Rationale and design of ACTIVE: the atrial fibrillation clopidogrel trial with irbesartan for prevention of vascular events.

BACKGROUND: Atrial fibrillation (AF) is the most frequently occurring cardiac arrhythmia with often serious clinical consequences. Many patients have contraindications to anticoagulation, and it is often underused in clinical practice. The addition of clopidogrel to aspirin (ASA) has been shown to reduce vascular events in a number of high-risk populations. Irbesartan is an angiotensin receptor-blocking agent that reduces blood pressure and has other vascular protective effects. METHODS AND RESULTS: ACTIVE W is a noninferiority trial of clopidogrel plus ASA versus oral anticoagulation in patients with AF and at least 1 risk factor for stroke. ACTIVE A is a double-blind, placebo-controlled trial of clopidogrel in patients with AF and with at least 1 risk factor for stroke who receive ASA because they have a contraindication for oral anticoagulation or because they are unwilling to take an oral anticoagulant. ACTIVE I is a partial factorial, double-blind, placebo-controlled trial of irbesartan in patients participating in ACTIVE A or ACTIVE W. The primary outcomes of these studies are composites of vascular events. A total of 14000 patients will be enrolled in these trials. CONCLUSIONS: ACTIVE is the largest trial yet conducted in AF. Its results will lead to a new understanding of the role of combined antiplatelet therapy and the role of blood pressure lowering with an angiotensin II receptor blocker in patients with AF.

Variation in patient management and outcomes for acute coronary syndromes in Latin America and North America: results from the Platelet IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial.

BACKGROUND: Although more than 9500 patients have been enrolled in major clinical trials in Latin America, practice patterns in this region have rarely been examined. We sought to compare characteristics, resource utilization, and outcomes of patients treated for acute coronary syndromes in Latin America with those in North America. METHODS: The Platelet IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Theraphy Trial (PURSUIT) enrolled 10,948 patients with non-ST-segment elevation acute coronary syndromes, including 585 in Latin America and 4358 in North America. We analyzed regional differences in patient groups, treatment patterns, and outcomes and used logistic regression analysis to identify association of enrollment region and survival. RESULTS: For patients in Latin America, the length of hospital stay was significantly longer (10 [7, 15] days vs 6 [4, 9], P <.001). Angiograms, angioplasty, and bypass surgery were significantly less common in Latin America (46.2%, 17.6%, and 11.3% vs 79.4%, 33.6%, and 19.4%, P <.001). Thirty-day death/myocardial infarction was not significantly higher, although mortality alone was significantly higher (6.8% vs 3.1%, P <.001). After adjustment for baseline characteristics, enrollment in Latin America remained an independent predictor for death at 30 days (odds ratio [OR] [95% confidence interval (CI)] 2.42 [1.60-3.67]) and persisted at 6 months (OR [95% CI] 2.5 [1.8-3.4]). CONCLUSIONS: Latin American patients treated for acute coronary syndromes were managed less invasively and were twice as likely as their North American counterparts to die within 6 months. This mortality difference was not explained by imbalances in baseline risk.

Usefulness of pharmacologic stress echocardiography in a chest pain center.

We tested the value of a stress echocardiography-based algorithm used in a chest pain center. The algorithm had superlative negative predictive value for cardiac events, allowing an early discharge.

Acute cardiac rupture during dobutamine-atropine echocardiography stress test.

We report an acute cardiac rupture during dobutamine-atropine echocardiography stress test on the sixth day after admission for an inferoposterior acute myocardial infarction complicated with mild pericardial effusion.

Cigarette smoking status and outcome among patients with acute coronary syndromes without persistent ST-segment elevation: effect of inhibition of platelet glycoprotein IIb/IIIa with eptifibatide. The PURSUIT trial investigators.

BACKGROUND: Studies have shown that cigarette smokers constitute a substantial proportion of patients with acute coronary syndromes (ACS) and have platelet-rich coronary thrombi. We characterized the influence of smoking status on outcome of patients with ACS without persistent ST-segment elevation and tested the hypothesis that selective inhibition of the platelet glycoprotein IIb/IIIa receptor with eptifibatide would improve outcomes among cigarette smokers. METHODS: The study population included patients enrolled in the PURSUIT trial (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy) with known smoking status presenting with ischemic chest pain

Single-bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: the ASSENT-2 double-blind randomised trial.

BACKGROUND: Bolus fibrinolytic therapy facilitates early efficient institution of reperfusion therapy. Tenecteplase is a genetically engineered variant of alteplase with slower plasma clearance, better fibrin specificity, and high resistance to plasminogen-activator inhibitor-1. We did a double-blind, randomised, controlled trial to assess the efficacy and safety of tenecteplase compared with alteplase. METHODS: In 1021 hospitals, we randomly assigned 16,949 patients with acute myocardial infarction of less than 6 h duration rapid infusion of alteplase (< or = 100 mg) or single-bolus injection of tenecteplase (30-50 mg according to bodyweight). All patients received aspirin and heparin (target activated partial thromboplastin time 50-75 s). The primary outcome was equivalence in all-cause mortality at 30 days. FINDINGS: Covariate-adjusted 30-day mortality rates were almost identical for the two groups--6.18% for tenecteplase and 6.15% for alteplase. The 95% one-sided upper boundaries of the absolute and relative differences in 30-day mortality were 0.61% and 10.00%, respectively, which met the prespecified criteria of equivalence (1% absolute or 14% relative difference in 30-day mortality, whichever difference proved smaller). Rates of intracranial haemorrhage were similar (0.93% for tenecteplase and 0.94% for alteplase), but fewer non-cerebral bleeding complications (26.43 vs 28.95%, p=0.0003) and less need for blood transfusion (4.25 vs 5.49%, p=0.0002) were seen with tenecteplase. The rate of death or non-fatal stroke at 30 days was 7.11% with tenecteplase and 7.04% with alteplase (relative risk 1.01 [95% CI 0.91-1.13]). INTERPRETATION: Tenecteplase and alteplase were equivalent for 30-day mortality. The ease of administration of tenecteplase may facilitate more rapid treatment in and out of hospital.

Clinical predictors of in-hospital prognosis in unstable angina: ECLA 3. The ECLA Collaborative Group.

OBJECTIVES: Because of recent changes in the treatment of unstable angina, we wanted to reassess the short-term prognostic value of clinical and echocardiographic variables. METHODS: This was an observational, prospective study that included 1038 nonselected consecutive patients admitted to coronary care units for unstable angina. RESULTS: Baseline characteristics were age 60.18 +/- 16 years, history of prior myocardial infarction in 336 patients (32%), and a history of previous angina in 817 patients (78.7%). Angina during the 48 hours before admission was observed in 1004 patients (96.7%) and ST-segment changes on admission electrocardiogram occurred in 385 patients (37%). In-hospital treatment consisted of nitrates in 81.4% of patients, aspirin in 88.6%, beta-blockers in 71%, intravenous heparin in 34.5%, subcutaneous heparin in 23%, and angioplasty or coronary artery bypass grafting in 25.1%. After admission, angina occurred in 443 patients (40.8%), refractory angina in 223 patients (21.5%), and death or myocardial infarction in 84 patients (8.1%). At admission, the independent predictors of myocardial infarction or death identified by multivariate logistic regression analysis were ST-segment depression (odds ratio [OR] 2.13, 95% confidence interval [CI] 1.23 to 3.68, P =.006), prior angina (OR 2.23, 95% CI 0.98 to 5.05, P =.05), number of episodes of angina within the previous 48 hours (OR 1.63, 95% CI 0.98 to 2.70, P =.05), and history of smoking (OR 0.69, 95% CI 0.56 to 0.85, P =.004). Age greater than 65 years (OR 1.49, 95% CI1.09 to 2.03, P = 0.03) was significantly related to in-hospital death. The area under the receiver operating characteristic curve for application of this model was 0.59. Sensitivity was 80% with a specificity of only 33%. Refractory angina after admission showed a strong relation with an adverse short-term outcome. CONCLUSIONS: With current therapy, clinical and electrocardiographic variables provide useful information about the short-term outcome of unstable angina. However, this model has low specificity to identify high-risk patients. Future studies about the incremental value of the new serum markers such as troponin T and C-reactive protein to assist in identification of high-risk patients are necessary.

Metabolic modulation of acute myocardial infarction. The ECLA (Estudios Cardiológicos Latinoamérica) Collaborative Group.

BACKGROUND: Several trials have been performed in the past using glucose, insulin, and potassium infusion (GIK) for the treatment of acute myocardial infarction (AMI). Because of continuing uncertainty about the potential role of this therapeutic intervention, we conducted a randomized trial to evaluate the impact of a GIK solution during the first hours of AMI. METHODS AND RESULTS: Four hundred seven patients with suspected AMI admitted within 24 hours of symptoms onset were enrolled. In a ratio of 2:1, 268 patients were allocated to receive GIK (high- or low-dose) and 139 to receive control. Phlebitis and serum changes in the plasma concentration of glucose or potassium were observed more often with GIK. A trend toward a nonsignificant reduction in major and minor in-hospital events was observed in patients allocated to GIK. In 252 patients (61.9%) treated with reperfusion strategies, a statistically significant reduction in mortality (relative risk [RR] 0.34; 95% CI: 0.15 to 0.78; 2P=0.008) and a consistent trend toward fewer in-hospital events in the GIK group were observed. CONCLUSIONS: Our results confirm that a metabolic modulation strategy in the first hours of an AMI is feasible, applicable worldwide, and has mild side effects. The statistically significant mortality reduction in patients who underwent a reperfusion strategy might have important implications for the management of AMI patients. It is now essential to perform a large-scale trial to reliably determine the magnitude of benefit.

Characteristics, clinical course, and in-hospital mortality of non-insulin-dependent diabetic and nondiabetic patients with acute myocardial infarction in Argentina.

The characteristics and clinical course of 1040 cases of acute myocardial infarction (AMI) among non-insulin-dependent diabetics (146) and nondiabetics (894) were compared. Patients with non-insulin-dependent diabetes mellitus (NIDDM) historically showed a greater percentage of AMI, angina, and risk factors than nondiabetic patients. Although the degree of left-ventricular function upon admission (according to the Killip and Kimball scores) was similar in both the diabetic and nondiabetic groups, the prevalence of hypertension and hypercholesterolemia was significantly higher in the NIDDM patients. All told, NIDDM cases were 1.73 [relative risk (RR)] times more likely to die of AMI than nondiabetic patients. The age factor and the presence of shock of any type also significantly increased the case-fatality rate. Diabetic patients showed signs of successful reperfusion less often than control subjects, an event that was closely associated with their case-fatality rate. In the NIDDM group, both the age and gender factor as well as a history of either casual or in-hospital clinical events such as cardiogenic shock, reinfarction, unsuccessful reperfusion, and incidence of anterior AMI along with either pain or previous angina were clear prognosticators of poor outcome from AMI. In the nondiabetic group, cardiogenic shock and hypertension were indicators of poor prognosis. These results would suggest that an improvement in the incidence of successful reperfusion in NIDDM patients, particularly in the face of clinical indicators of poor AMI prognosis, could decrease the high AMI mortality currently observed in these patients.

Acute myocardial infarction in the young--the role of smoking. The Investigators of the International Tissue Plasminogen Activator/Streptokinase Mortality Trial.

Patients who received thrombolytic therapy for acute myocardial infarction in a large international trial were divided into two groups on the basis of age; those < or = 40 years (n = 269) and those > 40 years (n = 7787). The younger group included more men (89.9% vs 75.9%, P = 0.009) and fewer patients had a history of coronary artery disease, hypertension, and diabetes mellitus. A family history of cardiovascular disease was significantly more prevalent among the young patients (53.4% vs 41.9%, P = 0.0002). Significantly more younger patients than older patients were smokers at the time of infarction (76.2% vs 42.9%, P < 0.0001) and the average number of cigarettes smoked per day was also significantly higher in young patients (27.8 +/- 14.3 vs 19.9 +/- 12.9, P < 0.01). Younger patients had a better outcome, with lower rates of cardiogenic shock (1.1% vs 7.0%, P = 0.0002), stroke (0.0% vs 1.9%, P = 0.02) and haemorrhage (1.9% vs 5.9%, P = 0.006), as well as a better Killip class at discharge (Killip > 1 in 4.5% vs 8.0%, P < 0.001), and lower hospital and 6-month mortality (0.7% and 3.1% vs 8.3% and 12%, P < 0.001, respectively). The better outcome of younger patients with acute myocardial infarction is related to their better baseline characteristics. Young patients with acute myocardial infarction have a strong family history of cardiovascular disease and a high prevalence of smoking. Smoking is the most important modifiable risk factor in these patients.

Outcome of thrombolytic therapy in relation to hospital size and invasive cardiac services. The Investigators of the International Tissue Plasminogen Activator/Streptokinase Mortality Trial.

OBJECTIVE: The outcome of patients with acute myocardial infarction who received thrombolytic therapy was assessed in relation to the size and comprehensiveness of cardiovascular services in the admitting hospitals. METHODS: Two characteristics were obtained for each of the 438 hospitals: number of beds and in-house availability of cardiovascular services (coronary catheterization laboratory and coronary angioplasty or bypass surgery). Hospitals were grouped into four categories on the basis of size (< or = 300 vs > 300 beds) and availability of cardiovascular services. Baseline and outcome variables were compared by chi 2 analysis and logistic regression. Patients were followed up for 6 months. RESULTS: Baseline variables were comparable among hospital categories except for significant differences in the distribution of antecedent angina and time to treatment. Significantly more coronary angioplasties and bypass surgeries were performed in patients first treated in hospitals with coronary revascularization services (4.1% and 4.2% vs 1.0% and 1.9%, P < .0001). Rates of strokes (1.9% vs 1.3% and 1.6%, P = .54), hospital mortality (11.9% vs 8.5%, (P = .11), and 6-month mortality (17.0% vs 11.8% and 12.3%, P = .03) were highest among patients treated in small hospitals that had coronary revascularization facilities. The rate of invasive procedures was higher in the smaller hospitals (odds ratio [OR], 1.44; 95% confidence limits [CL], 1.11 and 1.87; P = .006) and in hospitals with coronary revascularization services (OR, 4.05; 95% CL, 3.14 and 5.22; P < .0001); hemorrhage was more frequent in centers with coronary revascularization facilities (OR, 1.39; 95% CL, 1.13 and 1.71; P = .002). Rates of hospital mortality and 6-month mortality were similar. CONCLUSIONS: Patients with acute myocardial infarction treated with thrombolytic therapy have the same mortality in small centers without in-house coronary revascularization services as in larger centers with such services.

After correcting for worse baseline characteristics, women treated with thrombolytic therapy for acute myocardial infarction have the same mortality and morbidity as men except for a higher incidence of hemorrhagic stroke. The Investigators of the International Tissue Plasminogen Activator/Streptokinase Mortality Study.

BACKGROUND: In the prethrombolytic era, women with myocardial infarction were reported to have a worse outcome than men. This analysis evaluates the association of sex with morbidity and mortality after thrombolytic therapy. METHODS AND RESULTS: Data were analyzed from 8261 of the 8387 randomized patients with acute myocardial infarction who received thrombolytic therapy in the International Tissue Plasminogen Activator/Streptokinase Mortality Study (baseline data were missing for 126 patients) and were followed for 6 months. Women made up 23% (n = 1944) of the study population. Baseline characteristics were worse in women: they were 6 years older, were more likely to have a history of previous infarction (P < .01), antecedent angina (P < .01), hypertension (P < .0001), or diabetes (P < .0001); were in a higher Killip class on admission (P < .0002); and received thrombolytic therapy 18 minutes later than men (P < .0001). Fewer women were smokers (P < .0001). Women had a higher hospital (12.1% versus 7.2%, P < .0001) and 6-month mortality (16.6% versus 10.4%, P < .0001) and were more likely to develop cardiogenic shock (9.1% versus 6.3%, P < .0001), bleeding (7.2% versus 5.3%, P < .01), and hemorrhagic (1% versus 0.3%, P < .001) or total stroke (2.2% versus 1.1%, P < .0001) during hospitalization. Reinfarction rates and requirement for angioplasty or surgery did not differ. After correction for worse baseline characteristics, women had similar morbidity and mortality apart from a significantly higher incidence of hemorrhagic stroke, which remained significant even after accounting for weight and treatment allocation (odds ratio, 2.90; P < .01). CONCLUSIONS: After thrombolytic therapy for acute myocardial infarction, women have similar morbidity and mortality to men but suffer from a higher incidence of hemorrhagic stroke.

Significance of smoking in patients receiving thrombolytic therapy for acute myocardial infarction. Experience gleaned from the International Tissue Plasminogen Activator/Streptokinase Mortality Trial.

BACKGROUND: Despite the fact that smoking is a well-established risk factor for the development of coronary artery disease, some investigators have noted that hospital mortality after acute myocardial infarction is lower in patients who smoke than in nonsmoking patients. To evaluate the association of smoking with mortality during hospitalization after thrombolytic therapy and 6 months afterward, we analyzed the results of the International Tissue Plasminogen Activator/Streptokinase Mortality Trial. METHODS AND RESULTS: Patients were divided into three groups: nonsmokers (those who never smoked), ex-smokers, and active smokers. Multivariate and univariate comparisons were made with respect to baseline characteristics and clinical outcome. There were 2,366 nonsmokers, 2,244 ex-smokers, and 3,649 active smokers. The baseline characteristics of nonsmoking patients differed significantly from the ex-smokers and active smokers. The nonsmoking group included more women than the ex-smokers or active smokers (45% versus 10.6% and 17.6%, respectively), was older (67 +/- 10 years versus 64 +/- 10 years and 58 +/- 11 years), had a higher rate of diabetes mellitus (16.3% versus 11.1% and 7.5%), and had a worse Killip class at admission. Nonsmoking patients and ex-smokers experienced more in-hospital reinfarction than active smokers (4.7% and 5% versus 2.7%, p < 0.0001, respectively). Nonsmokers experienced more in-hospital shock than the ex-smokers or active smokers (9.2% versus 6.4% and 5.8%, p < 0.0001), stroke (1.9% versus 1.8% and 0.8%, p < 0.0001), and bleeding (7.2% versus 6.5% and 4.4%, p < 0.0001). They also experienced a higher in-hospital and 6-month mortality (12.8% and 17.6%) than ex-smokers (8.2% and 12.1%) or active smokers (5.4% and 7.8%) (p < 0.0001). A multivariate analysis accounting for all baseline characteristics demonstrated a significant association between nonsmoking and increased hospital mortality, with an odds ratio of 1.42 (confidence limits, 1.15-1.72). Among active smokers, there was a nonsignificant trend for mortality rates to decrease with increasing numbers of cigarettes smoked per day. CONCLUSIONS: This retrospective analysis indicates that smokers receiving thrombolytic therapy after acute myocardial infarction have significantly better hospital and 6-month outcome than nonsmokers or ex-smokers. However, smokers sustained their infarction at a significantly earlier age than nonsmokers, and strenuous efforts should continue to be made to decrease the incidence of new and continued smoking.