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E Braunwald

Publications and source records attributed to E Braunwald.

At least 127 records · Page 7Linked to original sources
PubMed1998

Pharmacokinetics of a slower clearing tissue plasminogen activator variant, TNK-tPA, in patients with acute myocardial infarction.

The rapid clearance of t-PA from plasma requires administration by intravenous (I.V.) infusion. A slower clearing, fibrin-specific rt-PA variant may allow single intravenous bolus administration, thereby simplifying dosing. This study was designed to characterize the pharmacokinetics of the slower clearing, fibrin-specific tissue-plasminogen activator variant, TNK-tPA, in patients with acute myocardial infarction (AMI) following a single I.V. bolus injection. Single I.V. bolus doses of 5 to 50 mg of TNK-tPA were studied in an open-label, multicenter, dose escalation study. A total of 113 AMI patients were enrolled. Blood sampling for pharmacokinetics was conducted in eighty-two patients (72 men, 10 women), with 5 to 27 patients per dose. TNK-tPA was administered as an I.V. bolus over 5-10 s. Following I.V. bolus administration, there was a biphasic elimination of TNK-tPA from plasma. The initial phase had a mean half-life that ranged from 11 +/- 5 to 20 +/- 6 min and was followed by a terminal phase with a mean half-life that ranged from 41 +/- 16 to 138 +/- 84 min. Mean TNK-tPA plasma clearance was 125 +/- 25 - 216 +/- 98 ml/min, and the initial volume of distribution was 4.3 +/- 2 - 8.4 +/- 6 1. A decrease in TNK-tPA plasma clearance with increasing TNK-tPA dose was noted. In addition, women and patients with lower body weight or older age had a slower plasma clearance. In conclusion, TNK-tPA has a slower plasma clearance in patients with AMI than that reported for rt-PA, allowing administration as a single I.V. bolus.

Adult↗
PubMed1998

Rationale and clinical evidence for the use of GP IIb/IIIa inhibitors in acute coronary syndromes.

Platelet glycoprotein (GP) IIb/IIIa blockade has the potential to advance treatment of acute coronary syndromes, both as a primary pharmacologic approach and an adjunct to interventional treatment strategies. The benefits of GP IIb/IIIa inhibition with the chimeric monoclonal antibody abciximab in preventing ischemic complications of interventional treatment have been well defined in patients with unstable angina. In the future, major therapeutic applications for this class of agents may include the stabilization of patients with unstable angina and potentially as single medical therapy, as several recently completed trials have suggested. Evidence also is accumulating on the use of GP IIb/IIIa blockade as adjunctive therapy in fibrinolytic approaches to treatment of acute myocardial infarction. Several ongoing trials are evaluating the safety and efficacy of this novel strategy. This article reflects a distillation of the views and consensus regarding the prospective use of GP IIb/IIIa inhibitors in patients with acute coronary syndromes expressed by a group of international experts convened in Davos, Switzerland, February 16, 1997. This report attempts to review clinical progress to date, formulate recommendations, and map out potentially fruitful lines of inquiry for future investigation.

Abciximab↗
PubMed1997

Sphygmomanometrically determined pulse pressure is a powerful independent predictor of recurrent events after myocardial infarction in patients with impaired left ventricular function. SAVE investigators. Survival and Ventricular Enlargement.

BACKGROUND: There is increasing evidence of a link between conduit vessel stiffness and cardiovascular events, although the association has never been tested in a large post-myocardial infarction patient population. METHODS AND RESULTS: We evaluated the relationship between baseline pulse pressure, measured by sphygmomanometry 3 to 16 days after myocardial infarction, and subsequent adverse clinical events in the 2231 patients enrolled in the SAVE Trial. Increased pulse pressure was associated with increased age, left ventricular ejection fraction, female sex, history of prior infarction, diabetes, and hypertension and use of digoxin and calcium channel blockers. Over a 42-month period, there were 503 deaths, 422 cardiovascular deaths, and 303 myocardial infarctions. Pulse pressure was significantly related to each of these end points as a univariate predictor. In a multivariate analysis, pulse pressure remained a significant predictor of total mortality (relative risk, 1.08 per 10 mm Hg increment in pulse pressure; 95% CI, 1.00 to 1.17; P<.05) and recurrent myocardial infarction (relative risk, 1.12; 95% CI, 1.01 to 1.23; P<.05) after control for age; left ventricular ejection fraction; mean arterial pressure; sex; treatment arm (captopril or placebo); smoking history; history of prior myocardial infarction, diabetes, or hypertension; and treatment with beta-blockers, calcium channel blockers, digoxin, aspirin, or thrombolytic therapy. CONCLUSIONS: These data provide strong evidence for a link between pulse pressure, which is related to conduit vessel stiffness, and subsequent cardiovascular events after myocardial infarction in patients with left ventricular dysfunction.

Adult↗
PubMed1997

Cardiovascular death and left ventricular remodeling two years after myocardial infarction: baseline predictors and impact of long-term use of captopril: information from the Survival and Ventricular Enlargement (SAVE) trial.

BACKGROUND: We quantified cardiovascular death and/or left ventricular (LV) dilatation in patients from the SAVE trial to determine whether dilatation continued beyond 1 year, whether ACE inhibitor therapy attenuated late LV dilatation, and whether any baseline descriptors predicted late dilatation. METHODS AND RESULTS: Two-dimensional echocardiograms were obtained in 512 patients at 11+/-3 days and 1 and 2 years postinfarction to assess LV size, percentage of the LV that was akinetic/dyskinetic (%AD), and LV shape index. LV function was assessed by radionuclide ejection fraction. Two hundred sixty-three patients (51.4%) sustained cardiovascular death and/or LV diastolic dilatation; 279 (54.5%) had cardiovascular death and/or systolic dilatation. In 373 patients with serial echocardiograms, LV end-diastolic and end-systolic sizes increased progressively from baseline to 2 years (both P<.01). More patients with LV dilatation had a decrease in ejection fraction: 24.8% versus 6.8% (P<.001) (diastole) and 25.7% versus 5.3% (P<.001) (systole). Captopril attenuated diastolic LV dilatation at 2 years (P=.048), but this effect was carried over from the first year of therapy because changes in LV size with captopril beyond 1 year were similar to those with placebo. Predictors of cardiovascular death and/or dilatation were age (P=.023), prior infarction (P<.001), lower ejection fraction (P<.001), angina (P=.007), heart failure (P=.002), LV size (P<.001), and infarct size (%AD) (P<.001). CONCLUSIONS: Cardiovascular death and/or LV dilatation occurred in >50% of patients by 2 years. LV dilatation is progressive, associated with chamber distortion and deteriorating function that is unaffected by captopril beyond 1 year.

Captopril↗
PubMed1997

Prospective validation of a composite end point in thrombolytic trials of acute myocardial infarction (TIMI 4 and 5). Thrombosis In Myocardial Infarction.

Although the use of composite end points in clinical trials has increased in recent years, few data are available on the validity of such an approach. In the Thrombolysis In Myocardial Infarction (TIMI) 4 and 5 trials, we set out to validate prospectively the nonfatal components of the "unsatisfactory outcome" end point. This end point consisted of the in-hospital occurrence or observation of new-onset severe congestive heart failure/shock, left ventricular ejection fraction <40% (or <30% for patients with prior myocardial infarction), reinfarction, reocclusion by sestamibi perfusion imaging, TIMI flow grade <2 at 90 minutes or 18 to 36 hours, intracranial hemorrhage, major spontaneous hemorrhage, or anaphylaxis. Among 576 patients in TIMI 4 and 5 with 1-year follow-up, a nonfatal unsatisfactory outcome end point was reached in hospital in 45% of patients. Compared with patients without such an end point, patients with an end point had a relative risk of 1-year mortality of 2.5 (95% confidence interval 1.4 to 5.6, p = 0.001). For individual components, new-onset severe congestive heart failure/shock had a relative risk of 4.6 (p = 0.001), left ventricular ejection fraction <40% had a relative risk of 3.5 (p = 0.006), recurrent myocardial infarction had a relative risk of 2.2 (p = 0.047), and TIMI flow grade <2 at 90 minutes had a relative risk of 2.2 (p = 0.005). Our findings show that these nonfatal in-hospital end points and the composite end point are associated with an increased risk of 1-year mortality and as such are valid predictive survival markers for use in clinical trials.

Aged↗
PubMed1997

Clinical significance of mitral regurgitation after acute myocardial infarction. Survival and Ventricular Enlargement Investigators.

BACKGROUND: Mitral regurgitation (MR) may complicate acute myocardial infarction (MI). However, it is not known whether mild MR is an independent predictor of post-MI outcome. METHODS AND RESULTS: The study cohort consisted of 727 Survival and Ventricular Enlargement Study patients who underwent cardiac catheterization, including left ventriculography, up to 16 days after MI. Left ventriculograms were analyzed for diastolic and systolic volumes, global left ventricular sphericity, extent of wall motion abnormality, and endocardial curvature. The presence of MR was related to the risk of developing a cardiovascular event during 3.5 years of follow-up. MR was present in 141 patients (19.4%). Severe (3+) MR was present in only 2 patients. Patients with MR were more likely to have a persistently occluded infarct artery (MR versus no MR, 27.3% versus 15.2%; P=.001). Although the ejection fractions were similar, MR patients had larger end-systolic and end-diastolic volumes and more spherical ventricles than patients without MR. Sphericity change from diastole to systole was also significantly reduced in MR patients. Patients with MR were more likely to experience cardiovascular mortality (29% versus 12%; P<.001), severe heart failure (24% versus 16%; P=.0153), and the combined end point of cardiovascular mortality, severe heart failure, or recurrent myocardial infarction (47% versus 29%; P<.001). The presence of MR was an independent predictor of cardiovascular mortality (relative risk, 2.00; 95% CI, 1.28 to 3.04). CONCLUSIONS: Mild MR is an independent predictor of post-MI mortality. As such, it adds important information for risk stratification of post-MI patients.

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PubMed1997

Rescue angioplasty in the thrombolysis in myocardial infarction (TIMI) 4 trial.

Rescue percutaneous transluminal coronary angioplasty (PTCA) has been used to establish reperfusion after failed thrombolysis, and the goal of this study was to examine the angiographic and clinical outcomes after rescue PTCA performed for an occluded artery 90 minutes after thrombolysis. Four hundred two patients with acute myocardial infarction were randomized to receive either anistreplase (APSAC), recombinant tissue plasminogen activator, or their combination in the Thrombolysis in Myocardial Infarction (TIMI) 4 trial. The angiographic and clinical outcomes of patients with a patent artery 90 minutes after thrombolysis were compared with those of patients with an occluded artery treated in a nonrandomized fashion with either rescue or no rescue PTCA. At 90 minutes, the number of frames required to opacify standard landmarks (corrected TIMI frame count) was significantly lower (i.e., flow was faster) after successful rescue PTCA (27 +/- 11) than that in patent arteries after successful thrombolysis (39 +/- 20, p < 0.001), and the incidence of TIMI grade 3 flow was correspondingly higher after successful rescue PTCA (87% vs 65%, p = 0.002). In-hospital adverse outcomes (death, recurrent acute myocardial infarction, severe congestive heart failure, cardiogenic shock or an ejection fraction <40%) occurred in 29% of successful rescue PTCAs and in 83% of failed rescue PTCAs (p = 0.01). Among all patients in whom rescue PTCA was performed (successes and failures combined), 35% of patients experienced an adverse outcome, which was the same as the 35% incidence observed in patients not undergoing rescue PTCA (p = NS) and tended to be higher than the 23% incidence observed in patients with patent arteries (p = 0.07). Although successful rescue PTCA for an occluded artery at 90 minutes results in restoration of flow that is superior to that of successful thrombolysis, the incidence of adverse events for the strategy of rescue PTCA as a whole was the same as that of undertaking no PTCA.

Age Factors↗
PubMed1997

Management of unstable angina pectoris and non-Q-wave acute myocardial infarction in the United States and Canada (the TIMI III Registry).

Management of Q-wave acute myocardial infarction (AMI) has been shown to differ between the United States and Canada, with more catheterization and revascularization procedures performed in the United States, but with little or no apparent difference in clinical outcomes. No previous studies have evaluated management differences for the acute coronary syndromes of unstable angina pectoris and non-Q-wave AMI. We therefore compared treatments and outcomes between 14 United States and 4 Canadian tertiary care centers participating in an observational registry of all consecutive admissions for unstable angina or non-Q-wave AMI between 1990 and 1993. A random, stratified sample was selected for detailed assessment and follow-up. There were 1,733 patients enrolled in United States centers and 642 in Canadian ones. In United States centers patients were less likely to receive intravenous nitroglycerin, heparin, beta blockers, calcium antagonists, or > or = 2 anti-ischemic agents. Coronary arteriography during index hospitalization was equally frequent in both countries (63.4% vs 66.9%, p = 0.781), but at 6 weeks and 1 year coronary arteriography was slightly less frequent in the United States patients. Revascularization by coronary angioplasty or bypass surgery was equivalent at 6 weeks and 1 year; however, there were trends toward less angioplasty and more bypass surgery in the United States than in Canada. Patients at United States centers stayed in the hospital fewer days than patients at Canadian centers (mean 8.2 vs 12.1 days, p <0.001). Death or AMI by 6 weeks was not different (4.8% vs 4.4%, p = 0.633), nor was it different at 1 year (10.0% vs 10.2%, p = 0.836). The combined outcome of death, AMI, or recurrent ischemia was more common in United States than in Canadian patients at 6 weeks (18.4% vs 13.9%, p = 0.004). Our findings indicate that United States physicians and hospitals did not consistently utilize more resources and were not more aggressive than their Canadian counterparts when treating acute coronary syndromes during this period.

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PubMed1997

Hemorrhagic events during therapy with recombinant tissue plasminogen activator, heparin, and aspirin for unstable angina (Thrombolysis in Myocardial Ischemia, phase IIIB trial).

This study assesses the effects of invasive procedures, hemostatic and clinical variables, and doses of recombinant tissue plasminogen activator (t-PA) on hemorrhagic events in the thrombolysis in myocardial ischemia (TIMI), phase 1B clinical trial (n = 1,425). Patients seen within 24 hours of the onset of ischemic chest pain at rest were randomized using a 2 x 2 factorial design for comparison of: (1) t-PA versus placebo as initial therapy, and (2) an early invasive (coronary arteriography with percutaneous angioplasty, if feasible) versus an early conservative strategy (coronary arteriography followed by revascularization if initial medical therapy failed). All patients received conventional medication for acute ischemic syndromes, including heparin, aspirin, beta blockers, nitrates, and calcium antagonists. The total dose of t-PA or placebo was 0.8 mg/kg, up to a maximum dose of 80 mg. In patients treated with t-PA, major and minor hemorrhagic events were more common than among those assigned to placebo (p < 0.001). Patients assigned to the invasive strategy arm had a higher hemorrhagic event rate than the noninvasive strategy, although the difference was not significant (p = 0.026). Patients > 75 years of age had higher intracranial hemorrhage rates than those < 75 years of age (6.7% vs 0.2%, respectively, p = 0.01). Major hemorrhagic events were more common in patients with higher heparin levels (p < 0.001), higher peak D-dimer levels (p = 0.007), and lower nadir fibrinogen levels (p = 0.005). Thus, increased morbidity due to hemorrhagic complications is associated with the use of t-PA, increased age, and selected hemostatic measures. Comparison to TIMI II demonstrates a significant association between the dose of t-PA and hemorrhagic complications.

Aged↗
PubMed1997

Circadian variation in the onset of unstable angina and non-Q-wave acute myocardial infarction (the TIMI III Registry and TIMI IIIB).

Circadian variation has been demonstrated in several types of acute cardiovascular disease, including acute myocardial infarction (AMI), sudden cardiac death, silent ambulatory ischemia, and thrombotic stroke. In contrast, no diurnal variation was observed in 1 study of non-Q-wave AMI, and limited data are available for unstable angina. To assess whether circadian variation is present in unstable angina and non-Q-wave AMI, we examined the time of onset of ischemic pain in 7,731 patients who were prospectively identified in the Thrombolysis in Myocardial Ischemia (TIMI) III Registry, 3,318 of whom were enrolled in the prospective study, and in 1,473 patients enrolled in the TIMI IIIB trial. A circadian variation in the onset of pain was observed, with an increase in the number of patients experiencing the onset of pain in the morning hours between 6 A.M. and 12 noon (p <0.001). This circadian variation was observed both in patients with unstable angina and in those with evolving non-Q-wave AMI. A similar circadian pattern was observed in all subgroups tested. These findings were confirmed in the TIMI IIIB trial and complement previous studies suggesting that circadian variation exists in the onset of the full spectrum of myocardial ischemic syndromes.

Aged↗
PubMed1997

TNK-tissue plasminogen activator in acute myocardial infarction. Results of the Thrombolysis in Myocardial Infarction (TIMI) 10A dose-ranging trial.

BACKGROUND: TNK-tissue plasminogen activator (TNK-TPA) is a genetically engineered variant of TPA, which in experimental models has a slower plasma clearance and greater fibrin specificity and is 80-fold more resistant to plasminogen activator inhibitor-1 than alteplase TPA. METHODS AND RESULTS: The thrombolysis in Myocardial Infarction (TIMI) 10A trial was a Phase 1, dose-ranging pilot trial designed to evaluate the pharmacokinetics, safety, and efficacy of TNK-TPA in patients with acute myocardial infarction. One hundred thirteen patients with acute ST-segment elevation myocardial infarction presenting within 12 hours and without contraindications to thrombolysis were enrolled and treated with a single bolus of TNK-TPA over 5 to 10 seconds with doses ranging from 5 to 50 mg. TNK-TPA demonstrated a plasma clearance of 151 +/- 55 mL/min and a half-life of 17 +/- 7 minutes. Comparable values for wild-type TPA are 572 +/- 132 mL/min and 3.5 +/- 1.4 minutes, respectively. Systemic fibrinogen and plasminogen levels fell by only 3% and 13%, respectively, at 1 hour after TNK-TPA administration. TIMI grade 3 flow at 90 minutes was achieved in 57% to 64% of patients at the 30- to 50-mg doses. Seven patients (6.2%) experienced a major hemorrhage, which occurred at a vascular access site in six patients. CONCLUSIONS: TNK-TPA has a prolonged half-life so it can be administered as a single bolus. TNK-TPA appears to be very fibrin specific, and the initial patency and safety profiles are encouraging. Further study of this new thrombolytic agent is ongoing.

Adult↗
PubMed1997

Myoglobin, creatine kinase MB, and cardiac troponin-I to assess reperfusion after thrombolysis for acute myocardial infarction: results from TIMI 10A.

BACKGROUND: The availability of a reliable, noninvasive serum marker of reperfusion may permit early identification of patients with occlusion after thrombolysis who might benefit from further interventions. METHODS: We measured myoglobin, creatine kinase MB (CK-MB), and cardiac troponin-I (cTnI) concentrations in sera obtained just before thrombolysis (T0) and 60 minutes later (T60) in 30 patients given TNK-tPA for acute myocardial infarction as part of the Thrombolysis in Myocardial Infarction (TIMI) 10A trial. RESULTS: Angiography at T60 showed reperfusion (TIMI flow grade 2 to 3; n = 19) or occlusion (TIMI flow grade 0 to 1; n = 8). The median serum T60 concentration, the ratio of the T60 and T0 serum concentration, and the slope of increase over a 60-minute period for each serum marker were significantly higher in patients with patent arteries compared with patients with occluded arteries. The areas under the receiver operator characteristics curve for diagnosis of occlusion were 0.96, 0.91, and 0.87 for the T60 concentration of myoglobin, CK-MB and cTnI, respectively. Although the T60 levels of <469 ng/ml for myoglobin, <11.5 ng/ml for CK-MB, and < 1.1 ng/ml for cTnI identified all patients with occlusion, the specificity of myoglobin (94%) was higher than that of CK-MB (61%) and cTnI (67%). Similar results were obtained for the 60-minute ratios and 60-minute slopes for each marker, with indexes for myoglobin having the highest specificity. CONCLUSIONS: In this pilot study, noninvasive diagnosis of occlusion 60 minutes after thrombolysis was achieved with a high degree of sensitivity and specificity with the myoglobin, CK-MB, and cTnI concentrations measured at that time point. These preliminary findings may permit a new strategy for assessment of the success of reperfusion, with triage to rescue angioplasty for patients in whom the 60-minute cardiac marker values or indexes are consistent with occlusion of the infarct-related artery.

Adult↗
PubMed1997

Outcome and profile of women and men presenting with acute coronary syndromes: a report from TIMI IIIB. TIMI Investigators. Thrombolysis in Myocardial Infarction.

OBJECTIVES: Women and men enrolled in the Thrombolysis in Myocardial Infarction (TIMI) IIIB trial of unstable angina and non-Q wave myocardial infarction (MI) were evaluated to determine gender differences in characteristics and outcome. BACKGROUND: Coronary heart disease is the leading cause of death for women and men. However, the characteristics and outcome of women compared with men with unstable angina and non-Q wave MI have not been extensively studied. METHODS: The characteristics, outcomes and proportion of 497 women and 976 men with unstable angina and non-Q wave MI at the time of enrollment were compared. When these proportions were noted to be significantly different, we compared them with the 7,731-patient TIMI IIIB Registry, which represents the non-trial, screened population with these syndromes at these centers. RESULTS: For both coronary syndromes, women were older, were less frequently white, had a higher incidence of diabetes and hypertension and were receiving more cardiac medications. The 42-day rate of death and MI in TIMI IIIB was similar for women and men (7.4% vs. 7.5%). Coronary angiography revealed less severe coronary artery disease for women than for men, with absence of critical obstructions in 25% versus 16% and mean ejection fractions 62 +/- 12% versus 57 +/- 13% for women versus men (p < 0.01). Medical management failed in women as often as in men, and rates of cardiac catheterization and percutaneous transluminal coronary angioplasty or coronary artery bypass graft surgery were similar for women and men in the conservative strategy arm as well as in the invasive strategy arm. Women in the TIMI IIIB trial had proportionately more unstable angina than did men. The proportion of unstable angina and non-Q wave MI for women was similar in the trial and Registry. However, proportionately more men in the trial had non-Q wave MI than men in the Registry. CONCLUSIONS: 1) Women with each acute coronary syndrome are older than men and have more comorbidity. 2) The outcome with unstable angina and non-Q wave MI is related to severity of illness and not gender. 3) Mortality associated with revascularization for unstable angina and non-Q wave MI was similar for women and men. 4) The proportion of women and men enrolled with each acute coronary syndrome is different. These rates reflect both the prevalence of disease and selection bias owing to trial eligibility criteria and other identified factors.

Age Factors↗
PubMed1997

The electrocardiogram predicts one-year outcome of patients with unstable angina and non-Q wave myocardial infarction: results of the TIMI III Registry ECG Ancillary Study. Thrombolysis in Myocardial Ischemia.

OBJECTIVES: We sought to determine the prognostic value of the admission electrocardiogram (ECG) in patients with unstable angina and non-Q wave myocardial infarction (MI). BACKGROUND: Although the ECG is the most widely used test for evaluating patients with unstable angina and non-Q wave MI, little prospective information is available on its value in predicting outcome in the current era of aggressive medical and interventional therapy. METHODS: ECGs with the qualifying episode of pain were analyzed in patients enrolled in the Thrombolysis in Myocardial Ischemia (TIMI) III Registry, a prospective study of patients admitted to the hospital with unstable angina or non-Q wave MI. RESULTS: New ST segment deviation > or = 1 mm was present in 14.3% of 1,416 enrolled patients, isolated T wave inversion in 21.9% and left bundle branch block (LBBB) in 9.0%. By 1-year follow-up, death or MI occurred in 11% of patients with > or = 1 mm ST segment deviation compared with 6.8% of patients with new, isolated T wave inversion and 8.2% of those with no ECG changes (p < 0.001 when comparing ST with no ST segment deviation). Two other high risk groups were identified: those with only 0.5-mm ST segment deviation and those with LBBB, whose rates of death or MI by 1 year were 16.3% and 22.9%, respectively. On multivariate analysis, ST segment deviation of either > or = 1 mm or > or = 0.5 mm remained independent predictors of death or MI by 1 year. CONCLUSIONS: The admission ECG is very useful in risk stratifying patients with non-Q wave MI. The new criteria of not only > or = 1-mm ST segment deviation but also > or = 0.5-mm ST segment deviation or LBBB identify high risk patients, whereas T wave inversion does not add to the clinical history in predicting outcome.

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