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Biomedical subjects

E Braunwald

Publications and source records attributed to E Braunwald.

At least 37 records · Page 2Linked to original sources
PubMed2001

Combination therapy with abciximab reduces angiographically evident thrombus in acute myocardial infarction: a TIMI 14 substudy.

BACKGROUND: Use of abciximab in combination with administration of thrombolytics has been shown to improve epicardial and microvascular coronary blood flow in acute myocardial infarction (AMI). As a potential mechanism, we hypothesized that combination therapy would reduce angiographically evident thrombus (AET) and would increase lumen diameter compared with thrombolytic monotherapy. METHODS AND RESULTS: Patients who received combination therapy in TIMI 14 (low-dose thrombolytic plus abciximab, n=732) were compared with patients who received thrombolytic monotherapy without abciximab in the TIMI 4, 10A, 10B, and 14 trials (n=1662). Thrombus burden was assessed 90 minutes after treatment, and quantitative angiography was performed in an angiographic core laboratory by investigators blinded to treatment assignment. The frequency of AET was reduced in patients who received abciximab combination therapy compared with thrombolytic monotherapy (26.6% versus 35.4%, P<0.001). Similar findings were observed when the analysis was restricted to patients with patent arteries (14.7% versus 20.8%, P=0.001). Residual percent diameter stenosis at 90 minutes was also improved in the abciximab therapy group both in patent arteries (64.6+/-16.6 versus 68.3+/-14.8, P<0.001) and between patent and occluded arteries (69.3+/-19.5 versus 73.8+/-17.9, P<0.001). The absence of AET was associated with an increased frequency of >70% ST-segment resolution by 90 minutes (37.2%, 110/296 versus 18.9%, 54/286, P<0.001). CONCLUSIONS: Compared with thrombolytic monotherapy, combination therapy with abciximab reduces AET, which in turn is associated with reduced residual stenosis and improved ST-segment resolution in AMI. These data provide a pathophysiological link between platelet inhibition, reduced thrombus, and improvements in both epicardial and microvascular perfusion in AMI.

Abciximab↗
PubMed2001

Association of white blood cell count with increased mortality in acute myocardial infarction and unstable angina pectoris. OPUS-TIMI 16 Investigators.

We observed in a study of 7,651 patients with acute coronary syndromes that a white blood cell (WBC) count of > 10,000 was associated with increased 30-day and 10-month mortality (6.2% vs 3.2% to 3.6% for WBC count < 10,000; p < 0.000). With its simplicity and widespread availability, WBC count could serve as a simple, inexpensive, new tool for risk stratification in acute coronary syndromes.

Aged↗
PubMed2001

Can we replace the 90-minute thrombolysis in myocardial infarction (TIMI) flow grades with those at 60 minutes as a primary end point in thrombolytic trials? TIMI Study Group.

The establishment of patency (Thrombolysis In Myocardial Infarction [TIMI] grade 2 or 3 flow) and/or TIMI grade 3 flow at 60 minutes after thrombolytic administration is both a univariate and multivariate predictor of in-hospital and 30-day mortality, and the odds ratios for mortality are nearly identical for TIMI grade 3 flow at 60 and 90 minutes. Thus, the 60-minute angiographic end point appears to be a valid alternative to that at 90 minutes and may permit earlier decisions regarding post-thrombolytic intervention.

Coronary Angiography↗
PubMed2001

Impact of contrast agent type (ionic versus nonionic) used for coronary angiography on angiographic, electrocardiographic, and clinical outcomes following thrombolytic administration in acute myocardial infarction.

The goal of this study was to examine the relationship between contrast agent type (ionic vs. nonionic) and angiographic, electrocardiographic, and clinical outcomes after thrombolytic administration. Ionic or nonionic contrast agents were selected in a nonrandomized fashion for 90-min angiography and percutaneous coronary intervention (PCI) following thrombolytic administration in the TIMI 14 trial [tissue plasminogen activator (tPA) or reteplase (rPA) vs. low-dose lytic + abciximab]. There was no relationship between contrast agent type and overall patency, rate of TIMI grade 3 flow, or corrected TIMI frame counts (CTFCs) in open culprit arteries and in post-PCI patency rates or post-PCI CTFCs. In patients treated with ionic contrast, ejection fractions at 90 min were slightly but significantly lower (56.2 +/- 16.5, n = 122, vs. 59.8 +/- 14.4, n = 322; P = 0.02), chest pain duration was longer (2.8 +/- 4.1 hr, n = 255, vs. 1.7 +/- 3.6, n = 550; P = 0.0003), and complete ST segment resolution was less frequent (41.5% vs. 50.8%; P = 0.04). While there was no difference in epicardial blood flow, ionic contrast agent use was associated with poorer ST segment resolution, longer chest pain duration, and poorer ejection fractions, perhaps as a result of microvascular dysfunction.

Aged↗
PubMed2001

Changing the practice of cardiovascular medicine.

Five large randomized trials of statins in primary and secondary prevention show the benefits of lipid-modifying therapy on cardiac morbidity and mortality. Evidence is beginning to accumulate showing that early and aggressive treatment of patients with acute coronary syndromes (acute myocardial infarction or unstable angina) can result in reduced mortality and morbidity and imparts a variety of mechanistic benefits. Nevertheless, recent surveys of coronary heart disease prevention in Europe and the US indicate that current evidence-based management of risk factors such as hypercholesterolemia is not uniformly employed. In fact, in Europe, only about a third of patients discharged from the hospital after an acute coronary syndrome are receiving prescriptions for statins. In US, more than a fourth of adults are eligible for treatment according to national guidelines but two thirds of them do not receive it. Among those treated, a considerable number do not reach their target levels. Therefore, strategies are needed to improve prescribing patterns among physicians and compliance among patients. It is essential that clinicians be aware of the evidence base supporting early and aggressive treatment of patients with acute coronary syndromes and that this is communicated to all clinicians involved in their care of patients with acute coronary syndromes.

Adult↗
PubMed2001

Geographic variation in patient and hospital characteristics, management, and clinical outcomes in ST-elevation myocardial infarction treated with fibrinolysis. Results from InTIME-II.

AIMS: We examined the geographic variations in InTIME-II, a randomized double-blind trial comparing alteplase with lanoteplase for myocardial infarction. METHODS AND RESULTS: We compared baseline characteristics, management, and outcomes in four regions (Western Europe, Eastern Europe, North America, and Latin America) and in countries with historically different management approaches (Germany vs the U.K., the U.S. vs Canada). Thirty-day mortality in Western Europe, Eastern Europe, North America and Latin America was 6.7%, 7.3%, 5.7%, 10.1%, P<0.0001. Adjusted mortality for Europe was intermediate between North America and Latin America (odds ratios (OR) [95% confidence intervals (CI)] compared to Western Europe: North America 0.84 [0.67-1.0], Eastern Europe 1.2 [1.0-1.4], and Latin America 1.8 [1.3-2.7]). Revascularization rates varied 10-fold but did not explain regional mortality differences. Germany and the U.K. had similar adjusted 1-year mortality (OR for the U.K. 1.16 [0.92-1.5]), although invasive procedures were four- to 10-fold more common in Germany. Similarly the U.S. and Canada had equal adjusted 1-year mortality (OR for Canada 0.85 [0.61-1.17]) despite three-fold higher use of invasive procedures in the U.S. CONCLUSIONS: Significant geographic variations in practice and adjusted mortality following fibrinolysis persist despite recent guidelines. These findings have important implications in the design and interpretation of international studies, identify under- and over-utilized therapies, and support further study of treatments with marked worldwide variations.

Adult↗
PubMed2001

Availability of on-site catheterization and clinical outcomes in patients receiving fibrinolysis for ST-elevation myocardial infarction.

AIMS: To compare management and clinical outcomes in hospitals stratified by the availability of on-site catheterization in InTIME-II, a multicentre trial comparing alteplase with lanoteplase for acute myocardial infarction. METHODS AND RESULTS: We studied 15,078 patients enrolled in 35 countries and 855 hospitals. Thirty-one percent of hospitals had 24-h, 25% day-only, and 44% no on-site catheterization facilities. Rates of cardiac angiography (57%, 38%, 26%) and revascularization (37%, 21%, 17%) were higher in hospitals with increasing access to on-site facilities(P<0.0001). The presence of a 24-h on-site facility was the strongest predictor of angiography during the index admission (odds ratio 4.17, 95% CI 3.85-4.54). There were no major differences in patient outcomes at 30 days when hospitals were stratified by availability of on-site catheterization. Adjusted 1-year mortality was similar between groups of hospitals (odds ratio for day-only 0.94 [0.80-1.09] and odds ratio for no availability 0.95 [0.83-1.10] compared to hospitals with 24-h facilities). CONCLUSIONS: There is a marked variation in procedure use by the availability of on-site catheterization with no major differences in patient outcomes. There is a need for additional randomized trials in the current era to address both the appropriate selection of patients and timing of invasive procedures in ST-elevation acute myocardial infarction.

Adolescent↗
PubMed2001

Determination of a weight-adjusted dose of TNK-tissue plasminogen activator.

BACKGROUND: TNK-tissue plasminogen activator (TNK-tPA) is a potent new thrombolytic agent for treatment of acute myocardial infarction. TNK-tPA was evaluated in 4214 patients in two dose-ranging trials (Thrombolysis in Myocardial Infarction [TIMI] 10B and Assessment of the Safety and Efficacy of a New Thrombolytic Agent [ASSENT] I). This article describes the rationale for the weight-adjusted dosing regimen of TNK-tPA that was selected for evaluation in the large phase III clinical trial ASSENT II. METHODS: Weight-based analyses were conducted with data from both the angiographic TIMI 10B trial, which compared TNK-tPA in doses of 30 mg, 40 mg, and 50 mg with the accelerated regimen of tPA in 889 patients, and the ASSENT I trial, which evaluated the safety of TNK-tPA in doses of 30 mg, 40 mg, and 50 mg in 3301 patients. Graphic and statistical analytic methods were used to assess relationships between weight and efficacy or safety measurements. RESULTS: The plasma clearance, initial plasma concentrations, and plasma steady-state volume of distribution all increased with decreasing body weight (all P<.001). The corrected TIMI frame count decreased (flow was faster) (P =.001) and the TIMI grade 3 flow increased with an increasing weight-standardized dose of TNK-tPA (P<.008). Mortality was inversely related to dose, but this relationship was not statistically significant. There was no clear relationship between intracranial hemorrhage and dose and weight. Serious bleeding events increased with increasing weight-standardized dose (P<.02). CONCLUSIONS: On the basis of these analyses, a weight-adjusted dosing regimen was devised for TNK-tPA that included five dosing increments and was based on a target weight-standardized dose of 0.53 mg/kg.

Aged↗
PubMed2001

Abciximab and early adjunctive percutaneous coronary intervention are associated with improved ST-segment resolution after thrombolysis: Observations from the TIMI 14 Trial.

BACKGROUND: Percutaneous coronary intervention (PCI) improves clinical outcomes in selected patients with failed thrombolysis but has not been proven to benefit patients who achieve a patent infarct-related artery. Even after successful epicardial reperfusion, myocardial perfusion may be inadequate. We sought to evaluate whether a strategy that uses a reperfusion regimen containing abciximab and a reduced-dose thrombolytic agent (combination therapy), followed by early adjunctive PCI, would result in improved myocardial perfusion, as assessed by ST-segment resolution. METHODS: ST resolution from 90 to 180 minutes after therapy was calculated for all 410 patients from the TIMI 14 trial who had evaluable electrocardiograms at both time points and who were treated with alteplase or reteplase. Patients were grouped according to whether they were treated with combination therapy or full-dose thrombolytic agent alone and whether they underwent PCI between the 90- and 180-minute electrocardiographic measurements. RESULTS: Among 105 patients who underwent adjunctive PCI between 90 and 180 minutes, mean ST resolution from 90 to 180 minutes was significantly greater in those who had received combination therapy versus those who had received full-dose thrombolytic alone (54% vs 8%; P =.002). Among 241 patients with TIMI grade 3 flow in the infarct-related artery at 90 minutes, adjunctive PCI significantly improved mean ST resolution in patients who had been treated with combination therapy (57% [PCI] vs 24% [no PCI]; P =.006), but PCI did not have this effect in patients who had received thrombolytic therapy alone (1% [PCI] vs 10% [no PCI]; P =.70). In a multivariate model controlling for factors that would be expected to independently influence 90- to 180-minute ST resolution, abciximab treatment remained significantly associated with greater ST resolution (P =.008). CONCLUSIONS: A strategy that uses a combination reperfusion regimen that includes abciximab, followed by early adjunctive PCI, is associated with greater ST-segment resolution, which may reflect enhanced tissue level and microvascular perfusion. Future studies should evaluate prospectively the clinical efficacy of this strategy.

Abciximab↗
PubMed2001

Lower-dose heparin with fibrinolysis is associated with lower rates of intracranial hemorrhage.

BACKGROUND: The optimal heparin dose as an adjunct to fibrinolysis and its role in causing intracranial hemorrhage (ICH) is unclear. METHODS: We reviewed the heparin regimens and rates of ICH in 3 sets of recent fibrinolytic trials: (1) studies with accelerated recombinant tissue plasminogen activator (TPA, alteplase) plus intravenous heparin, in which the heparin regimen was changed during the course of the trial; (2) phase III trials with accelerated TPA plus intravenous heparin; and (3) trials of new single-bolus fibrinolytic agents. RESULTS: Lower rates of ICH were observed among studies of accelerated TPA that reduced the heparin dose mid-trial (TIMI 9A --> 9B: 1.87% --> 1.07%, GUSTO-IIa --> IIb: 0.92% --> 0.71%, TIMI 10B: 2.80% --> 1.16%). Rates of ICH with accelerated TPA gradually increased from GUSTO-I (0.72%) in 1990 to 1993 to ASSENT-2 (0.94%) in 1997 to 1998. However, this trend was reversed in InTIME-II, which used the lowest heparin dose and most aggressive activated partial thromboplastin time monitoring and observed an ICH rate of 0.64% with accelerated TPA. Lower ICH rates were also observed when the heparin dose was reduced with single-bolus tenecteplase (TNK-TPA) and lanoteplase. CONCLUSIONS: Nonrandomized comparisons with accelerated TPA suggest that lower doses of intravenous heparin are associated with lower rates of ICH. This observation also appears to apply to single-bolus TNK-TPA and novel plasminogen activator. A lower-dose, weight-adjusted heparin regimen (60 U/kg bolus; maximum, 4000 U; 12 U/kg per hour infusion; maximum, 1000 U/h) with earlier monitoring of activated partial thromboplastin time is currently recommended in the revised American College of Cardiology/American Heart Association myocardial infarction guidelines and should be used in clinical practice.

Aged↗
PubMed2001

Myoglobin levels at 12 hours identify patients at low risk for 30-day mortality after thrombolysis in acute myocardial infarction: a Thrombolysis in Myocardial Infarction 10B substudy.

OBJECTIVE: We sought to identify, by use of serum cardiac markers, patients at low risk for 30-day mortality after ST-segment elevation myocardial infarction. BACKGROUND: Baseline cardiac markers are currently used to identify patients at increased risk for short-term events. We hypothesized that serum markers measured after treatment could identify patients at low risk for 30-day mortality. METHODS: A total of 839 patients from the Thrombolysis in Myocardial Infarction (TIMI) 10B study had myoglobin, cardiac-specific troponin-I, creatine kinase (CK)-MB measurements at the following time points; baseline, 90 minutes, and 3 and 12 hours after thrombolysis. By use of receiver operating characteristic analysis, thresholds were derived to predict 30-day mortality with at least 95% negative predictive value. RESULTS: Ninety minutes after thrombolysis myoglobin was superior to troponin-I or CK-MB in identifying patients at low risk for mortality. The 30-day mortality for 12-hour myoglobin < or = 239 ng/mL was 1.4% compared with 9.1% for levels > 239 ng/mL (P < .001). For 12-hour troponin-I (threshold 81.5 ng/mL), mortality was 1.9% versus 6.6% (P = .001) if above threshold; similarly for CK-MB at 12 hours (threshold 191 ng/mL) it was 3.3% versus 7.9% (P = .02). Multivariate analysis of baseline and posttreatment cardiac markers, age, sex, infarct artery location, and 90-minute TIMI flow grade identified only 12-hour myoglobin among the cardiac markers as independently predicting a low 30-day mortality (odds ratio 0.11, 95% confidence interval 0.02-0.50, P < .004). CONCLUSION: Serum cardiac markers can identify greater than two thirds of patients at low risk for 30-day mortality. A low 12-hour myoglobin level (< or = 239 ng/mL in this substudy) identifies such patients at low risk and could potentially assist in early risk stratification and triage after ST-segment elevation myocardial infarction.

Aged↗
PubMed2001

The A-to-Z Trial: Methods and rationale for a single trial investigating combined use of low-molecular-weight heparin with the glycoprotein IIb/IIIa inhibitor tirofiban and defining the efficacy of early aggressive simvastatin therapy.

BACKGROUND: The A-to-Z Trial is an ongoing international, multicenter, randomized study designed to investigate 2 issues concerning contemporary care of patients with acute coronary syndromes (ACS). The first issue is whether the use of low-molecular-weight heparin versus unfractionated heparin affects outcomes and safety when used as a therapy adjunctive to baseline treatment with tirofiban and aspirin in patients with non-ST-elevation (nSTE) ACS. The second issue is whether early use of an aggressively dosed statin is superior to a current trial-based "accepted care" regimen of a lower-dose statin started 3 to 6 months after an acute event. METHODS: The study is conceptually and functionally divided into 2 sequential parts-the "A" Aggrastat and "Z" Zocar phases. The primary A-phase end point is a composite of all-cause mortality, myocardial infarction (MI), and documented refractory ischemia at 7 days. Both nSTE-ACS patients from the A phase and patients with ST-elevation ACS who meet specific risk criteria are eligible to enter the subsequent "Z" (Zocor) chronic phase (Z phase). The primary end point of the Z phase is a composite of cardiovascular death, MI, readmission for ACS, and stroke. The trial will continue until 970 primary events have occurred in the Z-phase population. CONCLUSION: This trial is evaluating 2 temporally connected sequences of phamacotherapy for ACS. At completion, trial results will provide definitive evidence regarding efficacy and safety of early, intensive statin therapy and better define the role of low-molecular-weight heparin in patients with nSTE ACS.

Anticoagulants↗