Showing papers by "Eugene Braunwald published in 1998"
TL;DR: Evidence of inflammation after MI is associated with increased risk of recurrent coronary events, and therapy with pravastatin may decrease this risk, an observation consistent with a nonlipid effect of this agent.
Abstract: Background —We studied whether inflammation after myocardial infarction (MI) is a risk factor for recurrent coronary events and whether randomized treatment with pravastatin reduces that risk. Methods and Results —A nested case-control design was used to compare C-reactive protein (CRP) and serum amyloid A (SAA) levels in prerandomization blood samples from 391 participants in the Cholesterol and Recurrent Events (CARE) trial who subsequently developed recurrent nonfatal MI or a fatal coronary event (cases) and from an equal number of age- and sex-matched participants who remained free of these events during follow-up (control subjects). Overall, CRP and SAA were higher among cases than control subjects (for CRP P =0.05; for SAA P =0.006) such that those with levels in the highest quintile had a relative risk (RR) of recurrent events 75% higher than those with levels in the lowest quintile (for CRP RR=1.77, P =0.02; for SAA RR=1.74, P =0.02). The study group with the highest risk was that with consistent evidence of inflammation (elevation of both CRP and SAA) who were randomly assigned to placebo (RR=2.81, P =0.007); this risk estimate was greater than the product of the individual risks associated with inflammation or placebo assignment alone. In stratified analyses, the association between inflammation and risk was significant among those randomized to placebo (RR=2.11, P =0.048) but was attenuated and nonsignificant among those randomized to pravastatin (RR=1.29, P =0.5). Conclusions —Evidence of inflammation after MI is associated with increased risk of recurrent coronary events. Therapy with pravastatin may decrease this risk, an observation consistent with a nonlipid effect of this agent.
1,450 citations
TL;DR: Diabetic patients and nondiabetic patients with impaired fasting glucose are at high risk of recurrent coronary events that can be substantially reduced by pravastatin treatment.
Abstract: Background—Although diabetes is a major risk factor for coronary heart disease (CHD), little information is available on the effects of lipid lowering in diabetic patients. We determined whether li...
981 citations
TL;DR: Elevated CRP at presentation in patients with unstable angina or NQMI is correlated with increased 14-day mortality, even in Patients with a negative rapid cTnT assay, which provides complementary information for stratifying patients with regard to mortality risk.
774 citations
Journal Article•
TL;DR: These results support the use of ACE inhibitors early in the treatment of acute MI, either to a wide range of patients or selectively in patients with anterior MI and in those at increased risk of death.
Abstract: BACKGROUND
Several large-scale trials have demonstrated improved survival with ACE-inhibitor therapy started during acute myocardial infarction. A systematic overview was conducted to resolve uncertainties regarding time of initiation, time course of effect, and identification of patients in whom the benefits or the risks may be greater.
METHODS AND RESULTS
This overview aimed to include individual data from all randomized trials involving more than 1000 patients in which ACE-inhibitor treatment was started in the acute phase (0 to 36 hours) of myocardial infarction and continued for a short time (4 to 6 weeks). Data were available for 98,496 patients from 4 eligible trials, and the results were consistent among the trials. Thirty-day mortality was 7.1% among patients allocated to ACE inhibitors and 7.6% among control subjects, corresponding to a 7% (SD, 2%) proportional reduction (95% CI, 2% to 11%; 2P<0.004). This represented avoidance of approximately 5 (SD, 2) deaths per 1000 patients, with most of the benefit observed within the first week. The proportional benefit was similar in patients at different underlying risk. The absolute benefit was particularly large in some high-risk groups (ie, Killip class 2 to 3, heart rate > or = 100 bpm at entry) and in anterior MI. ACE-inhibitor therapy also reduced the incidence of nonfatal cardiac failure (14.6% versus 15.2%, 2P=0.01) but was associated with an excess of persistent hypotension (17.6% versus 9.3%, 2P<0.01) and renal dysfunction (1.3% versus 0.6%, 2P<0.01).
CONCLUSIONS
These results support the use of ACE inhibitors early in the treatment of acute MI, either to a wide range of patients or selectively in patients with anterior MI and in those at increased risk of death.
629 citations
TL;DR: The purpose of this article is to review some of the points made at the workshop in regard to areas of general agreement and controversy and, most importantly, to summarize the areas that need further research.
Abstract: On July 2–3, 1996, the National Heart, Lung, and Blood Institute sponsored a workshop in Columbia, Md, entitled “The Medical and Cellular Implications of Myocardial Stunning, Hibernation, and Preconditioning.” The goals of this workshop were to identify and discuss the areas of agreement and controversy regarding these important phenomena and in particular to identify areas of future research for each. One aspect of these goals included determination of the mechanisms of these phenomena. Stunning is a form of prolonged contractile dysfunction that occurs after relief of a discrete episode or episodes of ischemia; hibernation is a form of prolonged contractile dysfunction associated with ongoing low blood flow, although controversy exists as to whether absolute blood flow or coronary reserve is reduced and whether it may represent repetitive bouts of stunning. Preconditioning is a cardioprotective mechanism in which the heart is exposed to a controlled, short period of sublethal ischemia that attenuates cellular damage from a subsequent prolonged lethal episode of ischemia. Research efforts have not yet provided a clear understanding of all aspects of these conditions. The workshop presented the current state of both basic science knowledge and clinical knowledge of these disorders, promoted discussions between basic and clinical scientists, and identified likely mechanisms and new directions for research.
The meeting was chaired by Eugene Braunwald and cochaired by Roberto Bolli, Eduardo Marban, and Robert A. Kloner and was coordinated by Leslie Reinlib. Twenty participants represented a broad spectrum of expertise: basic and clinical scientists, pathologists, and surgeons. (A list of conference participants is provided in the Appendix.)
The purpose of this article is to review some of the points made at the workshop in regard to areas of general agreement and controversy and, most importantly, to summarize the areas that need further research. The following discussions briefly review the …
447 citations
TL;DR: The Cholesterol and Recurrent Events (CARE) trial investigated whether reducing average cholesterol levels by using pravastatin in patients who have had myocardial infarction would prevent recurrent cardiac events, and reported that patients who were older than the median age of 59 years had a reduced rate of coronary death, nonfatal myocardIAL infarctions, coronary artery bypass grafting, angioplasty, and stroke.
Abstract: Background: A majority of all myocardial infarctions occur in patients who are 65 years of age or older and have average cholesterol levels, but little information is available on whether cholester...
443 citations
TL;DR: The LDL concentrations achieved during treatment with pravastatin or placebo were associated with reduction in coronary events down to an LDL concentration of approximately 125 mg/dL, and triglyceride but not HDL concentrations during follow-up were weakly but significantly associated with the coronary event rate.
Abstract: Background—Although LDL lowering has been shown to reduce recurrent coronary events in patients with coronary heart disease, little direct information is available on the extent of LDL lowering required to achieve this outcome. Methods and Results—The Cholesterol and Recurrent Events (CARE) trial compared pravastatin and placebo in patients who had experienced myocardial infarction (MI) who had average concentrations of total cholesterol <240 mg/dL (baseline mean, 209 mg/dL) and LDL cholesterol (LDL) 115 to 174 mg/dL (mean, 139 mg/dL). Pravastatin reduced coronary death or recurrent MI by 24%. In multivariate analysis, the LDL concentration achieved during follow-up was a significant, although nonlinear, predictor of the coronary event rate (P=.007), whereas the extent of LDL reduction was not significant, whether expressed as an absolute amount (P=.97) or a percentage (P=.76). The coronary event rate declined as LDL decreased during follow-up from 174 to ≈125 mg/dL, but no further decline was seen in the...
341 citations
TL;DR: In this paper, patients with acute ST-elevation myocardial infarction presenting within 12 hours were randomized to receive either a single bolus of 30 or 50 mg TNK-tPA or frontloaded tPA and underwent immediate coronary angiography.
Abstract: Background—Bolus thrombolytic therapy is a simplified means of administering thrombolysis that facilitates rapid time to treatment. TNK-tissue plasminogen activator (TNK-tPA) is a highly fibrin-specific single-bolus thrombolytic agent. Methods and Results—In TIMI 10B, 886 patients with acute ST-elevation myocardial infarction presenting within 12 hours were randomized to receive either a single bolus of 30 or 50 mg TNK-tPA or front-loaded tPA and underwent immediate coronary angiography. The 50-mg dose was discontinued early because of increased intracranial hemorrhage and was replaced by a 40-mg dose, and heparin doses were decreased. TNK-tPA 40 mg and tPA produced similar rates of TIMI grade 3 flow at 90 minutes (62.8% versus 62.7%, respectively, P=NS); the rate for the 30-mg dose was significantly lower (54.3%, P=0.035) and was 65.8% for the 50-mg dose (P=NS). A prespecified analysis of weight-based TNK-tPA dosing using median TIMI frame count demonstrated a dose response (P=0.001). Similar dose respon...
323 citations
TL;DR: Treatment with antithrombotic agents and antiplatelet agents and tissue factor inhibitors is beneficial in this form of angina, caused by dynamic obstruction, ie, coronary vasoconstriction.
Abstract: Unstable angina results from an imbalance between myocardial oxygen supply and demand. Probably the most common cause is reduced myocardial perfusion resulting from a nonocclusive thrombus on a fissured or eroded atherosclerotic plaque that often had caused only mild to moderate obstruction previously.3 Nonocclusive thrombi in patients with unstable angina have been demonstrated by coronary angioscopy and arteriography.4 They occur most commonly on complex, irregular lesions.5 Plaques that have undergone disruption often have a core that is rich in cholesteryl esters and tissue factor. They have a thin fibrous cap; disruption is caused by shear forces acting on the shoulder of the plaque. In patients with unstable angina, products of aggregating platelets are released into the coronary circulation,6 and there appears to be continued thrombus formation, often for months, after the index event.7 Nonocclusive coronary thrombi often become organized and incorporated into the growing plaque.
Treatment with antithrombotic agents (unfractionated heparin8 and low-molecular-weight heparin9 ) and antiplatelet agents (aspirin,8 ticlopidine,10 and glycoprotein IIb/IIIa inhibitors2 ) is beneficial in this form of angina. Perhaps tissue factor inhibitors will prove useful as well.
A second form of unstable angina is caused by dynamic obstruction, ie, coronary vasoconstriction. Four subgroups are recognized. (1) The first is Prinzmetal’s variant angina, with intense focal spasm of a segment of an epicardial coronary artery not involved by coronary atherosclerosis. (2) In the second, also called Prinzmetal’s angina, the spasm occurs adjacent to a nonobstructive atheromatous plaque. Both of these forms of vasospastic angina appear to be due to hypercontractility of vascular smooth muscle and endothelial dysfunction occurring in the region of spasm. They are characterized by ST-segment elevation accompanying rest pain and …
257 citations
TL;DR: Pravastatin led to significant early reduction of a wide range of cardiovascular events in post-MI women with average cholesterol levels and improved plasma lipids similarly in men and women.
225 citations
TL;DR: These temporal observations are consistent with the concept of preconditioning by preinfarction angina but do not rule out other mechanisms.
Abstract: Background—The timing of onset of angina before myocardial infarction in relation to outcome is unknown. Methods and Results—We prospectively determined the importance of the time of onset of preinfarction angina in relation to 30-day outcomes in the TIMI-9B study from standardized forms. Of the 3002 patients entered into the study, 425 reported angina before their myocardial infarction. Patients with angina onset within 24 hours of infarction had a lower 30-day cardiac event rate (mortality, recurrent myocardial infarction, heart failure, or shock) at 4% than those with onset of angina >24 hours (17%; P=.030). A history of any angina alone was not associated with reduced event rate. Peak creatine kinase levels tended to be lower in the group with angina within 24 hours. These benefits were not due to higher rates of use of antianginal medicines or aspirin and were not a consequence of differences in baseline characteristics or disease states (hypertension, hypercholesterolemia) among subgroups. Conclusio...
TL;DR: The oral glycoprotein IIb/IIIa antagonist sibrafiban achieved effective, long-term platelet inhibition with a clear dose-response but at the expense of a relatively high incidence of minor bleeding.
Abstract: Background—Inhibitors of the platelet glycoprotein IIb/IIIa receptor given intravenously have been shown to be effective in reducing ischemic complications after coronary angioplasty and in unstable angina, making this a promising new class of agents for the treatment and prevention of ischemic events in patients with acute coronary syndromes. Sibrafiban (Ro 48–3657) is an oral, peptidomimetic, selective antagonist of the glycoprotein IIb/IIIa receptor. Methods and Results—The Thrombolysis in Myocardial Infarction (TIMI) 12 trial was a phase II, double-blind, dose-ranging trial designed to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of sibrafiban in 329 patients after acute coronary syndromes. In the PK/PD cohort of TIMI 12, 106 patients were randomized to receive one of seven dosing regimens of sibrafiban, ranging from 5 mg daily to 10 mg twice daily for 28 days. In the safety cohort, 223 patients were randomized to one of four dose regimens of sibrafiban (ranging ...
TL;DR: The Treat Angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy (TACTICS-TIMI 18) trial is an international, multicenter, randomized trial that is evaluating the clinical efficacy of early invasive and early conservative treatment strategies in patients with unstable angina or non–Q-wave AMI treated with tirofiban, heparin, and aspirin.
Abstract: In the management of unstable angina and non-Q-wave acute myocardial infarction (AMI), there is considerable debate regarding the use of invasive strategy versus conservative strategy. The Thrombolysis In Myocardial Infarction (TIMI) III B trial found similar clinical outcomes for the 2 strategies, but the Veterans Administration Non-Q-Wave Infarction Strategies in-Hospital trial found a higher mortality with the invasive strategy. Both these trials were conducted before platelet glycoprotein IIb/IIIa inhibition and coronary stenting, both of which improve clinical outcome. Thus, there is a need to reexamine the question of which management strategy is optimal in the current era of platelet glycoprotein IIb/IIIa inhibition and new coronary interventions. The Treat Angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy (TACTICS-TIMI 18) trial is an international, multicenter, randomized trial that is evaluating the clinical efficacy of early invasive and early conservative treatment strategies in patients with unstable angina or non-Q-wave AMI treated with tirofiban, heparin, and aspirin. Patients are randomized to an invasive strategy, involving cardiac catheterization within 4 to 48 hours and revascularization with angioplasty or bypass surgery if feasible, versus a conservative strategy, where patients are referred for catheterization only for recurrent pain at rest or provokable ischemia. The primary end point is death, MI, or rehospitalization for acute coronary syndromes through a 6-month follow-up. The trial is also testing the "troponin hypothesis," that baseline troponins T and I will be useful in selecting an optimal management strategy.
TL;DR: A positive rapid assay for troponin T at presentation identifies those patients at risk for higher rates of adverse clinical events and longer, more complicated hospital stays.
TL;DR: The hypothesis being tested in this trial is that patients with coronary disease and ejection fraction > or =40% who are treated with ACE inhibitors will experience a reduction in the incidence of cardiovascular death, nonfatal myocardial infarction, or a revascularization procedure compared with patients treated with conventional therapy.
Abstract: The Prevention of Events with Angiotensin-Converting Enzyme Inhibition (PEACE) trial is an 8,100 patient, randomized, double-blind, placebo-controlled trial designed to determine the usefulness of angiotensin-converting enzyme (ACE) inhibitors in treating coronary patients with preserved left ventricular ejection fraction. The hypothesis being tested in this trial is that patients with coronary disease and ejection fraction ≥40% who are treated with ACE inhibitors will experience a reduction in the incidence of cardiovascular death, nonfatal myocardial infarction, or a revascularization procedure compared with patients treated with conventional therapy. The design of the PEACE trial is described herein.
TL;DR: 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 for single intravenous bolus administration, thereby simplifying dosing.
Abstract: The rapid clearance of t-PA from plasma requires administration by intravenous (IV) 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 IV bolus injection. Single IV 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 IV bolus over 5–10 s. Following IV 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 l. 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 IV bolus.
TL;DR: Aspirin but not anti-ischemic therapy before hospitalization of patients with unstable angina was associated with a decreased incidence of non–Q-wave AMI on admission, which was best predicted by age and electrocardiographic changes with pain.
Abstract: Both aspirin and beta-adrenergic blocking drugs have been shown to reduce the risk of death or acute myocardial infarction (AMI) in patients with unstable angina, but their effect during chronic use on the presentation of acute coronary syndromes is less well defined Calcium antagonists and oral nitrates are also widely prescribed for patients with coronary disease, but their effect on presentation of acute myocardial ischemia is unknown We retrospectively examined the effects of prior aspirin and anti-ischemic medical therapy on clinical events in 410 patients hospitalized for unstable angina Ischemic pain occurred at rest for a duration of 5 to 60 minutes During hospitalization, 97% of patients received aspirin and all received the direct thrombin inhibitor bivalirudin for at least 72 hours Despite being older and more likely to have risk factors for coronary disease and poor outcome, patients receiving aspirin before admission were less likely to present with non-Q-wave AMI (5% vs 14% in patients not on aspirin, p = 0004) Prior beta blocker, calcium antagonist, or nitrate administration did not appear to modify presentation as unstable angina or non-Q-wave AMI In a multivariate model, the combined incidence of death, AMI not present at enrollment, or recurrent angina was best predicted by age (adjusted odds ratio [95% confidence interval] 238 [114 to 398]) and presence of electrocardiographic changes with pain on presentation (adjusted odds ratio 283 [150 to 535]) but was not related to prior or in-hospital medical therapy Thus, aspirin but not anti-ischemic therapy before hospitalization of patients with unstable angina was associated with a decreased incidence of non-Q-wave AMI on admission
TL;DR: In the mid 1980s, angiographic comparison of two thrombolytic agents showed the superiority of tissue plasminogen activator in inducing earlycoronary recanalization.
TL;DR: 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 as discussed by the authors.
Journal Article•
TL;DR: This report attempts to review clinical progress to date, formulate recommendations, and map out potentially fruitful lines of inquiry for future investigation on the prospective use of GP IIb/IIIa inhibitors in patients with acute coronary syndromes.
Journal Article•