Assessment of Age-Related Differences in Functional Capacity Using the Virtual Reality Functional Capacity Assessment Tool (VRFCAT).

Clinical trials for primary prevention and early intervention in preclinical AD require measures of functional capacity with improved sensitivity to deficits in healthier, non-demented individuals. To this end, the Virtual Reality Functional Capacity Assessment Tool (VRFCAT) was developed as a direct performance-based assessment of functional capacity that is sensitive to changes in function across multiple populations. Using a realistic virtual reality environment, the VRFCAT assesses a subject's ability to complete instrumental activities associated with a shopping trip. The present investigation represents an initial evaluation of the VRFCAT as a potential co-primary measure of functional capacity in healthy aging and preclinical MCI/AD by examining test-retest reliability and associations with cognitive performance in healthy young and older adults. The VRFCAT was compared and contrasted with the UPSA-2-VIM, a traditional performance-based assessment utilizing physical props. Results demonstrated strong age-related differences in performance on each VRFCAT outcome measure, including total completion time, total errors, and total forced progressions. VRFCAT performance showed strong correlations with cognitive performance across both age groups. VRFCAT Total Time demonstrated good test-retest reliability (ICC=.80 in young adults; ICC=.64 in older adults) and insignificant practice effects, indicating the measure is suitable for repeated testing in healthy populations. Taken together, these results provide preliminary support for the VRFCAT as a potential measure of functionally relevant change in primary prevention and preclinical AD/MCI trials.

Trends in the use of pharmacotherapies for acute myocardial infarction among physicians who design and/or implement randomized trials versus physicians in routine clinical practice: the MILIS-TIMI experience. Multicenter Investigation on Limitation of Infarct Size. Thrombolysis in Myocardial Infarction.

BACKGROUND: Although studies have documented that randomized, controlled trials (RCTs) have a measurable influence on clinical practice, investigators have uncovered important deficiencies in the application of RCT findings to the management of acute myocardial infarction (AMI). Little is known about the extent to which physicians who design and/or implement clinical trials differ from physicians in routine practice in their translation of the literature. METHODS: Our aims were to (1) evaluate recent trends in selected treatments of AMI in relation to the publication of RCTs, statistical overviews, and task-force guidelines, and (2) compare prescribing practices in AMI management between physicians in routine clinical practice and physicians who design and/or implement RCTs. We reviewed the use of aspirin, beta-blockers, angiotensin-converting enzyme inhibitors, and calcium channel blockers on entry and at discharge in patients enrolled in the MILIS, TIMI 1, 2, 4, 5, 6, and 9B trials with ST-elevation (and depression in MILIS) myocardial infarction for a period approaching 2 decades (August 1978 to September 1995). We hypothesized that physicians who participate in RCTs apply the findings of the published literature more promptly and thoroughly than physicians in routine practice. RESULTS: Use of aspirin, beta-blockers, and angiotensin converting enzyme inhibitors exhibited a statistically significant time-related increase at discharge and, excepting beta-blockers, at enrollment across the trials. Prescription of calcium channel blockers showed a statistically significant decrease at discharge only. For all medications under study, increases and decreases in use associated with publication of clinical data occurred earlier and more steeply for the discharge cohort (prescriptions by physicians participating in RCTs) than for the enrollment cohort (prescriptions by physicians in routine practice). Recent prescribing practices (1994 to 1995) among RCT investigators and their colleagues have higher concordance with published findings than those of physicians in routine practice. CONCLUSIONS: Physicians who design and/or implement RCTs translate the results of the medical literature more promptly and to a greater extent than physicians in routine clinical practice. Differences between different physician classes need to be studied further amid efforts to reconfigure health care delivery that currently favor more dominant roles for primary care physicians.

Distortion of the terminal portion of the QRS on the admission electrocardiogram in acute myocardial infarction and correlation with infarct size and long-term prognosis (Thrombolysis in Myocardial Infarction 4 Trial).

Previous studies have shown an association between distortion of the terminal portion of the QRS (QRS[+] pattern: emergence of the J point > or = 50%. of the R wave in leads with qR configuration or disappearance of the S wave in leads with an Rs configuration) on admission and in-hospital mortality in acute myocardial infarction (AMI). However, the mechanism for this association is not known. We assessed the relation between QRS(+) pattern and coronary angiographic findings, infarct size, and long-term prognosis in the Thrombolysis In Myocardial Infarction 4 trial. Patients were allocated into 2 groups based on the presence (QRS[+], n = 85) or absence (QRS[-], n = 293) of QRS distortion. The QRS(+) patients were older (mean +/- SD: 61.1 +/- 10.6 vs 57.5 +/- 10.6 years, p = 0.004), had more anterior AMI (49% vs 37%, p = 0.04), and less previous angina (42% vs 54%, p = 0.05). QRS(+) patients had larger infarct size as assessed by creatine kinase release over 24 hours (209 +/- 147 vs 155 +/- 129, p = 0.003), and predischarge sestamibi (MIBI) defect (17.9 +/- 15.9% vs 11.2 +/- 13.4%, p <0.001). When adjusting for difference in baseline characteristics, p values for the differences in 24-hour creatine kinase release were 0.03 and 0.64 for anterior and nonanterior AMI, respectively, and for MIBI defect size 0.03 and 0.02, respectively. One-year mortality (18% vs 6%, p = 0.03) was higher and the weighted end point of death, reinfarction, heart failure, or left ventricular ejection fraction <40% (0.33 +/- 0.37 vs 0.24 +/- 0.32, p = 0. 13), tended to be higher in the anterior AMI patients with QRS(+). No difference in clinical outcome was found in patients with non-anterior AMI. These findings suggest that this simple electrocardiographic definition of presence of QRS(+) pattern on admission may provide an early estimation of infarct size and long-term prognosis, especially in anterior AMI.

Previous angina alters in-hospital outcome in TIMI 4. A clinical correlate to preconditioning?

BACKGROUND: Ischemic preconditioning has been shown to reduce myocardial infarct size in experimental models, but its role in patients remains unclear. Angina before myocardial infarction reflects brief episodes of ischemia and may be a marker of preconditioning. As part of the Thrombolysis in Myocardial Infarction (TIMI) 4 study, we performed an analysis on the effect of a history of previous angina on in-hospital outcomes for patients with acute myocardial infarction. METHODS AND RESULTS: Patients eligible for thrombolytic therapy were enrolled into the study. Data were collected from case report forms regarding previous history of angina, in-hospital outcome and 6-week follow-up. Two hundred eighteen patients had a history of previous angina at any time before acute myocardial infarction, and 198 patients did not have previous angina. Patients with any previous history of angina were less likely than with those without angina to experience in-hospital death (3% versus 8%) (P = .03), severe congestive heart failure (CHF) or shock (1% versus 7%, P = .006), or the combined end point of in-hospital death, severe CHF, or shock (4% versus 12%, P = .004). Moreover, patients with any history of angina were more likely to have a smaller creatine kinase (CK)-determined infarct size (119 versus 154 CK integrated units; P = .01) and were less likely to have Q waves on their ECG (57% versus 69%; P = .01). In the subset of patients who experienced angina within the 48 hours before infarction (compared with those who did not), there was a trend toward less likely in-hospital death (3% versus 6%; P = .09), a lower incidence of severe CHF or shock (1% versus 6% P = .008), a lower combined end point of death, CHF, or shock (3% versus 10%; P = .006), smaller infarct size assessed by CK (115 versus 151 CK units; P = .03), and a trend toward fewer Q-wave infarcts. However, patients with a history of previous angina did have a trend toward more recurrent ischemic pain. Of importance is that the beneficial in-hospital effects of previous angina were not dependent on angiographically visible coronary collaterals. CONCLUSIONS: Previous angina confers a beneficial effect on in-hospital outcome after acute myocardial infarction. The reasons for this benefit are uncertain, but one potential mechanism for this observation may be ischemic preconditioning.

Comparison of long-term outcome after acute myocardial infarction in patients never graduated from high school with that in more educated patients. Multicenter Investigation of the Limitation of Infarct Size (MILIS).

The clinical course of 363 patients with acute myocardial infarction who did not complete high school education was compared with that of 453 who completed at least high school. Both the in-hospital and 4-year mortality rates were markedly greater for the less educated than for the more educated patients (13 vs 5% [p < 0.001], and 36 vs 17% [p < 0.001]). Adverse baseline characteristics were partially responsible for the increased in-hospital (p = 0.059 after adjustment) and long-term (p = 0.024 after adjustment) mortality. The less educated patients were not as likely to quit smoking after acute myocardial infarction as were the more educated ones (38 vs 49%; p < 0.05). Patients who continued smoking had a greater mortality than did those who quit (24 vs 15% [p < 0.05] for less educated, and 10 vs 4% [p < 0.05] for better educated). Therefore, greater effort should be directed to smoking cessation among the high-risk group of less educated patients. However, the smoking continuation was responsible for only a small portion of the mortality difference, suggesting unidentified causes of mortality, such as lack of compliance with therapy and possible social isolation. Despite the high-risk status of the less educated patients, cardiac catheterization tended not to be performed as frequently as in the more educated patients after discharge from the hospital (16 vs 21%; p < 0.06 at 6 months).

Reproducibility of noninvasive ultrasonic measurement of carotid atherosclerosis. The Asymptomatic Carotid Artery Plaque Study.

BACKGROUND AND PURPOSE: To determine the effect of a lipid-lowering agent and/or a low-dose antithrombotic agent on the progression of early-stage carotid atherosclerosis, noninvasive B-mode ultrasound was used to measure intimal-medial thickness in asymptomatic individuals with moderately elevated lipids as part of the ongoing multicenter Asymptomatic Carotid Artery Plaque Study. METHODS: Uniform ultrasonic scanning and reading protocols were implemented to obtain maximum intimal-medial thickness measurements in 12 standard segments in patients having a small to moderate wall thickness (1.5-3.5 mm) in at least one of the carotid arteries. Paired B-mode image recordings on 858 patients, performed 1 month apart and read at a core laboratory (each pair by the same reader), determined both within-sonographer (W, n = 405) and between-sonographer (B, n = 453) reproducibility. RESULTS: The primary end point (mean +/- SD), defined in each individual as the mean value of the 12 maximum intimal-medial thickness measurements, was 1.31 +/- 0.21 mm (W) and 1.32 +/- 0.22 (B) at the time of the second examination. The mean difference in the primary end point (exam 2-exam 1) was -0.01 +/- 0.13 mm (W) and 0.00 +/- 0.15 mm (B). The Pearson correlation coefficients were 0.79 (W) and 0.75 (B). In 90% of the patients, the absolute difference in the primary end point was less than 0.22 mm (W) and less than 0.24 mm (B). Variability of the secondary end point, defined as the single largest intimal-medial thickness measurement in a patient, was between three and four times larger than the variability for the primary end point. Differences in sonographer performance between clinical centers were very small. CONCLUSIONS: The results demonstrate that standardized noninvasive ultrasonic techniques yield highly reproducible measures of carotid intimal-medial thickness, which can serve as a measure of carotid atherosclerosis in clinical trials that monitor small rates of lesion progression.

Analysis strategies for serial multivariate ultrasonographic data that are incomplete.

Ultrasonographic measurement of intima-media thickness in the carotid artery has emerged as an important non-invasive means of assessing atherosclerosis, and has served to define primary outcome measures related to progression of arterial lesions in several large clinical trials and epidemiologic studies. It is characteristic that measurements often cannot be obtained from all sites during repeated examinations. This leads to incomplete multivariate serial data, for which the set and number of visualized sites may vary across time. We have contrasted several conditional and unconditional maximum likelihood analytical approaches, and have evaluated these with a simulation experiment based on characteristics of ultrasound measurements collected during the course of the Asymptomatic Carotid Artery Plaque Study. We examined analyses based on unweighted and generalized least squares regression in which we estimated cross-sectional summary statistics using raw means, unconditional maximum likelihood estimates and full maximum likelihood estimates. Since the genesis of missing data is not fully clear, and since the approaches we examined are based, to some degree, on the assumption that data are missing at random, we also examined the relative impact of deviations from such an assumption on each of the approaches considered. We found that maximum likelihood based approaches increased the expected efficiency of the analysis of serial ultrasound data over ignoring missing data by up to 21 per cent.

Analysis of possible triggers of acute myocardial infarction (the MILIS study).

Recent documentation of a circadian variation in acute myocardial infarction (AMI) suggests that AMI is not a random event, but may frequently result from identifiable triggering activities. The possible triggers reported by 849 patients enrolled in the Multicenter Investigation of Limitation of Infarct Size were analyzed. Possible triggers were identified by 48.5% of the population; the most common were emotional upset (18.4%) and moderate physical activity (14.1%). Multiple possible triggers were reported by 13% of the population. Younger patients, men and those without diabetes mellitus were more likely to report a possible trigger than were older patients, women and those with diabetes. The likelihood of reporting a trigger was not affected by infarct size. This study suggests that potentially identifiable triggers may play an important role in AMI. Because potential triggering activities are common in persons with coronary artery disease, yet infrequently result in AMI, further studies are needed to identify (1) the circumstances in which a potential trigger may cause an event, (2) the specific nature of potential triggering activites, (3) the frequency of such activities in individuals who do not develop AMI and (4) the presence or absence of identifiable triggers in various subgroups of patients with infarction.

Prognostic significance of mitral regurgitation in acute myocardial infarction. The MILIS Study Group.

To define the frequency, natural history and clinical correlates of the murmur of mitral regurgitation (MR) detected after myocardial infarction, clinical data from 849 patients with documented acute myocardial infarction were analyzed. A murmur suggestive of MR was present on admission in 76 patients (9%). Patients with MR on admission were older and more apt to be female and nonwhite. They also had a significantly greater frequency of prior infarction and signs and symptoms of congestive heart failure. There was no difference in the location (anterior or inferior) of infarction. Patients with MR on admission had a 36% mortality compared to 16% for those who developed MR later in the hospitalization and 15% for those without MR by auscultation (p less than 0.001). Correction for differences in baseline variables indicated that the presence of MR on admission did not contribute independently to mortality. Thus, the murmur of MR derives its prognostic significance from integration of multiple clinical, radiographic and electrocardiographic characteristics.

Ventricular septal and free wall rupture complicating acute myocardial infarction: experience in the Multicenter Investigation of Limitation of Infarct Size.

Left ventricular rupture was studied in 849 patients enrolled in the Multicenter Investigation of Limitation of Infarct Size. Although documented rupture occurred in only 14 cases (1.7%), it accounted for 14% of in-hospital mortality. Seven of the 14 ruptures occurred within 2 days and 10 within 4 days of the MB-creatine kinase-determined onset of infarction. Three easily determined baseline characteristics defined a set of patients with a markedly increased risk of myocardial rupture. Rupture was 9.2 times more likely to occur in patients with all of the following characteristics than in the remaining patients: (1) no history of previous angina or myocardial infarction, (2) ST segment elevation or signs of Q wave development on the initial ECG, and (3) peak MB-creatine kinase value (greater than or equal to 150 IU/L). The risk of myocardial rupture with these three characteristics was 5.5%. Although these predictors are likely to be of little therapeutic value for free wall rupture, since most patients with that complication die within minutes of its onset, they may aid in alerting physicians to the early diagnosis and timely surgical correction of ventricular septal rupture.

Pericarditis in acute myocardial infarction: characterization and clinical significance.

To determine the significance of pericarditis following acute myocardial infarction, the hospital course and 12-month follow-up were analyzed in 703 patients enrolled in the Multicenter Investigation of the Limitation of Infarct Size (MILIS). Pericarditis, defined by the detection of a pericardial rub, occurred in 20% of the patients (n = 141) and was more likely to follow Q wave than non-Q wave infarction (25% vs 9%, p less than 0.001). Patients with pericarditis experienced more serious myocardial damage compared to those without pericarditis, as evidenced by a larger infarct size (25 +/- 1 vs 17 +/- 1 MB-CK gm-Eq/m2, p less than 0.001), a lower admission left ventricular ejection fraction (42 +/- 1% vs 48 +/- 1%, p less than 0.001), and a higher incidence of congestive heart failure (47% vs 26%, p less than 0.001) and atrial tachyarrhythmias (16% vs 10%, p less than 0.05). When patients were classified by the presence of Q or non-Q wave infarction, these differences persisted although statistical significance was not always achieved due to smaller sample size. Mortality at 12-month follow-up for patients with pericarditis was 18% compared with 12% for patients without pericarditis (p = 0.055). This mortality difference could be accounted for in part by the lower ventricular ejection fraction in patients with pericarditis (p = 0.20 after adjustment).

Factors leading to shorter survival after acute myocardial infarction in patients ages 65 to 75 years compared with younger patients.

Although the number of elderly patients with acute myocardial infarction (AMI) has steadily increased and these patients are known to have a higher early subsequent mortality than younger patients, the reasons for this adverse prognosis are poorly understood. We compared the clinical courses of 217 patients, ages 65 to 75 years, with 631 patients younger than 65 years of age enrolled in the Multicenter Investigation of the Limitation of Infarct Size (MILIS). The older group had a higher prevalence of adverse baseline risk factors, including history of congestive heart failure (14 vs 7%, p less than 0.001), previous AMI (28 vs 22%, p less than 0.05), angina pectoris (42 vs 34%, p less than 0.05), systemic hypertension (64 vs 52%, p less than 0.01), diabetes mellitus (24 vs 17%, p less than 0.05) and female gender (37 vs 24%, p less than 0.001). Despite having a smaller infarct size index than younger patients (15 +/- 1 vs 18 +/- 1 CK-MB g-Eq/m2, p less than 0.002), the elderly patients had a lower admission left ventricular ejection fraction (43 +/- 1 vs 47 +/- 1%, p less than 0.01) and a higher frequency of clinical congestive heart failure (44 vs 28%, p less than 0.001) and in-hospital death (14 vs 7%, p less than 0.01). The 1-year mortality for elderly hospital survivors was also markedly greater (19 vs 5%, p less than 0.001) as was the 4-year mortality (35 vs 13%, p less than 0.001). Adjustment for 7 adverse baseline characteristics in the elderly could account for their increased in-hospital mortality. However, these and 12 additional in-hospital characteristics did not account for the increased 1- and 4-year mortalities of the elderly hospital survivors, which are presumably affected by variables not included in the present age-associated study.

Effects of gender and race on prognosis after myocardial infarction: adverse prognosis for women, particularly black women.

Controversy has arisen concerning whether gender influences the prognosis after myocardial infarction. Although some studies have shown there to be no difference between the sexes, most have indicated a worse prognosis for women, attributing this to differences in baseline characteristics. It has been further suggested that black women have a particularly poor prognosis after infarction. To determine the contribution of gender and race to the course of infarction, 816 patients with confirmed myocardial infarction who were enrolled in the Multicenter Investigation of the Limitation of Infarct Size (MILIS) were analyzed. Of those patients, 226 were women and 590 were men, 142 were black and 674 were white. The cumulative mortality rate at 48 months was 36% for women versus 21% for men (p less than 0.001, mean follow-up 32 months). The cumulative mortality rate by race was 34% for blacks versus 24% for whites (p less than 0.005). Both women and blacks exhibited more baseline characteristics predictive of mortality than did their male or white counterparts. It was possible to account for the greater mortality rate of blacks by identifiable baseline variables; however, even after adjustment, the mortality rate for women remained significantly higher (p less than 0.002). The poorer prognosis for women was influenced by a particularly high mortality rate among black women (48%); the mortality rate for white women was 32%, for black men 23% and for white men 21%. The mortality for black women was significantly greater than that of the other subgroups. Thus, findings in the MILIS population indicate that the prognosis after myocardial infarction is worse for women, particularly black women.