The effect of regular, moderate exercise on the lipoprotein subfractions of male survivors of myocardial infarction was studied. Nineteen men were randomly allocated to an incremental exercise program and 23 to a control group. Both groups were studied for 6 months. No change occurred in any lipoprotein class in the control group. In the trained group, total triglyceride and low-density lipoprotein (LDL) cholesterol concentrations decreased significantly (0.01 greater than p greater than 0.001 and 0.05 greater than p greater than 0.01, respectively) and high-density lipoprotein (HDL) cholesterol and apolipoprotein A-1 rose (both p less than 0.001). The concentration of the HDL2 subfraction increased with training (0.01 greater than p greater than 0.001) and HDL2 did not change. No relationship was found between changes in lipoproteins and treadmill exercise test performance. Thus, in survivors of myocardial infarction, exercise may alter plasma lipoprotein values beneficially.

We compared the effects of a cardioselective beta-adrenergic blocking drug, metoprolol, with a nonselective beta-adrenergic blocker, propranolol, on the response of 10 normal men to dynamic treadmill exercise. The volunteers underwent a standard graded exercise test to exhaustion while receiving placebo; propranolol, 40 mg every 6 hours; propranolol, 80 mg every 6 hours; metoprolol, 50 mg every 6 hours; or metoprolol, 100 mg every 6 hours. The drugs were given in a double-blind fashion for 48 hours before exercise. Five days were allowed between successive drug administrations and the order of drug administration was randomized. Heart rate, arterial pressure, oxygen consumption, minute ventilation and CO2 production were monitored. Plasma drug concentrations were measured at the time of exercise. Judged by plasma levels, propranolol was about three times more potent than metoprolol in attenuating heart rate. Both drugs produced a wide variation in plasma levels after a given oral dose, and both drugs attenuated the systolic blood pressure response to exercise. Neither drug affected diastolic blood pressure or maximum oxygen consumption, maximum minute ventilation or the anaerobic threshold. We conclude that there is no evidence that the cardioselective drug metoprolol is superior to propranolol in terms of the ability to perform or respond to short-term maximal exercise. In addition, the fact that maximal oxygen consumption and the anaerobic threshold were unaffected implies that fatigue during exercise while on beta-adrenergic blocking drugs is not due to an effect of these drugs in limiting blood flow to the exercising extremities.

Patients with their first myocardial infarction not initially complicated by severe atrioventricular block or power failure were given a skin test and then randomized to receive either hyaluronidase or placebo in double-blind fashion. Hyaluronidase, 500 IU/kg i.v., was given every 6 hours for 42 hours. Of the 48 eligible patients, 26 received hyaluronidase and 22 received placebo. The mean CK serum entry was 3140 +/- 2111 mIU/ml (mean +/- SD) in hyaluronidase patients and 3574 +/- 1476 mIU/ml in placebo patients (p less than 0.21). The mean infarct size was 54.6 +/- 35.8 CK gram-equivalents in the hyaluronidase patients and 64.0 +/- 31.1 CK gram-equivalents in the placebo patients (p less than 0.20). Among the 21 patients treated within 6 hours of the onset of infarction, the difference in infarct size was greater (p less than 0.15). There was no significant difference in the incidence of power failure, ventricular arrhythmias, recurrence of ischemic pain, infarct extension or mortality. No benefit of hyaluronidase was demonstrated in this study, which was designed to detect a 50% reduction of infarct size. However, to detect a 20% reduction in infarct size would require a much larger study population.

To examine which factors affect the reproducibility of ejection fraction (EF), pulmonary transit time (PTT) and segmental wall motion assessed from first-pass radionuclide angiograms (FPRA), 32 patients who had FPRA were randomized for site of injection of isotope (right or left arm) and projection (right or left anterior oblique [RAO or LAO]). The quality of injected bolus was measured from the full width at half maximum (FWHM) of the bolus time-activity curve in the superior vena cava. All patients had two sequential studies on each of two consecutive days, and each study was analyzed independently by two observers. For EF, inter- and intraobserver correlations ranged from 0.94-0.98. EF was higher in the RAO than the LAO projection (mean 47.4% vs 40.3%, p less than 0.001), but neither injection site nor bolus FWHM affected the results. For PTT, interobserver correlations ranged from 0.75-0.93 and intraobserver correlations from 0.61-0.85. Variability in PTT was large, and inter- and intraobserver variabilities were directly related to bolus FWHM (mean 0.60 +/- 0.21 second for interobserver differences in PTT of less than 2.0 seconds, mean 1.55 +/- 0.86 seconds for interobserver differences in PTT of greater than 2 seconds [p less than 0.005]). Differences in FWHM between sequential studies were 0.28 +/- 0.29 second when intraobserver differences in PTT were less than 2 seconds and 1.04 +/- 0.67 seconds when differences in PTT were greater than 2.0 seconds (p less than 0.005). Variations in PTT were not related to differences in projection or injection site. Wall motion was highly reproducible for both projections. In the RAO projection, one of 116 anterior segments (0.9%), one of 116 apical segments (0.9%), and four of 116 inferior segments (3%) were judged normal from one observer's images and abnormal from another. In the LAO view, discrepancies occurred in one of 126 septal segments (0.8%), two of 126 apical segments (1.6%) and four of 126 posterolateral segments (3%). This study shows that EF and wall motion are highly reproducible in any projection, but the choice of projection significantly affects the values for EF from FPRA. PTT measurements are less reliable, highly bolus dependent, and their use in clinical practice depends on quality control of the bolus of injected radionuclide.

We studied the association between the outcome of antihypertensive care and three items of that care among 230 hypertensive steelworkers who were referred to 83 physicians. The first item was the decision to treat some patients but not others: 63% of the patients were prescribed antihypertensive drugs and the mean decrease in their diastolic blood pressure (DBP) was greater than that among untreated patients (12.2 +/- 0.84 vs 7.8 +/- 0.83 mm Hg [+/- SEM], p less than 0.001). The second item was the vigor of prescribed medication: Patients prescribed more vigorous treatments had lower DBP (p less than 0.005). Third, patient compliance was related to achieving a goal DBP of less than 90 mm Hg (p less than 0.05) and the product of prescribed vigor and compliance was highly associated with DBP response (p less than 0.0001). These results stand in contrast to those of previous studies that failed to detect associations between various other items of the care process and the outcome of antihypertensive care.

Although serious hemorrhage during therapeutic coadministration of sulfinpyrazone and racemic warfarin occurs, no prospective studies have been done. In this study, single oral doses of racemic warfarin, 1.5 mg/kg, were administered to six normal subjects with and without oral sulfinpyrazone, 400 mg daily. Both the hypoprothrombinemia (p less than 0.001) and the plasma warfarin concentrations (p less than 0.05) were significantly augmented. To determine if this interaction was stereoselective, the experiments were repeated in the same subjects with R-and S-warfarin enantiomorphs. S-warfarin with sulfinpyrazone caused a highly significant augmentation of both the hypoprothrombinemia (p less than 0.001) and the plasma warfarin concentrations (p less than 0.001). R-warfarin with sulfinpyrazone did not significantly change the hypoprothrombinemia but significantly (p less than 0.05) reduced warfarin concentrations. Thus, sulfinpyrazone augmented the hypoprothrombinemia of racemic warfarin stereoselectively by reduced metabolic clearance of S-warfarin. Sulfinpyrazone and racemic warfarin are most dangerous when either drug is added to a stabilized regimen of the other drug.

Lidoflazine is a synthetic drug with calcium-channel blocking effects. In a 7-month study, 36 patients with stable angina pectoris were tested during a 3-month single-blind placebo phase. Nineteen were then randomized by double-blind methods to lidoflazine and 17 to placebo therapy. The lidoflazine group had a significant (p less than 0.01) reduction in anginal attacks; the placebo group did not. Exercise testing demonstrated that lidoflazine therapy was associated with a 34% increase in total work performance and a 15.6% increase in peak calculated oxygen uptake during double-blind treatment (both p less than 0.004 compared with the placebo group). Heart rate was significantly reduced at submaximal levels of exercise during lidoflazine therapy (p less than 0.04). Nitroglycerin consumption and electrocardiographic changes at the end of exercise did not change during the double-blind phase. In a second study of six similar patients, single-blind administration of lidoflazine was associated with improved myocardial perfusion during exercise as determined by thallium-201 stress scintigraphy. These studies demonstrate that lidoflazine therapy is associated with relief of angina, an increased physical work capacity, and improved regional myocardial perfusion during exercise.

The purpose of this study was to assess noninvasively the effects of intense aerobic training on cardiac structure and function in a group of healthy, college-age men (25 experimental and 11 control, mean age 22 years). Echocardiographic, electrocardiographic (ECG), and fitness measurements were obtained before and after a 3-month endurance training program and compared with similar measurements obtained in nonexercising subjects. The supervised training program consisted of 50-minute jogging sessions 5 days a week at 85% of maximal heart rate. Compared with the control group, echocardiography after training showed an increase in left ventricular (LV) end-diastolic dimension (p less than 0.05). LV posterobasal wall thickness, septal wall thickness and ejection fraction did not change significantly. ECG measurements revealed a decrease in resting heart rate (p less than 0.05) and an increase in R-wave voltage in leads V5 and V6 (p less than 0.01). The measured maximal oxygen consumption increased by 16% (p less than 0.001). These data indicate that intense aerobic training in college-age men results in a significant increase in resting LV end-diastolic dimension and volume. The increase in maximal stroke volume associated with exercise training may be partially explained by these changes in cardiac dimensions.

The antihypertensive efficacy and the incidence of side effects of prazosin and hydralazine were compared in a randomized, double-blind trial in 232 adult male hypertensives who could not be controlled with hydrochlorothiazide alone. There were no significant differences between regimens in the percentage of patients who attained goal blood pressure (reduction of diastolic blood pressure to below 90 mm Hg and at least 5 mm less than the baseline randomization pressure), effect on pulse rate or the incidence or reasons for terminations. Absolute reduction of blood pressure was similar for both drugs except for sitting systolic pressure at 3 and 6 months, when prazosin effected a 3.7- and 3.6-mm Hg greater response (p less than 0.05). Orthostatic dizziness (p less than 0.005), sexual dysfunction (p less than 0.02), and nightmares (p less than 0.02) were more frequent with prazosin than with hydralazine; nevertheless, patient compliance was similar for both drugs. An unexpected finding was the lack of pulse rate increase associated with hydralazine, particularly in older patients.

The realization that bias in patient selection may influence the results of clinical studies has helped to establish the randomized controlled clinical trial in medical research. However, bias can be equally important at other stages of a trial, especially at the time of analysis. Withdrawing patients from consideration in the analysis because of ineligibility on account of study entry criteria, lack of compliance to the protocol, or data of poor quality may be a source of systematic error. Examples to illustrate the possible consequences are taken from trials in the cardiovascular field. We recommended that reported study results should include outcome data from all subjects randomized in the group to which they were originally assigned.

Randomized clinical trials constitute the formal experiments in therapeutics. Many such trials in coronary heart disease have terminated inconclusively or in controversy. In this editorial, we analyze some of the methodologic issues that may lead to controversy; the main reason for the low success rate may lie in insufficient understanding of the complex biology of the disease and in failure to select the appropriate models for therapy. We argue that these difficulties only strengthen the need for the rigorous experimental approach to the evaluation of therapies for coronary heart disease.

We conducted a prospective, randomized study to evaluate the influence of oral anticoagulation on graft patency early after aortocoronary bypass surgery. Eighty-nine patients who received 251 distal venous anastomoses were treated with phenoprocoumon, a vitamin K antagonist, starting on the seventh postoperative day; 84 patients with 238 distal venous anastomoses received no anticoagulation. Both groups were comparable with respect to age, exercise hemodynamics, extent of coronary disease and left ventricular dysfunction. In each group, 2.8 distal anastomoses were constructed per patient. Graft patency after surgery was 90.4% in the treatment group and 84.6% in the control group (p less than 0.015). All anastomoses were patent in 81% and 67% of patients, respectively (p less than 0.02). Flow measurements in 279 grafts suggest that grafts with a flow of less than 90 ml/min benefit from oral anticoagulation. No graft with a flow of more than 90 ml/min was occluded.

Repeat angiography was performed at 63 +/- 9 months in 26 medically treated patients and at 66 +/- 10 months in 32 surgically treated patients with chronic angina. The native coronary arteries were divided into three major trunk vessels and 15 angiographic segments. Progression of disease was defined as the appearance of new (greater than 50%) obstruction or significant worsening of existing lesions in a segment or vessel. The incidence of progression was similar in medical and surgical patients, comparing individual segments (69 of 312 [22%] and 91 of [23%], respectively) or vessels (49 of 78 [63%] and 60 of 96 [63%], respectively). In both medical and surgical patients, segments initially free of disease showed a 14% incidence of developing new lesions, compared with the 37% progression in segments initially diseased (p less than 0.001). In the surgical patients, progression occurred in 48 of 219 (22%) nongrafted and 43 of 177 (24%) grafted segments (NS). When analyzed by major trunk vessel, progression occurred in 40 of 57 grafted arteries (70%) and 20 of 39 nongrafted arteries (51%) (NS). The incidence of new total occlusions was similar in medical and surgical patients (6% and 8%, respectively); new total occlusions occurred predominantly in diseases segments (15% and 22%, respectively). In patients with stable angina pectoris who have medical or surgical treatment assigned by randomization, progression of coronary disease at 5 years is not influenced by which mode of therapy was received. Vessels initially free of disease are at relatively low risk for development of disease within 5 years. In surgical patients, grafted and nongrafted vessels show similar rates of progression.

A multivariate risk function was developed on data from all 508 medical patients in the Veterans Administration (VA) randomized study of coronary bypass surgery. The variables, in order of importance, were ST-segment depression on resting ECG, history of myocardial infarction, history of hypertension and New York Heart Association functional classification III or IV. These noninvasive variables have been reported to be risk factors in natural-history studies of coronary heart disease (CHD). Applying the risk function to medical and surgical patients of the 1972-1974 cohort yielded a 5-year probability of dying for each patient. Investigation of treatment effects in approximate terciles obtained by collapsing the probability distribution into low-, middle- and high-risk groups showed that surgery was beneficial for patients in the high-risk tercile even after removal of patients with left main coronary artery disease (17% surgical vs 34% medical mortality at 5 years; p less than 0.01). This finding was accentuated when patients in the 10 hospitals with the lowest operative mortality (3.3%) were compared. Mortality results in the low-risk tercile favored medical treatment (medical vs surgical mortality 7% vs 17%; p less than 0.05). The risk function predicted mortality well not only for te VA medical group, but also for an independent symptomatic CHD population from the University of Alabama arteriography registry. This report further delineates the advantages and limitations of coronary bypass surgery in CHD patients with chronic stable angina.