Faculty Bibliography

Patient adherence to therapy is essential to assess treatment efficacy, particularly in clinical trials. Active treatment usually is expected to benefit patients. The healthy adherer effect, the association or greater adherence to all health-promoting behaviors, including medication and overall concern for health, explains the improved survival of more adherent patients in both active and placebo medication groups of several clinical trials. The Cardiac Arrhythmia Suppression Trial (CAST), a placebo-controlled double-blind clinical trial of post-myocardial infarction (MI) patients with asymptomatic ventricular arrhythmias, in which active medication (encainide or flecainide) led to increased mortality, provided an opportunity to examine the relationship of adherence to survival from a different perspective. We consider whether adherence to active treatment was related to arrhythmic mortality and whether a healthy adherer effect might counteract the effect of treatment on mortality among patients taking active medication. Adherence (average pill count) at the first follow-up visit did not differ in the active treatment (92.2%, standard deviation (SD) = 11.97, n = 574) and placebo (90.8%, SD = 13.66, n = 579) groups. In a Cox proportional hazard regression model, medication adherence predicted arrhythmic mortality among the active (P < 0.0062) but not the placebo medication group. The effect of adherence on arrhythmic mortality was significant beyond the effects of ejection fraction, race, spouse, smoking status, diuretic medication, and history of MI. A 10% increase in adherence led to more than a threefold increase of risk of arrhythmic death. The design of the CAST, which included a titration phase, may have tended to select relatively adherent patients since only those whose arrhythmias were suppressed with active medication were randomized into the trial. The data do not support a strong healthy adherer effect in the CAST. There was no evidence in this study that a healthy adherer effect counterbalanced the effect of the active medication

OBJECTIVE--To determine whether an interaction between encainide or flecainide and intercurrent ischaemia could account for the observed increase in cardiac and sudden deaths in the study group in the Cardiac Arrhythmia Suppression Trial (CAST) I. DESIGN--CAST I was a randomised, double blind, placebo controlled study in which patients received the drug which suppressed at least 6 premature ventricular contractions per minute by 80% or episodes of non-sustained ventricular tachycardia by 90%. Arrhythmic sudden death or aborted sudden death were the study end points. Measured secondary end points included recurrent myocardial infarction, new or increasing angina pectoris, congestive heart failure, and syncope. The CAST I database was analysed to determine which of three end points occurred first--cardiac death or cardiac arrest, angina pectoris, or non-fatal recurrent infarction. They were regarded as mutually exclusive end points. The triad of cardiac or sudden arrhythmic death plus congestive heart failure and syncope was similarly analysed. RESULTS--It was assumed that recurrent non-fatal infarction and new or increasing angina pectoris were ischaemic in origin. The sum of these non-fatal ischaemic end points and sudden death were nearly identical in the placebo group (N = 129) and the treatment group (N = 131). The one year event rate in each group was 21%. However, the treatment group had a much greater fatality rate (55 v 17; P < 0.0001) than the placebo group. The same relation was found when the data were examined on the basis of drug exposure rather than intention to treat. The temporal and circadian events were similar in each group and were consistent with an ischaemic pattern. No such patterns emerged from analysis of the presumed non-ischaemic end points of congestive heart failure and syncope. CONCLUSIONS--These data suggest that the interaction between active ischaemia and treatment with encainide or flecainide may have been responsible for the increased mortality seen in the treatment group in CAST I. This conversion of a non-fatal to a fatal event emphasises the need for future antiarrhythmic drugs to be screened in ischaemic models

OBJECTIVES. This study was performed to assess the effect of cigarette smoking cessation on overall mortality and the incidence of arrhythmic death in the population of the Cardiac Arrhythmia Suppression Trial (CAST). BACKGROUND. Cigarette smoking is a known risk factor for sudden cardiac death. Some of the adverse effects of smoking have been shown to dissipate with smoking cessation, but the time frame over which these changes occur and the population that stands to benefit have not been well delineated. CAST was a multicenter double-blind placebo-controlled study to determine whether suppression of ventricular ectopic activity by means of antiarrhythmic drugs in patients with left ventricular dysfunction after acute myocardial infarction would reduce the incidence of arrhythmic death. METHODS. Of 2,752 patients randomized to blinded therapy, 1,026 were smoking at the time of their baseline examination and completed a 4-month follow-up visit. Of these, 517 stopped smoking by the time of this visit ('quitters') and 509 continued to smoke ('smokers'). RESULTS. Over a mean follow-up period of slightly < 16 months, there were 17 arrhythmic deaths and 32 total deaths among the quitters versus 30 and 45, respectively, among the smokers; these differences were of marginal statistical significance. Most of the fatal events occurred in a group at high risk of ongoing ischemia: the 558 patients who did not have thrombolysis or undergo revascularization after their qualifying myocardial infarction. In this high risk cohort, smoking cessation greatly reduced the incidence of arrhythmic death and was associated with a statistically significant benefit in survival. CONCLUSIONS. Smoking cessation was accompanied by a marked reduction in arrhythmic death and overall mortality that achieved statistical significance in a high risk cohort. These data imply that smoking cessation is important in risk factor reduction in patients with advanced ischemic heart disease

Holter data from the 17,609 postmyocardial infarction patients in the CAST Registry were analyzed to study the effect of age on VPC and VT incidence and frequency. Multivariable analysis demonstrated that age is an important independent predictor of increased ventricular ectopy, with the median rate of VPCs/hour increasing from 0.4 (patients aged < 50 years) to 4.0 (patients aged 75 to 80 years), and the prevalence of VT increasing from 7.3% (patients aged < 50 years) to 15.3% (patients aged 75 to 80 years)

[Jonas Salk] obtained tissue cultures from Enders and in 1950 studied the effects of different strains of virus on monkey kidney tissue cultures. Salk continued to work meticulously, and then took the courageous step of endorsing human trials. On March 26, 1953, Salk spoke to the nation on radio, outlining the results of his experiments to date. While the nation eagerly waited, Salk showed the need for further experimentation before a dependable vaccine could be made available. In 1954, a massive vaccination trial was conducted on 1.8 million children with positive results. In April 1955, the news broke that Salk had developed a safe and effective vaccine, and that plans were made to inoculate 30 million children that year. People sent money and flowers, and colleges offered honorary degrees, but Salk felt uncomfortable and embarrassed by adulation and fame. His work was being disrupted by this activity. Then only 40, he simply wanted to get back to his lab to continue his work

[Jonas Salk] obtained tissue cultures from [John Enders] and in 1950 studied the effects of different strains of virus on monkey kidney tissue cultures. Salk continued to work meticulously, then took the courageous step of endorsing human trials. On March 26, 1953, Salk spoke to the nation on radio, outlining the results of his experiments to date. While the nation eagerly waited, Salk showed the need for further experimentation before a dependable vaccine could be made available. 1954 saw a massive vaccination trial in which 1.83 million children were inoculated, with positive results. In April 1955, the news broke that Salk had developed a safe and effective vaccine, and that plans were made to inoculate 30 million children that year. People sent money and flowers and colleges offered honorary degrees, but Salk felt uncomfortable and embarrassed by adulation and fame

OBJECTIVES. The goal of this study was to establish guidelines for the prognostic use of the time domain signal-averaged electrocardiogram (ECG) after myocardial infarction. BACKGROUND. Previous studies of the prognostic use of the signal-averaged ECG in postinfarction patients had one or more of the following limitations: a small study group, empiric definition of an abnormal recording and possible bias in the selection of high risk groups or classification of arrhythmic events, or both. To correct for these limitations, a substudy was conducted in conjunction with the Cardiac Arrhythmia Suppression Trial (CAST). METHODS. Ten centers recruited 1,211 patients with acute myocardial infarction without application of the ejection fraction or Holter criteria restrictions of the main CAST protocol. Several clinical variables, ventricular arrhythmias on the Holter recording, ejection fraction and six signal-averaged ECG variables were analyzed. Patients with bundle branch block were excluded from the analysis, and the remaining 1,158 were followed for up to 1 year after infarction. The classification of arrhythmic events was reviewed independently by the CAST Events Committee. RESULTS. During an average (+/- SD) follow-up of 10.3 +/- 3.2 months, 45 patients had a serious arrhythmic event (nonfatal ventricular tachycardia or sudden cardiac arrhythmic death). A Cox regression analysis with only the six signal-averaged ECG variables indicated that the filtered QRS duration at 40 Hz > or = 120 ms (QRSD-40 Hz) at a cutpoint > or = 120 ms was the most predictive criterion of arrhythmic events. In a regression analysis that included all clinical, Holter and ejection fraction variables, a QRSD-40 Hz > or = 120 ms was the most significant predictor (p < 0.0001). The positive, negative and total predictive accuracy and odds ratio for QRSD-40 Hz > or = 120 ms were 17%, 98%, 88% and 8.4, respectively, and improved to 32%, 97%, 94% and 16.7, respectively, after combination with ejection fraction < or = 40% and complex ventricular arrhythmias on the Holter recording. CONCLUSIONS. The signal-averaged ECG predicts serious arrhythmic events in the first year after infarction better than do clinical, ejection fraction and ventricular arrhythmia variables, and QRSD-40 Hz > or = 120 ms provides the best predictive criterion in this clinical setting

The Cardiac Arrhythmia Suppression Trial (CAST) showed antiarrhythmic drug suppression of asymptomatic or mildly symptomatic ventricular arrhythmias in survivors of myocardial infarction to be harmful. This study retrospectively searched the CAST results for evidence of mortality and morbidity reduction in patients receiving optional beta-blocker therapy. All enrolled (n = 2,611) and suppressed main study (n = 1,735) CAST patients with an ejection fraction of < or = 40% were examined using univariate analysis, Kaplan-Meier curves, and a Cox proportional-hazards multivariate analysis with respect to optional beta-blocker therapy prescribed at baseline. CAST patients receiving beta-blocker therapy had significantly enhanced survival at 30 days, and at 1 and 2 years of follow-up against all-cause and arrhythmic death or nonfatal cardiac arrest. Multivariate analysis showed beta-blocker therapy to be independently associated with a one-third reduction in arrhythmic death or cardiac arrest (p = 0.036). In CAST patients with a history of congestive heart failure, beta-blocker therapy was independently associated with longer time to occurrence of new or worsened congestive heart failure (p = 0.015). This study supports the secondary preventive benefit of beta-blocker therapy in high-risk post-myocardial infarction patients, and calls attention to the possible preventive benefit of beta-blocker therapy against proarrhythmic events experienced in the CAST

Thrombolytic therapy and angioplasty during the early phase of an acute myocardial infarction (AMI) have been shown to improve prognosis. Time-domain analysis of the signal-averaged electrocardiogram (SAECG) provides strong, independent prediction of arrhythmic events (arrhythmic death/resuscitated cardiac arrest) after AMI. To determine whether the prognostic significance of an abnormal SAECG (QRS duration > or = 120 ms) measured after AMI is influenced by thrombolytic therapy/angioplasty given in the AMI period, the predictive value of SAECG was compared in patients with and without prior thrombolysis/angioplasty in a substudy of the Cardiac Arrhythmia Suppression Trial. Information was available in 787 patients. The average follow-up was 10 +/- 3 months and arrhythmic events occurred in 33 patients (4.2%). The prevalence of abnormal SAECG in patients with and without thrombolytic therapy/angioplasty was 9.4% (34 of 363 patients) and 14.9% (63 of 424 patients), respectively (p < 0.02). The arrhythmic event rate for patients with abnormal SAECG with and without thrombolytic therapy/angioplasty was 20.6% (7 of 34 patients) and 20.6% (13 of 63 patients), respectively. The arrhythmic event rate for patients with normal SAECG with and without thrombolytic therapy/angioplasty was 0.9% (3 of 329 patients) and 2.8% (10 of 361 patients), respectively. It is concluded that in patients with an AMI (1) the use of thrombolytic therapy/angioplasty is associated with a significantly decreased prevalence of abnormal SAECG, (2) thrombolytic therapy/angioplasty associated with a normal SAECG portends an excellent prognosis, and (3) an abnormal SAECG is predictive of an increased incidence of arrhythmic events in all patients regardless of prior thrombolytic therapy/angioplasty.(ABSTRACT TRUNCATED AT 250 WORDS)

OBJECTIVES. This study was undertaken to determine the characteristics of worsening ventricular arrhythmia during antiarrhythmic drug titration. BACKGROUND. Proarrhythmia is an evolving concept in cardiology. Its definition, incidence and clinical significance in various patient settings require refinement. METHODS. The impact of early proarrhythmia was analyzed in 3,840 patients in the Cardiac Arrhythmia Suppression Trial (CAST). RESULTS. Drug therapy did not affect the incidence of new, sustained but nonfatal ventricular tachycardia (placebo 0.5%, active drug 0.4%). Nevertheless, there was a threefold increase in arrhythmic death (placebo 0.5% vs. active drug 1.6%). The incidence of increased ventricular premature depolarizations was equivalent (3% to 5%) for the three study drugs and indistinguishable from that seen with placebo. Patients with increased ventricular premature depolarizations on the first drug tested had fewer at baseline (65 +/- 94 vs. 137 +/- 260 per hour; mean +/- SD) (p < 0.01). When increased ventricular premature depolarizations occurred with the first drug, they were much more likely also to be present with the second drug (for example, 42% vs. 5%, p < 0.001). Increased ventricular premature depolarizations during initiation of therapy independently predicted increased risk of subsequent arrhythmic death (independent relative risk 2.34, p = 0.0053) in the absence of continued antiarrhythmic drug therapy. CONCLUSIONS. The overall incidence of early worsening of arrhythmia in the present study was low. In the absence of placebo control, the incidence of proarrhythmia will be overestimated. Increased ventricular premature depolarizations had characteristics that suggest they often represent spontaneous variability rather than proarrhythmia. The main finding is that markedly increased ventricular premature depolarizations during drug titration predict long-term increased risk of arrhythmic death in this patient population despite absence of long-term antiarrhythmic drug therapy