David Radley

Enoxaparin Prevents Death and Cardiac Ischemic Events in Unstable Angina/Non–Q-Wave Myocardial Infarction Results of the Thrombolysis In Myocardial Infarction (TIMI) 11B Trial

BACKGROUND Low-molecular-weight heparins are attractive alternatives to unfractionated heparin (UFH) for management of unstable angina/non-Q-wave myocardial infarction (UA/NQMI). METHODS AND RESULTS Patients (n=3910) with UA/NQMI were randomized to intravenous UFH for >/=3 days followed by subcutaneous placebo injections or uninterrupted antithrombin therapy with enoxaparin during both the acute phase (initial 30 mg intravenous bolus followed by injections of 1.0 mg/kg every 12 hours) and outpatient phase (injections every 12 hours of 40 mg for patients weighing <65 kg and 60 mg for those weighing >/=65 kg). The primary end point (death, myocardial infarction, or urgent revascularization) occurred by 8 days in 14.5% of patients in the UFH group and 12.4% of patients in the enoxaparin group (OR 0.83; 95% CI 0.69 to 1.00; P=0. 048) and by 43 days in 19.7% of the UFH group and 17.3% of the enoxaparin group (OR 0.85; 95% CI 0.72 to 1.00; P=0.048). During the first 72 hours and also throughout the entire initial hospitalization, there was no difference in the rate of major hemorrhage in the treatment groups. During the outpatient phase, major hemorrhage occurred in 1.5% of the group treated with placebo and 2.9% of the group treated with enoxaparin (P=0.021). CONCLUSIONS Enoxaparin is superior to UFH for reducing a composite of death and serious cardiac ischemic events during the acute management of UA/NQMI patients without causing a significant increase in the rate of major hemorrhage. No further relative decrease in events occurred with outpatient enoxaparin treatment, but there was an increase in the rate of major hemorrhage.

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

BACKGROUND Two phase III trials of enoxaparin for unstable angina/non-Q-wave myocardial infarction have shown it to be superior to unfractionated heparin for preventing a composite of death and cardiac ischemic events. A prospectively planned meta-analysis was performed to provide a more precise estimate of the effects of enoxaparin on multiple end points. METHODS AND RESULTS Event rates for death, the composite end points of death/nonfatal myocardial infarction and death/nonfatal myocardial infarction/urgent revascularization, and major hemorrhage were extracted from the TIMI 11B and ESSENCE databases. Treatment effects at days 2, 8, 14, and 43 were expressed as the OR (and 95% CI) for enoxaparin versus unfractionated heparin. All heterogeneity tests for efficacy end points were negative, which suggests comparability of the findings in TIMI 11B and ESSENCE. Enoxaparin was associated with a 20% reduction in death and serious cardiac ischemic events that appeared within the first few days of treatment, and this benefit was sustained through 43 days. Enoxaparins treatment benefit was not associated with an increase in major hemorrhage during the acute phase of therapy, but there was an increase in the rate of minor hemorrhage. CONCLUSIONS The accumulated evidence, coupled with the simplicity of subcutaneous administration and elimination of the need for anticoagulation monitoring, indicates that enoxaparin should be considered as a replacement for unfractionated heparin as the antithrombin for the acute phase of management of patients with high-risk unstable angina/non-Q-wave myocardial infarction.

Randomized trial of low molecular weight heparin (enoxaparin) versus unfractionated heparin for unstable Coronary artery disease : One-year results of the ESSENCE study

OBJECTIVES We sought to determine whether the observed benefits of enoxaparin were maintained beyond the early phase; a one-year follow-up survey was undertaken for patients enrolled in the Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q wave Coronary Events (ESSENCE) study. BACKGROUND We have previously reported a significant benefit of low molecular weight as compared with unfractionated heparin (UFH) in the 14- and 30-day incidence of a composite end point of death, myocardial infarction (MI) or recurrent angina in patients with unstable angina or non-Qwave MI. METHODS The study recruited 3,171 patients with recent-onset rest angina and underlying ischemic heart disease. All patients received oral aspirin daily and were randomized to receive enoxaparin subcutaneously every 12 h or UFH (intravenous bolus followed by continuous infusion) in a double-blind, double-dummy fashion for a median of 2.6 days. RESULTS The incidence of the composite triple end point at one year was lower among patients receiving enoxaparin as compared with those receiving UFH (32.0% vs. 35.7%, p = 0.022), with a trend toward a lower incidence of the secondary composite end point of death or MI (11.5% vs. 13.5%, p = 0.082). At one year, the need for diagnostic catheterization and coronary revascularization was lower in the enoxaparin group (55.8% vs. 59.4%, p = 0.036 and 35.9% vs. 41.2%, p = 0.002, respectively). CONCLUSIONS In patients with unstable angina or non-Qwave MI, enoxaparin therapy significantly reduced the rates of recurrent ischemic events and invasive diagnostic and therapeutic procedures in the short term with sustained benefit at one year.

Enoxaparin in unstable angina/non-ST-segment elévation myocardial infarction: Treatment benefits in prespecified subgroups

AbstractBackground: Two large-scale phase III clinical trials, the Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-wave Coronary Events (ESSENCE) trial and the Thrombolysis in Myocardial Infarction (TIMI) 11B study, have shown the low-molecular-weight heparin, enoxaparin, to be more effective than unfractionated heparin (UFH) in reducing the risk of death and severe cardiac events in patients with rest unstable angina and/or non-ST-segment elevation myocardial infarction (NSTEMI). However, patients with NSTEMI acute coronary syndromes are a heterogeneous group. Methods: A meta-analysis using pooled data from ESSENCE and TIMI 11B was performed to examine the efficacy of enoxaparin in different patient subgroups. In addition, a statistical model was developed to test which factors best predicted an enhanced treatment effect. Results: Enoxaparin was more effective than intravenous dose-adjusted UFH in reducing the incidence of the composite endpoint (including death, myocardial infarction or recurrent angina prompting urgent revascularization) in the majority of subgroups at 43 days after randomization. Univariate analyses revealed that there was a greater benefit with enoxaparin in patients with ST-segment deviation or elevated cardiac enzyme markers on admission, women, nonsmokers and patients with characteristics indicative of higher cardiac risk, including prior percutaneous coronary interventions, being at least 65 years old, prior angina and prior aspirin use. Multivariate statistical modelling of treatment effect revealed that ST-segment depression and electrocardiographic changes were the best predictors of an enhanced treatment effect. Conclusions: These data reinforce previous evidence suggesting that enoxaparin administered subcutaneously twice daily may be considered as an alternative to intravenous UFH in the acute treatment of a broad range of patients with unstable coronary artery disease. Abbreviated Abstract: Two clinical trials have shown the low-molecular-weight heparin, enoxaparin, to be more effective than unfractionated heparin in reducing risk of death and severe cardiac events in patients with rest unstable angina or non-ST-segment elevation myocardial infarction. A meta-analysis using pooled data was performed to examine the efficacy of enoxaparin in different patient subgroups. A statistical model was developed to aid prediction of enhanced treatment effect. The greater efficacy of enoxaparin in comparison with unfractionated heparin was demonstrated in the majority of patient groups. Statistical modeling of treatment effect showed ST-segment depression and electrocardiographic changes to be the best predictors of an enhanced treatment effect.

Impact of enoxaparin low molecular weight heparin in patients with Q-wave myocardial infarction

A subgroup meta-analysis from the Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events (ESSENCE) and the Thrombolysis in Myocardial Infarction (TIMI) 11B studies has shown that enoxaparin is superior to unfractionated heparin in reducing the composite end points of death, myocardial infarction, and emergency revascularization in patients with Q-wave myocardial infarction. The beneficial treatment effect was significant at 43 days.

A simple, readily available method for risk stratification of patients with unstable angina and non-ST elevation myocardial infarction.

The rationale for risk stratification of patients with unstable angina and non-ST elevation myocardial infarction (MI) includes the identification of patients at higher risk of recurrent events after index presentation to enable clinicians to triage patients to the most appropriate level of care in the inpatient or outpatient setting, and optimize the use of medications, revascularization options, and length of stay. Prior studies have shown that a variety of variables predict risk of clinical events, including the following: clinical criteria such as age and history of coronary artery disease1,2 ; ST-segment changes on admission electrocardiogram or Holter monitor3,4 ; detection of serum cardiac markers such as creatine kinase, creatine kinase- MB fraction, myoglobin, or cardiac-specific troponins5‐11 ; detection in the serum of other biochemical markers such as fibrinogen and C-reactive protein,12,13 and nuclear imaging modalities. 14 Detailed statistical models have been created that integrate these variables noted above in a number of trials. 15,16 A more detailed risk score for the Thrombolysis In Myocardial Infarction (TIMI) 11B cohort has been developed.17 This risk score requires 7 predictor variables, several of which may not be known at patient presentation, and is subject to patient recall and may require time to obtain. We tested a simple risk stratification scheme using age, ST deviation on the admission electrocardiogram, and the detection of elevated levels of serum cardiac markers, and evaluated its clinical usefulness in TIMI 11B, a large contemporary trial of patients presenting with unstable angina and non-ST elevation MI. ••• TIMI 11B, a multicenter, international, randomized, double-blind, placebo-controlled phase III trial of enoxaparin versus unfractionated heparin for unstable angina and non-ST elevation MI has been previously reported.18 All patients were required to have ischemic discomfort of at least 5 minutes at rest within 24 hours before randomization. At the start of the trial, patients were eligible if they had either a documented history of coronary artery disease, with a history of an abnormal angiogram, prior MI, coronary artery bypass surgery, or percutaneous transluminal coronary angioplasty, ST deviation, or elevated serum cardiac markers. Elevated cardiac-specific troponins were allowable as inclusion criteria per the study protocol; however, during the period of enrollment of patients, creatine kinase and creatine kinase-MB fraction were the predominant biomarkers used for routine clinical purposes at the participating sites. After about 40% of the target enrollment, the inclusion criteria were modified to focus on higher risk patients by requiring that all patients have either ST deviation or positive cardiac markers.

State Health System Performance: A Scorecard

In the United States, where a person lives determines the kind of health care available and the length and quality of life a person is likely to enjoy.