Showing papers by "Eugene Braunwald published in 1999"

Long-Term Effects of Pravastatin on Plasma Concentration of C-reactive Protein

Abstract: Background—Elevated plasma concentrations of C-reactive protein (CRP) are associated with increased cardiovascular risk. We evaluated whether long-term therapy with pravastatin, an agent that reduces cardiovascular risk, might alter levels of this inflammatory parameter. Methods and Results—CRP levels were measured at baseline and at 5 years in 472 randomly selected participants in the Cholesterol and Recurrent Events (CARE) trial who remained free of recurrent coronary events during follow-up. Overall, CRP levels at baseline and at 5 years were highly correlated (r50.60, P,0.001). However, among those allocated to placebo, median CRP levels and the mean change in CRP tended to increase over time (median change, 14.2%; P50.2 and mean change, 10.07 mg/dL; P50.04). By contrast, median CRP levels and the mean change in CRP decreased over time among those allocated to pravastatin (median change, 217.4%; P50.004 and mean change, 20.07 mg/dL; P50.002). Thus, statistically significant differences were observed at 5 years between the pravastatin and placebo groups in terms of median CRP levels (difference, 221.6%; P50.007), mean CRP levels (difference, 237.8%; P50.002), and absolute mean change in CRP (difference, 20.137 mg/dL; P50.003). These effects persisted in analyses stratified by age, body mass index, smoking status, blood pressure, and baseline lipid levels. Attempts to relate the magnitude of change in CRP to the magnitude of change in lipids in both the pravastatin and placebo groups did not reveal any obvious relationships. Conclusions—Among survivors of myocardial infarction on standard therapy plus placebo, CRP levels tended to increase over 5 years of follow-up. In contrast, randomization to pravastatin resulted in significant reductions in this inflammatory marker that were not related to the magnitude of lipid alterations observed. Thus, these data further support the potential for nonlipid effects of this agent. (Circulation. 1999;100:230-235.)

Enoxaparin prevents death and cardiac ischemic events in unstable angina/non-Q-wave myocardial infarction. Results of the thrombolysis in myocardial infarction (TIMI) 11B trial.

Abstract: Background—Low-molecular-weight heparins are attractive alternatives to unfractionated heparin (UFH) for management of unstable angina/non–Q-wave myocardial infarction (UA/NQMI). Methods and Results—Patients (n=3910) with UA/NQMI were randomized to intravenous UFH for ≥3 days followed by subcutaneous placebo injections or uninterrupted antithrombin therapy with enoxaparin during both the acute phase (initial 30 mg intravenous bolus followed by injections of 1.0 mg/kg every 12 hours) and outpatient phase (injections every 12 hours of 40 mg for patients weighing <65 kg and 60 mg for those weighing ≥65 kg). The primary end point (death, myocardial infarction, or urgent revascularization) occurred by 8 days in 14.5% of patients in the UFH group and 12.4% of patients in the enoxaparin group (OR 0.83; 95% CI 0.69 to 1.00; P=0.048) and by 43 days in 19.7% of the UFH group and 17.3% of the enoxaparin group (OR 0.85; 95% CI 0.72 to 1.00; P=0.048). During the first 72 hours and also throughout the entire initial ho...

Abciximab Facilitates the Rate and Extent of Thrombolysis Results of the Thrombolysis In Myocardial Infarction (TIMI) 14 Trial

Abstract: Background—The TIMI 14 trial tested the hypothesis that abciximab, the Fab fragment of a monoclonal antibody directed to the platelet glycoprotein (GP) IIb/IIIa receptor, is a potent and safe addition to reduced-dose thrombolytic regimens for ST-segment elevation MI. Methods and Results—Patients (n=888) with ST-elevation MI presenting <12 hours from onset of symptoms were treated with aspirin and randomized initially to either 100 mg of accelerated-dose alteplase (control) or abciximab (bolus 0.25 mg/kg and 12-hour infusion of 0.125 μg · kg−1 · min−1) alone or in combination with reduced doses of alteplase (20 to 65 mg) or streptokinase (500 000 U to 1.5 MU). Control patients received standard weight-adjusted heparin (70-U/kg bolus; infusion of 15 U · kg−1 · h−1), whereas those treated with a regimen including abciximab received low-dose heparin (60-U/kg bolus; infusion of 7 U · kg−1 · h−1). The rate of TIMI 3 flow at 90 minutes for patients treated with accelerated alteplase alone was 57% compared with 3...

Assessment of the Treatment Effect of Enoxaparin for Unstable Angina/Non–Q-Wave Myocardial Infarction TIMI 11B–ESSENCE Meta-Analysis

Abstract: Background—Two phase III trials of enoxaparin for unstable angina/non–Q-wave myocardial infarction have shown it to be superior to unfractionated heparin for preventing a composite of death and cardiac ischemic events. A prospectively planned meta-analysis was performed to provide a more precise estimate of the effects of enoxaparin on multiple end points. Methods and Results—Event rates for death, the composite end points of death/nonfatal myocardial infarction and death/nonfatal myocardial infarction/urgent revascularization, and major hemorrhage were extracted from the TIMI 11B and ESSENCE databases. Treatment effects at days 2, 8, 14, and 43 were expressed as the OR (and 95% CI) for enoxaparin versus unfractionated heparin. All heterogeneity tests for efficacy end points were negative, which suggests comparability of the findings in TIMI 11B and ESSENCE. Enoxaparin was associated with a 20% reduction in death and serious cardiac ischemic events that appeared within the first few days of treatment, and...

Reduction of Stroke Incidence After Myocardial Infarction With Pravastatin The Cholesterol and Recurrent Events (CARE) Study

Abstract: Background—The role of lipid modification in stroke prevention is controversial, although increasing evidence suggests that HMG-CoA reductase inhibition may reduce cerebrovascular events in patients with prevalent coronary artery disease. Methods and Results—To test the hypothesis that cholesterol reduction with pravastatin may reduce stroke incidence after myocardial infarction, we followed 4159 subjects with average total and LDL serum cholesterol levels (mean, 209 and 139 mg/dL, respectively) who had sustained an infarction an average of 10 months before study entry and who were randomized to pravastatin 40 mg/d or placebo in the Cholesterol and Recurrent Events (CARE) trial. Using prospectively defined criteria, we assessed the incidence of stroke, a prespecified secondary end point, and transient ischemic attack (TIA) over a median 5-year follow-up period. Patients were well matched for stroke risk factors and the use of antiplatelet agents (85% of subjects in each group). Compared with placebo, prav...

Relationship Between TIMI Frame Count and Clinical Outcomes After Thrombolytic Administration

Abstract: Background —The corrected TIMI frame count (CTFC) is the number of cine frames required for dye to first reach standardized distal coronary landmarks, and it is an objective and quantitative index of coronary blood flow. Methods and Results —The CTFC was measured in 1248 patients in the TIMI 4, 10A, and 10B trials, and its relationship to clinical outcomes was examined. Patients who died in the hospital had a higher CTFC (ie, slower flow) than survivors (69.6±35.4 [n=53] versus 49.5±32.3 [n=1195]; P =0.0003). Likewise, patients who died by 30 to 42 days had higher CTFCs than survivors (66.2±36.4 [n=57] versus 49.9±32.1 [n=1059]; P =0.006). In a multivariate model that excluded TIMI flow grades, the 90-minute CTFC was an independent predictor of in-hospital mortality (OR=1.21 per 10-frame rise [95% CI, 1.1 to 1.3], an ≈0.7% increase in absolute mortality for every 10-frame rise; P 40 ( P =0.003). Although the risk of death, recurrent myocardial infarction, shock, congestive heart failure, or left ventricular ejection fraction ≤40% was 13.0% among patients with TIMI grade 3 flow (CTFC ≤40), the CTFC tended to segregate patients into lower-risk (CTFC ≤20, risk of adverse outcome of 7.9%) and higher-risk subgroups (CTFC >20 to ≤40, risk of adverse outcome of 15.5%; P =0.17). Conclusions —Faster (lower) 90-minute CTFCs are related to improved in-hospital and 1-month clinical outcomes after thrombolytic administration in both univariate and multivariate models. Even among those patients classified as having normal flow (TIMI grade 3 flow, CTFC ≤40), there may be lower- and higher-risk subgroups.

Factors associated with failure of medical therapy in patients with unstable angina and non-Q wave myocardial infarction. A TIMI-IIIB database study.

Abstract: Context Current management of patients with unstable angina and non-Q wave myocardial infarction generally consists of intensive medical therapy, with angiography and revascularization sometimes limited to those who fail such therapy. Aim To determine if certain baseline characteristics are predictive of patients who fail medical therapy, since such patients could then be expeditiously directed to a more invasive strategy in a cost-effective manner. Methods The study cohort consisted of the 733 patients in the Thrombolysis in Myocardial Ischemia (TIMI) IIIB study who were randomized to conservative strategy. Patients were to be treated with bedrest, anti-ischaemic medications, aspirin, and heparin, and were to undergo risk-stratifying tests, consisting of an exercise test with ECG and thallium scintigraphy, scheduled to be performed within 3 days prior to, or 5 days after, hospital discharge and 24h Holter monitoring scheduled to begin 2–5 days after randomization. Baseline clinical and ECG characteristics were compared between patients who ‘failed’ medical therapy and those who did not ‘fail’. Failure was defined using clinical end-points (death, myocardial infarction, or spontaneous ischaemia by 6 weeks after randomization) or a strongly positive risk-stratifying test. For each test an ordered failure profile of results was calculated and consisted of death, myocardial infarction, or rest ischaemia occurring prior to performance of the test, a markedly abnormal test result, and no abnormality. Results Clinical end-points occurred in 241 (33%) patients and were more likely to occur in patients who at presentation were older, had ST-segment depression on the qualifying ECG, or were being treated with heparin or aspirin. Characteristics independently predictive of developing a clinical event or an abnormal exercise treadmill test included: ST-segment depression on the qualifying ECG, history of prior angina, family history of premature coronary disease (i.e. onset <55 years of age), prior use of heparin or aspirin, and increasing age. By combining these baseline risk characteristics for each outcome the incidence of developing a clinical event ranged from 8% if none was present to 63% if all six were present, and of developing a markedly abnormal risk stratifying test from 8–21% if none were present to approximately 90% if all six were present. Conclusions Baseline characteristics associated with developing a clinical event or a markedly abnormal risk stratifying test were similar: rest anginal episode accompanied by ST-segment depression and occurring despite treatment with aspirin and heparin, a history of angina, older age, and family history of coronary disease. Patients with these characteristics are appropriate candidates for expeditious cardiac catheterization and consideration for revascularization, while patients without them may be suitable for medical management alone.

Clinical trials in cardiovascular disease : a companion to Braunwald's heart disease

Abstract: Part I: Methodology. Contribution of Basic Research, Observational Epidemiology and Randomized Trials. Methodology of Randomized Trials. Special Features of Primary Prevention Vs. High-Risk Vs. Secondary Prevention Trials. Strengths and Limitations of Large, Simple Trials Vs. Small Trials. Principles of Data Monitoring Boards in Trials. Meta-Analysis. Part Ii: Treatment Trials. Aspirin and Heparin. Thrombolytic Therapy. Beta-Blockers. Ace Inhibitors. Calcium Channel Blockers. Magnesium. Nitrates. Direct Thrombin Inhibitors. Glycoprotein Iib/Iiia Receptor Inhibitors. Primary and Rescue Angioplasty. Lipid-Lowering Agents. Anti-Arrhythmia Therapy in Ischemic Heart Disease. Anti-Arrhythmia Therapy in Atrial Fibrillation. Anti-Platelet Agents and Anticoagulation in Ischemic Heart Disease. Anti-Platelet Agents and Anticoagulation in Atrial Fibrillation. Angioplasty and Bypass Surgery. Exercise. Congestive Heart Failure. Part Iii: Prevention Trials: Cholesterol Reduction. Blood Pressure Reduction. Smoking Cessation. Weight Reduction/Exercise. Stress Reduction. Aspirin Prophylaxis. Postmenopausal Hormone Replacement Therapy. Antioxidant Vitamins. Other Dietary Interventions. Multiple Risk Factor Intervention Trials. Prevention Strategies: Population-Based, Community-Based, Worksite, Targeted High Risk Subgroups. Part Iv: Future Needs.

Weight-Adjusted Dosing of TNK-Tissue Plasminogen Activator and Its Relation to Angiographic Outcomes in the Thrombolysis In Myocardial Infarction 10B Trial

Abstract: Fixed doses of thrombolytic agents are generally administered to patients of varying body weights, and the dose-response relation may be confounded by the variability in patient weight. We hypothesized that higher doses of TNK-tissue plasminogen activator (tPA) per unit body weight would be related to improved flow at 90 minutes after thrombolytic administration. A total of 886 patients with acute myocardial infarction were randomized to receive either a single bolus of 30, 40, or 50 mg of TNK-tPA or front-loaded tPA in the Thrombolysis In Myocardial Infaction (TIMI) 10B trial. The dose of TNK-tPA administered was divided by the patient’s weight to arrive at the TNK-tPA dose (mg) per unit body weight (kg), and patients were stratified into tertiles based on mg/kg of TNK-tPA: low dose, 0.2 to 0.39 mg/kg; mid-dose, 0.40 to 0.51 mg/kg; high dose, 0.52 to 1.24 mg/kg. Flow in the culprit and nonculprit arteries was analyzed using the TIMI flow grades and the corrected TIMI frame count (CTFC). The median CTFC in culprit arteries differed between the tertiles (3-way p = 0.007), with the CTFC being 7.2 frames faster in high-dose than in low-dose patients (43.1 ± 30.1, median 31.2, n = 171 vs 54.6 ± 34.8, median 38.4, n = 166, 2-way p = 0.002). Patients in the mid- and high-dose tertiles achieved patency more frequently (TIMI grade 2 or 3 flow) by 60 minutes (p = 0.02), and the 90-minute percent diameter stenosis was less severe in patients in the high- versus low-dose tertile (p = 0.03). In nonculprit arteries, the CTFC was faster in high- than in low-dose tertiles (29.6 ± 13.4, median 26.9, n = 130 vs 34.7 ± 16.3, median 32.8, n = 108, 3-way p = 0.03, 2-way p = 0.008). In patients who underwent percutaneous transluminal coronary angioplasty (PTCA), the CTFC in culprit arteries after PTCA was fastest in the high- and mid-dose tertiles than in those receiving low doses (2- way p = 0.05). Thus, higher doses per unit body weight of TNK-tPA result in not only faster culprit artery flow, but also faster nonculprit, global, and post-PTCA flow, which may reflect earlier opening, reduced stunning, or improved microvascular function. The greater effectiveness of thrombolysis must be weighed against any increase in risk.

Management of unstable angina based on considerations of aetiology

Abstract: Unstable angina is not a specific disease but a clinical syndrome, more akin to hypertension than to streptococcal endocarditis. The classification of unstable angina has, until now, been based on simple clinical descriptors, such as whether the ischaemic pain is on exertion and accelerating, or whether it occurs at rest,1 and whether or not ischaemia persists despite vigorous anti-ischaemic treatment. The ECG, particularly the presence or absence of changes in the ST segment, has also been useful as a classification tool. In addition, markers of myocardial damage, such as the cardiac specific troponins T or I are being used increasingly in the classification of these patients.2 Such clinical and laboratory descriptors are valuable in predicting prognosis, but they provide little or no information about the aetiology of unstable angina. Such information is important because it allows specific rather than empiric management. To return to the analogy with hypertension, the identification of specific subtypes such as renovascular hypertension or mineralocorticoid induced hypertension has allowed specific and more effective treatment to be developed. Similar advances may be anticipated in unstable angina. The work of Maseri has been fundamental in the development of our thinking about the cause of unstable angina.3 From an aetiological perspective, unstable angina may be classified as thrombosis, severe progressive arterial obstruction, coronary vasospasm/vasoconstriction, inflammation and increased myocardial oxygen consumption.4 ### TYPE I: THROMBOSIS A non-occlusive thrombus at the site of a fissured or ruptured atherosclerotic plaque is the most frequent pathogenic mechanism in unstable angina. Rational treatment should therefore be aimed directly at the thrombus, by means of antithrombotic agents. These have consisted of unfractionated heparin and aspirin. The recent results of the ESSENCE5 and TIMI 11B6 trials provide evidence that the low molecular weight heparin (LMWH) enoxaparin may be more effective than unfractionated heparin in …

Advances in unstable angina: the role of low molecular weight heparins

Abstract: The clinical syndromes of unstable angina and non-Q wave myocardial infarction (MI) have been the focus of much interest in recent years and, as a result, our understanding of the pathology and management of these conditions has increased dramatically. It is now clear that these conditions are more complicated than originally considered. The sudden rupture of an atheromatous plaque, leading rapidly to thrombosis and subtotal arterial occlusion, has long been established as a cause of unstable angina. This explained how unstable angina might easily progress to full MI but was incompatible with subsequent findings that …