The potential role of anticoagulant therapy for the secondary prevention of ischemic events post-acute coronary syndrome.

Abstract The use of dual antiplatelet therapy has led to a substantial reduction in ischemic events post-acute coronary syndrome (ACS). Despite this, recurrent event rates remain high. Recent research has combined antiplatelet with anticoagulant therapy to reduce recurrent event rates further. Compared with standard medical therapy, rivaroxaban demonstrated improved efficacy outcomes and significantly reduced mortality after an ACS. Although clear benefits of novel oral anticoagulants post-ACS have been proven, concerns regarding bleeding are still a barrier to widespread use. This review explores key trials of dual antiplatelet therapy and examines the latest research in anticoagulation aiming to optimize clinical outcomes post-ACS.

Relationship of QRS duration at baseline and changes over 60 min after fibrinolysis to 30-day mortality with different locations of ST elevation myocardial infarction: results from the Hirulog and Early Reperfusion or Occlusion-2 trial.

OBJECTIVE: To discern if the prognostic meaning of QRS prolongation differs according to the location of ST elevation acute myocardial infarction DESIGN: Measuring QRS duration in patients with normal conduction or right bundle branch block SETTING: HERO-2 trial with prospective collection of electrocardiograms at randomisation and at 60 min after fibrinolytic therapy PATIENTS: 12 456 patients with normal conduction at both randomisation and 60-min time points and 510 with right bundle branch block (RBBB) at both time points MAIN OUTCOME MEASURE: 30-day mortality. RESULTS: On the baseline ECG, there was a positive association between QRS duration and 30-day mortality with anterior acute myocardial infarction (AMI) (p<0.0001 for those with normal conduction and = 0.007 for those with RBBB) but not with inferior AMI (p = 0.29 and p = 0.32, respectively). For anterior AMI, with or without RBBB, an increment of 20 ms increase in QRS duration predicted a significant 30-40% relative increase in 30-day mortality both before and after adjusting for clinical and ECG variables including baseline ST elevation and presence of Q waves. The association was not present for inferior AMI. Changes in QRS duration over 60 min after fibrinolytic therapy were uncommon and unrelated to mortality. CONCLUSION: Baseline QRS duration independently stratifies 30-day mortality in patients with anterior AMI, even when unaccompanied by RBBB, but does not stratify mortality risk in patients with inferior AMI.

Variations in the use of emergency PCI for the treatment of re-infarction following intravenous fibrinolytic therapy: impact on outcomes in HERO-2.

BACKGROUND: Patients who suffer re-infarction during initial hospitalization for ST-elevation myocardial infarction (STEMI) have decreased survival compared to patients without re-infarction, so treatment of re-infarction may influence survival. METHODS AND RESULTS: To determine whether the utilization of reperfusion therapies varied within 12 h of re-infarction and was associated with 30-day mortality, we studied 552 patients with re-infarction of 17,073 patients with STEMI enrolled in HERO-2 in five regions (Russia, Eastern Europe, Western Countries, Asia, and Latin America). Patients presenting within 6 h of symptom-onset were randomized to receive either bivalirudin or unfractionated heparin intravenously just prior to streptokinase. Re-infarction occurred in 2.8 and 3.6% of bivalirudin and heparin treated patients, respectively (P = 0.004), but treatment assignment did not influence mortality after re-infarction. Patients with re-infarction had a higher 30-day mortality than those without re-infarction (24 vs. 10%; P < 0.001 by Cox model). Within 12 h of re-infarction, fibrinolytic therapy was administered to 12.0 and 8.2% underwent percutaneous coronary intervention (PCI); these two treatments were more frequently utilized in patients from Western countries (n = 112), compared to patients from other countries (n = 440) (34.8 and 16.1% compared to 6.1 and 6.1%, respectively, P < 0.001). Mortality was 15% in patients receiving reperfusion therapy for re-infarction and 27% for those with conservative management, hazard ratio (HR) 0.53 (95% CI 0.32-0.88), P = 0.01. In multiple Cox regression analysis which included adjustment for clinical variables and randomized treatment assignment, 30-day mortality after re-infarction varied by region (highest Latin America 29%, lowest Western countries 15%; P = 0.01). Other independent prognostic factors included age, time from randomization to re-infarction, and Killip class at randomization. The HR for PCI treatment of re-infarction was 0.18 [(95% CI 0.04-0.76), P = 0.02] in analyses which excluded deaths within 12 h. CONCLUSION: Treatment of re-infarction with reperfusion therapies was markedly under-utilized, especially in non-western countries. PCI for re-infarction, in particular, was associated with a lower 30-day mortality, which may reflect both patient selection and effects of treatment.

Slowed ST segment recovery despite early infarct artery patency in patients with Q waves at presentation with a first acute myocardial infarction. Implications of initial Q waves on myocyte reperfusion.

BACKGROUND: The presence of Q waves at presentation with a first acute myocardial infarction reflects a more advanced stage of the infarction process. When infarct-related artery patency (Thrombolysis in Myocardial Infarction 2 or 3 flow) is restored, resolution of ST segment elevation indicating successful myocyte reperfusion may differ according to how far the infarction process has progressed. METHODS AND RESULTS: In 144 patients with a first acute myocardial infarction treated with streptokinase in the first Hirulog Early Reperfusion Occlusion trial, information was obtained from continuous ST segment monitoring, the presenting electrocardiogram and early angiography performed at a median time of 99 min after the commencement of streptokinase (interquartile range 89-108 min). We determined how many patients had 50% ST recovery within 120 min and in how many cases it was sustained over 4h. In the 109 patients with patent infarct-related arteries, 50% ST recovery occurred in 95% of patients without vs 80% of those with initial Q waves (P=0.03), and sustained ST recovery occurred in 67% of patients without vs 47% of those with initial Q waves (P=0.03). On multivariate analysis including the time from symptom onset to streptokinase therapy, the presence of Q waves at presentation was the only predictor of failure to achieve 50% ST recovery (odds ratio 5.08, 95% confidence interval 1.29-20.01, P=0.02). TIMI 2 flow, as opposed to TIMI 3 flow, was the only predictor of failure to achieve stable ST recovery (odds ratio 2.63, 95% confidence interval 1.15-5.88,P =0.02). CONCLUSION: The presence of initial Q waves predicts slower and less complete ST recovery, reflecting reduced myocyte reperfusion, even in those with early infarct artery patency. These patients may be targeted for new therapeutic strategies to improve microvascular reperfusion.

Usefulness of the presenting electrocardiogram in predicting myocardial salvage with thrombolytic therapy in patients with a first acute myocardial infarction.

AIMS: Patients with Q waves and T-wave inversion are generally at a later stage of the infarction process than patients without these changes. Our aim was to investigate whether a single assessment of electrocardiographic parameters at presentation would predict the proportion of myocardium salvageable by thrombolytic therapy. METHODS AND RESULTS: Electrocardiographic algorithms to calculate the potential and final infarct size have been developed and allow the proportion of myocardium salvageable with therapy to be calculated. This was measured in 146 patients with acute myocardial infarction who had angiography at a median of 91 min after streptokinase. The relationship between myocardial salvage and the electrocardiographic parameters at presentation (Q waves, T-wave inversion, quantitative ST segment changes, and the initial QRS score), was examined together with the 90-min angiographic parameters (TIMI flow grade and collateral grade), clinical parameters (haemodynamics and age), and time to therapy. Parameters that correlated with myocardial salvage included the initial QRS score (r=-0.56, P<0.0001), Q wave grade (r=-0.36, P<0.0001), number of leads with ST depression (r=0.28, P<0.001), maximum ST depression (r=0.27, P<0.01), T-inversion grade (r=-0.26, P<0.01), and TIMI flow grade at 90 min (r=0.21, P<0.02). The time from symptom onset to thrombolytic therapy did not correlate with salvage (r=-0.09). On multivariate analysis, only the initial QRS score and T-inversion grade on the initial electrocardiogram were independent predictors of salvage (multivariate r using both variables combined=0.57, P<0.001). CONCLUSIONS: The QRS score and T-wave inversion grade on the presenting electrocardiogram provide important information in predicting myocardial salvage. These parameters may help triage patients to appropriate therapies.

Prophylactic lidocaine use in acute myocardial infarction: incidence and outcomes from two international trials. The GUSTO-I and GUSTO-IIb Investigators.

BACKGROUND: Early meta-analyses suggested that prophylactic lidocaine use reduces ventricular fibrillation but increases mortality rates after acute myocardial infarction. We determined the frequency and effect on clinical outcomes with its use in the thrombolytic era. METHODS AND RESULTS: We studied 43,704 patients enrolled in GUSTO-I or GUSTO-IIb who had ST-segment elevation, underwent thrombolysis, and survived at least 1 hour after enrollment. Odds ratios (OR) and confidence intervals (CI) were calculated for the risk of asystole, atrioventricular block, ventricular fibrillation, and ventricular tachycardia during hospitalization; for 24-hour, in-hospital, and 30-day mortality rates; and for 24-hour and 30-day mortality rates after adjustment for baseline predictors of death. In GUSTO-I and GUSTO-IIb, 16% and 3.5% of patients, respectively, received prophylactic lidocaine. They had a lower risk of death at 24 hours (OR 0.81, 95% CI 0.67 to 0.97) and trends toward lower odds of in-hospital death (OR 0.90, 95% CI 0.81 to 1.01) and death at 30 days (OR 0.92, 95% CI 0.82 to 1. 02). After adjustment for baseline characteristics, however, the odds of death were similar with or without lidocaine (OR 0.90 and 0. 97, respectively). Outside the United States, lidocaine was associated with higher incidences of all serious arrhythmias, but in US patients it conferred a lower likelihood of ventricular fibrillation and no increase in asystole, atrioventricular block, or mortality rates. CONCLUSIONS: Prophylactic lidocaine use has decreased with the advent of thrombolysis, although its use may not be associated with increased mortality rates.

Usefulness of the presenting electrocardiogram in predicting successful reperfusion with streptokinase in acute myocardial infarction.

The presenting electrocardiogram may contain information indicating the probability of successful reperfusion. The relation between 3 parameters in the presenting electrocardiogram (pathologic Q waves, T-wave inversion, and the slope of ST elevation) and Thrombolysis in Myocardial Infarction trial (TIMI) grade 3 flow in the infarct-related artery was assessed angiographically 90 minutes after beginning streptokinase in 362 patients. TIMI grade 3 flow was more common in patients without Q waves (55%) than in those with Q waves (35%; p <0.001), and more common in patients without T-wave inversion (50%) than in those with T-wave inversion (30%; p <0.002). There was no relation between the slope of the ST segment or the magnitude of its deviation and the achievement of TIMI grade 3 flow. Only 20% of the 59 patients with both Q waves and T-wave inversion had TIMI grade 3 flow, compared with 50% of the remaining patients (p <0.0001). Among patients treated within 3 hours, TIMI grade 3 flow was seen in 68% of those without versus 44% of those with Q waves (p <0.01), and in 62% of those without versus 43% of those with T-wave inversion (p = 0.06). Among patients treated after 3 hours, TIMI grade 3 flow was seen in 38% of those without versus 30% of those with Q waves (p = NS), and in 38% of those without versus 23% of those with T-wave inversion (p <0.05). On multivariate analysis, the absence of Q waves, the time from the onset of chest pain to treatment, and age were independent predictors of TIMI grade 3 flow. Pathologic Q waves in the presenting electrocardiogram provide valuable information as to the probability of achieving successful reperfusion following administration of streptokinase, and may be helpful for triage of patients to alternative reperfusion strategies, including percutaneous revascularization.

One-year survival among patients with acute myocardial infarction complicated by cardiogenic shock, and its relation to early revascularization: results from the GUSTO-I trial.

BACKGROUND: Although 30-day survival is increased in patients with acute myocardial infarction complicated by cardiogenic shock who undergo coronary revascularization, the longer-term outcome in such patients and the duration of benefit from revascularization are unknown. METHODS AND RESULTS: We analyzed 30-day survivors of acute myocardial infarction in the Global Utilization of Streptokinase and Tissue-Plasminogen Activator for Occluded Coronary Arteries (GUSTO-I) trial and identified 36 333 who had not had cardiogenic shock (systolic blood pressure <90 mm Hg for >/=1 hour, group 1) and 1321 patients who had shock (group 2). Group 2 patients were older and sicker. At 1 year, 97.4% of group 1 patients were alive versus 88.0% of group 2 (P=0.0001). Among group 2 patients, 578 (44%) had undergone revascularization within 30 days (group 2A) and 728 (56%) had not (group 2B). Revascularization was not required by protocol but was selected by the attending physicians. At 1 year, 91.7% of group 2A patients were alive versus 85.3% of group 2B (P=0.0003). With the use of multivariable logistic regression analysis to adjust for differences in baseline characteristics of shock patients alive at 30 days, revascularization within 30 days was independently associated with reduced 1-year mortality (odds ratio 0.6, [95% confidence interval 0.4, 0.9], P=0.007). CONCLUSIONS: Most patients (88%) with acute myocardial infarction complicated by cardiogenic shock who are alive at 30 days survived at least 1 year. Shock patients who underwent revascularization within 30 days had improved survival at 1 year compared with shock patients who did not receive revascularization, even after adjustment for differences in baseline characteristics between the 2 groups.

Angiographic frame counts 90 minutes after streptokinase predict left ventricular function at 48 hours following myocardial infarction.

OBJECTIVE: To assess whether the 90 minute corrected thrombolysis in myocardial infarction frame count (CTFC) in the infarct related artery predicts left ventricular function at 48 hours in patients with myocardial infarction treated with aspirin, streptokinase, and either heparin or Hirulog. DESIGN AND SETTING: Analysis of 251 patients with acute myocardial infarction enrolled in the international, multicentre Hirulog early reperfusion/occlusion (HERO-1) trial, who underwent both 90 minute coronary angiography and 48 hour left ventriculography. MAIN OUTCOME VARIABLES: The CTFC was determined in the infarct related artery 90 minutes after starting intravenous streptokinase (1.5 x 106 U over 30 to 60 minutes), and compared with indices of left ventricular function assessed by contrast ventriculography at 48 hours. RESULTS: A CTFC of 2 SD below normal (37% v 51%, p = 0.005), and trends towards higher left ventricular ejection fractions (60.9% v 58.2%, p = 0.11) and lower end systolic volumes (50.1 ml v 55.9 ml, p = 0.23). A CTFC of 2 SD below normal (41% v 52%, p = 0.025), a smaller end systolic volume (49.1 ml v 59.3 ml, p = 0.02), and a higher left ventricular ejection fraction (60.4% v 56.5%, p = 0.03). CONCLUSIONS: The 90 minute CTFC predicts left ventricular function at 48 hours following streptokinase. The CTFC associated with better ventricular function may be higher than values determined from a non-infarct population.

Use of bedside activated partial thromboplastin time monitor to adjust heparin dosing after thrombolysis for acute myocardial infarction: results of GUSTO-I. Global Utilization of Streptokinase and TPA for Occluded Coronary Arteries.

BACKGROUND: The safety and efficacy of bedside monitors of activated partial thromboplastin time (aPTT) have not been examined in a large population receiving intravenous heparin after thrombolytic treatment for acute myocardial infarction. We compared outcomes among patients monitored with these devices versus standard monitoring methods. METHODS AND RESULTS: Investigators chose the bedside device (n = 1713 patients) or their standard method (n = 26,162) for all aPTT measurements at their sites. Clinical outcomes at 30 days, 1-year mortality rate, and aPTT levels at 6, 12, and 24 hours were compared. Bedside-monitored patients had significantly less moderate/severe bleeding (10% vs 12%, P < .01), fewer transfusions (7% vs 11%, P < .001), and a smaller decrease in hematocrit (5.5% vs 6.7%, P < .001) but significantly more recurrent ischemia (22% vs 20%, P = .01). Fewer bedside-monitored patients had subtherapeutic aPTT levels at 12 and 24 hours. Among patients with subtherapeutic levels at 6 and 12 hours, more bedside-monitored patients had therapeutic levels when next monitored. After adjustment for baseline differences, no significant difference in mortality rate was observed in bedside-monitored patients at 30 days (4.3% vs 4.8%, P = .27) and at 1 year (7.1% vs 7.7%, P = .38). The groups had similar rates of reinfarction, shock, heart failure, and stroke. CONCLUSIONS: This prospective substudy supports the use of bedside monitoring of heparin anticoagulation after thrombolysis.

Intervention with PTCA and CABG following thrombolysis for acute myocardial infarction. Australian data from GUSTO 1 (1991-3) and International Study Group r-TPA-Streptokinase Mortality (1989) trials. Global Utilisation of Streptokinase and Tissue.

The patterns of revascularisation with percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass graft (CABG) surgery in the GUSTO 1 trial patients in Australia are described. In comparison with rates documented in earlier trials of thrombolytic therapy in Australia, the rates of revascularisation post-thrombolysis increased by 50%, primarily due to a doubling in the rate of use of PTCA. However, the rates were low by international comparisons. There were marked variations in the rates of revascularisation between States, but no correlation with differences in mortality between States. The main predictors of post thrombolysis PTCA were prior angina, mild infarction and access to PTCA facilities.

Recurrent ischemia after thrombolysis: importance of associated clinical findings. GUSTO-I Investigators. Global Utilization of Streptokinase and t-PA [tissue-plasminogen activator] for Occluded Coronary Arteries.

OBJECTIVES: We sought to assess the incidence and clinical relevance of examination data to recurrent ischemia within an international randomized trial. BACKGROUND: Ischemic symptoms commonly recur after thrombolysis for acute myocardial infarction. METHODS: Patients (n = 40,848) were prospectively evaluated for recurrent angina and transient electrocardiographic (ECG) or hemodynamic changes. Five groups were developed: Group 1, patients with no signs or symptoms of recurrent ischemia; Group 2, patients with angina only; Group 3, patients with angina and ST segment changes; Group 4, patients with angina and hemodynamic abnormalities; and Group 5, patients with angina, ST segment changes and hemodynamic abnormalities. Baseline clinical and outcome variables were compared among the five groups. RESULTS: Group 1 comprised 32,717 patients, and Groups 2 to 5 comprised 20% of patients (4,488 in Group 2; 3,021 in Group 3; 337 in Group 4; and 285 in Group 5). Patients with recurrent ischemia were more often female, had more cardiovascular risk factors and less often received intravenous heparin. Significantly more extensive and more severe coronary disease, antianginal treatment, angioplasty and coronary bypass surgery were observed as a function of ischemic severity. The 30-day reinfarction rate was 1.6% in Group 1, 6.5% in Group 2, 21.7% in Group 3, 13.1% in Group 4 and 36.5% in Group 5 (p < 0.0001); in contrast, the 30-day mortality rate was significantly lower (p < 0.0001) in Groups 1, 2 and 3 (6.6%, 5.4% and 7.7%, respectively) than in Groups 4 and 5 (21.8% and 29.1%). CONCLUSIONS: Postinfarction angina greatly increases the risk of reinfarction, especially when accompanied by transient ECG changes. However, mortality is markedly increased only in the presence of concomitant hemodynamic abnormalities.

Randomized, double-blind comparison of hirulog versus heparin in patients receiving streptokinase and aspirin for acute myocardial infarction (HERO). Hirulog Early Reperfusion/Occlusion (HERO) Trial Investigators.

BACKGROUND: Thrombolytic therapy improves survival after myocardial infarction through reperfusion of the infarct-related artery. Thrombin generated during thrombolytic administration may reduce the efficacy of thrombolysis. A direct thrombin inhibitor may improve early patency rates. METHODS AND RESULTS: Four hundred twelve patients presenting within 12 hours with ST-segment elevation were given aspirin and streptokinase and randomized in a double-blind manner to receive up to 60 hours of either heparin (5000 U bolus followed by 1000 to 1200 U/h), low-dose hirulog (0.125 mg/kg bolus followed by 0.25 mg x kg(-1) x h(-1) for 12 hours then 0.125 mg x kg(-1) x h(-1)), or high-dose hirulog (0.25 mg/kg bolus followed by 0.5 mg x kg(-1) x h(-1) for 12 hours then 0.25 mg x kg(-1) x h(-1)). The primary outcome was Thrombolysis In Myocardial Infarction trial (TIMI) grade 3 flow of the infarct-related artery at 90 to 120 minutes. TIMI 3 flow was 35% (95% CI, 28% to 44%) with heparin, 46% (95% CI, 38% to 55%) with low-dose hirulog, and 48% (95% CI, 40% to 57%) with high-dose hirulog (heparin versus hirulog, P=.023; heparin versus high-dose hirulog, P=.03). At 48 hours, reocclusion had occurred in 7% of heparin, 5% of low-dose hirulog, and 1% of high-dose hirulog patients (P=NS). By 35 days, death, cardiogenic shock, or reinfarction had occurred in 25 heparin (17.9%), 19 low-dose hirulog (14%), and 17 high-dose hirulog patients (12.5%) (P=NS). Two strokes occurred with heparin, none with low-dose hirulog, and two with high-dose hirulog. Major bleeding (40% from the groin site) occurred in 28% of heparin, 14% of low-dose hirulog, and 19% of high-dose hirulog patients (heparin versus low-dose hirulog, P<.01). CONCLUSIONS: Hirulog was more effective than heparin in producing early patency in patients treated with aspirin and streptokinase without increasing the risk of major bleeding. Direct thrombin inhibition may improve clinical outcome.

Coronary revascularization surgery after myocardial infarction: impact of bypass surgery on survival after thrombolysis. GUSTO Investigators. Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries.

OBJECTIVES: This study sought to investigate the impact of surgical revascularization on outcome after myocardial infarction. BACKGROUND: Small variations in rates of coronary artery bypass graft surgery (CABG) were noted among thrombolytic regimens in the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) trial, prompting the question of whether survival differences were partly related to differences in CABG rates. METHODS: Patients in the GUSTO trial were randomized to one of four thrombolytic strategies. Of 40,861 patients with complete data, 3,526 underwent surgical revascularization during their initial hospital admission. Thirty-day and 1-year mortality rates were estimated using Kaplan-Meier techniques, and the impact of CABG as a time-dependent covariate on death was evaluated using a Cox survival model, adjusting for baseline prognostic factors. RESULTS: The median time from study enrollment to CABG was 7 days across treatment groups. A 15% reduction in mortality for the tissue-type plasminogen activator (t-PA)-treated group was evident by the seventh day. Bypass surgery was a significant independent predictor of 30-day mortality (risk ratio 1.87) and a weaker predictor of 1-year mortality (risk ratio 1.21). Operative mortality was highest in patients with acute mitral regurgitation, ventricular septal defect or poor left ventricular function and in those undergoing CABG within the first 4 days of randomization. CONCLUSIONS: The survival benefit of accelerated t-PA was not related to surgical revascularization. Bypass surgery was associated with excess mortality in the first year, but the added short-term mortality associated with CABG may be balanced by anticipated long-term benefit in specific groups of patients.

Relation of increased arterial blood pressure to mortality and stroke in the context of contemporary thrombolytic therapy for acute myocardial infarction. A randomized trial. GUSTO-I Investigators.

BACKGROUND: Despite concern that hypertension increases the risk for intracranial hemorrhage during thrombolysis for acute myocardial infarction, the exact nature of the risk remains unclear. OBJECTIVE: To assess the effects of previous hypertension and blood pressure at study entry on the outcomes of patients who had acute myocardial infarction and received thrombolysis. DESIGN: Randomized trial. SETTING: 1081 hospitals in 15 countries. PATIENTS: 41,021 patients who had myocardial infarction accompanied by ST-segment elevation and who presented to hospitals within 6 hours of symptom onset. INTERVENTION: One of four thrombolytic regimens. MAIN OUTCOME MEASURES: Mortality, stroke subtypes, and death plus disabling stroke in patients with previous hypertension and as functions of blood pressure at entry. Logistic regression analysis of relations among blood pressure at entry, baseline characteristics, and treatment effects. RESULTS: The incidence of total stroke and intracranial hemorrhage increased as systolic blood pressure at entry increased and was particularly high for systolic pressures of about 175 mm Hg or more (incidence of total stroke, 3.4% compared with 1.17% for pressures between 100 and 124 mm Hg). Patients who had systolic blood pressure of 175 mm Hg or more at entry and who received accelerated alteplase therapy had a lower rate of death within 30 days (4.3% compared with 7.8%; P = 0.044) and a lower rate of death plus disabling stroke (4.9% compared with 8.9%; P = 0.031) than patients treated with streptokinase, despite having higher rates of total and hemorrhagic stroke (incidence of hemorrhagic stroke, 2.3% compared with 1.5%). Assumptions based on previous trials and rates of stroke from the GUSTO-1 (Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries) trial suggest that in hypertensive patients with low risk for death from cardiac causes (no previous infarction, Killip class I), the risk-to-benefit ratio with thrombolysis is about unity, with about 13 lives saved per 1000 persons treated at the risk of about 13 intracranial hemorrhages. CONCLUSIONS: Patients with myocardial infarction and very elevated blood pressure who have thrombolysis and risk for stroke is higher in the former group. Future studies should assess 1) the risk-to-benefit ratio of thrombolysis in these patients, especially those at low risk for death from cardiac causes, and 2) whether decreasing elevated blood pressure before thrombolysis reduces the incidence of stroke without increasing mortality rates.

Age and outcome with contemporary thrombolytic therapy. Results from the GUSTO-I trial. Global Utilization of Streptokinase and TPA for Occluded coronary arteries trial.

BACKGROUND: Elderly patients with acute myocardial infarction have much to gain from reperfusion with thrombolytic therapy but are also at increased risk of adverse events. We examined outcomes according to age of patients receiving thrombolysis in an international trial. METHODS AND RESULTS: Patients were randomized to streptokinase plus subcutaneous heparin, streptokinase plus intravenous heparin, accelerated tissue plasminogen activator (TPA) plus intravenous heparin, or streptokinase and TPA plus intravenous heparin. Clinical outcomes at 30 days (death, stroke, and nonfatal, disabling stroke) and 1-year mortality were summarized descriptively for patients aged < 65 (n = 24,708), 65 to 74 (n = 11,201), 75 to 85 (n = 4625), and > 85 years (n = 412) and assessed as continuous functions of age. Older patients had a higher-risk profile with regard to baseline clinical and angiographic characteristics. Mortality at 30 days increased markedly with age (3.0%, 9.5%, 19.6%, and 30.3% in the four groups, respectively), as did stroke, cardiogenic shock, bleeding, and reinfarction. Combined death or disabling stroke occurred less often with accelerated TPA in all but the oldest patients, who showed a weak trend toward a lower incidence with streptokinase plus subcutaneous heparin: odds ratio 1.13; 95% confidence interval 0.6, 2.1. Similarly, accelerated TPA treatment resulted in lower 1-year mortality in all but the oldest patients (47% TPA versus 40.3% streptokinase). CONCLUSIONS: Lower mortality and greater net clinical benefit were seen with accelerated TPA in patients aged < or = 85 years. Because data are limited for patients aged > 85 years, the relative superiority of a given thrombolytic regimen cannot be determined. The interactions of stroke and mortality with newer thrombolytic strategies must be examined explicitly in older patients.

Time from symptom onset to treatment and outcomes after thrombolytic therapy. GUSTO-1 Investigators.

OBJECTIVES: This study sought to examine the relations among patient characteristics, time to thrombolysis and outcomes in the international GUSTO-I trial. BACKGROUND: Studies have shown better left ventricular function and decreased infarct size as well as increased survival with earlier thrombolysis, but the relative benefits of various thrombolytic agents with earlier administration are uncertain. METHODS: We evaluated the relations of baseline characteristics to three prospectively defined time variables: symptom onset to treatment, symptom onset to hospital arrival (presentation delay) and hospital arrival to treatment (treatment delay). We also examined the relations of delays to clinical outcomes and to the relative 30-day mortality benefit with accelerated tissue-type plasminogen activator (t-PA) versus streptokinase. RESULTS: Female, elderly, diabetic and hypertensive patients had longer delays at all stages. Previous infarction or bypass surgery was an additional risk factor for treatment delay. Early thrombolysis was associated with lower overall mortality rate (< 2 h, 5.5%; > 4 h, 9.0%), but no additional relative benefit resulted from earlier treatment with accelerated t-PA versus streptokinase (p = 0.38). Longer presentation and treatment delays were both associated with increased mortality rate (presentation delay < 1 h, 5.6% and > 4 h, 8.6%; treatment delay < 1 h, 5.4%, and > 90 min, 8.1%). As time to treatment increased, the incidence of recurrent ischemia or reinfarction decreased, but the rates of shock, heart failure and stroke increased. CONCLUSIONS: Earlier treatment resulted in better outcomes, regardless of thrombolytic strategy. Elderly, female and diabetic patients were treated later, adding to their already substantial risk.

Comparisons of characteristics and outcomes among women and men with acute myocardial infarction treated with thrombolytic therapy. GUSTO-I investigators.

OBJECTIVE: To compare baseline characteristics, complications, and treatment-specific outcomes of women and men with acute myocardial infarction treated with thrombolytic therapy. DESIGN: Randomized controlled trial. PATIENTS AND SETTING: A total of 10315 women and 30706 men with acute myocardial infarction treated in 1081 hospitals in 15 countries as part of the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-I). INTERVENTION: One of four thrombolytic regimens: (1) streptokinase with subcutaneous heparin; (2) streptokinase with intravenous heparin; (3) streptokinase plus alteplase (tissue-type plasminogen activator) with intravenous heparin; or (4) accelerated alteplase with intravenous heparin. MAIN OUTCOME MEASURES: Mortality, stroke, and nonfatal complications during 30-day follow-up. RESULTS: Women were on average 7 years older than men and delayed 18 minutes (median) longer after symptom onset before presenting to the hospital. After adjustment for age, women more often had a history of diabetes, hypertension, and smoking than men. Time to treatment was significantly longer in women (1.2 vs 1.0 hours; P<.001). Women had more nonfatal complications after treatment, including shock (9% vs 5%; P<.001), congestive heart failure (22% vs 14%; P<.001), serious bleeding (15% vs 7%; P<.001), and reinfarction (5.1% vs 3.6%; P<.001). Women had twice as many total strokes as men (2.1% vs 1.2%; P<.001), secondary to their older age at presentation. The unadjusted mortality rate was twice as high in women as men (11.3% vs 5.5%; P<.001); the relative risk (RR) of death was greater among women than men after adjustment for differences in baseline characteristics (RR=1.15; 95% confidence interval, 1.0 to 1.31). Although women and men underwent angiography at similar rates, there were small but significant differences in their rates of revascularization procedures (angioplasty: 35% of women and 32% of men; bypass surgery: 7% of women and 9% of men; P<.001 for both). The higher rate of stroke in women after treatment with alteplase (2.0% vs 1.9% with streptokinase and intravenous heparin) was offset by a greater relative reduction in mortality (10.3% vs 11.1%). CONCLUSION: Women who received thrombolytic therapy for treatment of acute myocardial infarction were at greater risk for both fatal and nonfatal complications than men.

Stroke after thrombolysis. Mortality and functional outcomes in the GUSTO-I trial. Global Use of Strategies to Open Occluded Coronary Arteries.

BACKGROUND: Stroke is the most feared complication of thrombolysis for acute myocardial infarction because of the resulting mortality and disability. We analyzed the incidence, timing, and outcomes of stroke in an international trial. METHODS AND RESULTS: Patients were randomly assigned to one of four thrombolytic strategies. Neurological events were confirmed clinically and anatomically and were adjudicated by a blinded committee. Stroke survivors, categorized by residual deficit and disability, assessed their quality of life with a time trade-off technique. Multivariable regression identified patient characteristics associated with intracranial hemorrhage. Over-all, 1.4% of the patients had a stroke (93% anatomic documentation). The risk ranged from 1.19% with streptokinase/subcutaneous heparin therapy to 1.64% with combination thrombolytic therapy (P = .007). Primary intracranial hemorrhage rates ranged from 0.46% with streptokinase/subcutaneous heparin to 0.88% with combination therapy (P < .001). Of all strokes, 41% were fatal, 31% were disabling, and 24% were nondisabling, with no significant treatment-related differences. Stroke subtype affected prognosis: 60% of patients with primary intracranial hemorrhage died and 25% were disabled versus 17% dead and 40% disabled with nonhemorrhagic infarctions. Patients with moderate or severe residual deficits showed significantly decreased quality of life. Advanced age, lower weight, prior cerebrovascular disease or hypertension, systolic and diastolic blood pressures, randomization to tissue plasminogen activator, and an interaction between age and hypertension were significant predictors of intracranial hemorrhage. CONCLUSIONS: Stroke remains a rare but catastrophic complication of thrombolysis. Additional studies should assess the net clinical benefit of thrombolysis in high-risk subgroups, particularly the elderly and patients with prior cerebrovascular events.