Acute hemodynamic effects of the prostacyclin analog 15AU81 in severe congestive heart failure.

This multicenter, open-label study provides the first assessment of the safety and acute hemodynamic effects of a short-term infusion of 15AU81, a chemically stable analog of prostacyclin, in patients with New York Heart Association class III or IV heart failure. Twelve patients underwent sequential dose escalation by increasing the rate of the infusion at 15-minute intervals until the drug was no longer tolerated. Patients then received a 90-minute infusion at their maximum tolerated dose. The infusion was then discontinued and the subjects were observed during a 90-minute washout segment. Serial hemodynamic measurements were made throughout the dose-ranging, maintenance, and washout segments. A significant decrease in systemic vascular resistance (1,935 +/- 774 vs 1,243 +/- 351 dynes.s.cm-5; p < 0.001) and pulmonary vascular resistance (395 +/- 335 vs 223 +/- 198 dynes.s.cm-5; p = 0.008) occurred from the infusion of vehicle to the maximum tolerated dose. During dose titration, there was a a significant increase in cardiac index (1.9 +/- 0.7 vs 2.6 +/- 0.6 liters/min/m2; p < 0.001) and a tendency for a mild reduction in pulmonary artery wedge pressure (18 +/- 7 vs 17 +/- 6; p = 0.055) for the 8 patients with values on vehicle and maximum tolerated dose. These hemodynamic changes persisted during the maintenance infusion and disappeared rapidly during the washout segment. The most common adverse event to limit dose-ranging was headache, which occurred at a mean maximum tolerated dose of 36 +/- 15 ng/kg/min. Administration of 15AU81 was associated with significant acute hemodynamic improvement in patients with severe heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)

A randomized, double-blind trial of fluorouracil plus placebo versus fluorouracil plus oral leucovorin in patients with metastatic colorectal cancer.

PURPOSE: A prospectively randomized trial was performed to determine whether the combination of fluorouracil (FU) plus leucovorin (FU-LV) administered orally is more effective than equitoxic FU for patients with metastatic colorectal cancer. PATIENTS AND METHODS: A double-blind, placebo-controlled trial design was used to eliminate observer bias. An escalating FU dosing schedule was used to achieve equal toxicity. End points were response, time to treatment failure (TTF), and eight quality-of-life (QL) parameters. A crossover arm allowed FU-treated patients to receive FU-LV combination treatment after treatment failure. RESULTS: Response rate was 32% for FU-LV versus 23% for FU (P = .15). Median TTF was 22 versus 16 weeks (P = .27). Median survival time was 44 versus 54 weeks (P = .26). QL was the same for both treatments, except for days of hospitalization, which was greater for FU-LV (P < .001). Toxicities were similar to those previously reported for FU-LV and FU alone. CONCLUSION: Oral LV-FU produces the same efficacy and toxicity pattern as has been reported for intravenous LV-FU. When FU-LV is compared with equitoxic doses of FU, there is no difference in patient outcome. These results suggest that patients with advanced disease should receive FU at doses adequate to produce toxicity.

A comparison of paramedic versus basic emergency medical care of patients at high and low risk during acute myocardial infarction.

This prospective study compares the outcome of patients with acute myocardial infarction managed by mobile intensive care (paramedic phase) with that of similar patients managed by basic emergency medical care (control phase) in the same community before the introduction of paramedics. All paramedic-transported patients were managed according to a standard chest pain protocol with use of prophylactic lidocaine and, as needed, treatment for sinus bradycardia, hypotension and life-threatening ventricular arrhythmia. There were no specific interventions for supraventricular tachyarrhythmia or hypertension. All patients were treated under similar in-hospital protocols. Percent mortality in patients with hypotension, the highest risk subgroup in the control phase, was significantly lowered with paramedic-level care (69 versus 10%, p = 0.01). Patients with hypertension, a relatively low risk subgroup during the control phase (16% mortality), were also at lower risk during the paramedic phase (10% mortality). In fact, there was no mortality in either study phase for patients with an initial systolic blood pressure greater than 180 mm Hg. During the combined study phases, patients with normotension and tachycardia demonstrated a tendency toward higher percent mortality (33%) than either patients with normotension without tachycardia (10%) or those with hypertension and tachycardia (6%). Although the overall percent mortality was reduced by 24% (from 21 to 16%), this decrease was largely due to the improvement of patients with hypotension. Investigation into the feasibility of prehospital interventions for the high risk patient with acute myocardial infarction normotension and tachycardia appears warranted.

Prognostic effect of bundle branch block related to coronary artery bypass grafting.

The incidence and prognostic effect of the development of new perioperative ventricular conduction abnormalities were examined in all patients undergoing coronary artery bypass surgery at Duke University Medical Center between 1976 and 1981. Of the 913 patients included, transient (resolved before discharge) ventricular conduction abnormalities developed in 156 (17%) and persistent (until discharge) changes developed in 126 (14%). Complete right bundle branch block (BBB) was the most frequent type of new ventricular conduction abnormality, followed by left anterior hemiblock and incomplete right BBB (found in 60%, 26%, and 9%, respectively, of all patients with transient changes and 29%, 33% and 26% of all patients with persistent changes). Development of new ventricular conduction abnormalities was most strongly related to date of operation (p less than 0.0001, univariate chi 2 = 122), increasing from 2% transient and 7% persistent in 1976 to 36% transient and 22% persistent in 1981. The incidence was also higher in older patients. Preoperative ejection fraction and number of diseased vessels were related to development of perioperative ventricular conduction abnormalities but were not independently related after adjustment for other baseline characteristics. Contrary to findings in other studies, development of new perioperative ventricular conduction abnormalities, including isolated new left BBB, did not worsen the survival rate in patients followed up to 3 years after surgery.

Prognostic implications of angiographically normal and insignificantly narrowed coronary arteries.

The clinical presentation and prognosis of 1,977 consecutive patients with normal coronary arteries or "insignificant" coronary artery disease (CAD) (no major epicardial artery with 75% or more luminal diameter narrowing) were examined. Compared with patients with significant CAD, these patients had a lower frequency of traditional cardiac risk factors and abnormalities on the rest and exercise electrocardiogram. Cardiac survival was 99% at 5 years of follow-up and 98% at 10 years for patients with normal or insignificantly narrowed coronary arteries. Patients with normal coronary arteries differed from those with insignificant CAD in their myocardial infarction free survival rate: 99% at 5 years and 98% at 10 years for patients with normal coronary arteries, compared with 97% at 5 years and 90% at 10 years for patients with insignificant CAD. A strong relation occurred between the amount of insignificant CAD and follow-up cardiac events (chi 2 = 21.5, p less than 0.0001). Cardiac risk factors were statistically related to the risk of follow-up cardiovascular events when considered alone (chi 2 = 4.93, p = 0.026), but this relation lost significance after adjusting for the effect of coronary anatomy. Patients in both groups continued to have cardiac symptoms that resulted in frequent hospitalizations, medication use and job disability. Almost 50% in any given year of follow-up could not perform activities of high metabolic equivalent requirement and 70% had continuing symptoms of chest discomfort. Although these patients are at low risk of death, many remain functionally impaired for years.

Psychosocial and physical predictors of anginal pain relief with medical management.

This study was undertaken to identify psychosocial and physical characteristics that independently predict anginal pain relief. The original study group comprised over 570 patients in whom the characteristics were identified at the time of coronary arteriography and who were followed up after 6 months of standard medical therapy. In the subset of 382 of these patients who were assessed as having NYHA Class III or IV angina at the time of angiography, a multivariable analysis of 101 baseline descriptors showed that higher scores on the MMPI hypochondriasis scale, unemployment, and more severe right coronary occlusion were significant independent predictors of failure to achieve two-class improvement at follow-up. These three characteristics also predicted continuing severe angina in a subsequent, independent sample of 91 new patients. These findings could help physicians select appropriate treatment by prospectively identifying patients who are unlikely to respond to standard medical treatment of angina.

Value of radionuclide angiography for predicting specific cardiac events after acute myocardial infarction.

The value of rest and exercise radionuclide angiography (RNA) for predicting specific events including death, recurrent acute myocardial infarction (AMI), coronary care unit readmission for unstable chest pain, and medically refractory angina after AMI was studied in 106 consecutive survivors of AMI. Analysis of the RNA variables using the Cox proportional hazards regression model yielded significant associations of the time to death with ejection fraction at rest and during exercise (X2 = 11.1 and 14.0, respectively). Both variables added significant prognostic information to the clinical assessment (X2 = 4.3 and 5.7, respectively). The change in ejection fraction from rest to exercise predicted the time to coronary artery bypass grafting for medically refractory angina before (X2 = 21.0) and after (X2 = 13.2) adjustment for the clinical descriptors, but did not predict death or other non-fatal events. Significant correlations were found between RNA variables and a variety of clinical descriptors previously reported to have prognostic significance. Clinical and RNA variables that are measures of left ventricular function were predictive of subsequent mortality, whereas those that reflect residual potentially ischemic myocardium were predictive of subsequent nonfatal ischemic events. Rest and exercise RNA after AMI provides significant prognostic information regarding specific events during follow-up independent of that provided by clinical assessment.

Basic emergency medical care of patients with acute myocardial infarction: initial prehospital characteristics and in-hospital complications.

This prospective study documents the natural history of the prehospital phase of 110 patients with acute myocardial infarction transported by a basic emergency medical system during a 22 month period. Ambulances in a mixed urban-rural county were staffed by basic emergency medical technicians certified in basic life support and the administration of intravenous fluids. Systolic blood pressure, pulse rate and cardiac rhythm were noted for all patients at the time of ambulance arrival and intermittently during transport. Analyses of patient data were performed to determine the relation between the occurrence of subsequent in-hospital urgent complications and death and 1) patient delay time, 2) initial pulse rate, 3) initial systolic blood pressure, and 4) initial cardiac rhythm. Twenty-three (21%) of the 110 patients died and 66 (60%) experienced at least one in-hospital urgent complication. When initial rhythm, pulse rate and blood pressure were considered, patients with hypotension had a higher mortality rate than did those who were either normotensive or hypertensive. The 10 patients with initial sinus bradycardia but no hypotension constituted a subgroup with zero mortality. These results identify high and low risk patient subgroups that may benefit from either providing or withholding interventions directed toward hemodynamic stabilization during the prehospital phase of acute myocardial infarction.

Effects of physical conditioning on left ventricular ejection fraction in patients with coronary artery disease.

To address the hypothesis that physical conditioning may improve left ventricular function in patients with coronary artery disease, we performed first-pass radionuclide ventriculography in 53 patients at rest and during upright bicycle exercise before and after 6 to 12 months of exercise training. The peak bicycle workload achieved before the onset of fatigue, dyspnea, or angina increased by an average of 22% (p = .0001) after training, and mean heart rate at a workload equal to the pretraining maximum workload was decreased by 10 beats/min after training (p = .0002). Of 21 subjects with angina or exertional ST segment depression before training, 15 (71%) were able to exercise to the same workload without these manifestations of ischemia after training. Whereas neither mean resting left ventricular ejection fraction (LVEF) nor LVEF at peak exertion was significantly altered, mean LVEF at the pretraining maximum workload was increased from 0.50 to 0.54 (p = .002) after training. There was a significant correlation between the magnitude of training bradycardia and the increment in LVEF at the pretraining maximum workload (p = .009). We conclude that the relative bradycardia at comparable exercise workloads produced by exercise conditioning is associated with improvements in left ventricular performance as assessed by the LVEF. This observation is compatible with the hypothesis that training bradycardia in conditioned subjects with ischemic heart disease is associated with lower myocardial oxygen demand and lesser degrees of ischemia at comparable workloads. However, training effects on ventricular afterload or on ischemia contractile performance of the heart cannot be excluded.

Unimproved chest pain in patients with minimal or no coronary disease: a behavioral phenomenon.

Patients with chest pain and minimal or no coronary disease have a good prognosis for survival, yet many continue to have pain. In our experience with 821 medically treated patients there were three cardiac deaths (0.3%) and two nonfatal myocardial infarctions (0.2%) in the first year after angiography, which had revealed insignificant (less than 75% narrowing of the luminal diameter) or no coronary artery stenosis. In a subset of 548 patients selected with no apparent systematic difference from the inception cohort of 821 patients, there was complete absence of chest pain in 178 (33%) patients but 155 (28%) had similar or worse pain. From an analysis of clinical history and catheterization data entered in a stepwise logistic regression function, unimproved chest pain was significantly associated with female sex (p = 0.01) and an index of five chest pain descriptors (p = 0.0005). After adding selected behavioral variables available for a representative sample of 217 patients, a high hypochondriasis score (scale I from the Minnesota Multiphasic Personality Inventory) became the strongest determinant of continued pain (p less than 0.0001). In our experience, an exaggerated preoccupation with personal health is prospectively associated with continued chest pain in patients with minimal or no coronary disease.

"Left main equivalent" coronary artery disease: its clinical presentation and prognostic significance with nonsurgical therapy.

The clinical characteristics and nonsurgical prognosis of 55 patients with "left main (LM) equivalent" coronary artery disease (CAD) were evaluated and defined as: (1) greater than or equal to 75% diameter reduction of the left anterior descending coronary artery (LAD) before the takeoff of any large septal perforator or anterolateral (diagonal) branches; (2) greater than or equal to 75% diameter reduction of the left circumflex artery (LC) before the takeoff of any large marginal branch; and (3) absence of greater than or equal to 50% stenosis of the LM coronary artery. Compared with nonsurgically treated patients with greater than or equal to 75% stenosis of the LM artery, patients with LM equivalent CAD had a shorter duration of symptoms (median of 51 months vs 66 months) and more often had a Q wave on the electrocardiogram (60 vs 39%). Survival in patients with LM equivalent CAD (78% at 1 year and 55% at 5 years) was better than that in patients with LM disease with nonsurgical therapy (65% at 1 year and 40% at 5 years) (p = 0.02), although the rate of freedom from cardiovascular events was not significantly different. Compared with other nonsurgically treated patients with 2- or 3-vessel CAD involving the LAD and LC (28 and 42%, respectively, with progressive angina), patients with LM equivalent CAD had more severe anginal symptoms (55% with progressive angina) and a longer duration of symptoms (medians of 20 months in 2-vessel CAD, 36 months in 3-vessel CAD and 51 months in LM equivalent CAD).(ABSTRACT TRUNCATED AT 250 WORDS)

Out-of-hospital management of cardiac arrest by basic emergency medical technicians.

The outcome in 126 consecutive patients with nontraumatic out-of-hospital cardiac arrest was analyzed to determine the effectiveness of a standard ambulance system over 22 months. Therapy was limited to basic life support (that is, administration of oxygen by mask, i.v. fluids, closed-chest massage and artificial respiration) by emergency medical technicians in a community in which less than 1% of the population had been trained in cardiopulmonary resuscitation (CPR). Analyses of patient data were performed to determine the relations between survival to hospital admission or discharge and 6 variables; response time, prior CPR, initial rhythm, acute myocardial infarction, initial blood pressure and initial pulse. Of 126 patients, 28 (22%) survived to hospital admission and 11 (9%) to hospital discharge. Two patient subgroups had a higher discharge rate: those with an initial rhythm of ventricular tachycardia or fibrillation (7 of 50, 14%), and those with an initial blood pressure greater than or equal to 90 mm Hg and a pulse rate of greater than 50 beats/min (3 of 6, 50%). For patients in arrest before ambulance arrival, there was no difference in outcome between those who did or those who did not receive prior CPR. Results of this study can be used as a basis for evaluating and comparing interventions directed toward stabilization of patients during the prehospital phase of cardiac arrest.

Prognostic value of ventricular arrhythmias associated with treadmill exercise testing in patients studied with cardiac catheterization for suspected ischemic heart disease.

The prognostic information provided by ventricular arrhythmias associated with treadmill exercise testing was evaluated in 1,293 consecutive nonsurgically treated patients undergoing an exercise test within 6 weeks of cardiac catheterization. The 236 patients with simple ventricular arrhythmias (at least one premature ventricular complex, but without paired complexes or ventricular tachycardia) had a higher prevalence of significant coronary artery disease (57 versus 44%), three vessel disease (31 versus 17%) and abnormal left ventricular function (43 versus 24%) than did patients without ventricular arrhythmias. Patients with paired complexes or ventricular tachycardia had an even higher prevalence of significant coronary artery disease (75%), three vessel disease (39%) and abnormal left ventricular function (54%). In the 620 patients with significant coronary artery disease, patients with paired complexes or ventricular tachycardia had a lower 3 year survival rate (75%) than did patients with simple ventricular arrhythmias (83%) and patients with no ventricular arrhythmias (90%). Ventricular arrhythmias were found to add independent prognostic information to the noninvasive evaluation, including history, physical examination, chest roentgenogram, electrocardiogram and other exercise test variables (p = 0.03). Ventricular arrhythmias made no independent contribution once the cardiac catheterization data were known. In patients without significant coronary artery disease, no relation between ventricular arrhythmias and survival was found.

Comparative rates of resolution of QRS changes after operative and nonoperative acute myocardial infarcts.

An independently developed and previously validated QRS scoring system for estimating myocardial infarct size has been used to compare the development and regression of changes associated with myocardial infarcts occurring in 2 different clinical settings. It is known that QRS changes suggesting myocardial infarction occur after coronary artery bypass grafting. This study compares the magnitudes and time courses of these QRS changes in 40 patients with the QRS changes observed in a control group of 46 patients with nonoperative acute myocardial infarcts. Only patients in both groups who had a baseline electrocardiogram (ECG) with no evidence of previous myocardial infarcts, ventricular hypertrophy, or bundle branch block were included. Both groups attained similar peak QRS scores during the acute phase but different rates of resolution of scores were observed. During the subsequent 2 months, regression of QRS changes occurred more rapidly in the perioperative group than in the control group (43 versus 19%). Rates of regression were similar in both groups during the remainder of the follow-up period, attaining total decreases of 62% in the operative group and 37% in the nonoperative group by 18 months. These results could mean either that factors other than acute infarction are responsible for the perioperative QRS changes or that the infarct healing process in the 2 clinical settings are quite different.

Prognostic implications of ventricular arrhythmias during 24 hour ambulatory monitoring in patients undergoing cardiac catheterization for coronary artery disease.

The prognostic importance of ventricular arrhythmias detected during 24 hour ambulatory monitoring was evaluated in 395 patients with and 260 patients without significant coronary artery disease. Ventricular arrhythmias were found to be strongly related to abnormal left ventricular function. A modification of the Lown grading system (ventricular arrhythmia score) was the most useful scheme for classifying ventricular arrhythmias according to prognostic importance. When only noninvasive characteristics were considered, the score contributed independent prognostic information, and the complexity of ventricular arrhythmias as measured by this score was inversely related to survival. However, when invasive measurements were included, the ventricular arrhythmia score did not contribute independent prognostic information. Furthermore, ejection fraction was more useful than the ventricular arrhythmia score in identifying patients at high risk of sudden death.