ventricular Fibrillation

BACKGROUND Left ventricular hypertrophy (LVH) is associated with multiple cellular electrophysiological abnormalities, susceptibility to ventricular arrhythmias, and an increased risk of sudden death. Several pharmacological therapies have been shown to produce regression of hypertrophy, but the value of regression is unclear. The present study examines whether pharmacological regression of LVH has effects on the susceptibility to ventricular arrhythmia or the cellular electrophysiological abnormalities of LVH. METHODS AND RESULTS Rabbits underwent unilateral renal artery banding and contralateral nephrectomy to induce LVH or were placed in the control group. Both groups were studied 3 months later by in vivo and in vitro electrophysiological techniques. Banded rabbits had increased mean arterial pressure, increased left ventricular weight and wall thickness, increased dispersion of refractoriness, and lower ventricular fibrillation thresholds than control rabbits. Action potential duration and cell capacitance were also greater in the banded group. Additional rabbits were treated beginning 3 months after banding with either captopril (5 mg x kg(-1) x d(-1)) or vehicle added to their diet for an additional 3 months. These rabbits and age-matched controls were then studied by in vivo and in vitro electrophysiological techniques. In banded rabbits that received vehicle and were studied 6 months after banding, increased dispersion of refractoriness, a lower ventricular fibrillation threshold, and action potential prolongation persisted and were unchanged from animals studied 3 months after banding. Captopril, started 3 months after banding, caused regression of hypertrophy and normalization of the in vivo and in vitro electrophysiological abnormalities. Addition of captopril to the tissue bath during in vitro electrophysiological study showed no effect on cells from control or banded rabbits. CONCLUSIONS Pharmacological regression of LVH with captopril normalizes the in vivo and in vitro electrophysiological abnormalities of ventricular hypertrophy and reduces the vulnerability to ventricular fibrillation in a renovascular model of LVH.

Effect of Left Ventricular Hypertrophy and Its Regression on Ventricular Electrophysiology and Vulnerability to Inducible Arrhythmia in the Feline Heart

BACKGROUND Left ventricular hypertrophy (LVH) is associated with an increased risk of death, susceptibility to ventricular arrhythmia, and multiple electrophysiological abnormalities. The purpose of the present study was to determine whether the susceptibility to arrhythmia and electrical abnormalities persists after regression of hypertrophy in an animal model of LVH. METHODS AND RESULTS We placed constricting bands on the ascending aorta of cats (n = 9) or performed sham operations (n = 9). Serial cardiac echocardiography was performed to measure left ventricular wall thickness. After LVH had developed in the banded animals, the constricting bands were removed and serial echocardiograms were used to monitor for regression of hypertrophy. Electrophysiological studies were performed in cats that showed regression of LVH (Regress, n = 5), those that showed no change in LV wall thickness (No Regress, n = 4), and in the sham-operated animals (Sham). Cats with persistent LVH had a higher incidence of inducible polymorphic ventricular tachycardia (4 of 4) compared with Regress (1 of 5) or Sham (1 of 9) cats (P < .05) and had lower ventricular fibrillation thresholds (9 +/- 2 mA) than Regress (17 +/- 4 mA) or Sham (16 +/- 3 mA) cats (P < .05). Persistent LVH in the No Regress group was associated with prolongation of epicardial monophasic action potential duration (MAPD) in the left but not the right ventricle. Dispersion of refractoriness was greater in the No Regress group (P < .05 versus Regress or Sham). Regress cats were identical to Sham cats in having a low incidence of inducible polymorphic ventricular arrhythmia, high fibrillation threshold, and MAPD measurements (P = NS versus Sham). CONCLUSIONS LVH produces multiple electrophysiological abnormalities and increased vulnerability to inducible polymorphic ventricular arrhythmia in this model of LVH. Cats that show regression of hyperthrophy have normal ventricular electrophysiology and have the same low vulnerability to inducible ventricular arrhythmia as Sham animals.

Atrial fibrillation, anticoagulation, and stroke

There is a demonstrated statistical association between atrial fibrillation, rheumatic valvular disease, and embolic stroke. This article assesses the results of 6 major clinical trials (AFASAK, BAATAF, SPINAF, SPAF [parts I and II], CAFA and EAFTA--see text for trial names). Multivariate analysis revealed 4 independent clinical features that identified patients with atrial fibrillation at an increased risk for stroke: hypertension, increasing age, previous transient ischemic attack, and diabetes mellitus. Without anticoagulation therapy, patients with any of these risk factors had a 4% annual risk of stroke. Patients with cardiac disorders such as congestive heart failure and coronary artery disease have a stroke rate 3 times higher than patients without any risk factors; patients with atrial fibrillation but no concomitant risk factors or structural heart disease seemed to have little concomitant risk for stroke. Meta-analysis revealed a 64% reduction of risk for stroke in patients treated with warfarin, as compared with placebo. The value of warfarin therapy in patients > 75 years old is less clear because of a high risk of hemorrhagic complications.

Clinical outcome of patients who develop PAF after CABG surgery.

KOWEY, P.R., et al.: Clinical Outcome of Patients Who Develop PAF After CABG Surgery. This was a retrospective analysis of patients who had CABG surgery at our hospital over a 12‐month period to determine the intermediate‐term prognosis of those who had developed PAF after their operation before hospital discharge. Of 317 patients who were operated by a single surgical group, 116 (37%) had AF postoperatively of whom 112 had the paroxysmal form. Of these, 36 were treated with class I or III antiarrhythmic drugs and rate control drugs (group 1) and 76 were treated with rate control alone (group 2). Group 3 consisted of 151 randomly selected patients who did not have AF. All patients were reevaluated at 6 weeks to determine their rhythm and clinical status. Only one patient each in groups 1 and 2 was in AF 6 weeks after discharge. There was a trend toward a higher mortality and morbidity in group 2 patients. PAF after coronary surgery appears to be a self‐limited disease process. In this cohort of patients, the rate of recurrence of AF after discharge was similar in patients receiving class I or class III antiarrhythmic drugs together with rate control agents compared to those receiving rate control drugs alone.

Effectiveness of Digitalis With or Without Acebutolol in Preventing Atrial Arrhythmias After Coronary Artery Surgery

In this study, a beta-adrenergic blocker in combination with digoxin provided marginal protection against atrial fibrillation/flutter after coronary artery surgery. The economic comparison of patients who did and did not develop atrial fibrillation/flutter indicates that prevention of these arrhythmias can have a significant impact on length of hospital stay and cost of this common surgical procedure.

Does programmed stimulation really help in the evaluation of patients with nonsustained ventricular tachycardia? Results of a meta-analysis.

There has been considerable debate regarding the value of programmed electrical stimulation in patients who present with asymptomatic, or minimally symptomatic, nonsustained VT. Unfortunately, there has never been a sufficiently large study of an untreated group of patients to make any sense of the issue. We culled the literature for reports published between 1986 and 1990 that met certain minimum requirements, the most important of which were adequate patient profiling and outcome data. The survey identified 12 studies of 926 patients, mean age 61 years, with a 5:1 male preponderance. Underlying heart disease was coronary in 818 patients, including 665 who had experienced previous but not recent myocardial infarctions. Of these, 302 (33%) had inducible sustained ventricular arrhythmias (monomorphic VTs in 264). Eighty-three percent of these patients were treated with antiarrhythmic drugs compared to only 13% of the noninducible group (p less than 0.0001). Sudden death or a sustained arrhythmic event occurred in 54 (18%) of the 302 patients in the inducible group compared with 46 (7%) of the 624 in the noninducible group (p less than 0.001). The sensitivity, specificity, and positive and negative predictive accuracies of the test were 54%, 70%, 18%, and 93%, respectively. Thus a patient with an inducible sustained arrhythmia who manifests nonsustained VT is two and a half times as likely to have a major arrhythmic event, but a negative result bodes well for the patient. However, widespread application of the technique cannot be recommended until these results are confirmed in a large, prospective study in which antiarrhythmic therapy is controlled.

Outcome of patients with nonsustained ventricular tachycardia and severely impaired ventricular function who have negative electrophysiologic studies

Twenty-nine consecutive patients with a prior myocardial infarction, severely reduced left ventricular ejection fraction (26% +/- 8%), and asymptomatic nonsustained ventricular tachycardia were enrolled in a prospective trial. After a negative programmed electric stimulation study (3 extrastimuli at 2 sites with 2 drive trains), the 26 men and 3 women (mean age 71) were monitored for a mean of 13 months without antiarrhythmic drug therapy. Five patients died suddenly or had sustained ventricular tachycardia; three others had a cardiac, nonarrhythmic death. Events occurred in the first 13 months of the surveillance period. Clinical factors associated with a poor outcome included congestive heart failure and lack of beta-blocker therapy. In addition, patients with events tended to have lower ejection fractions than those without (21% vs 28%, p not significant). Thus a negative programmed electric stimulation study does not necessarily imply a benign outcome in patients with a prior infarction and nonsustained ventricular tachycardia if they also have severe left ventricular dysfunction and a history of heart failure. These data have important implications for the design and conduct of contemporary clinical trials.

Atrial Fibrillation Trials: Will They Teach Us What We Need to Know?

Atrial fibrillation (AF) has captured the imagination of clinical investigators who have initiated trials to examine several aspects of this multifaceted arrhythmia. We will review the protocol designs of ongoing trials that are examining the relative value of rhythm versus rate control, new methods for pharmacologic restoration and maintenance of sinus rhythm (including prophylaxis after cardiac surgery), and nonpharmacologic interventions such as pacing and atrial defibrillation. We antic ipate that the results of these studies will have a major impact on the care of patients with AF in the new millennium.

Electrophysiologic testing in patients who respond acutely to intravenous amiodarone for incessant ventricular tachyarrhythmias

The outcome of patients who receive intravenous amiodarone for suppression of incessant ventricular tachyarrhythmia has not been studied conclusively. We conducted a prospective study in which all patients who responded acutely to intravenous amiodarone and went on to receive a subsequent oral loading dose were subjected to electrophysiologic testing before hospital discharge to determine whether additional or alternative therapy would be required. Among 18 patients (17 with ischemic heart disease) who entered the protocol, 16 had a clinical response to intravenous amiodarone alone (12 patients) or in combination with another antiarrhythmic drug (4 patients) and survived to study. Of these, 10 had monomorphic ventricular tachycardia (VT) when first seen, five had polymorphous VT or ventricular fibrillation (VF), and three had both. In seven patients sustained monomorphic VT was inducible (group 1), and in nine it was not (group 2). The only clinical factor that distinguished group 1 from group 2 was age (group 1 > group 2). Five patients in group 1 and one in group 2 received an implantable cardioverter defibrillator; one patient in group 1 had a successful endocardial resection. During a mean follow-up period of 11 months, four patients in group 1 have had appropriate implantable cardioverter defibrillator discharges, whereas only one patient in group 2 has had a clinical event (sudden death). We conclude that intravenous amiodarone is a highly effective drug used alone or in combination to suppress spontaneous incessant VT/VF. Predischarge electrophysiologic testing, even in patients who have polymorphous VT, has predictive value over and above the observed clinical response. These preliminary results favor predischarge testing and aggressive device treatment in this cohort.