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Objective: Cardiogenic shock is a major cause of death in ST elevation myocardial infarction. We investigated whether determination of plasma [corrected] B-type natriuretic peptide and the N-terminal fragment of its pro-hormone in the acute phase of ST elevation myocardial infarction could identify patients prone to development of cardiogenic shock., Design: Retrospective analysis of a multicenter, randomized open-label trial (ASSENT-4 PCI; ClinicalTrials.gov Identifier: NCT00168792)., Methods: Plasma B-type natriuretic peptide and the N-terminal fragment of its pro-hormone were determined in available stored samples of 1016 ST elevation myocardial infarction patients without signs of cardiogenic shock at randomization to primary percutaneous coronary intervention or to full-dose tenecteplase before percutaneous coronary intervention. The end point of the present analysis was in-hospital cardiogenic shock., Interventions: None., Measurements and Main Results: In total, 57 (5.6%) patients had cardiogenic shock during index hospitalization. In-hospital cardiogenic shock increased precipitously with higher baseline concentrations of plasma B-type natriuretic peptide and the N-terminal fragment of its pro-hormone (B-type natriuretic peptide and the N-terminal fragment of its pro-hormone < or =67 pg/mL: 1.9%; 68-1482 pg/mL: 5.9%; >1482 pg/mL: 14.9%; p < .001). Higher plasma [corrected] B-type natriuretic peptide and the N-terminal fragment of its pro-hormone concentrations were predictors of in-hospital shock, especially among those patients with relatively low clinical risk (no requirement of inotropic support before angiography, systolic blood pressure >100 mm Hg, heart rate <100 bpm, Global Utilization of Streptikonase and Tissue-Plasminogen Activator for Occluded Coronary Arteries score of <122). In multivariate Cox regression analysis, higher plasma B-type natriuretic peptide and the N-terminal fragment of its pro-hormone concentrations remained significant predictors of shock, in addition to age, systolic blood pressure, heart rate, and randomization to facilitated percutaneous coronary intervention and Killip classification. Furthermore, plasma B-type natriuretic peptide and the N-terminal fragment of its pro-hormone significantly predicted in-hospital shock independently of the validated Global Utilization of Streptikonase and Tissue-Plasminogen Activator for Occluded Coronary Arteries score (p = .014)., Conclusion: Plasma B-type natriuretic peptide and the N-terminal fragment of its pro-hormone concentrations measured early in the acute phase of ST elevation myocardial infarction are useful in predicting the development of in-hospital cardiogenic shock.

Background: We investigated the prognostic significance of plasma N-terminal fragment of the prohormone B-type natriuretic peptide (Nt-proBNP) concentrations in addition to time to reperfusion and Thrombolysis in Myocardial Infarction (TIMI) flow before and after coronary intervention in patients with ST elevation myocardial infarction (STEMI) from the database of the Assessment of the Safety and Efficacy of a New Treatment Strategy with Percutaneous Coronary Intervention (ASSENT IV-PCI) trial., Methods: Plasma Nt-proBNP was available in 1,037 patients with STEMI. Patients were randomized either to primary (p-PCI) or to full-dose tenecteplase before PCI (f-PCI).The study end point was the composite of death, cardiogenic shock, or congestive heart failure at 90 days., Results: According to classification tree analysis, patients with Nt-proBNP levels >694 pg/mL had the highest primary end point rates (33.8% vs 11%, P < .001). In Cox regression analysis, Nt-proBNP >694 pg/mL strongly predicted 90-day survival even among patients with short treatment delay (f-PCI < or =3 hours: hazard ratio [HR] 2.63, P = .002 and p-PCI < or =3 hours: HR 4.87, P < .001, respectively). Patients with TIMI 3 flow after coronary intervention were at significantly higher risk of the primary end point if admission Nt-proBNP exceeded 694 pg/mL (f-PCI: HR 2.88, P < .001 and p-PCI: HR 3.84, P < .001, respectively). In multivariable analysis, Nt-proBNP >694 pg/mL significantly (P = .001) predicted 90-day survival in addition to age (P < .001), TIMI flow after PCI (P < .001), body mass index (P = .026), anterior wall infarction (P = .035), and systolic blood pressure at randomization (P = .036), respectively., Conclusion: Elevated plasma concentrations of Nt-proBNP in the early phase of STEMI determine in-hospital and 90-day outcome after infarction irrespective of time to treatment and pre- or postinterventional TIMI flow., (Copyright 2010 Mosby, Inc. All rights reserved.)

Objectives: We have performed a retrospective analysis of the data stratified by time to treatment and by enrollment site: percutaneous coronary intervention hospitals (PCIH), nonpercutaneous coronary intervention hospitals (NoPCIH), or in a pre-hospital setting (PreH)., Background: The ASSENT-4 PCI (Assessment of the Safety and Efficacy of a New Treatment Strategy with Percutaneous Coronary Intervention) trial intended to test the hypothesis that in ST-segment elevation myocardial infarction (STEMI) patients an upfront fibrinolytic bolus before PCI ("facilitated PCI") compared with primary PCI would benefit STEMI patients facing a long pre-PCI delay., Methods: Seven hundred forty-nine patients (45%) presented directly to PCIH, 578 (34%) presented to NoPCIH, and 334 (20%) were randomized and initially treated in the PreH setting., Results: Patients in the PreH-facilitated group had the shortest delays (pain-to-fibrinolytic treatment 125 min) and the lowest 90-day mortality (3.1%). Among patients randomized to primary PCI, the shortest time from pain to first balloon was similarly in the PreH group (223 min). They had the lowest mortality of the primary PCI patient groups (4.1%). The highest mortality (8.4%) was in patients presenting to a PCIH and assigned to the facilitated strategy. Their pain-to-lysis time was 174 min and pain-to-PCI time 266 min (or 92 min after lysis)., Conclusions: Few patients fit the target population, long delays to PCI for whom facilitated PCI was designed. Patients treated early after pain onset in the PreH setting do well after a facilitated approach. Despite limitations of post hoc subgroup analysis, these observations suggest caution in extrapolating the results of the ASSENT-4 trial to the "real world" where many patients might have potentially short pain-to-fibrinolysis time but are facing a long transport time to primary PCI.

We developed a regional strategy to decrease the time to percutaneous coronary intervention (PCI) for patients with acute ST-segment elevation myocardial infarction (STEMI). Protocols were created for paramedics and referring hospitals to identify and directly triage all patients with STEMI to a single PCI center. Time to PCI reperfusion and in-hospital mortality were assessed in 233 consecutive patients with STEMI. Ninety-minute initial hospital door-to-patent infarct artery was achieved in 58.3% of paramedic-diagnosed and directly triaged patients compared with 37.5% of "walk-ins" to the PCI hospital and with only 5.2% of those transferred from another hospital emergency department (ED; p <0.001). Overall in-hospital mortality was 2.1%, 0% in paramedic identified patients, and 0% in those walk-ins to the PCI hospital ED compared with 4.3% for those transferred from a referring hospital ED (p = 0.007). Paramedic diagnosis of STEMI and direct triage to a prealerted interventional hospital for primary PCI was associated with a high percentage of patients achieving <90-minute infarct artery patency. Substantial delays remained for those who presented initially to a non-PCI hospital ED despite the expedited protocol. In conclusion, this observational study suggests that wider use of paramedic electrocardiographic STEMI diagnosis and direct triage to a prealerted PCI hospital catheterization team may help improve outcomes of patients with STEMI.

Aims: The purpose of this analysis was to determine whether the efficacy of adenosine vs. placebo was dependent on the timing of reperfusion therapy in the second Acute Myocardial Infarction Study of Adenosine (AMISTAD-II)., Methods and Results: Patients presenting with ST-segment elevation anterior AMI were randomized to receive placebo vs. adenosine (50 or 70 microg/kg/min) for 3 h starting within 15 min of reperfusion therapy. In the present post hoc hypothesis generating study, the results were stratified according to the timing of reperfusion, i.e. > or = or < the median 3.17 h, and by reperfusion modality. In patients receiving reperfusion < 3.17 h, adenosine compared with placebo significantly reduced 1-month mortality (5.2 vs. 9.2%, respectively, P = 0.014), 6-month mortality (7.3 vs. 11.2%, P = 0.033), and the occurrence of the primary 6-month composite clinical endpoint of death, in-hospital CHF, or rehospitalization for CHF at 6 months (12.0 vs. 17.2%, P = 0.022). Patients reperfused beyond 3 h did not benefit from adenosine., Conclusion: In this post hoc analysis, 3 h adenosine infusion administered as an adjunct to reperfusion therapy within the first 3.17 h onset of evolving anterior ST-segment elevation AMI enhanced early and late survival, and reduced the composite clinical endpoint of death or CHF at 6 months.

Objectives: The purpose of this research was to determine the effect of intravenous adenosine on clinical outcomes and infarct size in ST-segment elevation myocardial infarction (STEMI) patients undergoing reperfusion therapy., Background: Previous small studies suggest that adenosine may reduce the size of an evolving infarction., Methods: Patients (n = 2,118) with evolving anterior STEMI receiving thrombolysis or primary angioplasty were randomized to a 3-h infusion of either adenosine 50 or 70 microg/kg/min or of placebo. The primary end point was new congestive heart failure (CHF) beginning >24 h after randomization, or the first re-hospitalization for CHF, or death from any cause within six months. Infarct size was measured in a subset of 243 patients by technetium-99m sestamibi tomography., Results: There was no difference in the primary end point between placebo (17.9%) and either the pooled adenosine dose groups (16.3%) or, separately, the 50-microg/kg/min dose and 70-microg/kg/min groups (16.5% vs. 16.1%, respectively, p = 0.43). The pooled adenosine group trended toward a smaller median infarct size compared with the placebo group, 17% versus 27% (p = 0.074). A dose-response relationship with final median infarct size was seen: 11% at the high dose (p = 0.023 vs. placebo) and 23% at the low dose (p = NS vs. placebo). Infarct size and occurrence of a primary end point were significantly related (p < 0.001)., Conclusions: Clinical outcomes in patients with STEMI undergoing reperfusion therapy were not significantly improved with adenosine, although infarct size was reduced with the 70-microg/kg/min adenosine infusion, a finding that correlated with fewer adverse clinical events. A larger study limited to the 70-microg/kg/min dose is, therefore, warranted.

The clinically available IIb/IIIa antagonists have been studied in small angiographic trials of patients who receive these adjuncts combined with reduced doses of fibrinolytics for the purpose of evaluating their impact on infarct artery patency restoration in acute myocardial infarction. Larger clinical endpoint trials have then looked at some of these combinations, particularly with abciximab, to characterize mortality, morbidity and adverse event frequencies when compared with more traditional full dose fibrinolytic therapy. Similarly these agents have been evaluated (without fibrinolytics) for their potential to improve the results of mechanical reperfusion techniques. This article will summarize these experiences in terms of benefits and adverse events. The value of these drugs in STEMI seems modest at best.

Objectives: The purpose of this study was to quantify the effect of time delays to reperfusion on ventricular function after myocardial infarction. This allows one to identify a group of patients in whom a strategy using antecedent pharmacologic reperfusion therapy before planned direct angioplasty may offer significant benefit., Background: Direct angioplasty for myocardial infarction is associated with a high rate of successful reperfusion compared with pharmacologic reperfusion. However, there is an inherent time delay to treatment with angioplasty compared with pharmacologic therapy. There currently are insufficient data to determine the consequences of incremental time delays to reperfusion on ventricular function., Methods: We determined, by logistic regression analysis, the probability of observing a decrement in postmyocardial infarction ventricular function as a function of incremental time delays to reperfusion., Results: Time delays of 30, 60, 90, or 120 minutes to reperfusion increased the likelihood of a worse ventricular function outcome by 1.1-, 1.3-, 1.5-, and 1.7-fold, respectively (P <.02). The upper 95% confidence limits around these odds ratios are as high as 1.3 or 2.7 for 30- and 120-minute delays, respectively. Time from symptom onset to patency remained a significant determinant of ventricular function after adjustment for clinical and procedural factors., Conclusions: Delay in time to reperfusion, measured in minutes, results in significant loss of ventricular function after myocardial infarction. Interventional strategies designed for treatment of myocardial infarction when "door-to-balloon" time is expected to exceed 60 minutes should strongly consider incorporation of pharmacologic reperfusion therapy into the therapeutic paradigm.

In the treatment of acute myocardial infarction, delayed reperfusion therapy is associated with increased mortality. Predictors of delay have been described for fibrinolysis but not for primary percutaneous transluminal coronary angioplasty (pPTCA). Therefore, we studied 40,017 consecutive patients with acute myocardial infarction who underwent pPTCA in the National Registry of Myocardial Infarction between June 1994 and April 2000. Median door-to-balloon times were calculated, and factors independently associated with a delay of >120 minutes were determined by logistic regression. The median door-to-balloon time among all patients was 111 minutes (interquartile range 84 to 152). The proportion of patients with a delay of >2 hours was greater among those aged > or = 65 years (49% vs 41%), women (50% vs 42%), patients with contraindications to fibrinolysis (60% vs 41%), and those without chest pain on admission (61% vs 43%, all p <0.0001). Delay was also more common with transfer from another hospital (87% vs 38%), with presentation outside the hours of 8 A.M. to 4 P.M. (51% vs 38%), and in hospitals performing <49 pPTCAs/year (47% vs 41%, all p <0.0001). The strongest independent predictor of delay was hospital transfer, along with non-daytime presentation and low-volume centers. Older age, female sex, and non-white race were weaker predictors. Both patient and hospital factors are associated with delay in pPTCA after presentation. These findings may help design treatment algorithms to minimize delay, thus improving the survival benefit of pPTCA. These results may also help design trials of combination reperfusion strategies.

Background: Adjunctive unfractionated heparin (UFH) during thrombolytic therapy for acute myocardial infarction (AMI) promotes the speed and magnitude of coronary artery recanalization and reduces reocclusion. Low-molecular-weight heparins offer practical and potential pharmacological advantages over UFH in multiple applications but have not been systematically studied as adjuncts to fibrinolysis in AMI., Methods and Results: Four hundred patients undergoing reperfusion therapy with an accelerated recombinant tissue plasminogen activator regimen and aspirin for AMI were randomly assigned to receive adjunctive therapy for at least 3 days with either enoxaparin or UFH. The study was designed to show noninferiority of enoxaparin versus UFH with regard to infarct-related artery patency. Ninety minutes after starting therapy, patency rates (thrombolysis in myocardial infarction [TIMI] flow grade 2 or 3) were 80.1% and 75.1% in the enoxaparin and UFH groups, respectively. Reocclusion at 5 to 7 days from TIMI grade 2 or 3 to TIMI 0 or 1 flow and TIMI grade 3 to TIMI 0 or 1 flow, respectively, occurred in 5.9% and 3.1% of the enoxaparin group versus 9.8% and 9.1% in the UFH group. Adverse events occurred with similar frequency in both treatment groups., Conclusions: Enoxaparin was at least as effective as UFH as an adjunct to thrombolysis, with a trend toward higher recanalization rates and less reocclusion at 5 to 7 days.

Background: Reports from Japan suggest effective myocardial infarction (MI) treatment in Asian patients with much lower doses of tissue plasminogen activators (tPA) than used in European and American regimens. Because increasing doses of fibrinolytics lead to increased bleeding complications, identification of patients who respond to reduced doses is of importance. We conducted a trial in the People's Republic of China in which reduced-dose recombinant tPA was compared with the standard local therapy, urokinase., Methods: Four hundred patients with acute MI within 12 hours of symptom onset were to be randomized to an 8-mg bolus of recombinant tPA followed by a 42-mg 90-minute infusion or 1.5 million units of urokinase as a 30-minute infusion. Patients received aspirin and heparin and underwent angiography to determine infarct artery patency 90 minutes after the start of therapy., Results: The Data and Safety Monitoring Board recommended premature termination after 342 patients were recruited. Infarct artery patency (grade 2 or 3) occurred in 79% of patients receiving recombinant tPA and in 53% of patients receiving urokinase (P <.001); Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow was 48% and 28%, respectively (P <.001). The higher-patency-rate recombinant tPA growth had better posttreatment left ventricular ejection fractions, 58.6% versus 54.7%, P <.01. Adverse events were infrequent and not significantly different in the 2 groups., Conclusions: This study confirms that a substantially lower dose of recombinant tPA is effective in Asian patients compared with that required in Western patients even after consideration of body weight. Specific dose-response studies should be performed with fibrinolytic regimens to avoid overdosage with its attendant risks of excess bleeding.

Background: Despite the significant survival benefit associated with successful reperfusion therapy for acute myocardial infarction, global indices of outcome left ventricular function, such as ejection fraction, have often demonstrated little or no improvement. Although these measurements are confounded by numerous clinical, physiologic, and angiographic variables, no comprehensive analysis of this issue in a large series of patients is available. We used the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-I) database to better understand this phenomenon by determining independent predictors of left ventricular function and their interplay with regard to outcome ventricular function and improvement in function during the initial postinfarction week., Methods: Ninety-minute and 5- to 7-day posttreatment global and regional indices derived from left ventriculograms were analyzed from a population of 676 patients. These observations were combined with clinical data to describe independent determinants of ventricular function outcome., Results: Clinical factors predictive of global and regional ventricular function as well as improvement in function between 90 minutes and 5 to 7 days included time to treatment, early infarct-related artery flow grade, and body mass index. These same factors contribute significantly to compensatory hyperkinesis of the noninfarct zone, which is critical to maintenance of global ventricular function during this time period., Conclusions: The ventricular function benefits of early complete reperfusion after myocardial infarction are readily demonstrable after adjustment for multiple covariables and include (1) maintenance of global ventricular function and (2) prevention or delay in ventricular dilatation.

Background: The grade of ischemia, as detected by the relation between the QRS complex and ST segment on the admission electrocardiogram, is associated with larger infarct size and increased mortality rates in acute myocardial infarction., Methods: We assessed the correlation between left ventricular function and the admission electrocardiogram in 151 patients with first anterior acute myocardial infarction who received thrombolytic therapy and underwent cardiac catheterization at 90 minutes and before hospital discharge. The number of leads with ST elevation, sum of ST elevation, maximal Selvester score, and the presence of severe (grade 3) ischemia were determined in each electrocardiogram. Left ventricular ejection fraction, the number of chords with wall motion abnormalities, and the severity of dysfunction (SD/chord) were determined., Results: At 90 minutes, the 39 ischemia grade 3 patients had lower ejection fraction than the 112 grade 2 patients. Both at 90 minutes and at hospital discharge, the grade 3 group had more chords with wall motion abnormalities and more severe regional dysfunction (SD/chord). However, the number of leads with ST elevation, sum of ST elevation, and maximal Selvester score had no correlation with ejection fraction at 90 minutes and only mild correlation with the extent of dysfunction (number of chords) at 90 minutes. There was no correlation between either the number of leads with ST elevation or the sum of ST elevation and the severity of regional dysfunction., Conclusions: The number of leads with ST elevation, sum of ST elevation, and maximal Selvester score had only mild correlation with the extent of myocardial dysfunction but not with the severity of dysfunction. Grade 3 ischemia is predictive of more extensive myocardial involvement and greater severity of regional dysfunction.

Background: Post-myocardial infarction global ejection fraction and infarct-related artery patency might be expected to be associated with health-related quality-of-life (HRQOL) outcomes, but this association has not been previously shown. The GUSTO-I Angiographic Study cohort 2-year follow-up afforded an examination of such potential relationships., Methods and Results: A total of 1848 patients (87.7% response rate) who were enrolled in the GUSTO-I Angiographic Study were contacted for a telephone interview regarding their current HRQOL (physical function, psychological well-being, perceived health status, and social function) 2 years after MI. In multivariable models, left ventricular ejection fraction (EF) was significantly related to physical (P:=0.021) and social (P:=0.014) function, psychological well-being (P:=0.042), and perceived health status (P:=0.024). Infarct-related artery patency was not directly related to any HRQOL outcome. A decreasing EF was predictive of poorer outcomes in each HRQOL dimension. Men consistently had better outcomes in all HRQOL dimension with the exception of perceived health status. Increasing age was predictive of poorer outcomes in all dimensions of HRQOL except for psychological well-being where the inverse occurred; younger patients experienced greater depression, anxiety and worry than their older counterparts. The presence of comorbidities increased the likelihood of worse outcomes in all dimensions., Conclusions: This is the first study to demonstrate a significant relationship between EF and long-term HRQOL outcomes. This advantage in left ventricular function preservation should be added to the mortality advantage when considering the impact of treatment strategies for myocardial infarction.

Background: Antithrombotic adjuncts to fibrinolytic drugs for acute myocardial infarction increase the rate and speed of infarct artery recanalization., Hypothesis: A low-molecular-weight heparin might be preferable to unfractionated heparin for this indication, as it has been shown to be in several other thrombus-related vascular disorders., Methods: We performed a pilot study in 20 patients, all receiving aspirin and recombinant tissue plasminogen activator. Randomization was to standard dose intravenous unfractionated heparin or enoxaparin (the first dose given intravenously and followed by a subcutaneous administration). The endpoint was stability of anticoagulant effect., Results: Enoxaparin produced stable therapeutic anti-Xa levels with minimal effect on activated partial thromboplastin times. Unfractionated heparin produced wide swings of these parameters, often outside desired levels., Conclusions: Enoxaparin may be a better antithrombotic agent than conventional unfractionated heparin when used in conjunction with fibrinolytics.

Objectives: The study evaluated the efficacy and safety of a short-acting reduced-dose fibrinolytic regimen to promote early infarct-related artery (IRA) patency during the inherent delay experienced by infarct patients referred for angioplasty as the principal recanalization modality., Background: Previous approaches using long-acting, full-dose thrombolytic infusions rarely showed benefit, but they did increase adverse event rates., Methods: Following aspirin and heparin, 606 patients were randomized to a 50-mg bolus of recombinant tissue-type plasminogen activator (rt-PA) (alpha half-life 4.5 min) or to placebo followed by immediate angiography with angioplasty if needed. The end points included patency rates on catheterization laboratory (cath lab) arrival, technical results when PTCA (percutaneous transluminal coronary angioplasty) was performed, complication rates, and left ventricular (LV) function by treatment assignment and time to restored patency following angioplasty., Results: Patency on cath lab arrival was 61% with rt-PA (28% Thrombolysis in Myocardial Infarction trial [TIMI]-2, 33% TIMI-3), and 34% with placebo (19% TIMI-2, 15% TIMI-3) (p = 0.001). Rescue and primary PTCA restored TIMI-3 in closed arteries equally (77%, 79%). No differences were observed in stroke or major bleeding. Left ventricular function was similar in both treatment groups, but convalescent ejection fraction (EF) was highest with a patent IRA (TIMI-3) on cath lab arrival (62.4%) or when produced by angioplasty within an hour of bolus (62.5%). However, in 88% of angioplasties, the delay exceeded 1 h: convalescent EF 57.3%., Conclusions: Tailored thrombolytic regimens compatible with subsequent interventions lead to more frequent early recanalization (before cath arrival), which facilitates greater LV function preservation with no augmentation of adverse events.

Rapid restoration of patency of the infarct-related artery is the key to preserving myocardium and improving survival. This understanding has led to the application of genetic engineering to develop new plasminogen activators with specific clinical features. These novel activators may provide faster and more complete reperfusion in a greater number of patients, and do so with less risk of bleeding and intracranial hemorrhage. This article reviews the pharmacologic profiles and clinical performance of several novel plasminogen activators engineered from the human tissue plasminogen activator molecule or developed from animal and bacterial proteins.

This study assessed whether differences in the underlying mechanisms for various patterns of precordial ST-segment depression with inferior acute myocardial infarction (AMI) are associated with poorer prognoses. We studied 1,155 patients with inferior AMI who underwent thrombolysis in the Global Utilization of Streptokinase and TPA for Occluded arteries (GUSTO-I) angiographic substudy: those without precordial ST depression (n = 412; 35.7%), those with maximum ST depression in leads V1 to V3 (n = 547; 47.4%), and those with maximum ST depression in leads V4 to V6 (n = 196; 17.0%) on admission electrocardiogram. We compared the infarct-related artery, presence of left anterior descending or multivessel coronary artery disease, and left ventricular function among groups. Patients with maximum ST depression in leads V4 to V6 more often had 3-vessel disease (26.0%) than those without precordial ST depression (13.5%) or those with ST depression in leads V1 to V3 (15.7%; p = 0.002), and they had a lower ejection fraction (median 54% vs 60% and 55%, respectively; p <0.001). Patients with maximum ST depression in leads V1 to V3 less often had AMIs due to proximal right coronary artery obstruction (23.9%) than patients without precordial ST depression (35.2%) or those with ST depression in leads V4 to V6 (40.0%; p = 0.001) and had larger AMIs as estimated by peak creatine kinase. Different patterns of precordial ST depression are associated with distinctive coronary anatomy. ST depression in leads V4 to V6, but not V1 to V3, confers a greater likelihood of multivessel coronary artery disease.

Objectives: The purpose of this study was to determine patient characteristics that are a priori predictors of early infarct related artery patency following thrombolytic therapy, and to provide a paradigm which may identify patients who would be most likely to achieve restoration of normal (TIMI 3) coronary flow in response to thrombolytic therapy., Background: Restoration of infarct-related artery perfusion in acute myocardial infarction is necessary for preservation of ventricular function and mortality reduction. Clinical variables that are a priori predictors of early patency with currently available thrombolytic regimens have not been fully characterized., Methods: The probability of early infarct-related artery patency (TIMI 3 flow) was determined by multivariable logistic regression. We determined a reduced (parsimonious) model for predicting early (90 min) infarct-related artery patency (TIMI grade 3) based on data from 1,030 patients in the GUSTO-I Angiographic study., Results: Predictors of 90 min TIMI 3 flow are use of an accelerated t-PA regimen (vs. streptokinase containing regimens) (chi2=39.1; p < or = 0.0001), infarct related artery (RCA/Lcx vs. LAD) (chi2=12.7; p=0.0004), body weight (chi2=10.3; p=0.001) and history of smoking (chi2=7.4; p=0.007). Time from symptom onset to treatment was not significant (p=0.71)., Conclusions: The efficacy of currently available thrombolytic regimens is chiefly dependent on choice of thrombolytic regimen, body weight, infarct-related coronary artery and smoking history. Clinical variables alone correctly predict a priori TIMI 3 flow in the infarct-related artery 64% of the time. Patients with body weights greater than 85 kg are at a significant disadvantage with regard to achieving successful thrombolysis compared to those with lesser body weights.

Objectives: We sought to assess the angiographic outcome, complication rates and clinical features of percutaneous transluminal coronary angioplasty (PTCA) after failed thrombolysis for acute myocardial infarction., Background: "Rescue angioplasty" refers to mechanical reopening of an occluded infarct-related artery (IRA) after failed intravenous thrombolysis. Although the procedure is commonly performed, data describing its technical and clinical outcome are sparse. Early reports suggested that rescue PTCA is less often successful and produces more complications than primary PTCA. Other reports have described beneficial effects of successful rescue PTCA but adverse outcomes when PTCA is unsuccessful., Methods: Using data from the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-1) angiographic substudy, we compared clinical and angiographic outcomes of 198 patients selected for a rescue PTCA attempt with those of 266 patients with failed thrombolysis but managed conservatively and, for reference, with those of 1,058 patients with successful thrombolysis., Results: Patients offered rescue PTCA had more impaired left ventricular function than those in whom closed vessels were managed conservatively. Rescue successfully opened 88.4% of closed arteries, with 68% attaining Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow. The interventions did not increase catheterization laboratory or postprocedural complication rates. Multivariate analysis identified severe heart failure to be a determinant of a failed rescue attempt. Successful rescue PTCA resulted in superior left ventricular function and 30-day mortality outcomes, comparable to outcomes in patients with closed IRAs managed conservatively, but less favorable than in patients in whom thrombolytic therapy was initially successful. The mortality rate after a failed rescue attempt was 30.4%; however, five of the seven patients who died after failed rescue PTCA were in cardiogenic shock before the procedure., Conclusions: Rescue PTCA tends to be selected for patients with clinical predictors of a poor outcome. It is effective in restoring patency. Patients who die after a failed rescue attempt are often already in extremis before the angioplasty attempt.

Background: Reperfusion therapy for myocardial infarction, understood to reduce mortality by preserving left ventricular function, was initially expected to provide increasing benefits over time. Surprisingly, large controlled thrombolysis trials demonstrated maximum benefit at 4 to 6 weeks with no subsequent increased treatment advantage. Such studies, however, compared groups by assigned treatment, not physiological effectiveness., Methods and Results: We calculated 2-year survival differences among 2431 myocardial infarction patients according to early infarct artery patency and outcome left ventricular ejection fraction using Kaplan-Meier curves. Hazard ratios for significant survival determinants were derived from Cox regression models. Two-year vital status (minimum, 688 days) was determined in 2375 patients (97.7%). A substantial mortality advantage for early complete reperfusion (Thrombolysis in Myocardial Infarction [TIMI] grade 3) and for preserved ejection fraction occurred beyond 30 days. The unadjusted hazard ratio for the TIMI 3 group compared with lesser grades at 30 days was 0.57 (95% confidence interval [CI], 0.35 to 0.94) and 30 days to > or = 688 days was 0.39 (95% CI, 0.22 to 0.69). Consequently, early TIMI 3 flow was associated with approximately a 3 patient per 100 mortality reduction the first month with an additional 5 lives per 100 from 30 days to 2 years. For ejection fraction >40% compared with < or = 40%, the unadjusted hazard ratio was 0.25 (95% CI, 0.16 to 0.37) at 30 days and 0.22 (95% CI, 0.15 to 0.33) after 30 days through 2 years (lives saved, approximately 9 and 11 per 100, respectively)., Conclusions: Successful reperfusion and myocardial salvage produce significant mortality benefits that are amplified beyond the initial 30 days.

Objectives: We sought to assess the effects of antithrombotic therapy after thrombolysis for acute myocardial infarction on markers of thrombin generation and activity and to determine the relation of these markers with clinical outcomes., Background: Thrombin activation and generation often occur with thrombolysis for acute myocardial infarction. Antithrombotic regimens have been developed to reduce the resulting thrombotic complications., Methods: We sampled plasma markers of thrombin generation and activity after thrombolysis in 292 patients. We assessed the relations of these markers with clinical outcomes at 30 days., Results: Fibrinopeptide A (FPA), a marker of thrombin activity toward fibrinogen, was elevated at baseline (12.3 ng/ml) and increased to 18.4 ng/ml by 90 min after streptokinase and subcutaneous heparin treatment. With intravenous heparin, this increase was attenuated, but intravenous heparin did not prevent thrombin generation, as measured by prothrombin fragment 1.2 (F1.2). Heparin level, measured by anti-Xa activity, correlated with activated partial thromboplastin time (aPTT, r = 0.62 to 0.67). Thrombin activity, measured by FPA, was as closely related to aPTT as to the heparin level. Baseline levels of F1.2 were significantly related to the risk of death or reinfarction at 30 days (p = 0.008); values 12 h after enrollment also were related to 30-day mortality (p = 0.05)., Conclusions: Although intravenous heparin partly suppresses the increased thrombin activity associated with thrombolysis, it does not inhibit thrombin generation. The aPTT was as good a measure of suppression of thrombin activity as the heparin level itself. Hematologic markers of thrombin generation were found to be related to the subsequent risk of thrombotic events.

Background: Although the stratification of patients with myocardial infarction into ECG subsets based on the presence or absence of new Q waves has important clinical and prognostic utility, systematic evaluation of the impact of thrombolytic therapy on the subsequent development and prognosis of non-Q-wave infarction has been limited to date., Methods and Results: We examined 12-lead ECG, coronary anatomy, left ventricular function, and mortality among 2046 patients with ST-segment elevation infarction from the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries angiographic subset to gain further insight into the pathophysiology and prognosis of Q- versus non-Q-wave infarction in the thrombolytic era. Non-Q-wave infarction developed in 409 patients (20%) after thrombolytic therapy. Compared with Q-wave patients, non-Q-wave patients were more likely to present with lesser ST-segment elevation in a nonanterior location. The infarct-related artery in non-Q-wave patients was more likely to be nonanterior (67% versus 58%, P=.012) and distally located (33% versus 39%, P=.021). Early (90-minute, 77% versus 65%, P=.001) and complete (54% versus 44%, P<.001) infarct-related artery patency was greater among the non-Q-wave group. Non-Q-wave patients had better global (ejection fraction, 66% versus 57%; P<.0001) and regional left ventricular function (10 versus 24 abnormal chords, P=.0001). In-hospital, 30-day, 1-year, and 2-year (6.3% versus 10.1%, P=.02) mortality rates were lower among non-Q-wave patients., Conclusions: The excellent prognosis among the subgroup of patients who develop non-Q-wave infarction after thrombolysis is related to early, complete, and sustained infarct-related artery patency with resultant limitation of left ventricular infarction and dysfunction.

The primary objective of this study was to characterize a large cohort of patients receiving thrombolytic therapy for acute myocardial infarction with respect to the group with a prior event. Patients were randomly assigned to 1 of 4 thrombolytic strategies. Baseline characteristics, 30-day outcomes, and 1-year mortality were compared between patients with (n = 6,704) and without (n = 34,143) prior myocardial infarction. Patients with prior myocardial infarction presented to the hospital earlier than those having their first event, but institution of thrombolytic therapy was delayed. Mortality at 30 days (11.7% vs 5.9%, p = 0.001) and 1 year (17.3% vs 8.2%, p < 0.001) was greater among patients with prior infarction, and independent of other demographic variables. Accelerated alteplase was more effective than streptokinase or combination therapy (30-day mortality 10.4% vs 12.2%, p = 0.012; 1-year mortality 15.9% vs 17.8%, p = 0.041). Infarct vessel patency did not differ between those with and without prior myocardial infarction (67.3% vs 67% at 90 minutes, p = 0.92); however, recurrent ischemia was more common in patients with prior myocardial infarction. Patients with healed myocardial infarction should be educated to ensure early hospital admission if they develop symptoms suggestive of acute infarction, and upon hospital arrival should be promptly triaged to receive reperfusion therapy with accelerated alteplase.

Background: Left ventricular remodeling is an important sequela of myocardial infarction (MI). Although remodeling occurs soon after MI, the effect of early left ventricular dilatation on outcome is not established and may be useful for early risk stratification. We assessed whether end-systolic volume index (ESVI) at 90 to 180 minutes into thrombolytic therapy for MI is associated with adverse outcomes., Methods and Results: In the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO)-I study, 41021 patients with evolving MI received one of four thrombolytic regimens. At 90 or 180 minutes into reperfusion therapy, 1300 patients underwent left ventriculography. ESVI was measured and correlated with adverse outcomes: 30-day and 1-year mortality and in-hospital congestive heart failure, shock, and reinfarction. Clinical variables were also tested in a stepwise logistic regression analysis to determine predictors of left ventricular dilatation. ESVI was directly related to all adverse outcomes with univariate analysis. ESVI of > or = 40 mL/m2 was independently associated with mortality (adjusted odds ratio [95% confidence interval]: 30-day, 3.4 [2.0 to 5.9]; 1-year, 4:1 [2.6 to 6.2], both P < .001). Male sex, prior angina or MI, weight of < 70 kg, heart rate of > or = 80 bpm, systolic blood pressure of < 110 mm.Hg, and anterior infarction were independent predictors of an ESVI of > or = 40 mL/m2., Conclusions: Left ventricular ESVI early into reperfusion therapy for MI strongly predicts adverse outcomes, including early and late mortality. The study establishes the role of very early left ventricular dilatation on outcome in MI and may be useful in identifying high-risk patients who might benefit from aggressive treatment, including the early use of ACE inhibitors.

We evaluated allergic reactions in 20,201 patients randomized to the streptokinase arms of The Global Utilization of Streptokinase and t-PA (Tissue Plasminogen Activator) in Occluded Coronary Arteries (GUSTO-I) trial, and tested the hypothesis that patients with streptokinase allergy would exhibit higher mortality. After adjusting for baseline variables and time of death, we found comparable coronary patency, left ventricular function, mortality, and bleeding complications between patients with versus those without streptokinase allergy.

Objectives: This study sought to 1) determine the effect of gender on early and late infarct-related artery patency and reocclusion after thrombolytic therapy for acute myocardial infarction; 2) examine the effect of gender on left ventricular function in response to injury/reperfusion; and 3) assess the independent contribution of gender to early (30-day) mortality after acute myocardial infarction., Background: Women have a higher mortality rate than men after myocardial infarction. However, the effect of gender on infarct-related coronary artery patency and left ventricular response to injury/reperfusion have not been fully defined in the thrombolytic era., Methods: Patency rates and global and regional left ventricular function were determined in patients at 90 min and 5 to 7 days after thrombolytic therapy for acute myocardial infarction. The effect of gender on infarct-related artery patency and left ventricular function was determined. Thirty-day mortality differences between women and men were compared., Results: Women were significantly older and had more hypertension, diabetes, hypercholesterolemia, heart failure and shock. They were less likely to have had a previous myocardial infarction, history of smoking or previous bypass surgery. Ninety-minute patency rates (Thrombolysis in Myocardial Infarction [TIMI] flow grade 3) in women and men were 39% and 38%, respectively (p = 0.5). Reocclusion rates were 8.7% in women versus 5.1% in men (p = 0.14). Women had more recurrent ischemia than men (21.4% vs. 17.0%, respectively, p = 0.01). Ninety-minute ejection fraction and regional ventricular function were clinically similar in women and men with TIMI 2 or 3 flow (ejection fraction [mean +/- SD]: 63.4 +/- 6% vs. 59.4 +/- 0.7%, p = 0.02; number of chords: 21.4 +/- 0.9 vs. 21.0 +/- 1.9, p = 0.7; SD/chord: -2.4 +/- 08 vs. -2.4 +/- 0.2, p = 0.9, respectively). No clinically significant differences in left ventricular function were noted at 5- to 7-day follow-up. Women had a greater hyperkinetic response than men in the noninfarct zone (SD/chord: 2.4 +/- 0.2 vs. 1.7 +/- 0.1, p = 0.005). The 30-day mortality rate was 13.1% in women versus 4.8% in men (p < or = 0.0001). After adjustment for other clinical and angiographic variables, gender remained an independent determinant of 30-day mortality., Conclusions: Women do not differ significantly from men with regard to either early infarct-related artery patency rates or reocclusion after thrombolytic therapy or ventricular functional response to injury/reperfusion. Gender was an independent determinant of 30-day mortality after acute myocardial infarction.

Objectives: This study sought to determine whether diabetes mellitus, in the setting of thrombolysis for acute myocardial infarction, affects 1) early infarct-related artery patency and reocclusion rates; and 2) global and regional ventricular function indexes. We also sought to assess whether angiographic or baseline clinical variables, or both, can account for the known excess mortality after myocardial infarction in the diabetic population., Background: Mortality after acute myocardial infarction in patients with diabetes is approximately twice that of nondiabetic patients. It is uncertain whether this difference in mortality is due to a lower rate of successful thrombolysis, increased reocclusion after successful thrombolysis, greater ventricular injury or a more adverse angiographic or clinical profile in diabetic patients., Methods: Patency rates and global and regional left ventricular function were determined in patients enrolled in the GUSTO-I Angiographic Trial. Thirty-day mortality differences between those with and without diabetes were compared., Results: The diabetic cohort had a significantly higher proportion of female and elderly patients, and they were more often hypertensive, came to the hospital later and had more congestive heart failure and a higher number of previous myocardial infarctions and bypass surgery procedures. Ninety-minute patency (Thrombolysis in Myocardial Infarction [TIMI] flow grade 3) rates in patients with and without diabetes were 40.3% and 37.6%, respectively (p = 0.7). Reocclusion rates were 9.2% vs. 5.3% (p = 0.17). Ejection fraction at 90 min after thrombolysis was similar in diabetic and nondiabetic patients ([mean +/- SEM] 6.10 +/- 1.6% vs. 60.1 +/- 0.7%, p = 0.7), as was regional ventricular function (number of abnormal chords: 19.1 +/- 2.0 vs. 17.5 +/- 0.8, p = 0.3; SD/chord: -2.3 +/- 0.2 vs. -2.4 +/- 0.1, p = 0.6). Diabetic patients had less compensatory hyperkinesia in the noninfarct zone (SD/ chord: 1.3 +/- 0.2 vs. 1.7 +/- 0.1, p < or = 0.01). No significant difference in ventricular function was noted at 5- to 7-day follow-up. The 30-day mortality rate was 11.3% in diabetic versus 5.9% in nondiabetic patients (p < or = 0.0001). After adjustment for clinical and angiographic variables, diabetes remained an independent determinant of 30-day mortality (p = 0.02)., Conclusions: Early (90-min) infarct-related artery patency as well as regional and global ventricular function do not differ between patients with and without diabetes after thrombolytic therapy, except for reduced compensatory hyperkinesia in the noninfarct zone among patients with diabetes. Diabetes remained an independent determinant of 30-day mortality after correction for clinical and angiographic variables.

Background: Patients with early Thrombolysis in Myocardial Infarction (TIMI) grade 2 flow after thrombolysis appear to have outcomes similar to thrombolytic failures. To evaluate the origin and evolution of early TIMI 2 flow, we examined early and late angiographic and ventriculographic data from the Global Utilization of Streptokinase and TPA for Occluded Arteries (GUSTO-1) angiographic study., Methods and Results: Of the 914 patients with both 90-minute and 5- to 7-day catheterizations, 278 patients had TIMI grade 2 flow at 90 minutes. At follow-up, 188 (67%) had improved to TIMI grade 3 flow. At 90 minutes, patients with TIMI grade 2 flow had greater infarct vessel narrowing and a significantly greater incidence of thrombus than patients with TIMI grade 3 flow. At the 5- to 7-day follow-up, patients whose flow had improved from TIMI grade 2 at 90 minutes to grade 3 flow at follow-up had larger-caliber vessels (minimum luminal diameter, 0.99 +/- 0.47 versus 0.84 +/- 0.48 mm; P = .03) and a lower incidence of visible thrombus (26% versus 38%, P = .04) than those with persistent TIMI grade 2 flow. These patients also had a higher mean ejection fraction (57.5 +/- 14.1% versus 52.8 +/- 12.9%, P = .02) and better infarct zone wall motion (-2.1 +/- 1.5 versus -2.6 +/- 1.3 SD per chord, P = .01) at the 5- to 7-day follow-up. Patients in whom flow improved from TIMI grade 2 at 90 minutes to TIMI grade 3 by 5 to 7 days had significantly better left ventricular function than patients with persistent TIMI grade 0, 1, or 2 flow and constituted a group whose left ventricular function was intermediate between those who had no reperfusion (TIMI grades 0 and 1) and those whose reperfusion was complete (TIMI grade 3)., Conclusions: These data suggest that incomplete clot lysis plays a significant role in the pathogenesis of TIMI grade 2 flow. Furthermore, early TIMI grade 2 flow may be sufficient to provide prolonged myocyte viability, which will further recover if flow normalizes.

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.

Objective: This study sought to determine whether the recovery of regional and global left ventricular function is reduced in elderly patients despite successful thrombolytic therapy for acute myocardial infarction. Comparisons were made between elderly (> or = 75 years old, n = 47) and adult (< 75 years old, n = 434) patients enrolled in the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) angiographic trial who underwent catheterization at 90 min and 5 to 7 days after thrombolysis and who had an open infarct-related artery with Thrombolysis in Myocardial Infarction (TIMI) grade 2 to 3 flow at both times., Background: The morbidity and mortality of acute myocardial infarction is increased in elderly patients, presumably because of multiple adverse coexistent baseline variables. However, functional recovery after thrombolysis has not been characterized in the elderly., Methods: Ejection fraction, end-systolic volume index, infarct and noninfarct zone contractile function (SD/chord) and infarct extent (number of chords) were determined., Results: At 90 min, elderly patients with an open infarct-related artery had decreased infarct zone contractile function (-2.8 +/- 0.2 vs. -2.3 +/- 0.1 SD/chord in adults, p < or = 0.05) and a greater extent of injury (26.0 +/- 2.6 vs. 20.7 +/- 0.8 chords in adults, p < or = 0.05). At 5- to 7-day follow-up ventriculography, ejection fraction was reduced, and end-systolic volume index was significantly increased in elderly patients compared with adults. The severity of regional wall motion dysfunction in the infarct zone was also greater in the elderly than in adults at 5- to 7-day follow-up (-2.6 +/- 0.2 vs. -1.9 +/- 0.1 SD/chord, respectively, p < or = 0.005). Non-infarct zone contractile function at 90-min ventriculography was similar in both groups. Despite a patent infarct-related artery at 90-min, the 30-day mortality rate in the elderly remained elevated (17.8%) compared with that of adults (4%) (p < or = 0.0001). Elderly patients were predominantly female and had a higher prevalence of hypertension, multivessel coronary disease, previous infarction, anterior infarctions and later time to treatment (between 3 and 6 h) than adults. However, age > or = 75 years remained an independent determinant by multivariable regression analysis of 1-week postinfarction end-systolic volume index, regional left ventricular dysfunction (p = 0.02 and p < or = 0.008, respectively) and 30-day mortality (p < or = 0.0001)., Conclusions: Elderly patients had increased damage in the infarct zone and had persistently increased mortality despite sustained infarct-related artery patency after successful thrombolysis. Although the causes are probably multifactorial, a more rapid progression of ischemic injury or a blunted postreperfusion recovery appears to contribute to the poorer outcomes in elderly patients.

Background: Diminished heart rate variability is associated with less favorable prognosis after myocardial infarction. However, the prognostic value of early (first 48 hours) measurement and the influence of thrombolytic strategies, myocardial infarction location, left ventricular function, ST-segment shift, and infarct-related artery patency on heart rate variability have not been examined comprehensively., Methods and Results: Heart rate variability and ST-segment analysis of 48-hour Holter tapes were performed with the use of a commercial system in 204 patients who were part of an ST-monitoring substudy of the Global Utilization of Streptokinase and TPA for Occluded Arteries (GUSTO-I) trial. Both time-domain measures (SD of the average normal RR interval for all 5-minute segments of a 24-hour ECG recording [SDANN] and percent difference between adjacent normal RR intervals > 50 ms computed over the entire 24-hour ECG recording [pNN50]) and frequency-domain measures (low frequency [LF], high frequency [HF], and LF/HF ratio) were assessed on days 1 and 2 after acute myocardial infarction. Coronary angiography performed within the first 24 hours was also available in 75% of the patients. All heart rate variability measures decreased between day 1 and day 2 (P = .001) except the LF/HF ratio. There was no difference in heart rate variability among groups assigned to one of four different thrombolytic treatment strategies (streptokinase/subcutaneous heparin, streptokinase/intravenous heparin, accelerated tissue plasminogen activator, and combination streptokinase/tissue plasminogen activator). Heart rate variability measures were lower in anterior versus nonanterior infarcts (SDANN, 53 +/- 21 versus 63 +/- 24 ms; P < .005) and increased with TIMI grade 3 flow (LF, 5.3 +/- 1.0 versus 4.8 +/- 1.2 ms2; P < .01) and better ejection fraction (r = .2, P < .03). An inverse correlation between the duration of ST shift and frequency domain measures was observed (LF, r = -.2, P < .009; HF, r = -2, P < .03). Lower LF/HF ratio by 24 hours after myocardial infarction was seen in those who ultimately died at 30 days (1.0 +/- 0.2 versus 1.3 +/- 0.2, P < .001) or at 1 year (1.17 +/- 0.14 versus 1.26 +/- 0.19, P = .05)., Conclusions: Changes in heart rate variability occurred early after thrombolysis and may be of prognostic value. Heart rate variability measures were improved in patients with better ejection fraction and greater angiographic patency. This suggests a possible mechanism for the enhanced survival observed with TIMI grade 3 flow in the GUSTO angiographic substudy. These data indicate that early heart rate variability assessment after myocardial infarction may be useful in noninvasive risk stratification.

Background: There are few data comparing clinical outcome and potential indications for routine post-myocardial infarction cardiac catheterization and revascularization of patients who sustain a non-Q-wave versus Q-wave infarct after thrombolytic therapy., Methods and Results: A secondary analysis of 2634 patients enrolled in the TIMI II trial with a first myocardial infarction was performed to determine 6-week and 1-year cardiac event rates and identify clinical and angiographic differences between the 1867 patients (70.9%) who evolved a Q-wave infarct and the 767 patients (29.1%) who sustained a non-Q-wave infarct after treatment with intravenous thrombolytic therapy. Male sex (85.3% versus 75.6%; P < .001) and anterior wall infarcts (53.8% versus 43.7%; P < .001) were more frequent in the Q-wave versus the non-Q-wave group. During recombinant tissue-type plasminogen activator (rTPA) infusion, a greater percentage of non-Q-wave patients (37.3% versus 23.5%; P = .001) had normalization of initial ST-segment elevation. Infarct-related artery patency (TIMI flow grade 2 or 3) (P = .02), complete infarct-related artery reperfusion (TIMI 3 flow grade) (P < .001), and the percentage of patients with a predischarge resting left ventricular ejection fraction > 55% (P < .001) were greater in the non-Q-wave group. New congestive heart failure during hospitalization developed more frequently in Q-wave patients (18.9% versus 11.6%; P < .001). After 42 days, the occurrences of reinfarction (P = .76), death (P = .76), and combined death or reinfarction (P = .43) were similar in patients assigned to the invasive or conservative postlytic management strategy, regardless of infarct type. One-year mortality was 3.4% versus 4.4% for non-Q-wave versus Q-wave infarct type, respectively (P = .25)., Conclusions: Angiographic and clinical differences were observed between patients who present with initial ST-segment elevation and evolve early non-Q-wave versus Q-wave myocardial infarcts after treatment with rTPA, heparin, and aspirin. Early mortality and adverse clinical cardiac events in these patients are not significantly different after a conservative compared with an invasive treatment strategy, regardless of whether the infarct type is non-Q wave or Q wave.

Objectives: We examined the results of coronary artery bypass graft surgery after thrombolytic therapy in the Thrombolysis in Myocardial Infarction trial, Phase II (TIMI II) with particular emphasis on patient characteristics, the impact of antecedent percutaneous transluminal coronary angioplasty and morbidity and mortality in certain subgroups., Background: Coronary bypass surgery is frequently used after thrombolytic therapy, but there is relatively little information with regard to early and late outcomes., Methods: We analyzed 3,339 patients enrolled in the TIMI II trial. Bypass surgery was performed in 390 patients (11.7%): 54 (14%) within 24 h after entry into the trial or within 24 h of coronary angioplasty and 336 (86%) between 24 h and 42 days after entry., Results: Perioperative mortality rates were, respectively, 16.7% and 3.9% (p < 0.001); perioperative myocardial infarction rates were 5.6% and 6.2%, respectively; and major hemorrhagic events occurred in 74% and 50.9%, respectively (p = 0.002). On multivariate analysis, the only independent predictor of perioperative mortality was bypass surgery within 24 h after entry or after coronary angioplasty. Among patients undergoing bypass surgery within 24 h of entry or after coronary angioplasty, the prevalence of multivessel disease (59.1% vs. 77.8%) and use of the internal thoracic artery (18.5% vs. 62.5%) were lower than in the remaining surgical patients. Among the 322 perioperative survivors, the 1-year mortality rate after discharge was only 2.2% and 1.9%, respectively, in the two groups. Only one patient had a documented recurrent myocardial infarction during the first year., Conclusions: The increased mortality rate with bypass surgery after thrombolytic therapy, particularly in patients undergoing operation within 24 h of coronary angioplasty or during the involving phase of infarction, must be balanced against the excellent 1-year prognosis and perioperative survivors, who are in general a group at higher risk of death or recurrent infarction. These data provide a basis for comparison for future studies.

Background: A paradoxical increased risk of death has been reported during the first 24 hours after thrombolysis for myocardial infarction. The mechanism of this phenomenon is not known, nor is its relation to the success or failure of reperfusion. The present study was a prospectively designed analysis of deaths occurring within the first 24 hours in the GUSTO trial., Methods and Results: There were 41,021 patients enrolled in GUSTO, a randomized comparison of streptokinase with intravenous or subcutaneous heparin, accelerated tissue-type plasminogen activator (TPA), and combination of streptokinase and TPA. An angiographic mechanistic substudy examined reperfusion (using the TIMI flow grading criteria) 90 minutes after the assigned thrombolytic regimen was begun in 1567 patients. There were 1125 deaths (2.8%) within 24 hours ("early deaths") and 1726 additional deaths (4.2%) after 24 hours but within 30 days ("later deaths"). At the time of presentation, the most potent predictors of early death were hypotension and sinus tachycardia. In a multiple logistic regression model, lower systolic blood pressure, shorter height, higher heart rate, and the absence of prior smoking distinguished early death from later death. Reinfarction occurred in 26 patients (2.4%), shock in 572 patients (52%), atrioventricular block in 308 patients (28%), and tamponade in 106 patients (10%) dying early compared with 262 (15%), 788 (46%), 396 (23%), and 74 (4%) respective patients dying later. There were no differences in early mortality among the thrombolytic regimens for the first 6 hours after randomization. By 24 hours, however, mortality was 2.89% for streptokinase recipients, 2.84% for combination therapy recipients, and 2.36% for accelerated TPA recipients (P = .005). There was little difference among patients with differing flow grades in the infarct artery during the first 4 hours, although mortality was 2.35% for patients with flow grade 0 or 1, 2.92% for patients with flow grade 2, and 0.89% for patients with flow grade 3., Conclusions: Even with aggressive management regimens, mortality within the first 24 hours accounted for a large proportion of postthrombolytic deaths. Patients dying early were more likely to present with pump failure than were those dying later and were more likely to diet of events related to left ventricular dysfunction, although cardiac tamponade also accounted for a significant minority of these deaths. Thus, the severity of the clinical presentation rather than the underlying risk factors predicts early mortality. Based on the angiographic substudy data, it appears that rather than hastening early mortality, successful restoration of complete antegrade flow in the infarct-related artery protects against early death.

Despite impressive clinical advantages proven for reperfusion (thrombolytic) therapy in acute myocardial infarction, considerable controversy persists regarding patient selection, choice of fibrinolytics, adjunctive therapies, and the role of angioplasty. Accruing new information supports the understanding that only very early reperfusion substantially salvages jeopardized myocardium, but that by other mechanisms some regimens produce a mortality benefit when administered as late as 12 h after infarct onset. Evidence that fibrin selective plasminogen activators lyse coronary thrombi faster than systemic agents has expanded along with clinical trial data demonstrating a concomitant greater dependence on intense anticoagulation to maintain this speed of patency advantage. The clinical value of such strategies is still under evaluation (the "GUSTO" Trial). Newly reported comparisons of reperfusion by angioplasty suggest that in optimal circumstances this approach produces results comparable with thrombolytic therapy.

Objectives: This double-blind, randomized, multicenter trial was designed to compare the effects of treatment with anistreplase (APSAC) and alteplase (rt-PA) on convalescent left ventricular function, morbidity and coronary artery patency at 1 day in patients with acute myocardial infarction., Background: Anistreplase (APSAC) is a new, easily administered thrombolytic agent recently approved for treatment of acute myocardial infarction. Alteplase (rt-PA) is a rapidly acting, relatively fibrin-specific thrombolytic agent that is currently the most widely used agent in the United States., Methods: Study entry requirements were age less than or equal to 75 years, symptom duration less than or equal to 4 h, ST segment elevation and no contraindications. The two study drugs, APSAC, 30 U/2 to 5 min, and rt-PA, 100 mg/3 h, were each given with aspirin (160 mg/day) and intravenous heparin. Prespecified end points were convalescent left ventricular function (rest/exercise), clinical morbidity and coronary artery patency at 1 day. A total of 325 patients were entered, stratified into groups with anterior (37%) or inferior or other (63%) acute myocardial infarction, randomized to receive APSAC or rt-PA and followed up for 1 month., Results: At entry, patient characteristics in the two groups were balanced. Convalescent ejection fraction at the predischarge study averaged 51.3% in the APSAC group and 54.2% in the rt-PA group (p less than 0.05); at 1 month, ejection fraction averaged 50.2% versus 54.8%, respectively (p less than 0.01). In contrast, ejection fraction showed similar augmentation with exercise at 1 month after APSAC (+4.3% points) and rt-PA (+4.6% points), and exercise times were comparable. Coronary artery patency at 1 day was high and similar in both groups (APSAC 89%, rt-PA 86%). Mortality (APSAC 6.2%, rt-PA 7.9%) and the incidence of other serious clinical events, including stroke, ventricular tachycardia, ventricular fibrillation, heart failure within 1 month, recurrent ischemia and reinfarction were comparable in the two groups; and mechanical interventions were applied with equal frequency. A combined clinical morbidity index was determined and showed a comparable overall outcome for the two treatments., Conclusions: Convalescent rest ejection fraction was high after both therapies but higher after rt-PA; other clinical outcomes, including exercise function, morbidity index, and 1-day coronary artery patency, were favorable and comparable after APSAC and rt-PA.

Having previously shown in the Heparin Aspirin Reperfusion Trial that the empiric use of early intravenous heparin after recombinant tissue-type plasminogen activator (rt-PA) is an important component in the overall treatment strategy, we examine in this report the specific relation between the degree of prolongation of activated partial thromboplastin time and coronary artery patency. To evaluate the hypothesis that arterial patency after administration of rt-PA for acute myocardial infarction is sustained by effective anticoagulation, activated partial thromboplastin time of heparin recipients was determined 8 and 12 h after the start of thrombolysis. Mean activated partial thromboplastin time was higher among patients with an open infarct-related artery than in those with a closed artery (81 +/- 4 vs. 54 +/- 9 s, p less than 0.02). Only 45% of patients with values less than 45 s at both 8 and 12 h had Thrombolysis in Myocardial Infarction (TIMI) flow grade 2 or 3 in the infarct-related artery at 18 h. In contrast, 88% of patients with activated partial thromboplastin time greater than 45 s and 95% of those with values greater than 60 s had an open infarct-related artery at 18 h (p = 0.003 and 0.0006, respectively). Among patients with an initially patent infarct-related artery who underwent repeat angiography at 7 days, activated partial thromboplastin time was similar in those with a persistently patent artery and those with late reocclusion. Excessive anticoagulation did not appear to increase hemorrhagic risk except that access site-related hemorrhage was more common in patients with activated partial thromboplastin time greater than 100 s at 8 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Sustained infarct artery patency is an important determinant of survival in patients with acute myocardial infarction. We studied 61 patients with acute myocardial infarction who received intravenous recombinant tissue-type plasminogen activator, aspirin or heparin within 6 hours of symptom onset, to determine if infarct artery patency after intravenous thrombolytic therapy influences myocardial electrical stability as measured by the prevalence of spontaneous ventricular ectopy or late potential activity. Infarct artery patency was determined by angiographic evaluation 2.5 +/- 3 days after infarction. Forty-eight patients (79%) had a patent infarct-related artery and 13 (21%) patients had an occluded vessel. The mean number of ventricular premature complexes (VPCs)/hour (p less than 0.01) and the prevalence of late potentials (54 vs 19%; p less than 0.03) were significantly higher in patients with an occluded versus patent-infarct related vessel. Although VPC frequency and late potentials were not influenced by the time to thrombolytic treatment, patients with a patent infarct-related artery had a lower prevalence of late potentials regardless of whether treatment was initiated less than or equal to 2 hours (25% patent vs 50% occluded; p = not significant) or 2 to 6 hours (16% patent vs 55% occluded; p greater than 0.03) after symptom onset. Thus, successful thrombolysis decreases the frequency of ventricular ectopic activity and late potentials in the early postinfarction phase. The reduction in both markers of electrical instability may help explain why the prognosis after successful thrombolysis is improved after acute myocardial infarction.

Background: We report the results of the Heparin-Aspirin Reperfusion Trial, a collaborative study comparing early intravenous heparin with oral aspirin as adjunctive treatment when recombinant tissue plasminogen activator (rt-PA) is used for coronary thrombolysis during acute myocardial infarction., Methods: Two hundred five patients were randomly assigned to receive either immediate and then continuous intravenous heparin (starting with a 5000-unit bolus; n = 106) or immediate and then daily oral aspirin (80 mg; n = 99) together with rt-PA (100 mg intravenously over a six-hour period) initiated within six hours of the onset of symptoms. We evaluated the patency of the infarct-related artery by angiography 7 to 24 hours after beginning rt-PA infusion, the frequency of reocclusion of the artery by repeat angiography on day 7, and ischemic or hemorrhagic complications during the hospital stay., Results: At the time of the first angiogram, 82 percent of the infarct-related arteries in the patients assigned to heparin were patent, as compared with only 52 percent in the aspirin group (P less than 0.0001). Of the initially patent vessels, 88 percent remained patent after seven days in the heparin group, as compared with 95 percent in the aspirin group (P not significant). The numbers of hemorrhagic events (18 in the heparin and 15 in the aspirin group) and recurrent ischemic events (8 in the heparin and 2 in the aspirin group) were similar in the two groups., Conclusions: Coronary patency rates associated with rt-PA are higher with early concomitant systemic heparin treatment than with concomitant low-dose oral aspirin. This observation has important implications for clinical practice and should be considered in the design and interpretation of clinical trials involving coronary thrombolytic therapy.

The role of angioplasty in acute myocardial infarction has been extensively studied in the past few years. Although angioplasty in some circumstances can be the primary reperfusion intervention, logistic problems and the excellent results of intravenous thrombolytic therapy have resulted in postlytic angioplasty being the preferred use of this interventional strategy. Clinical trials of this strategy have not supported its routine use, however, and a much more selective application of postthrombolytic coronary artery dilation is advocated at this time.

The TIMI Trials consist of three primary studies plus numerous ancillary observations. TIMI I was the direct reperfusion comparison between streptokinase and TPA. The central observations were: Higher reperfusion rates with TPA; Equivalent frequencies of bleeding complications; No differences in clinical outcome parameters; Only early reperfusion produced LV function improvement. TIMI IIA compared routine post-IV lytic therapy (TPA) immediate PTCA with a delayed interventional approach at 18-48 hours post lysis. The study demonstrated: Equivalent outcome LV function; Equivalent mortality rates; More emergency CABG in the "immediate" group; More hemorrhagic complications in the immediate group. TIMI IIB compared delayed but routine interventional post-lytic care (PTCA) with a more conservative strategy. Additionally patients were secondarily randomized to acute administration of IV beta blocker (metoprolol) or delayed administration of beta blocker, starting on Day 6. The primary results of this investigation include: A very low early (2 week) mortality rate with either strategy (about 5%); preserved low mortality at the one year follow up for both groups; no difference (routine intervention versus conservative strategy) in outcome LV function; no difference in comparative mortality rates; less recurrent ischemia in the routine PTCA group; 13% need for PTCA in the conservative group; no difference in LV function based upon beta blockade assignment but some decrease in mortality in acute beta blockade subgroups.

The long-term prognostic implications of the electrocardiographic location of a myocardial infarction and the subsequent retention or disappearance of diagnostic Q waves were examined in patients enrolled in the Aspirin Myocardial Infarction Study (AMIS). The 4524 participants, ages 30-69 years, had sustained a myocardial infarction 8 weeks to 60 months before randomization to aspirin and placebo groups. Subjects were followed for at least 3 years (average 38.2 months). Using the Minnesota Code, myocardial infarctions were classified according to three electrocardiographic locations: lateral, inferior and anterior, with further subdivision into major, moderate and minor criteria based on Q-wave duration and Q/R rations. Total mortality was not significantly different among patients with single infarct sites: lateral 11.8%, inferior 8.0% and anterior 9.4%. Patients with multiple electrocardiographic infarct locations had a significantly higher mortality (14.6%, p less than 0.0002). Participants with Minnesota Code major criteria of infarction also had a significantly higher mortality (10.6%) than those with moderate (7.2%) or minor (7.4%) criteria (p less than 0.01). Loss of a previously documented diagnostic Q wave occurred in 14.2% of participants. Mortality among patients who lost Q waves (6.5%) was not significantly different from that among those with persistent Q waves in a single infarct location (8.7%). No long-term prognostic significance can be attributed to the site of infarction or loss of Q wave on the resting ECG. However, major Q-wave criteria and extent of infarction based on multiple coded sites are associated with a higher 3-year mortality.

We evaluated the recently proposed concern that ECG anterior ST segment depression in patients with acute inferior wall myocardial infarction represents an additional area of ischemia and therefore implies worsened prognosis. We studied patients enrolled in the Aspirin Myocardial Infarction Study (AMIS), ages 30 to 69 years, who sustained an inferior myocardial infarction within 6 months from the start of the study. Two hundred nineteen patients who met those criteria were followed for an average of 38.2 months. One hundred ten patients had significant anterior lead ST depression (greater than or equal to 0.1 mV) during their acute inferior infarction and their 3-year mortality rate was 9.1%. One hundred nine patients had no anterior ST abnormality and a mortality rate of 10.1% (p = ns). Only one patient with significant depression had a subsequent anterior wall myocardial infarction. Anterior ST depression correlated closely with the magnitude of inferior ST segment elevation. Since ST depression does not alter long-term mortality but relates to magnitude of ST elevation, it probably represents a reciprocal change.

Recent studies have shown that the use of thrombolytic therapy in patients with acute myocardial infarction can reduce mortality 20 to 52%. However, patient selection issues remain to be resolved. These issues include the time window for therapy, treatment based on the site of infarction, treatment based on electrocardiographic criteria and treatment of the elderly population.

The rationale for the therapy of acute myocardial infarction is logically based upon recognition of the etiologic role of acute thrombosis; hence the primary therapeutic goal is to restore coronary artery patency (and subsequently to preserve that patency). Multiple thrombolytic drugs are variably successful in accomplishing that objective as, in special circumstances, are acute mechanical interventions. After reperfusion, additional strategies are advocated both to preserve patency and to enhance the benefit of reperfusion. The state of our current understanding has been achieved through a productive combination of individual observations and inventiveness as well as painstaking clinical trials. While the major questions now appear to have satisfactory answers, numerous secondary questions have been generated in an effort to further refine the therapeutic algorithms as well as possibly expand the indications to a wider cohort of patients than have been traditionally treated and/or studied to date.

To better characterize the changes in left ventricular ejection fraction after myocardial infarction, we compared radionuclide ventriculograms obtained acutely and 2 weeks after acute myocardial infarction in 40 patients. These patients underwent angiography within a mean of 4 hr and 20 min after the onset of symptoms of infarction and either received no therapy (32 patients who were control subjects in a thrombolysis trial) or did not experience reperfusion (eight patients) despite receiving streptokinase infusions. In all 40 patients, the change in left ventricular ejection fraction over 2 weeks was small (+2.6%). Patients were then grouped according to the presence or absence of residual flow on their angiograms. Residual flow was considered to be present in 21 patients, in 12 by virtue of subtotal occlusion of the artery supplying the area of infarct and in nine because of well-developed coronary collaterals to the distal infarct artery. Mean change in ejection fraction for patients with residual flow was +6.9 +/- 2.3% vs -2.2 +/- 1.7% for patients without residual flow (p less than .01). Fourteen of 21 (67%) patients with residual flow had a spontaneous rise in ejection fraction of greater than 5%, as compared with two of 19 (11%) patients without residual flow (p less than .01). Time to peak level of creatine kinase (CK) was significantly shorter in the residual flow group (15 vs 23 hr, p less than .01), while the peak level of CK was lower (1550 vs 2220 IU) in these patients. This latter difference did not reach statistical significance (p = .10).(ABSTRACT TRUNCATED AT 250 WORDS)