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.

Low molecular weight heparin versus regular heparin or aspirin in the treatment of unstable angina and silent ischemia.

OBJECTIVES: This study was designed to test the hypothesis that low molecular weight heparin may lessen the severity of ischemic events in patients with unstable angina. BACKGROUND: Unstable angina is a thrombotic process that requires intensive medical treatment. Although current treatments can reduce the number of complications, serious bleeding continues to occur. Nadroparin calcium, a low molecular weight heparin, seems to be a safe therapeutic agent that does not require laboratory monitoring. METHODS: A total of 219 patients with unstable angina entered the study at a mean time of 6.17 h after the last episode of rest pain. Patients were randomized to receive aspirin (200 mg/day [group A]), aspirin plus regular heparin (400 IU/kg body weight per day intravenously and titered by activated partial thromboplastin time [group B]) and aspirin plus low molecular weight heparin (214 UIC/kg anti-Xa twice daily subcutaneously [group C]). The major end points determined for the in-hospital period were 1) recurrent angina, 2) myocardial infarction, 3) urgent revascularization, 4) major bleeding, and 5) death. Minor end points were 1) silent myocardial ischemia, and 2) minor bleeding. Event rates were tested by chi-square analysis. RESULTS: Recurrent angina occurred in 37%, 44% and 21% of patients in groups A, B and C, respectively, and was significantly less frequent in group C than in either group A (odds ratio 2.26, 95% confidence interval [CI] 1 to 5.18, p = 0.03) or group B (odds ratio, 3.07, 95% CI 1.36 to 7.00, p = 0.002). Nonfatal myocardial infarction was present in seven patients in group A, four in group B and none in group C (group B vs. A, p = 0.5; group C vs. A, p = 0.01). Urgent revascularization was performed in nine patients in group A, seven in group B and one in group C (C vs. A, p = 0.01). Two episodes of major bleeding occurred in group B. Silent myocardial ischemia was present in 38%, 41% and 25% of patients in groups A, B and C, respectively, and was significantly less frequent in group C than group B (odds ratio 2.12, 95% CI 0.97 to 4.69, p = 0.04). Minor bleeding was detected in 10 patients in group B, 1 patient in group C (B vs. C, p = 0.01) and no patient in group A (A vs. B, p = 0.003). CONCLUSIONS: In this study, treatment with aspirin plus a high dose of low molecular weight heparin during the acute phase of unstable angina was significantly better than treatment with aspirin alone or aspirin plus regular heparin.

Randomized trial of low molecular weight heparin (enoxaparin) versus unfractionated heparin for unstable coronary artery disease: one-year results of the ESSENCE Study. Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q Wave Coronary Events.

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.

Superiority of enoxaparin versus unfractionated heparin for unstable angina/non-Q-wave myocardial infarction regardless of activated partial thromboplastin time.

BACKGROUND: Whether the clinical superiority of enoxaparin versus unfractionated heparin (UFH) depends on a more stable antithrombotic effect or the proportion of patients not reaching the therapeutic level with UFH has not been addressed. METHODS: All patients participating in the Thrombolysis In Myocardial Infarction 11B trial who received UFH and had sufficient activated partial thromboplastin time (aPTT) data (n = 1893) were compared with patients who received enoxaparin (n = 1938). Patients receiving UFH were divided into 3 categories depending on mean aPTT values throughout 48 hours: subtherapeutic, for those in whom the average aPTT fell below 55 seconds; therapeutic, between 55 and 85 seconds; and supratherapeutic, longer than 85 seconds. Events and bleeding rates were determined at 48 hours. RESULTS: A small portion of patients (6. 7%) had a subtherapeutic average aPTT value (n = 127). Forty-seven percent of patients (n = 891) fell within the therapeutic range, and 46% were in the supratherapeutic level (n = 875). Event rates were 7. 0% in the UFH group versus 5.4% with enoxaparin (P =.039). Events rates were higher in every aPTT strata compared with enoxaparin and statistically significant in the supratherapeutic group (odds ratio 0.65; 95% confidence interval, 0.47-0.89). Major bleeding rates were 0%, 0.6%, and 0.9% for the subtherapeutic, target, and supratherapeutic strata, respectively, and 0.8% with enoxaparin. Minor hemorrhages occurred in 5.1% of patients receiving enoxaparin versus 3.9%, 2%, and 2.3%, respectively, for the UFH subgroups (P <. 001 for all UFH groups vs enoxaparin). CONCLUSIONS: Enoxaparin showed a better clinical profile compared with every level of anticoagulation with UFH. Potential mechanisms for enoxaparin superiority are stable antithrombotic activity, lack of rebound thrombosis, and intrinsic superiority.

Serum neopterin levels and the angiographic extent of coronary arterial narrowing in unstable angina pectoris and in non-Q-wave acute myocardial infarction.

Systemic serum markers of inflammation are elevated in diseases due to atherosclerosis, but have not been associated with the extent of atherosclerotic disease. We examined the role of neopterin, a byproduct of activated macrophage metabolism, in patients with unstable angina. Baseline neopterin samples and clinical histories were obtained in 52 patients admitted with unstable angina pectoris. Coronary angiograms of 27 patients were reviewed using Sullivan's method to assess the total atherosclerotic burden in the coronary arteries. Twenty-six of the 52 patients were eventually diagnosed with a non-Q-wave acute myocardial infarction (AMI) and had higher neopterin levels (10.1 +/- 6.7 vs 7.2 +/- 4.0 nmol/L, p = 0.06) than patients with a final diagnosis of unstable angina. Patients with neopterin >8.7 were more likely to be diagnosed with a non-Q-wave AMI (75% vs 39%, p = 0.035) and were more likely to have significantly more severe and extensive angiographically determined atherosclerosis than patients with low neopterin levels. Neopterin levels correlated with the score of atherosclerotic extension (Spearman's rank correlation coefficient 0.4807, p = 0.034). This study demonstrates a correlation between immune cell activation and the extent of angiographically determined atherosclerosis and the degree of myocardial ischemia.

Low-molecular-weight heparins in non-ST-segment elevation ischemia: the ESSENCE trial. Efficacy and Safety of Subcutaneous Enoxaparin versus intravenous unfractionated heparin, in non-Q-wave Coronary Events.

Combination antithrombotic therapy with heparin plus aspirin decreases the risk of recurrent ischemic events in patients with acute coronary syndromes without persistent ST-segment elevation. Compared with standard unfractionated heparin, low-molecular-weight heparin (LMWH) has a more predictable antithrombotic effect, is easier to administer, and does not require coagulation monitoring. At 176 hospitals in 3 continents, 3,171 patients with rest unstable angina or non-wave myocardial infarction were randomly assigned to either enoxaparin (a LMWH), 1 mg/kg twice daily subcutaneously, or to continuous intravenous unfractionated heparin, for a minimum of 48 hours to a maximum of 8 days. Trial medication was administered in a double-blind, placebo-controlled fashion. At 14 days, the primary endpoint, the composite risk of death, myocardial infarction, or recurrent angina with electrocardiographic changes or prompting intervention, was significantly lower in patients assigned to enoxaparin compared with heparin (16.6% vs 19.8%; odds ratio [OR] 1.24; 95% confidence interval [CI] 1.04-1.49; p = 0.019). At 30 days, the composite risk of death, myocardial infarction, or recurrent angina remained significantly lower in the enoxaparin group compared with the unfractionated heparin group (19.8% vs 23.3%, OR 1.23; 95% CI 1.0-1.46, p = 0.016). The rate of revascularization procedures at 30 days was also significantly lower in patients assigned to enoxaparin (27.1% vs 32.2%, p = 0.001). The 30-day incidence of major bleeding complication was 6.5% versus 7.0% (p = not significant), but the incidence of minor bleeding was significantly higher in the enoxaparin group (13.8% vs 8.8%, p <0.001) due primarily to injection-site ecchymosis. Thus, combination antithrombotic therapy with enoxaparin plus aspirin is more effective than unfractionated heparin plus aspirin in decreasing ischemic outcomes in patients with unstable angina or non-Q-wave myocardial infarction in the early (30 days) phase. The lower recurrent ischemic event rate seen with the LMWH, enoxaparin, is achieved without an increase in major bleeding, but with an increase in minor bleeding complications due mainly to injection-site ecchymosis.

Fast platelet suppression by lysine acetylsalicylate in chronic stable coronary patients. Potential clinical impact over regular aspirin for coronary syndromes.

BACKGROUND: The rapid utilization of fibrinolytics following Q-wave myocardial infarction has clearly modified the evolution of this disease. However, it is still not known whether the immediate inhibition of platelet aggregation (PA) during the coronary event improves outcomes. HYPOTHESIS: The present study was designed to test, in patients with known coronary artery disease (chronic stable angina), whether the particular kinetic pattern of lysine acetylsalicylate (LA) compared with aspirin may affect the time to onset of inhibition of platelet aggregation. METHODS: Ten patients suffering from chronic stable angina participated in this study to compare the efficacy and speed of the inhibition of PA with 320 mg of LA versus 320 mg of aspirin. All patients discontinued the use of aspirin and any other anti-inflammatory agents for 15 days prior to the beginning of the study. They were randomly assigned to LA or aspirin. Blood specimens were obtained to measure the PA at admission, and 5, 10, 20, 30, and 60 min after ingestion. Patients continued to take the assigned drug once a day for the following 4 days. On Day 5, a new blood sample was taken. After this, patients underwent a 15-day wash-out period, and then crossed over to the opposite drug. The samples were analyzed immediately using platelet-rich plasma stimulated with adenosine diphosphate (ADP) 2 mumol/l, collagen 1 microgram/ml, epinephrine 20 mumol/l, and sodium arachidonate acid 0.75 mm/l. RESULTS: The same level of PA inhibition after 30 and 60 min of aspirin administration can be obtained with LA 5 min following ingestion (sodium arachidonate acid: LA: 16.3 +/- 25.9 vs. aspirin 57.6 +/- 8.2; p = 0.00014; collagen: LA 18.9 +/- 20.1 vs. aspirin 47.2 +/- 10.5; p = 0.00092; ADP: LA 27.3 +/- 18.4 vs. aspirin 39.7 +/- 21.8, p = 0.18; epinephrine: LA 22.0 +/- 9.9 vs. aspirin 55.4 +/- 10.9, p = 0.00002. CONCLUSIONS: Platelet aggregation inhibition immediately following LA may have significant clinical implications for the treatment of coronary syndromes.

Sex-related differences in the presentation, treatment and outcomes among patients with acute coronary syndromes: the Global Registry of Acute Coronary Events.

OBJECTIVE: To assess whether sex differences exist in the angiographic severity, management and outcomes of acute coronary syndromes (ACS). METHODS: The study comprised 7638 women and 19 117 men with ACS who underwent coronary angiography and were included in GRACE (Global Registry of Acute Coronary Events) from 1999-2006. Normal vessels/mild disease was defined as <50% stenosis in all epicardial vessels; advanced disease was defined as >or=one vessel with >or=50% stenosis. RESULTS: Women were older than men and had higher rates of cardiovascular risk factors. Men and women presented equally with chest pain; however, jaw pain and nausea were more frequent among women. Women were more likely to have normal/mild disease (12% vs 6%, p<0.001) and less likely to have left-main and three-vessel disease (27% vs 32%, p<0.001) or undergo percutaneous coronary intervention (65% vs 68%, p<0.001). Women and men with normal and mild disease were treated less aggressively than those with advanced disease. Women with advanced disease had a higher risk of death (4% vs 3%, p<0.01). After adjustment for age and extent of disease, women were more likely to have adverse outcomes (death, myocardial infarction, stroke and rehospitalisation) at six months compared to men (odds ratio 1.24, 95% confidence interval 1.14 to 1.34); however, sex differences in mortality were no longer statistically significant. CONCLUSIONS: Women with ACS were more likely to have cardiovascular disease risk factors and atypical symptoms such as nausea compared with men, but were more likely to have normal/mild angiographic coronary artery disease. Further study regarding sex differences related to disease severity is warranted.

Intervention in acute coronary syndromes: do patients undergo intervention on the basis of their risk characteristics? The Global Registry of Acute Coronary Events (GRACE).

OBJECTIVE: To determine whether revascularisation is more likely to be performed in higher-risk patients and whether the findings are influenced by hospitals adopting more or less aggressive revascularisation strategies. METHODS: GRACE (Global Registry of Acute Coronary Events) is a multinational, observational cohort study. This study involved 24,189 patients enrolled at 73 hospitals with on-site angiographic facilities. RESULTS: Overall, 32.5% of patients with a non-ST elevation acute coronary syndrome (ACS) underwent percutaneous coronary intervention (PCI; 53.7% in ST segment elevation myocardial infarction (STEMI)) and 7.2% underwent coronary artery bypass grafting (CABG; 4.0% in STEMI). The cumulative rate of in-hospital death rose correspondingly with the GRACE risk score (variables: age, Killip class, systolic blood pressure, ST segment deviation, cardiac arrest at admission, serum creatinine, raised cardiac markers, heart rate), from 1.2% in low-risk to 3.3% in medium-risk and 13.0% in high-risk patients (c statistic = 0.83). PCI procedures were more likely to be performed in low- (40% non-STEMI, 60% STEMI) than medium- (35%, 54%) or high-risk patients (25%, 41%). No such gradient was apparent for patients undergoing CABG. These findings were seen in STEMI and non-ST elevation ACS, in all geographical regions and irrespective of whether hospitals adopted low (4.2-33.7%, n = 7210 observations), medium (35.7-51.4%, n = 7913 observations) or high rates (52.6-77.0%, n = 8942 observations) of intervention. CONCLUSIONS: A risk-averse strategy to angiography appears to be widely adopted. Proceeding to PCI relates to referral practice and angiographic findings rather than the patient's risk status. Systematic and accurate risk stratification may allow higher-risk patients to be selected for revascularisation procedures, in contrast to current international practice.

[Guidelines for the diagnosis and treatment of unstable angina and non-Q myocardial infarction: proposed changes]. / Directrices para el diagnóstico y tratamiento de la angina inestable y el IM no-Q: modificaciones propuestas.

In 1994, the United States Agency for Health Care Policy and Research issued clinical practice guidelines for the diagnosis and management of unstable angina and non-Q-wave myocardial infarction. In the past 5 years, rapid progress has been made in the management of patients with unstable coronary syndromes, and treatment guidelines should be revised to reflect these advances. An international forum of cardiology investigators convened to discuss areas in which the diagnosis and treatment of unstable angina/non-Q-wave myocardial infarction should be modified. Although there were areas of controversy, it was agreed that there is sufficient evidence to recommend the following changes: 1) the use of serum cardiac markers should be expanded to include troponin I and T levels as diagnostic and prognostic tools, 2) low-molecular-weight heparins should replace UH as antithrombin agents, 3) new classes of antiplatelet agents are recommended in addition to aspirin, 4) the use of cholesterol-lowering drugs is appropriate in the long-term management of these patients. The rationale for these suggested revisions, including evidence from pertinent clinical trials, is discussed in detail in the accompanying document.

Emerging role of antibiotics in atherosclerosis.

It has been shown that plaque composition changes significantly in the setting of acute events, macrophages and T cells being the predominant pattern at the immediate site of fissure or erosion. There appears to be a relation between physical blood stream factors, plaque morphology, and the distribution of inflammatory cells. Furthermore, there is cumulative evidence for the presence of intracellular pathogens in the arterial wall, namely Chlamydia pneumoniae and cytomegalovirus, which affect endothelial cells, monocytes, and macrophages. The ROXIS trial has shown some encouraging evidences for the potential role of intracellular pathogens in acute coronary syndromes. The ongoing WIZARD trial evaluates in a large population whether the addition of an antibiotic provides better outcome for coronary patients.

Enoxaparin in unstable angina/non-ST-segment elevation myocardial infarction: treatment benefits in prespecified subgroups.

BACKGROUND: 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.

Low-molecular-weight heparin alone versus a combination of unfractionated heparin and low-molecular-weight heparin.

OBJECTIVES: We analyzed the effect of the pharmacologic combination of 2 indirect antithrombin drugs--enoxaparin (low-molecular-weight heparin) and unfractionated heparin--versus enoxaparin alone on the recurrence of ischemia. BACKGROUND: Blocking some key factors of the coagulation cascade supports the concept that an antithrombin effect is needed during the acute phase of ischemia. METHODS: This was a prospective, randomized, pilot trial in patients with an acute coronary ischemic event occurring within the previous 24 hours. A total of 126 patients were allocated to receive aspirin (200 mg/day orally) plus 1 mg/kg subcutaneous enoxaparin at 8 AM and 12.500 IU of subcutaneous unfractionated heparin at 8 PM (group A) or subcutaneous enoxaparin 1 mg/kg (group B). RESULTS: Severe recurrent ischemia provoking urgent coronary revascularization occurred in 12 patients (9.5%), 3 (5%) in group A and 9 (13%) in group B (P = .1). Refractory angina was present in 27 patients (21%), 10 (17%) in group A and 17 (25%) in group B (P = .45). The combination of severe recurrent ischemia and refractory angina occurred in 23% of group A, and 37% of group B (odds ratio 0.49; 95% confidence intervals, 0.21-1.15; P = .07). A total of 7 patients (5%) had acute nonfatal myocardial infarction develop, 3 (5%) in group A and 4 (6%) in group B. Two (1.6%) deaths were observed in the study, both in group B. The incidence of the double end point (death plus nonfatal myocardial infarction) was 5% in group A versus 9% in group B (P = .5) and the triple end point (death, nonfatal myocardial infarction, and severe recurrent ischemia) was 10.5% in group A vs 22% in group B (odds ratio 0.42, 95% confidence intervals, 0.13-1.29; P = .09). CONCLUSIONS: The combination of 2 indirect antithrombin drugs capable of intermittently blocking the coagulation system is not associated with a significant loss of safety.

IgG antibodies to chlamydial and mycoplasma infection plus C-reactive protein related to poor outcome in unstable angina.

OBJECTIVES: Evidence exists showing an association between Chlamydial infection and infarction. Our purpose was to identify an interactive relationship between Chlamydia pneumoniae and unstable angina. METHODS: We analyzed IgG antibodies for Chlamydia pneumoniae, Mycoplasma pneumoniae, and C reactive protein in patients during the acute phase of unstable angina. RESULTS: Chlamydia antibodies were present in 16.92% (11 cases) of the unstable angina patients. They were also present in 34.61% of those patients who experienced ischemic events vs 5.1% who did not (odds ratio 9.79, 95% CL 1.65 to 75.26, p = 0.002). Mycoplasma pneumoniae antibodies were present in 12.30% of patients but did not emerge as a predictive variable. C-reactive protein was present in 22 cases (33.84%), 9 of which were associated with recurrent events (34.61%) vs 13 which were free of them (odds ratio, p = 0.5). The interactive relationship between infection plus C-reactive protein achieved a statistical significant association with ischemic events (odds ratio 14, 95% CI 1.49-331.1; p = 0.003). CONCLUSIONS: These findings suggest a pathophysiologically based relationship between infective and inflammatory processes related to poor clinical outcome during the in-hospital stay in the setting of unstable angina patients.

Anti-human skeletal muscle glycolipid antibodies in unstable angina.

BACKGROUND: We studied whether the level of anti-skeletal muscle glycolipid antibodies (AGA), a marker of acute rejection in heart transplantation, may be associated with an adverse prognosis in unstable angina. METHODS AND RESULTS: The in-hospital evolution of 50 patients with unstable angina (Braunwald class III B) was assessed. We determined the incidence of death, myocardial infarction, and refractory angina. Blood was collected at admission and 24 hours later for determination of AGA levels by enzyme-linked immunosorbent assay. Twenty-three patients showed a decrease in the AGA level at 24 hours after admission. Ten in-hospital cardiac events occurred in these patients (43.4%) as compared with 4 (14.8%) in the 27 patients who did not show a decrease (P =.025). In patients with previous myocardial infarction (n = 26), the AGA assay was a powerful predictor of outcome. In this subgroup, 66.6% of patients who had decreased AGA levels (8 of 12) had cardiac events as compared with 14.2% (2 of 14) of those who did not have that decrease (P =.001). CONCLUSIONS: We conclude that a decrease of AGA levels 24 hours after admission is associated with a complicated in-hospital course. This finding may provide new insights in the phenomenon of plaque instability involved in the development of acute coronary syndromes.

Geographic variation in patient and hospital characteristics, management, and clinical outcomes in ST-elevation myocardial infarction treated with fibrinolysis. Results from InTIME-II.

AIMS: We examined the geographic variations in InTIME-II, a randomized double-blind trial comparing alteplase with lanoteplase for myocardial infarction. METHODS AND RESULTS: We compared baseline characteristics, management, and outcomes in four regions (Western Europe, Eastern Europe, North America, and Latin America) and in countries with historically different management approaches (Germany vs the U.K., the U.S. vs Canada). Thirty-day mortality in Western Europe, Eastern Europe, North America and Latin America was 6.7%, 7.3%, 5.7%, 10.1%, P<0.0001. Adjusted mortality for Europe was intermediate between North America and Latin America (odds ratios (OR) [95% confidence intervals (CI)] compared to Western Europe: North America 0.84 [0.67-1.0], Eastern Europe 1.2 [1.0-1.4], and Latin America 1.8 [1.3-2.7]). Revascularization rates varied 10-fold but did not explain regional mortality differences. Germany and the U.K. had similar adjusted 1-year mortality (OR for the U.K. 1.16 [0.92-1.5]), although invasive procedures were four- to 10-fold more common in Germany. Similarly the U.S. and Canada had equal adjusted 1-year mortality (OR for Canada 0.85 [0.61-1.17]) despite three-fold higher use of invasive procedures in the U.S. CONCLUSIONS: Significant geographic variations in practice and adjusted mortality following fibrinolysis persist despite recent guidelines. These findings have important implications in the design and interpretation of international studies, identify under- and over-utilized therapies, and support further study of treatments with marked worldwide variations.

Predictors of recurrent ischemic events and death in unstable coronary artery disease after treatment with combination antithrombotic therapy.

BACKGROUND: Patients with non-Q-wave acute coronary syndromes (ACS) have substantial rates of recurrent ischemic events, but prognostic studies have been small or preceded the routine use of aggressive combination antithrombotic therapy. We sought to identify predictors of these events after antithrombotic treatment of non-Q-wave ACS. METHODS: We assessed 30-day rates of a composite triple end point (death, infarction, or refractory angina) and double end point (death or infarction) among 3171 patients with non-ST-segment elevation ACS randomly assigned to enoxaparin or heparin, plus aspirin, for 2 to 8 days. We created multivariable regression models to predict these end points from baseline factors. RESULTS: Overall, 682 patients (21%) reached the triple end point and 220 (6.8%) reached the double end point. Independent predictors of the triple end point were admission with myocardial necrosis, ST-segment depression, prior angina severity, symptom duration, and allocation to enoxaparin treatment in patients with ST-segment depression (significant interaction). Independent predictors of the double end point were admission with myocardial necrosis, ST-segment depression, enrollment region, age >75 years, prior angina severity, and rales. By deciles, the average predicted risk for the double end point ranged from 2% to 20%: a patient aged <75 years with no risk factors had a 3.5% risk, whereas a patient aged >75 years with 2 additional high-risk features (myonecrosis and ST depression) had a risk of death or reinfarction of 26%. CONCLUSIONS: Patients with non-ST-segment elevation ACS exhibit a broad range of risk of adverse recurrent ischemic events. The predictive power of the model for the triple end point, using baseline variables, was modest. However, a subgroup at very low risk of the double end point (average 2%) can be identified with baseline variables.

Prior aspirin users with acute non-ST-elevation coronary syndromes are at increased risk of cardiac events and benefit from enoxaparin.

BACKGROUND: The aim of this article was to investigate whether prior aspirin use in patients with acute coronary syndromes affects clinical outcome. The Efficacy Safety Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events Study (ESSENCE) and Thrombolysis in Myocardial Infarction (TIMI) 11B trials have shown superiority of enoxaparin over unfractionated heparin (UFH) in patients with unstable angina and non-ST-segment elevation myocardial infarction (UA/NSTEMI). However, the treatment effect of enoxaparin in the subset of patients reporting prior aspirin use has not been determined. METHODS: The rate of death, myocardial infarction, and urgent revascularization at days 8 and 43 after randomization was compared among patients who received aspirin within the week before randomization with those who did not receive aspirin in the TIMI 11B trial. A total of 3275 patients (84%) were prior aspirin users. RESULTS: The admission diagnosis was similar for prior and nonprior aspirin users. At both day 8 and day 43 the event rate was higher for prior aspirin users than for nonprior aspirin users (odds ratio 1.6 [1.24-2.08], P =.0004 at day 43), even after correction for baseline characteristics. Compared with those prior aspirin users taking UFH, enoxaparin-treated prior aspirin users had a reduced rate of the composite end point of death, myocardial infarction, and urgent revascularization at day 8 (odds ratio 0.82 [0.67-1.00], P =.046) and day 43 (odds ratio 0.83 [0.70-0.98], P =.032). CONCLUSION: Patients with UA/NSTEMI and prior aspirin use had a 60% higher risk of death and cardiac ischemic events compared with nonprior aspirin users. On the basis of this subanalysis, enoxaparin is superior to UFH in all patients. In prior aspirin users the benefit is more clearly demonstrated.