The open-artery theory is alive and well--again.
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Humans↗
Biomedical subjects
E Braunwald
Publications and source records attributed to E Braunwald.
Relation between clinical presentation and angiographic findings in unstable angina pectoris, and comparison with that in stable angina.
The diagnosis of unstable angina encompasses a broad spectrum of patients with myocardial ischemia, varying widely in cause, prognosis and responsiveness to therapy. A new clinical classification of unstable angina is based on the following 2 components: severity, and the clinical setting in which unstable angina develops. The hypothesis that this clinical classification correlates with the underlying coronary artery anatomy was tested. In 238 consecutive patients, an unstable angina score ranging from 2 to 6 was determined by adding the scores for severity (1 = unstable angina without pain at rest; 2 = pain at rest > 48 hours before angiography; and 3 = pain at rest < or = 48 hours before angiographic evaluation) and the clinical setting of unstable angina (1 = unstable angina secondary to a noncardiac condition; 2 = primary unstable angina; and 3 = early postinfarction unstable angina). Fifty concurrently studied consecutive patients with stable angina were assigned a score of 0. Patients with unstable angina averaged 63 +/- 11 years of age, and 165 were men (69%). Pain at rest occurred in 202 of 238 patients (85%), and angiography was performed < or = 48 hours in 139 of these patients (69%). Among patients with unstable angina, 5 (2%) had secondary unstable angina, 143 (60%) had primary unstable angina, and 90 (38%) had postinfarction unstable angina. Multivariable regression analysis identified the unstable angina score as the most important predictor of intracoronary thrombus (p = 0.011) and lesion complexity (p = 0.004) in the ischemia-related artery.(ABSTRACT TRUNCATED AT 250 WORDS)
Aged↗
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).
Aged↗
Anticoagulant effects of hirulog, a novel thrombin inhibitor, in patients with coronary artery disease.
Selective thrombin inhibitors are a new class of antithrombotic drugs that, unlike heparin, can effectively inhibit clot-bound thrombin and escape neutralization by activated platelets. Hirulog is a 20 amino acid hirudin-based synthetic peptide that has shown promise in experimental models of thrombosis. Little information is available about the effects of hirulog in patients with coronary artery disease. Forty-five patients undergoing cardiac catheterization, who were taking aspirin, were randomized to receive either (1) hirulog, 0.05 mg/kg intravenous bolus followed by 0.2 mg/kg/hour intravenous infusion until the end of the catheterization; (2) hirulog, 0.15 mg/kg intravenous bolus followed by 0.6 mg/kg/hour intravenous infusion; or (3) heparin; 5,000 U intravenous bolus. Serial activated partial thromboplastin time (APTT), prothrombin time, activated clotting time and fibrinopeptide A were measured. Hirulog produced a dose-dependent prolongation of all coagulation parameters; the 0.6 mg/kg/hour dose prolonged the APTT to 218 +/- 50% of baseline after 2 minutes and 248 +/- 50% of baseline after 15 minutes. The half-life of the effect on APTT was 40 minutes. The hirulog blood level correlated well with the APTT, prothrombin time and activated clotting time (r = 0.77, 0.73, and 0.82 respectively, all p < 0.001). Both doses of hirulog potently suppressed the generation of fibrinopeptide A (p < 0.05). There were no major hemorrhagic, thrombotic or allergic complications in patients treated with hirulog or heparin. Thus, hirulog, a direct thrombin inhibitor, provides a predictable level of anticoagulation and appears to have a potent yet well-tolerated anticoagulant profile in patients with coronary artery disease.
Amino Acid Sequence↗
Impact of treatment strategy on predischarge exercise test in the Thrombolysis in Myocardial Infarction (TIMI) II Trial.
Predischarge supine bicycle ergometry was used to assess persistent myocardial ischemia in postinfarction patients who received thrombolytic therapy and were randomized to an invasive versus conservative strategy in the Thrombolysis in Myocardial Infarction (TIMI) II trial. The frequency of ischemic responses in both strategies, and the 1-year prognostic importance of the different exercise test outcomes were examined. At 14 days, the percentage of patients with any adverse outcome (including death, presence of exercise-induced ST-segment depression, or inability to perform the exercise test) was 33.7% of 1,681 randomly assigned to the invasive strategy compared with 34.6% of 1,658 randomly assigned to the conservative strategy (p = 0.57). The 1-year mortality was greater in patients who did not perform the predischarge exercise test (7.7%) than in those who did (1.8%) (p < 0.001); the former were older, and a greater proportion were women, had a more frequent history of myocardial infarction, and more extensive coronary artery disease (p < 0.01 for each comparison). The 1-year mortality in patients with exercise-induced ST-segment depression or chest pain was only 1.4% (3 of 22) among those randomly assigned to the conservative strategy where coronary angiography and revascularization were recommended if the test result was abnormal (relative risk compared with those without ST-segment depression or chest pain 0.6; 99% confidence interval 0.1 to 2.9).(ABSTRACT TRUNCATED AT 250 WORDS)
Angioplasty, Balloon, Coronary↗
Two- and three-year results of the Thrombolysis in Myocardial Infarction (TIMI) Phase II clinical trial.
OBJECTIVES: This report describes the survival and reinfarction rates for 2- and 3-year follow-up in the Thrombolysis in Myocardial Infarction (TIMI) Phase II clinical trial. BACKGROUND: Patients enrolled in TIMI II were randomly assigned to an invasive (1,681 patients) or a conservative (1,658 patients) management strategy to follow receipt of intravenous recombinant tissue-type plasminogen activator for acute myocardial infarction. METHODS: Eligibility required presentation within 4h of onset of symptoms and at least 1-mV ST segment elevation in two contiguous electrocardiographic leads. The invasive strategy group underwent cardiac catheterization 18 to 48 h after study entry and, when appropriate, percutaneous transluminal coronary angioplasty or coronary artery bypass grafting. In the conservative strategy group these diagnostic and revascularization procedures were reserved for recurrent spontaneous ischemia or ischemia on low level exercise at the time of hospital discharge. RESULTS: Complete 2-year follow-up data are available for 3,187 patients (95.4%). Cumulative life-table rates of death or reinfarction were 17.6% for the invasive strategy group and 17.9% for the conservative strategy group (p = NS) and mortality was 8.9% and 8.7% (p = NS), respectively. Complete data are available for 1,959 (90.1%) of the 2,174 patients enrolled for 3 years. Rates of death or reinfarction were 21.0% for the invasive strategy group with 20.0% for the conservative strategy group (p = NS), with mortality of 11.5% and 11.0% (p = NS), respectively. In this cohort, the mortality was 1.3% in the 2nd year and 1.7% in the 3rd year from study entry. CONCLUSIONS: TIMI II invasive and conservative strategies resulted in similar favorable outcomes after 2 and 3 years. Mortality and reinfarction rates in the two strategies were comparable. Deaths were infrequent in the 2nd and 3rd years from study entry.
Aged↗
Potential benefits of late reperfusion of infarcted myocardium. The open artery hypothesis.
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Animals↗
Modifiers of timing and possible triggers of acute myocardial infarction in the Thrombolysis in Myocardial Infarction Phase II (TIMI II) Study Group.
OBJECTIVES: The aim of this study was to provide insight into the mechanism of acute myocardial infarction by determining the modifiers of timing and possible triggers of onset of infarction. BACKGROUND: A higher frequency of onset of acute myocardial infarction has been reported in the morning with a peak in the 1st 3 h after awakening. This observation suggests that the onset of infarction may be triggered by activity in the morning and at other times of the day. METHODS: The clinical history of the 3,339 patients entered into the Thrombolysis in Myocardial Infarction phase II study was analyzed to determine characteristics predicting a higher frequency of infarction between 6 AM and noon, and onset of infarction during exertion. RESULTS: A higher proportion (34.4%) of infarctions began in the morning (6 AM to noon) compared with other times of the day. Characteristics independently predicting a higher frequency between 6 AM to noon were no beta-adrenergic blocking agent use in the 24 h before infarction, no discomfort other than the index pain in the preceding 48 h, occurrence of the infarction on a weekday and no history of current smoking. In 18.7% of patients, infarction occurred during moderate or marked physical activity. Independent predictors of exertion-related infarction included male gender, no history of current smoking, white race, no use of calcium channel blocking agents or nitrates in the preceding 24 h, the absence of either chest pain at rest in the 3 weeks before infarction or any pain in the preceding 48 h, the absence of new onset angina and the presence of exertional pain in the preceding 3 weeks. Compared with patients whose infarction occurred at rest or during mild activity, those with exertion-related infarction had fewer coronary vessels with > or = 60% stenosis (p = 0.002) and were more likely to have an occluded infarct-related vessel after thrombolytic therapy (p = 0.01). CONCLUSIONS: Further study of the timing and activity at onset of infarction may provide insight into the pathophysiologic mechanisms causing acute myocardial infarction and provide clues to preventive measures.
Analysis of Variance↗
Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators.
BACKGROUND: Left ventricular dilatation and dysfunction after myocardial infarction are major predictors of death. In experimental and clinical studies, longterm therapy with the angiotensin-converting--enzyme inhibitor captopril attenuated ventricular dilatation and remodeling. We investigated whether captopril could reduce morbidity and mortality in patients with left ventricular dysfunction after a myocardial infarction. METHODS: Within 3 to 16 days after myocardial infarction, 2231 patients with ejection fractions of 40 percent or less but without overt heart failure or symptoms of myocardial ischemia were randomly assigned to receive doubleblind treatment with either placebo (1116 patients) or captopril (1115 patients) and were followed for an average of 42 months. RESULTS: Mortality from all causes was significantly reduced in the captopril group (228 deaths, or 20 percent) as compared with the placebo group (275 deaths, or 25 percent); the reduction in risk was 19 percent (95 percent confidence interval, 3 to 32 percent; P = 0.019). In addition, the incidence of both fatal and nonfatal major cardiovascular events was consistently reduced in the captopril group. The reduction in risk was 21 percent (95 percent confidence interval, 5 to 35 percent; P = 0.014) for death from cardiovascular causes, 37 percent (95 percent confidence interval, 20 to 50 percent; P less than 0.001) for the development of severe heart failure, 22 percent (95 percent confidence interval, 4 to 37 percent; P = 0.019) for congestive heart failure requiring hospitalization, and 25 percent (95 percent confidence interval, 5 to 40 percent; P = 0.015) for recurrent myocardial infarction. CONCLUSIONS: In patients with asymptomatic left ventricular dysfunction after myocardial infarction, long-term administration of captopril was associated with an improvement in survival and reduced morbidity and mortality due to major cardiovascular events. These benefits were observed in patients who received thrombolytic therapy, aspirin, or beta-blockers, as well as those who did not, suggesting that treatment with captopril leads to additional improvement in outcome among selected survivors of myocardial infarction.
Adult↗
Do the results of randomized clinical trials of cardiovascular drugs influence medical practice? The SAVE Investigators.
BACKGROUND: Medical practice patterns change in response to a variety of stimuli, one of which may be the publication of the results of randomized clinical trials. We assessed the temporal association between the publication of clinical trials on myocardial infarction and changes in treatment practices for this disorder. METHODS: We analyzed the use of aspirin before and after myocardial infarction and that of calcium antagonists after myocardial infarction in 2231 survivors of myocardial infarction enrolled in the Survival and Ventricular Enlargement (SAVE) study over a three-year period (from January 1987 through January 1990). The proportion of patients using these treatments was analyzed before and after the publication dates of three clinical trials: the Physicians' Health Study, published in January 1988, which supported the use of aspirin to prevent a first myocardial infarction; the Second International Study of Infarct Survival (ISIS-2), published in August 1988, which supported the use of aspirin after myocardial infarction; and the Multicenter Diltiazem Postinfarction Trial, published in August 1988, which reported a deleterious effect of diltiazem in some patients after myocardial infarction. RESULTS: The use of aspirin before myocardial infarction increased from 16.2 percent to 23.9 percent between January 1987 and January 1990 (P less than 0.001). Enrollment in the study after the publication of the Physicians' Health Study independently predicted aspirin use before myocardial infarction (odds ratio, 1.43; 95 percent confidence interval, 1.11 to 1.85). The use of aspirin after myocardial infarction increased from 38.8 percent to 71.9 percent (P less than 0.001) during the three-year study period. Enrollment in the study after the publication of ISIS-2 independently predicted the use of aspirin after myocardial infarction (odds ratio, 2.28; 95 percent confidence interval, 1.89 to 2.76). The use of calcium antagonists after myocardial infarction decreased from 57.1 percent to 33.1 percent (P less than 0.001) during the study period. Enrollment in the study after the publication of the Multicenter Diltiazem Postinfarction Trial independently predicted the use of calcium antagonists after myocardial infarction (odds ratio, 0.47; 95 percent confidence interval, 0.39 to 0.57). CONCLUSIONS: These observations suggest that randomized clinical trials have a measurable influence on medical practice patterns.
Adult↗
Cholesterol and total mortality: need for larger trials.
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Anticholesteremic Agents↗
Front-loaded accelerated infusions of tissue plasminogen activator: putting a better foot forward.
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Humans↗
The rt-PA versus streptokinase. Controversy--II.
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Humans↗
Mechanisms of early death despite thrombolytic therapy: experience from the Thrombolysis in Myocardial Infarction Phase II (TIMI II) study.
Mechanisms of death among patients who died within 18 h of enrollment in the Thrombolysis in Myocardial Infarction Phase II (TIMI II) study were analyzed. Of 3,339 patients enrolled, 32 died within the 1st 4 h and 31 died within the subsequent 14 h. Thirteen of the 63 patients had shock at enrollment; 22 had advanced hemodynamic compromise without shock and 28 initially had minimal to no compromise. Prior infarction was present in 16 patients (25%). Pump failure was responsible for 39 early deaths (62%), ventricular rupture for 10 (16%), arrhythmia for 8 (13%) and complications of therapy for 6 (10%). Nine of 720 patients randomized to immediate intravenous beta-adrenergic blocking agent therapy had an early death compared with 6 of 714 assigned to deferred beta-blocker therapy. Thus, mortality is highest in the early hours after myocardial infarction, even in patients treated with thrombolytic therapy and is most frequently due to pump failure. These results imply that efforts to reduce mortality during this critical time period should be directed at prevention, limitation or palliation of early pump failure.
Adrenergic beta-Antagonists↗
One-year results of the Thrombolysis in Myocardial Infarction investigation (TIMI) Phase II Trial.
BACKGROUND: The Thrombolysis in Myocardial Infarction (TIMI) Phase II Trial randomized 3,339 patients to either an invasive (INV, n = 1,681) or a conservative (CON, n = 1,658) strategy after intravenous recombinant tissue-type plasminogen activator (rt-PA) for acute myocardial infarction. METHODS AND RESULTS: The patients assigned to the INV strategy routinely underwent cardiac catheterization, and when anatomically appropriate, percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass grafting 18-48 hours after infarction. CON patients had these procedures only in response to the occurrence of spontaneous or provoked ischemia. One-year follow-up data are available in 3,316 patients (99.3%). The primary trial end point, death and nonfatal reinfarction, occurred in 14.7% of INV patients and in 15.2% of CON patients (p = NS). When analyzed individually, there was no difference (p = NS) in death (INV, 6.9%; CON, 7.4%) or recurrent infarction (INV, 9.4%; CON, 9.8%) between the two groups. Anginal status at 1 year was also similar. Cardiac catheterization and PTCA were performed more often in INV (98.0% and 61.2%, respectively) compared with CON (45.2% and 20.5%, respectively) patients. At 1 year, the cumulative number of patients who underwent coronary bypass surgery (INV, 17.5%; CON, 17.3%) was similar in the two groups. CONCLUSIONS: The INV and CON strategies resulted in similar favorable outcomes at 1 year of follow-up. In particular, the rates of mortality and reinfarction were not different and were impressively low in both groups. One possible advantage of the INV strategy was detected in subgroup analyses. In patients with a history of myocardial infarction, the data are suggestive that 1-year mortality was lower in INV patients (10.3%) than in CON patients (17.0%) (p = 0.03).
Angioplasty, Balloon, Coronary↗
Predictors of early morbidity and mortality after thrombolytic therapy of acute myocardial infarction. Analyses of patient subgroups in the Thrombolysis in Myocardial Infarction (TIMI) trial, phase II.
BACKGROUND: Thrombolysis has altered treatment of acute myocardial infarction (AMI). Therefore, reevaluation of predictors of outcome and treatment strategies is appropriate. METHODS AND RESULTS: Clinical variables collected prospectively for the 3,339 patients of the Thrombolysis in Myocardial Infarction II study were analyzed retrospectively to identify predictors of clinical events at 42 days and earlier and to identify subgroups in which an invasive or conservative strategy might be superior. Pulmonary edema/cardiogenic shock presented as the strongest independent correlate with death (relative risk, 6.0). In two subgroups, mortality differed between the invasive and conservative strategies: 1) Patients with versus without prior AMI had a higher mortality in the conservative strategy (11.5% versus 3.5%, p less than 0.001); in the invasive strategy, the mortality rates were similar (6.0% and 5.1%). 2) Patients with diabetes mellitus and no prior AMI had a higher mortality in the invasive than in the conservative strategy (14.8% versus 4.2%, p less than 0.001). Reinfarction was not independently correlated with baseline characteristics except with history of angina (relative risk, 1.9). Mortality was lower in current smokers and ex-smokers versus never-smokers (3.6% and 4.8% versus 8.0%, p less than 0.001). Current smokers had a lower risk profile (p less than 0.001), including age, pulmonary edema/cardiogenic shock, history of hypertension, and diabetes. The rate of reinfarction was lower in current smokers versus ex-smokers and never-smokers (4.6% versus 8.3% and 8.8%, p less than 0.001). "Not current smoker" was an independent correlate with reinfarction (relative risk, 1.9). The coronary anatomy did not differ among the current smokers, ex-smokers, and never-smokers. CONCLUSIONS: The strong independent correlation of pulmonary edema/cardiogenic shock with death suggests that thrombolysis is not sufficient to improve survival in these patients. The higher mortality in patients with versus without prior AMI in the conservative strategy suggests that early catheterization and revascularization of these patients might be beneficial. Conversely, the higher mortality in diabetes without prior AMI in the invasive than in the conservative strategy suggests that early aggressive management might not be suitable in this subgroup except for clinical indications. Reinfarction was not predictable by clinical variables except by history of angina. The finding that "not current smoker" was an independent correlate with reinfarction was unexpected.
Female↗
An approach to evaluating thrombolytic therapy in acute myocardial infarction. The 'unsatisfactory outcome' end point.
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Cerebrovascular Disorders↗
Clot-selective coronary thrombolysis with low-dose synergistic combinations of single-chain urokinase-type plasminogen activator and recombinant tissue-type plasminogen activator. The Pro-Urokinase for Myocardial Infarction Study Group.
The effect of simultaneous infusions of low-dose recombinant tissue-type plasminogen activator (t-PA) and single-chain urokinase-type plasminogen activator (scu-PA, pro-urokinase) on coronary arterial thrombolysis was investigated in 23 patients treated within 6 hours (mean 2.6 +/- 1.1, range 1.2 to 5.9) of symptoms of an acute myocardial infarction. Infarct artery patency at 90 minutes was achieved in 16 (70%, 95% confidence limits of 0.47 to 0.87) of 23 patients after a 1-hour intravenous infusion of 20 and 16.3 mg of t-PA and scu-PA, respectively. At 90 minutes, the fibrinogen concentration decreased from 369 +/- 207 to 316 +/- 192 mg/dl (p = not significant), while plasminogen decreased to 69 +/- 24% (p = 0.001) and alpha-2-antiplasmin to 77 +/- 24% (p = 0.001) of pretreatment values. Although no bleeding requiring termination of drug infusion or transfusion occurred, 1 patient with cerebrovascular amyloidosis had a fatal intracerebral hemorrhage. These findings suggest that combination therapy may allow substantial reductions in total thrombolytic doses while still achieving effective fibrin-specific coronary thrombolysis.
Adult↗