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Biomedical subjects

E Braunwald

Publications and source records attributed to E Braunwald.

At least 109 records · Page 6Linked to original sources
PubMed1998

Effect of pravastatin on cardiovascular events in older patients with myocardial infarction and cholesterol levels in the average range. Results of the Cholesterol and Recurrent Events (CARE) trial.

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 cholesterol lowering in such patients reduces the rate of recurrent cardiovascular disease. OBJECTIVE: To determine whether pravastatin reduces the rate of recurrent cardiovascular events in older patients. DESIGN: Subset analysis of a randomized, controlled trial. SETTING: 80 hospitals and affiliates in the United States and Canada. PATIENTS: 1283 patients aged 65 to 75 years who had had myocardial infarction and had a plasma total cholesterol level less than 6.2 mmol/L (240 mg/dL) and a low-density lipoprotein cholesterol level of 3.0 to 4.5 mmol/L (115 to 174 mg/dL). INTERVENTION: Pravastatin, 40 mg/d, or placebo. MEASUREMENTS: Five-year event rates of major coronary events (coronary death, nonfatal myocardial infarction, angioplasty, or bypass surgery) and stroke. RESULTS: Major coronary events occurred in 28.1% of placebo recipients and 19.7% of pravastatin recipients (difference, 9.0 percentage points [95% CI, 4 to 13 percentage points]; relative risk reduction, 32%; P < 0.001). Coronary death occurred in 10.3% of the placebo group and in 5.8% of the pravastatin group (difference, 4.6 percentage points [CI, 1.9 to 6.5 percentage points]; relative risk reduction, 45%; P = 0.004). Stroke incidence was 7.3% in the placebo group and 4.5% in the pravastatin group (absolute reduction, 2.9 percentage points [CI, 0.3 to 4.5 percentage points]; relative reduction, 40%; P = 0.03). The numbers of older patients needed to treat for 5 years were 11 (CI, 8 to 24) to prevent a major coronary event and 22 (CI, 15 to 53) to prevent a coronary death. For every 1000 older patients treated, 225 cardiovascular hospitalizations would be prevented compared with 121 hospitalizations in 1000 younger patients. CONCLUSIONS: In older patients with myocardial infarction and cholesterol levels in the average range, pravastatin is associated with a clinically important reduction in risk for major coronary events and stroke. Given the high cardiovascular event rate in older patients, the potential for absolute benefit in this age group is substantial.

Aged↗
PubMed1998

Invasive versus conservative strategies in unstable angina and non-Q-wave myocardial infarction following treatment with tirofiban: rationale and study design of the international TACTICS-TIMI 18 Trial. Treat Angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy. Thrombolysis In Myocardial Infarction.

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.

Adolescent↗
PubMed1998

Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events (CARE) Investigators.

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.

Aged↗
PubMed1998

Prevention of events with angiotensin-converting enzyme inhibition (the PEACE study design). Prevention of Events with Angiotensin-Converting Enzyme Inhibition.

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 > 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. The design of the PEACE trial is described herein.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1998

Relationship between plasma LDL concentrations during treatment with pravastatin and recurrent coronary events in the Cholesterol and Recurrent Events trial.

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 approximately 125 mg/dL, but no further decline was seen in the LDL range from 125 to 71 mg/dL. In multivariate analysis, triglyceride but not HDL concentrations during follow-up were weakly but significantly associated with the coronary event rate. CONCLUSIONS: 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. LDL concentrations <125 mg/dL during treatment were not associated with further benefit. Absolute or percentage reduction in LDL had little relationship to coronary events.

Adult↗
PubMed1998

Prospective temporal analysis of the onset of preinfarction angina versus outcome: an ancillary study in TIMI-9B.

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. CONCLUSIONS: These temporal observations are consistent with the concept of preconditioning by preinfarction angina but do not rule out other mechanisms.

Aged↗
PubMed1998

Effects of prior aspirin and anti-ischemic therapy on outcome of patients with unstable angina. TIMI 7 Investigators. Thrombin Inhibition in Myocardial Ischemia.

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 = 0.004). 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] 2.38 [1.14 to 3.98]) and presence of electrocardiographic changes with pain on presentation (adjusted odds ratio 2.83 [1.50 to 5.35]) 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.

Adrenergic beta-Antagonists↗
PubMed1998

Randomized trial of an oral platelet glycoprotein IIb/IIIa antagonist, sibrafiban, in patients after an acute coronary syndrome: results of the TIMI 12 trial. Thrombolysis in Myocardial Infarction.

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 from 5 mg twice daily to 15 mg once daily) or aspirin for 28 days. High levels of platelet inhibition were achieved: mean peak values ranged from 47% to 97% inhibition of 20 micromol/L ADP-induced platelet aggregation on day 28 across the seven doses. Twice-daily dosing provided more sustained platelet inhibition (mean inhibition, 36% to 86% on day 28), whereas platelet inhibition returned to baseline levels by 24 hours with once-daily dosing. Major hemorrhage occurred in 1.5% of patients treated with sibrafiban and in 1.9% of patients treated with aspirin. Protocol-defined "minor" bleeding, usually mucocutaneous, occurred in 0% to 32% of patients in the various sibrafiban groups and in none of the patients treated with aspirin. Minor bleeding was related to total daily dose (P=.002), once- versus twice-daily dosing (P<.0001), renal function (P<.0001), and presentation with unstable angina (P<.01). CONCLUSIONS: 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. Oral IIb/IIIa inhibition deserves further study as a new treatment strategy in patients after acute coronary syndromes.

Acute Disease↗
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.

Acute Disease↗
PubMed1998

Time to positivity of a rapid bedside assay for cardiac-specific troponin T predicts prognosis in acute coronary syndromes: a Thrombolysis in Myocardial Infarction (TIMI) 11A substudy.

OBJECTIVES: We sought to determine whether the rapid bedside assay for troponin T identified patients at risk for a more complicated hospital stay and a higher rate of adverse clinical events. BACKGROUND: In patients with an acute coronary syndrome, the amount of cardiac-specific troponin T released bears a stoichiometric relation to the extent of myocardial damage. METHODS: In 597 patients with unstable angina or non-Q wave myocardial infarction participating in the Thrombolysis in Myocardial Infarction (TIMI) 11A substudy, a rapid bedside assay and simultaneous quantitative serum measurement for troponin T were obtained at enrollment. RESULTS: The composite end point of the sum of death, nonfatal myocardial infarction or recurrent ischemia through day 14 occurred in 33.6% of patients with a positive assay compared with only 22.5% of patients with a negative assay (p = 0.01). Those patients in whom the rapid assay became positive in < or = 10 min had the highest mortality rate of 4.2% through day 14 compared with 1.1% in those patients who had either a late-appearing positive assay (> 10 min) or a negative assay. The duration of hospital stay in the 116 patients (19%) with a positive rapid assay at enrollment was a median of 5 days compared with only 3 days in the 481 patients (81%) with a negative rapid assay at enrollment (p = 0.002). CONCLUSIONS: 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. Stratification of patients by time to development of a positive rapid assay identifies those patients at highest mortality risk.

Aged↗
PubMed1998

C-reactive protein is a potent predictor of mortality independently of and in combination with troponin T in acute coronary syndromes: a TIMI 11A substudy. Thrombolysis in Myocardial Infarction.

OBJECTIVES: We evaluated C-reactive protein (CRP) alone and in conjunction with a rapid qualitative assay for cardiac-specific troponin T (cTnT) for predicting 14-day mortality in patients with unstable angina or non-Q wave myocardial infarction (NQMI). BACKGROUND: Elevated CRP has been found to correlate with higher risk for cardiac events in patients with coronary disease. METHODS: At enrollment into the Thrombolysis in Myocardial Infarction (TIMI) 11A trial, a dose-ranging trial of enoxaparin for unstable angina and NQMI, serum was obtained for CRP measurement and rapid cTnT assay. RESULTS: Quantitative CRP and rapid cTnT assays were performed in all patients. CRP was higher among patients who died than in survivors (7.2 vs. 13 mg/dl, p = 0.0038). The probability of a positive rapid cTnT assay rose with increasing CRP concentration (p < 0.0001). Among patients with a negative rapid cTnT assay, the mortality rate was higher among patients with CRP > or = 1.55 mg/dl (5.80% vs. 0.36%, p = 0.006). Patients with both an early positive rapid cTnT assay (< or = 10 min until assay positive) and CRP > or = 1.55 mg/dl had the highest mortality, followed by those with either CRP > or = 1.55 mg/dl or an early positive rapid cTnT assay, whereas patients with both a negative rapid cTnT assay and CRP < 1.55 mg/dl were at very low risk (9.10% vs. 4.65% vs. 0.36%, p = 0.0003). CONCLUSIONS: 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. Quantitative CRP and a rapid cTnT assay provide complementary information for stratifying patients with regard to mortality risk.

Angina, Unstable↗
PubMed1998

Effect of pravastatin on cardiovascular events in women after myocardial infarction: the cholesterol and recurrent events (CARE) trial.

OBJECTIVES: We sought to determine the effect of pravastatin on recurrent cardiovascular events in women with average cholesterol levels after myocardial infarction (MI). BACKGROUND: Little information is available on the effectiveness of lipid lowering in secondary prevention of coronary heart disease (CHD) in women; in particular, those with CHD and average cholesterol levels. METHODS: In the Cholesterol and Recurrent Events (CARE) trial, 576 postmenopausal women, between 3 and 20 months after MI, with a total cholesterol level <240 mg/dl and a low density lipoprotein cholesterol level 115 to 174 mg/dl, were randomized to receive pravastatin 40 mg/day or matching placebo for a median follow-up period of 5 years. The main outcome measures were combined coronary events (coronary death, nonfatal MI, percutaneous transluminal coronary angioplasty [PTCA] or coronary artery bypass graft surgery [CABG]), the primary trial end point (coronary death or nonfatal MI) and stroke. RESULTS: Women treated with pravastatin had a risk reduction of 43% for the primary end point (p = 0.035), 46% for combined coronary events (p = 0.001), 48% for PTCA (p = 0.025), 40% for CABG (p = 0.14) and 56% for stroke (p = 0.07). The 3,583 men in the CARE trial also showed a reduction in risk, but the magnitude tended to be less. Pravastatin improved plasma lipids similarly in men and women. There were no differences in risk of coronary events in the placebo group between men and women. Minor differences between men and women were present in baseline characteristics and treatment for MI, in general, conferring a higher risk status and a lower incidence of CABG in the women. CONCLUSIONS: Pravastatin led to significant early reduction of a wide range of cardiovascular events in post-MI women with average cholesterol levels.

Adult↗