Efficacy And Safety Of Subcutaneous Enoxaparin In Non-Q-Wave Coronary Events Research Articles

Validation of Bleeding Classifications in Coronary Artery Bypass Grafting

Perioperative bleeding is a determinant of poor outcome in patients undergoing coronary artery bypass grafting (CABG), but there is a lack of adequate stratification of its severity. The ability of the European registry of Coronary Artery Bypass Grafting (E-CABG), Universal Definition of Perioperative Bleeding (UDPB), Study of Platelet Inhibition and Patient Outcomes (PLATO), Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events-Seventh Organization to Assess Strategies in Ischemic Syndromes (CURRENT-OASIS 7), Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q Wave Coronary Events (ESSENCE), and SafeTy and Efficacy of Enoxaparin in Percutaneous coronary intervention patients, an internationaL randomized Evaluation (STEEPLE) bleeding classifications to predict early mortality, stroke, acute kidney injury (AKI) stage 3, and deep sternal wound infection/mediastinitis was investigated in 3,730 patients from the prospective, multicentre E-CABG registry. Increasing grades of the E-CABG, UDPB, PLATO, and CURRENT-OASIS 7 classifications were associated with increasing risks of early mortality, had similar receiver-operating characteristic area under the curves (>0.7), and were predictive also when adjusted for EuroSCORE II. The E-CABG and UDPB classifications had satisfactory area under the curves (>0.6) in predicting stroke, AKI stage 3, and deep sternal wound infection/mediastinitis even when adjusted for EuroSCORE II. The PLATO and CURRENT-OASIS 7 classifications had similar predictive ability for stroke and AKI stage 3 as confirmed by multivariate analysis adjusted for EuroSCORE II but showed inferior ability in predicting severe wound infection compared to the E-CABG and UDPB classifications. The STEEPLE and ESSENCE classifications had a poor ability of predicting all these adverse events. Decision curve analysis showed a benefit of the E-CABG bleeding classification over the other classifications in predicting alladverse events. In conclusion, the E-CABG, UDPB, PLATO, and CURRENT-OASIS 7bleeding classifications have a satisfactory ability in predicting adverse events afterCABG. Decision curve analysis showed that the E-CABG bleeding classification had the best predictive performance.

Standard medical care of patients with systemic lupus erythematosus (SLE) in large specialised centres: data from the Russian Federation, Ukraine and Republic of Kazakhstan (ESSENCE)

ObjectivesTo describe disease characteristics and treatment regimens for adult patients with systemic lupus erythematosus (SLE) with autoantibody positive disease in three countries (the Russian Federation, Ukraine and Republic of Kazakhstan).MethodsThe...

Validation of the Thrombolysis In Myocardial Infarction (TIMI) risk score for unstable angina pectoris and non–ST-elevation myocardial infarction in the TIMI III registry

The 1.4 million patients admitted with unstable angina pectoris and non‐ST-elevation myocardial infarction (UAP/NSTEMI) each year are a heterogenous population with varying risks of death and recurrent cardiac events. The Thrombolysis In Myocardial Infarction (TIMI) risk score for UAP/NSTEMI was created to better stratify patients according to easily obtainable information gathered from the initial history, electrocardiogram, and cardiac markers. 1 The TIMI risk score was derived and validated in the TIMI 11B and Efficacy and Safety of Subcutaneous Enoxaparin in Non‐Q-wave Coronary Events (ESSENCE) trials and accurately predicted adverse outcomes through 14 days. It has also been applied in the Platelet Receptor Inhibition for Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) and Treat Angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy (TACTICS)-TIMI 18 Trials. 2,3 However, because clinical trials of UAP/ NSTEMI usually select higher risk patients (with electrocardiographic changes and/or positive cardiac markers), there has been questions whether the TIMI risk score would be valid in an unselected population of patients representative of general clinical practice. The goal of this study was to validate the TIMI risk score in a large unselected population of patients with UAP/NSTEMI and assess its long-term predictive value. ••• The details of the TIMI III Registry have been previously reported. 4 Briefly, patients admitted be

Enoxaparin: an update of its clinical use in the management of acute coronary syndromes.

Enoxaparin (enoxaparin sodium) is a low molecular weight heparin (LMWH) indicated for use in the treatment of ischaemic complications of unstable angina and non-Q wave myocardial infarction (MI). Unfractionated heparin (UFH) has for many years represented the standard in anticoagulant therapy for patients with acute coronary syndromes; however, recent studies suggest that enoxaparin is also a viable option for anticoagulant therapy in these patients. The ESSENCE (Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q wave Coronary Events) and the TIMI 11B (Thrombolysis in Myocardial Infarction) studies reported that twice daily enoxaparin was significantly more effective than a continuous infusion of UFH in reducing the composite triple endpoint of death, MI, or recurrent angina or urgent revascularisation. Follow-up of both patient populations showed continued benefit associated with enoxaparin. Enoxaparin has been compared with tinzaparin in the treatment of unstable coronary artery disease using a nonblind study design. There was no difference between treatment groups in the therapeutic endpoints. Three nonblind studies have also compared the effects of enoxaparin and UFH in patients receiving thrombolytic therapy following acute MI. The HART II (Heparin and Aspirin Reperfusion Therapy), the ASSENT 3 (Assessment of the Safety and Efficacy of a New Thrombolytic Regimen) and the ENTIRE-TIMI 23 (Enoxaparin and Tenecteplase with or without glycoprotein IIb/IIIa Inhibitor as Reperfusion strategy in ST Elevation MI - Thrombolysis in Myocardial Infarction) studies have revealed that enoxaparin in combination with alteplase or tenecteplase is at least equivalent (HART II and ENTIRE-TIMI 23), and possibly superior (ASSENT 3) to UFH. Enoxaparin is administered as a twice-daily subcutaneous injection. In contrast, UFH is administered as an intravenous infusion which requires routine monitoring of the activated partial thromboplastin time to ensure adequate levels of anticoagulation are maintained. During the acute phase of the the ESSENCE and TIMI 11B studies, the incidence of major bleeding was similar in patients receiving enoxaparin to that in patients receiving UFH. In contrast, the rates of minor bleeding were higher in patients receiving enoxaparin than in those receiving UFH throughout these studies. Data from the ESSENCE, TIMI 11B and ASSENT 3 studies have prompted calls for those LMWHs which have been shown to be superior to UFH, to be considered as first choice treatment for anticoagulation in unstable coronary syndromes. To date, these suggestions are not reflected in current guidelines which consider UFH and LMWHs equally. Irrespective, the clinical data reported in this review support the use of enoxaparin in the treatment of acute coronary syndromes. These data suggest that enoxaparin shows certain clinical and practical advantages over standard treatment with UFH and represents an important development in the treatment of acute coronary syndromes.

Enoxaparin: a pharmacoeconomic review of its use in the prevention and treatment of venous thromboembolism and in acute coronary syndromes.

The pharmacoeconomics of the low molecular weight heparin (LMWH) enoxaparin in the prophylaxis and treatment of venous thromboembolism have mostly been investigated in cost-effectiveness studies that estimated direct costs associated with treatment, using decision analyses and clinical outcome data from randomised controlled trials. These studies have shown enoxaparin to be cost effective compared with unfractionated heparin (UFH) and warfarin in short-term thromboprophylaxis for hospital inpatients undergoing orthopaedic surgery and in thromboprophylaxis following trauma. Outpatient treatment of acute proximal deep vein thrombosis with enoxaparin has also been shown to be cost effective compared with inpatient treatment using UFH. In general surgery, however, it remains to be determined whether enoxaparin is a cost-effective alternative to UFH. The cost effectiveness of enoxaparin compared with UFH in the treatment of unstable angina and non-Q-wave myocardial infarction has also been investigated in several countries using clinical outcomes data from the Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-wave Coronary Events (ESSENCE) randomised trial. ESSENCE demonstrated that enoxaparin was superior to UFH in terms of tolerability and efficacy, and cost saving at both 30-day and 1-year follow-ups. An increasing number of studies indicate enoxaparin to be of economic benefit when used for prevention and treatment of venous thromboembolism and treatment of acute coronary symdromes.

Prior aspirin use in unstable angina predisposes to higher risk: the aspirin paradox

Background: Aspirin is the most widely prescribed agent used in prevention of coronary thrombosis. Thus, many patients presenting with acute coronary syndromes have a history of aspirin usage. Methods: To assess response to medical therapy in patients taking aspirin prior to admission with an acute coronary syndrome, we reviewed outcomes data from the Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-wave Coronary Events (ESSENCE) and Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) studies. Results: Patients with acute coronary syndromes who had taken aspirin prior to enrolment were less likely to have non-Q-wave myocardial infarction on admission (ESSENCE: 16.0% vs. 29.2%, p<0.001; PRISM-PLUS: 34.2% vs. 57.7%, p<0.001). However, prior aspirin users were more likely to be failed by standard medical therapy with unfractionated heparin than non-prior aspirin users (ESSENCE: 21.5% vs. 16.5%, p=0.017; PRISM-PLUS: 23.5% vs. 12.1%, p<0.001). Prior aspirin users received greater benefit from both enoxaparin (21.5% vs. 16.8%, p=0.009) and tirofiban with unfractionated heparin (23.5% vs. 16.0%, p=0.007) than from unfractionated heparin alone. Non-prior aspirin users presented with higher rates of non-Q-wave myocardial infarction. Conclusions: Prior aspirin users admitted with acute coronary syndromes may have a more benign presentation, but are more likely to be failed by medical therapy with unfractionated heparin and should be considered as a high-risk group. Enoxaparin or the combination of tirofiban and unfractionated heparin are both more effective than unfractionated heparin in this group.

Antithrombotic therapy in acute coronary syndromes: Key notes from ESSENCE and TIMI 11B

Platelet activation and thrombus formation are key events in the pathogenesis of acute coronary syndromes (unstable angina and non-Q-wave myocardial infarction). Therefore, current management of these conditions consists of antithrombotic and antiplatelet therapy, principally heparin and oral aspirin. However, such treatment is unsuccessful in a significant proportion of patients. Two recent large studies with the low-molecular-weight heparin (LMWH) enoxaparin have shown that this agent significantly reduces the risk of major ischemic events compared with unfractionated heparin. In the Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events (ESSENCE) study, treatment with enoxaparin for 2 to 8 days reduced the risk of death, myocardial infarction, or recurrent angina by 20% at 14 days compared with treatment with unfractionated heparin. In the Thrombolysis in Myocardial Infarction (TIMI) 11B study, enoxaparin was associated with a significant reduction in the risk of death, myocardial infarction, or urgent revascularization compared with unfractionated heparin, which became apparent within 48 hours; this benefit was maintained during outpatient treatment for 5 weeks. A meta-analysis of these two studies showed that the risk of death or myocardial infarction was consistently approximately 20% lower in enoxaparin-treated patients than in heparin-treated patients. In contrast, studies with other LMWHs have not shown consistent superiority over unfractionated heparin. This may reflect the pharmacologic heterogeneity of LMWH and/or differences in trial design.

Inter-regional differences and outcome in unstable angina; analysis of the international ESSENCE trial. Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-wave Coronary Events.

Worldwide there is a large variation in outcome (death, myocardial infarction and recurrent myocardial infarction) in patients with unstable angina or non-Q wave myocardial infarction. These variations may be explained by differences in characteristics of the presenting patients. Here we describe differences in patient presentation, treatment protocols and outcome and we investigate their relationship using data from the ESSENCE (Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-wave Coronary Events) trial. A total of 2981 patients from six countries which enrolled more than 100 patients were included in the present analysis: United States, Canada, Argentina, France, the Netherlands and United Kingdom. Logistic regression analysis was performed to determine the effect of baseline characteristics on regional outcome. At day 30, the lowest triple end-point rate, irrespective of study drug treatment, was noted in the Netherlands (18.9%) and the highest in Argentina (30.5%). A model including the variables age > or = 65 years, prior angina, diabetes, prior aspirin use, ECG changes at baseline and diagnosis of non-Q wave myocardial infarction and dummy variables for Argentina and France resulted in concordance of about 60%. Inter-regional differences in outcome in unstable angina and non-Q wave myocardial infarction patients can reasonably well be explained by differences in patient characteristics. However, other so far unidentified variables present in Argentina and France also contributed to differences in outcome and their effect warrants further investigation.

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.

Will the use of low-molecular-weight heparin (enoxaparin) in patients with acute coronary syndrome save costs in Canada?

Background One-year follow-up data from the Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events (ESSENCE) trial show that use of low-molecular-weight heparin (enoxaparin) compared with unfractionated heparin in patients hospitalized with unstable angina or non-Q-wave myocardial infarction is associated with a 10% reduction in the cumulative 1-year risk of death, myocardial infarction, or recurrent angina. Given the higher acquisition cost of enoxaparin relative to unfractionated heparin, we assessed whether the reduced use of revascularization procedures and related care makes enoxaparin a cost-saving therapy in Canada. Methods and Results We analyzed cumulative 1-year resource use data on the 1259 ESSENCE patients enrolled in Canadian centers (40% of the total ESSENCE sample). Patient-specific data on use of drugs, diagnostic cardiac catheterization, percutaneous transluminal coronary angioplasty, coronary artery bypass grafting, and hospital days were available from the initial hospital stay and cumulative to 1 year. Hospital resources were costed with the use of data from a teaching hospital in southern Ontario that is a participant in the Ontario Case Costing Project. During the initial hospital stay, use of enoxaparin was associated with reduced use of diagnostic catheterization and revascularization procedures, with the largest effect being reduced use of percutaneous transluminal coronary angioplasty (15.0% vs 10.6%; P = .03). At 1 year, the reduced risk and costs of revascularization more than offset increased drug costs for enoxaparin, producing a cost-saving per patient of $1485 (95% confidence interval $-93 to $3167; P = .06). Sensitivity analysis with lower hospital per diem costs from a community hospital in Ontario still predicts cost savings of $1075 per patient over a period of 1 year. Conclusions The acquisition and administration cost of enoxaparin is higher than for unfractionated heparin ($101 vs $39), but in patients with acute coronary syndrome, the reduced need for hospitalization and revascularization over a period of 1 year more than offsets this initial difference in cost. Evidence from this Canadian substudy of ESSENCE supports the view that enoxaparin is less costly and more effective than unfractionated heparin in this indication.

Antithrombotics and Anticoagulants in Coronary Syndromes and Stroke

The low-molecular-weight heparins (LMWHs) have been proven superior to placebo in reducing the incidence of acute coronary ischemic syndromes. Comparative studies vs. unfractionated heparin have not demonstrated superiority in favor of the LMWH dalteparin. In the Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-wave Coronary Events (ESSENCE) trial, enoxaparin was demonstrated to have a benefit over heparin. The results have contributed to a better understanding of the relative efficacy of LMWHs in acute coronary syndromes. A second trial with enoxaparin supported the conclusions of the ESSENCE trial. The antithrombotic effects of LMWHs have also been evaluated for the management of ischemic stroke with varied results. A trial assessing tinzaparin in acute ischemic stroke has completed enrollment, and its results may shed new light on the use of an LMWH for the management of stroke.

Can we differentiate the low-molecular-weight heparins?

The low-molecular-weight heparins (LMWHs) have a number of therapeutic advantages, relative to standard unfractionated heparin (UFH). They are readily bioavailable when injected subcutaneously and can be given in fixed doses, allowing for far simpler administration. Several LMWHs are now commercially available, each demonstrating different physical and chemical properties and different activities in animal models of anticoagulation or hemorrhage. In clinical comparisons with placebo in the treatment of unstable coronary artery disease (UCAD), the LMWHs dalteparin sodium and nadroparin calcium have demonstrated good anticoagulant efficacy. In comparisons with UFH, on the other hand, only enoxaparin has shown superior anticoagulant activity, as reported in the results of the Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-wave Coronary Events (ESSENCE) and Thrombolysis In Myocardial Infarction (TIMI) 11B trials. However, close scrutiny of the methodology of the clinical trials in UCAD reveals considerable differences in study designs, dosage regimens, duration of administration of active treatments, and the timing and definition of endpoints. Therefore, it would not be scientifically sound to compare results with the different LMWHs based on the current available studies. It is also not possible to draw any conclusions with regard to the relative efficacy of the different LMWHs, since there are no properly-sized comparative data between dalteparin sodium, enoxaparin sodium, and nadroparin calcium.

Enoxaparin. A review of its clinical potential in the management of coronary artery disease.

Enoxaparin (enoxaparin sodium) is a low molecular weight heparin (LMWH) that is widely used in the prevention of deep venous thrombosis and pulmonary embolism in patients undergoing orthopaedic or general surgery. Its efficacy in these indications has led to study of its use in patients with coronary artery disease, particularly those with unstable angina, who have a high risk of myocardial infarction and death. A double-blind multicentre study [ESSENCE (Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q Wave Coronary Events)] showed that subcutaneous enoxaparin was more effective than intravenous unfractionated heparin (UFH) in reducing the incidence of the composite end-point of death, myocardial infarction or recurrent angina after 14 days in 3171 patients with recent-onset resting angina (i.e. unstable angina). There were no statistically significant between-group differences for the secondary end-point of death or myocardial infarction. Preliminary reports of long term follow-up data indicate that the clinical benefit of enoxaparin over UFH is maintained after 1 year. The only significant difference in tolerability between enoxaparin and UFH in ESSENCE was for minor haemorrhage (mostly injection-site ecchymosis), which was more common with the LMWH. Prospective pharmacoeconomic substudies of the ESSENCE trial suggest that total medical costs (including those for subsequent revascularisation procedures) for enoxaparin treatment are lower than those for UFH. The ESSENCE study is the first double-blind trial to show that a LMWH is more effective than UFH in patients with unstable angina. The superiority of enoxaparin was attributable mainly to its effects on recurrent angina. The level of anticoagulation achieved in the UFH group raises a number of issues which might have affected the apparent relative efficacy of enoxaparin and UFH. Preliminary data suggest that enoxaparin is at least as effective as UFH in reducing the incidence of subsequent cardiac events in patients receiving thrombolysis for acute myocardial infarction, and a randomised comparison with no additional treatment (other than aspirin) has demonstrated its efficacy in this indication. Enoxaparin has been ineffective in preventing restenosis after angioplasty The ESSENCE study has shown that enoxaparin is more effective than UFH in patients with unstable angina. Although clarification of some methodological issues would be beneficial, the available efficacy data, together with the practical advantages of LMWHs in general, suggest that enoxaparin is an effective and convenient means of treating unstable angina and should provide cost savings compared with UFH.

Low-molecular-weight heparins and unstable angina--current perspectives.

Thrombosis is responsible for most acute manifestations of coronary artery disease, including unstable angina and non-Q-wave myocardial infarction (MI). Antiplatelet therapy plays a major role in reducing the risk of ischaemic events in such patients. Since thrombin generation is key in the pathogenesis of thrombosis, recent studies have focussed on thrombin inhibition in the management of acute ischaemia. Heparin is the most widely used anticoagulant for acute management of thrombosis and is the treatment of choice in the prevention and treatment of venous thromboembolism. Heparin given in therapeutic doses intravenously has been shown to be more effective than aspirin at reducing the risk of death or MI in patients with unstable angina. Low-molecular-weight heparins (LMWHs) have improved pharmacologic and pharmacokinetic properties over standard heparin that may result in greater efficiency and safety. LMWH may be given in fixed doses subcutaneously without monitoring, resulting in greater clinical utility and cost-effectiveness compared with standard heparin. A number of LMWHs-dalteparin, enoxaparin and nadroparin-have been evaluated in unstable angina. In a small open trial, nadroparin reduced the risk of ischaemic outcomes compared with aspirin alone or a combination of aspirin and standard heparin. Dalteparin has been evaluated in two large clinical trials in the management of unstable angina. The low-Molecular-Weight Heparin (Fragmin) During Instability in Coronary Artery Disease (FRISC) trial showed that dalteparin resulted in a 63% reduction in risk of death or acute MI compared with aspirin alone. The Fragmin in Unstable Coronary Artery Disease (FRIC) trial showed that dalteparin was as effective as intravenous heparin. Enoxaparin resulted in a statistically significant 16% reduction in the combined outcome of death, MI and recurrence of angina in comparison with standard heparin in the Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events (ESSENCE) trial. There is accumulating evidence that LMWHs are safe and effective alternatives to standard heparin in unstable coronary artery disease and that they offer practical and therapeutic advantages.