Time to arrhythmic, ischemic, and heart failure events: exploratory analyses to elucidate mechanisms of adverse drug effects in the Cardiac Arrhythmia Suppression Trial.

In this study we investigated the time to the first arrhythmic, ischemic, or failure event for encainide-flecainide and moricizine versus their respective placebo comparison groups in the Cardiac Arrhythmia Suppression Trial. The purpose was to explore possible mechanisms for the excessive deaths associated with active therapy that have been previously reported. Differences were noted between the active drugs. In particular, encainide-flecainide appeared to convert an ischemic event into death in more cases and more promptly than moricizine. However, the excessive deaths noted on encainide-flecainide were as likely to occur subsequent to a failure event as an ischemic event; for both encainide-flecainide and moricizine, the vast majority of excess deaths appeared to be the result of an increase in arrhythmia events without any protective effect of the drug. We were unable to identify any specific mechanism to explain the adverse effect of encainide and flecainide.

Electrocardiographic diagnosis of left ventricular hypertrophy in the presence of bundle branch block.

Autopsy and echocardiographic studies indicate that ECG criteria for LVH tend to maintain their sensitivity in the presence of LBBB, with the exception of left precordial lead criteria alone. With RBBB, ECG criteria for LVH using right precordial S waves and combination criteria of right precordial S waves and left precordial R waves have a marked reduction in sensitivity, whereas left precordial R wave criteria have modestly reduced sensitivity. Limb lead criteria for LVH have increased sensitivity in the presence of RBBB and, to a lesser extent, in the presence of LBBB. Acceptable sensitivity for the diagnosis of LVH in patients with bundle branch block requires a combination of limb and precordial lead voltage criteria and/or other nonvoltage ECG criteria, since the prevalence of LVH in the presence of RBBB or LBBB appears higher than the sensitivity of individual criteria.

Events in the Cardiac Arrhythmia Suppression Trial (CAST): mortality in the entire population enrolled.

To test the hypothesis that suppression of ventricular arrhythmias by antiarrhythmic drugs after myocardial infarction improves survival, the Cardiac Arrhythmia Suppression Trial (CAST) was initiated. Suppression was evaluated before randomization during an open label titration period. Patients whose arrhythmias were suppressed were randomized in the main study and those whose arrhythmias were partially suppressed were randomized in a substudy. Overall survival and survival free of arrhythmic death or cardiac arrest were lower [corrected] in patients treated with encainide or flecainide than in patients treated with placebo. However, the death rate in patients randomized to placebo therapy was lower than expected. This report describes the survival experience of all patients enrolled in CAST and compares it with mortality in other studies of patients with ventricular arrhythmias after myocardial infarction. As of April 18, 1989, 2,371 patients had enrolled in CAST and entered prerandomization, open label titration: 1,913 (81%) were randomized to double-blind, placebo-controlled therapy (1,775 patients whose arrhythmias were suppressed and 138 patients whose arrhythmias were partially suppressed during open label titration); and 458 patients (19%) were not randomized because they were still in titration, had died during titration or had withdrawn. Including all patients who enrolled in CAST, the actuarial (Kaplan-Meier) estimate of 1-year mortality was 10.3%. To estimate the "natural" mortality rate of patients enrolled in CAST, an analysis was done that adjusted for deaths that might be attributable to encainide or flecainide treatment either during prerandomization, open label drug titration or after randomization. Because the censoring procedure excluded patients treated with encainide or flecainide after randomization, the mortality estimate will be less than the unadjusted mortality estimate of 10.3%.(ABSTRACT TRUNCATED AT 250 WORDS)

Avoiding interpretive pitfalls when assessing arrhythmia suppression after myocardial infarction: insights from the long-term observations of the placebo-treated patients in the Cardiac Arrhythmia Pilot Study (CAPS)

The Cardiac Arrhythmia Pilot Study (CAPS) was a 1 year trial that analyzed the safety and effectiveness of arrhythmia suppression in 502 patients surviving acute myocardial infarction who had greater than or equal to 10 ventricular premature depolarizations/h or greater than or equal to 5 runs of ventricular tachycardia on a Holter recording obtained 6 to 60 days after the acute infarction. Because 100 of these patients received placebo in a double-blind fashion for 1 year, a comprehensive objective analysis was performed of spontaneous arrhythmia changes based on real data rather than statistical estimates. In the CAPS placebo group, 19% developed some serious clinical event in 1 year (death, heart failure, proarrhythmia) that could likely be attributable to antiarrhythmic drug toxicity. A significant reduction in the frequency of ventricular premature depolarizations (p = 0.004) occurred in the first few weeks of "therapy" with a further significant (p less than 0.04) decrease between 3 to 12 months. After initiation of placebo antiarrhythmic therapy, 27% had "apparent ventricular premature depolarization suppression" (greater than or equal to 70% reduction) after one Holter recording evaluation and nearly half (48%) after six Holter recordings to assess suppression were performed.(ABSTRACT TRUNCATED AT 250 WORDS)

Coronary heart disease morbidity and mortality in hypercholesterolemic men predicted from an exercise test: the Lipid Research Clinics Coronary Primary Prevention Trial.

A positive exercise electrocardiogram (ECG) has been proved to predict cardiovascular events in asymptomatic normolipidemic men. To study whether it is also predictive for hypercholesterolemic men, data from 3,806 asymptomatic hypercholesterolemic men in the Lipid Research Clinics Coronary Primary Prevention Trial were analyzed. All the men had performed a submaximal treadmill exercise test at baseline, before they were assigned to the cholestyramine or placebo treatment group. Because of missing or inconclusive data, 31 men were excluded from the analyses. A test was positive if the ST segment was displaced by greater than or equal to 1 mm (visual code) or there was greater than or equal to 10 microV-s change in the ST integral (computer code), or both. The prevalence of a positive test was 8.3%. During the 7 to 10 year (mean 7.4) follow-up period, the mortality rate from coronary heart disease was 6.7% (21 of 315) in men with a positive test and 1.3% (46 of 3,460) in men with a negative test (placebo and cholestyramine groups combined). The age-adjusted rate ratio for a positive test, compared with a negative test, was 6.7 in the placebo group and 4.8 in the cholestyramine group. With use of Cox's proportional hazards models, it was found that the risk of death from coronary heart disease associated with a positive test was 5.7 times higher in the placebo group and 4.9 times higher in the cholestyramine group after adjustment for age, smoking history, systolic blood pressure, high density lipoprotein cholesterol and low density lipoprotein cholesterol. A positive test was not significantly associated with nonfatal myocardial infarction.(ABSTRACT TRUNCATED AT 250 WORDS)

Electrocardiographic criteria for diagnosis of left ventricular hypertrophy in the presence of complete right bundle branch block.

The usual electrocardiographic criteria recommended for left ventricular (LV) hypertrophy may be unreliable in the presence of complete right bundle branch block (BBB). Thirty-six standard electrocardiographic criteria for LV hypertrophy were evaluated in 100 patients (mean age +/- standard deviation 67 +/- 11 years) with right BBB and technically satisfactory echocardiograms. Eight additional electrocardiographic criteria derived from this study also were evaluated. LV mass index was determined from the echocardiogram using the Penn method. LV hypertrophy defined as LV mass index greater than 132 g/m2 in men and 109 g/m2 in women was present in 56 of the 100 patients. Electrocardiographic criteria with the highest sensitivity were SIII + (R + S) maximal precordial lead greater than or equal to 30 mm (sensitivity 68%), specificity 66%), left axis deviation of -30 degrees to -90 degrees (sensitivity 59%, specificity 71%) and combination of left axis deviation and SIII + (R + S) maximal precordial lead greater than or equal to 30 mm (sensitivity 52%, specificity 84%). The electrocardiographic criteria with the highest sensitivity and specificity greater than 90% were left axis deviation of -30 degrees to -90 degrees and SV1 greater than 2 mm (sensitivity 34%), point-score system, RaVL greater than 12 mm and RI + SIII greater than 25 mm (each with a sensitivity of 27%). In general, limb lead voltage criteria such as RaVL greater than 11 mm (sensitivity 29%, specificity 86%) had higher sensitivities than criteria using right precordial lead S-wave voltage criteria such as SV1 + RV5, V6 greater than 35 mm (sensitivity 2%, specificity 100%).(ABSTRACT TRUNCATED AT 250 WORDS)

Thallium-201/technetium-99m-RP-30A disparity in the course of myocardial infarction after attempted reperfusion.

Recent reports have established that 201Tl may be taken up in areas of recent myocardial infarction after myocardial blood flow is re-established. In addition, there is accelerated 201Tl "washout" from these regions producing a pattern of "reverse redistribution." We present a case in which these phenomena may have contributed to a disparity of findings between a 201Tl stress imaging study and a repeat stress imaging study performed with a [99mTc] isonitrile (99mTc-RP-30A).

Association between extent of coronary artery disease and ventricular premature beat frequency after myocardial infarction.

Severe coronary artery disease (CAD) and frequent ventricular premature beats (VPBs) on ambulatory ECG monitoring in the late hospital phase after myocardial infarction are independent predictors of prognosis. To study the relationship between extent of CAD and VPB frequency, 128 consecutive (91 men, 37 women) patients surviving 6 days after myocardial infarction underwent 24-hour ECG, coronary angiography, and left ventriculography. CAD was graded as zero to one-, two-, and three-vessel (V), and also by a previously validated "jeopardy score" with 0 to 12 as grades of incremental CAD severity. Average VPB frequency was significantly correlated with CAD by V, CAD by jeopardy score, and by left ventricular ejection fraction (p less than 0.01 for all three). With the use of a multivariate ordinal logistic regression model, both VPB frequency and left ventricular ejection fraction were found to have independent association with CAD. The median VPB frequency was 1/hr, 0.6/hr, and 6/hr in zero to one-, two-, and three-V CAD, respectively (zero to one- and two-V CAD vs three-V CAD p less than 0.01, one-V CAD vs two-V CAD p = NS). In conclusion, frequent VPBs following myocardial infarction are associated with extensive CAD and are independent of left ventricular ejection fraction. Therefore, the prognostic value of frequent VPBs may be related to severe underlying ischemic disease.

Mortality in the beta blocker heart attack trial: circumstances surrounding death.

In the Beta Blocker Heart Attack Trial, a double blind, randomized, controlled study, patients taking propranolol (180 or 240 mg/day) initiated 5-21 days post myocardial infarction had 26% fewer deaths than those taking placebo over a 25 month (mean) followup. Detailed analysis of the circumstances surrounding the BHAT deaths failed to reveal any striking difference between propranolol and placebo in the type of clinical event preceding death, the incidence and type of acute and prodromal signs and symptoms, the location of death, the activity preceding death or the percentage of deaths that were sudden or instantaneous, suggesting that propranolol may exert an "across the board" effect and improve survival by a combination of mechanisms. An unexpected finding was that the protective effect of propranolol appeared to occur during the hours of 10 p.m. to 7 a.m.

Doppler echocardiographic evaluation of Hancock and Björk-Shiley prosthetic values.

Doppler echocardiographic characteristics of normally functioning Hancock and Björk-Shiley prostheses in the mitral and aortic positions were studied in 50 patients whose valvular function was considered normal by clinical evaluation. Doppler studies were also performed in 46 patients with suspected malfunction of Hancock and Björk-Shiley valves and who subsequently underwent cardiac catheterization. Mean gradients were estimated for both mitral and aortic valve prostheses and valve area was calculated for the mitral prostheses. Doppler prosthetic mitral valve gradient and valve area showed good correlation with values obtained with cardiac catheterization (r = 0.93 and 0.97, respectively) for both types of prosthetic valves. The correlation coefficient (r = 0.93) for mean prosthetic aortic valve gradient was also good, although Doppler echocardiography overestimated the mean gradient at lower degrees of obstruction. Regurgitation of Hancock and Björk-Shiley prostheses in the mitral and aortic positions was correctly diagnosed. These results suggest that Doppler echocardiography is a reliable method for the characterization of normal and abnormal prosthetic valve function.

Dyslipoproteinemias and manifestations of coronary heart disease. The Lipid Research Clinics Program Prevalence Study.

The Lipid Research Clinics Prevalence Study population underwent a noninvasive evaluation to assess the odds of coronary heart disease (CHD) among individuals with various types of dyslipoproteinemia (DLP) relative to the odds for individuals free of DLP in a nonselected population. The noninvasive evaluation included the Rose questionnaire for angina, a resting electrocardiogram, and a graded treadmill exercise test. The presence of manifestations of CHD was assessed by a combination of these findings. Multiple linear regression and multiple logistic regression analyses were used to evaluate associations between CHD and DLP, with adjustments for the following covariates: age, body mass, systolic blood pressure, alcohol consumption, and cigarette use. There were no consistent associations in women or in men 30 to 49 years old. In men 50 to 69 years old, the mean high-density lipoprotein cholesterol (HDL-C) values and HDL-C/cholesterol ratio were significantly lower in the definite CHD and angina categories, compared with the negative (no evidence of CHD) group. Higher odds ratios for CHD were present in those classified as having type IIa, type IV, and hypoHDL DLPs, relative to those classified as normal by the phenotyping algorithm. These associations were consistent across the several categories of CHD manifestations, but did not reach statistical significance after adjustment for multiple testing. A statistically significant lower odds ratio for CHD was observed in men 50 to 69 classified as having hyperHDL when compared with those without DLPs. The associations between CHD and the various forms of DLP were consistent with those observed between CHD and the plasma lipid and lipoprotein-cholesterol concentrations. The Lipid Research Clinics Prevalence Study confirmed the relationship between elevated low-density lipoprotein cholesterol, decreased HDL-C, and noninvasively determined CHD in a free-living asymptomatic population of older men.

Arrhythmias on ambulatory electrocardiographic monitoring in women without apparent heart disease.

Cardiac arrhythmias were evaluated in apparently normal women by randomly selecting within the age decades of 20 to 60, 200 of the 788 women employees of a company. After exclusions for cardiac and medical reasons and refusals to participate, 101 subjects underwent 24-hour ambulatory electrocardiographic monitoring. The mean heart rate was 82 beats/min, but was higher in smokers (p less than 0.05). Premature supraventricular contractions were present in 28 of 101 subjects (28%); the prevalence increased with age (p less than 0.001), but the frequency was less than 1 per hour in 24 of 28. PVCs occurred in 34 of 101 subjects (34%); the frequency was less than 1 per hour in 25 of 34. The PVCs were complex (Lown grade 3 or higher) in 10 (10%) and multifocal in 9 of 10; there was 1 couplet each in 3 and 1 run of 4 PVCs in 1 subject. PVCs were present in 20 of 42 subjects (48%) taking any medication (primarily oral contraceptives, estrogenic hormones and maintenance thyroid), compared with 14 of 59 subjects (24%) not taking medication (p less than 0.01). In women younger than 40 years, PVCs were present in 8 of 15 women (53%) taking contraceptives, compared with 4 of 33 (12%) not taking contraceptives (p less than 0.001). PVCs occurred in 7 of 12 subjects (58%) taking thyroid medication, compared with 27 of 89 (30%) not taking thyroid medication (p less than 0.03). In the 59 subjects not taking medication only 1 subject averaged more than 1 PVC/hour and 1 had 1 couplet.(ABSTRACT TRUNCATED AT 250 WORDS)

Timing, mechanism and clinical setting of witnessed deaths in postmyocardial infarction patients.

The temporal distribution and mechanism of death were studied in a large multicenter secondary prevention trial (Aspirin Myocardial Infarction Study) in which acute witnessed death represented 72% (270 of 376) of the deaths due to arteriosclerotic heart disease. Instantaneous deaths represented 28.9% (78 of 270) of the acute witnessed deaths; 45.2% (122 of 270) occurred in the first hour after the onset of symptoms and were defined as sudden deaths. In the subsequent 23 hours, an additional 113 deaths (41.8%) occurred and were defined as intermediate deaths; 29 late deaths (10.7%) occurred after 24 hours. Cardiac arrhythmia was the mechanism of death in 83% (194 of 235) of deaths within 24 hours. Univariate analysis of baseline clinical and electrocardiographic characteristics indicates that a history of congestive heart failure, cardiomegaly, angina pectoris, multiple myocardial infarctions and therapy with digitalis and nitroglycerin were more common in those who died than in survivors, regardless of the timing of death.

Diagnosis of aortic insufficiency: comparison of auscultation and M-mode echocardiography to angiography.

We compared auscultation and M-mode echocardiography to supravalvular aortography in 75 patients with chronic aortic insufficiency. Angiographic evidence of aortic insufficiency was present in 66 patients and absent in nine. Auscultation had a sensitivity of 72.7% (48/66) and a specificity of 77.8% (7/9). Echocardiography had a sensitivity of 75.8% (50/66) and specificity of 77.8% (7/9). When both methods were used in combination, their sensitivity for diagnosis of aortic insufficiency increased to 92.9% (61/66). The specificity did not change. Our data suggest that when used alone neither auscultation nor echocardiography is a sensitive method for detecting aortic insufficiency, but when used in combination they are excellent indicators for the presence or absence of aortic insufficiency.

Prevalence and significance of arrhythmias in long-term survivors of cardiac transplantation.

The prevalence and significance of arrhythmias after cardiac transplantation were evaluated in the absence of acute rejection in 13 long-term survivors (greater than 3 months). ECGs were obtained daily for the first 70 days 8- and 24-hour ambulatory electrocardiographic monitoring was performed 3 months after the transplantation and every 6 months thereafter. Junctional rhythm occurred during the early transplant period (less than 70 days) in nine of 13 patients. Complex premature ventricular depolarizations (Lown grade III or higher) were present in the late transplant period (greater than 70 days) in all five patients in whom severe coronary artery disease was found in the donor heart at postmortem, compared with two of the eight remaining patients (six survivors and two patients who died but did not have coronary artery disease at postmortem) (p less than 0.05). The high prevalence of junctional rhythm in the early transplant period appeared to be due to sympathetic denervation and reversible surgical damage to and ischemia of the sinus node region of the donor heart. Routine ambulatory electrocardiographic monitoring detected complex premature ventricular depolarizations, which were a sensitive marker for the subsequent mortality related to accelerated atherosclerosis of chronic rejection in the donor heart.