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Unlabelled: In evolving myocardial infarction the extent of ST segment deviation reflects the existing ischemic myocardial injury and thus conveys very useful early prognostic information. In recent years, the sum of ST segment elevation resolution (sum STR) has been proven to be an excellent early prognostic indicator. However, the predictive power of sum STR has never been systematically compared with that of other methods of evaluation of ST segment deviation recovery. We, therefore, proposed to compare the prognostic power of ST segment changes evaluated by either sum STR or by ST segment resolution in only the one lead showing the maximal deviation (lead STR) or only by the existing ST segment deviation in the single ECG lead of maximum ST deviation present at a given time point after thrombolysis (lead STE)., Methods and Results: In conjunction with the Intravenous nPA for Treatment of Infarcting Myocardium Early (InTIME) II Study, which compared mortality in patients with acute myocardial infarction randomized within 6 hours of symptom onset to receive either Lanoteplase or Alteplase, all 3593 German and Polish patients participated in an ST segment resolution substudy. A 12-lead ECG was recorded at baseline and at 90 and at 180 minutes after start of thrombolytic therapy. The areas under the receiver-operating characteristic (ROC) curves to compare the power to predict 30 day cardiac mortality for sum STR, lead STR, and lead STE were at 90 min 0.686, 0.714, and 0.761 (p < 0.002), and at 180 min 0.678, 0.703, and 0.755 (p < 0.001), respectively. In multivariate analysis lead STE was an independent predictor of outcome even when adjustment was made for sum STR, lead STR, and clinical variables. Cardiac mortality rates at 30 days for lead STE risk groups, classified as low, medium, or high (percent of patients in brackets), were at 90 min 1.0% (43%), 4.0% (32%), and 12.8% (25%), and at 180 min 1.5% (55%), 3.8% (31%), and 15.2% (14%), respectively., Conclusions: Simple measurement of the ST segment deviation existing in the one ECG lead with the greatest deviation on the ECG recorded 90 or 180 minutes after thrombolysis enables the identification of the major subsets of patients who are either at very low or exceptionally high risk of mortality.

Aims The purpose of this study was to validate ST segment resolution as a non-invasive marker for patency of the infarct-related artery 90 min after the start of streptokinase therapy in patients with acute myocardial infarction. Methods and Results In the HIT-4 angiographic substudy, 447 patients with acute myocardial infarction or =70% ST resolution (n=70) had a 92% probability of TIMI 2/3 flow, while <30% ST resolution (n=172) was associated with the absence of TIMI 3 flow in 84% of patients. Conclusions Despite fairly good sensitivities and specificities the prediction of infarct vessel patency by ST resolution in the individual patient is limited. However, patients with > or =70% ST resolution are likely to have a patent infarct artery and <30% ST resolution predicts epicardial vessel occlusion or, since persistent ST elevation reflects the existing ischaemic myocardial injury, absence of myocardial perfusion., (Copyright 2001 The European Society of Cardiology.)

Aims: Thrombolytic therapy restores coronary patency in patients with acute myocardial infarction, although normal perfusion (TIMI 3 flow) is not achieved in all patients. In an attempt to improve TIMI 3 flow, a combination of full-dose streptokinase, aspirin and escalating dosages of a platelet glycoprotein IIb/IIIa receptor blocker, eptifibatide, vs placebo were tested., Methods and Results: A bolus of 180 microg. kg(-1)of eptifibatide was administered in each group, followed by a 72 h continuous infusion of 0.75 (44 patients), 1.33 (n=45) and 2.00 microg. kg(-1). min(-1)(n = 30); 62 patients received placebo. Normal perfusion (TIMI 3 flow) at 90 min was observed in 31% of placebo patients compared to 46, 42 and 45% in the ascending eptifibatide groups (44% for combined eptifibatide groups, P = 0.07). Patency (TIMI 2 and 3 flow combined) increased from 61% (placebo) to 78% for the combined eptifibatide groups (P = 0.02). Reocclusion was infrequent. No differences were observed in TIMI flow grades among eptifibatide groups. Major and minor bleeding was increased and occurred mainly at the arterial puncture site., Conclusion: A combination of full dose streptokinase with different eptifibatide regimens enhanced coronary perfusion, but bleeding risk was excessive. Additional trials are needed with different dosage regimens to determine the optimal combination of fibrinolytic agents and platelet glycoprotein IIb/IIIa receptor blockers., (Copyright 2000 The European Society of Cardiology.)

Acute myocardial infarction (AMI) remains a leading cause of morbidity and mortality in the developed countries. Thrombotic occlusion of a coronary artery has been shown to cause acute myocardial infarction in over 90% of the cases. Early and complete restoration of bloodflow in the infarct-related coronary artery is the principal mechanism by which reperfusion therapy improves outcomes in patients with acute myocardial infarction. Thrombolytic therapy has been shown to reduce mortality when given early after symptom onset. However, even the most effective, approved thrombolytic regimens achieve normal (so-called TIMI 3) flow in the infarct vessel at 60-90 minutes only in about half of the patients and reocclusion occurs in 5-10%. Bleeding events, especially intracranial bleedings, observed in up to 1% of the patients, are the most severe complication of thrombolysis. Primary percutaneous transluminal coronary angioplasty (PTCA) is associated with somewhat higher patency rates and significantly fewer strokes than thrombolysis, but confers a reocclusion rate of about 5-10% and it is not universally available. While smaller randomized studies suggested a significant advantage of PTCA over thrombolysis, these results could not be confirmed in the larger GUSTO IIb angioplasty study in over 1000 patients and in non-randomized comparisons in large registries. Therefore, a general mortality advantage of PTCA over thrombolysis could not be demonstrated. Primary PTCA should be preferred in patients with contraindications against thrombolysis, patients with a high risk for intracranial bleedings (age > 75 and high blood pressure on admission) and hemodynamically unstable patients. There are several approaches to improve outcome of patients with acute myocardial infarction: new fibrinolytic agents may improve early infarct related patency, single bolus administration of thrombolytics may reduce time-to-treatment, stent implantation may improve direct PTCA, enhanced thrombin and platelet inhibition may facilitate both, thrombolysis and primary PTCA, enhance reperfusion on the cellular level and reduce reocclusions and ultimately improve prognosis of patients with acute myocardial infarction.

Aims: Previous studies revealed that >/=70% or <30% ST segment elevation resolution 180 min after the start of thrombolysis is a strong predictor of either favourable or poor outcome. The aim of this study was to compare the prognostic value of ST segment elevation resolution at 90 and 180 min after the start of streptokinase infusion., Methods and Results: The Hirudin for Improvement of Thrombolysis (HIT)-4 study of 1208 patients compared streptokinase therapy in conjunction with either r-hirudin or heparin. Complete ST segment elevation resolution (>/=70%) at 90 and 180 min identified 25% and 50%, respectively, of all patients with a 30 day cardiac mortality of less than 2%. Forty-four percent of patients had no ST segment elevation resolution (<30%) at 90 min and the 30 day cardiac mortality was 7.3%. At 180 min, the no ST segment elevation resolution group decreased to 15% of all patients while the mortality risk increased to 13.6%., Conclusions: ST segment elevation resolution is a useful tool for early risk stratification and the strategy of rescue angioplasty. Complete ST segment elevation resolution within 180 min of the start of streptokinase therapy indicates excellent survival prospects in 50% of patients. A half of these low risk patients can be identified at 90 min. A high risk group appears to be best characterized by no ST segment elevation resolution at 180 min rather than at 90 min.

Objectives: The purpose of this study was to compare recombinant hirudin and heparin as adjuncts to streptokinase thrombolysis in patients with acute myocardial infarction (AMI)., Background: Experimental studies and previous small clinical trials suggest that specific thrombin inhibition improves early patency rates and clinical outcome in patients treated with streptokinase., Methods: In a randomized double-blind, multicenter trial, 1,208 patients with AMI < or =6 h were treated with aspirin and streptokinase and randomized to receive recombinant hirudin (lepirudin, i.v. bolus of 0.2 mg/kg, followed by subcutaneous (s.c.) injections of 0.5 mg/kg b.i.d. for 5 to 7 days) or heparin (i.v. placebo bolus, followed by s.c. injections of 12,500 IU b.i.d. for 5 to 7 days). A total of 447 patients were included in the angiographic substudy in which the primary end point, 90-min Thrombolysis in Myocardial Infarction (TIMI) flow grade 3 of the infarct-related artery, was evaluated, while the other two-thirds served as "safety group" in which only clinical end points were evaluated. As an additional efficacy parameter the ST-segment resolution at 90 and 180 min was measured in all patients., Results: TIMI flow grade 3 was observed in 40.7% in the lepirudin and in 33.5% in the heparin group (p = 0.16), respectively. In the entire study population the proportion of patients with complete ST resolution at 90 min (28% vs. 22%, p = 0.05) and at 180 min (52% vs. 48%, p = 0.18) after start of therapy tended to be higher in the lepirudin group. There was no significant difference in the incidence of hemorrhagic stroke (0.2% vs. 0.3%) or total stroke (1.2% vs. 1.5%), reinfarction rate (4.6% vs. 5.1%) and total mortality rate (6.8% vs. 6.4%) at 30 days, as well as the combined end point of death, nonfatal stroke, nonfatal reinfarction, rescue-percutaneous transluminal coronary angioplasty and refractory angina (22.7 vs. 24.3%) were not statistically different between the two groups., Conclusions: Lepirudin as adjunct to thrombolysis with streptokinase did not significantly improve restoration of blood flow in the infarct vessel as assessed by angiography, but was associated with an accelerated ST resolution. There was no increase in the risk of major bleedings with lepirudin compared to heparin.

Long-term follow-up of placebo-controlled thrombolysis trials has proven that the survival benefit from thrombolysis in acute myocardial infarction (AMI) is maintained for up to 10 years. Ongoing research is being conducted with the aim to further improve early restoration of blood flow in the infarct vessel and, thus, reperfusion of the infarcted myocardium in patients with AMI, with the ultimate goal to improve survival. In two recent mega-trials, two new single-bolus fibrinolytics (lanoteplase and TNK-tissue plasminogen activator) were shown to be equivalent to front-loaded alteplase in reducing infarct mortality. The ease of application of these agents might help reduce the time from symptom onset to start of therapy. More potent thrombin inhibitors such as hirudin and hirulog seem to speed up thrombolysis with streptokinase and reduce the rate of reinfarctions. Very promising results are derived from angiographic trials combining reduced doses of thrombolytics with glycoprotein IIb/IIIa inhibitors. Advances in mechanical revascularization can be achieved with the use of stents and better conjunctive therapies. All of these developments are expected to further improve clinical outcome of patients with AMI in the near future.

Since reperfusion of the infarct-related coronary artery has been established as a mainstay in the treatment of acute myocardial infarction (AMI) mechanical recanalization by direct angioplasty has been used as an alternative to the standard treatment with thrombolysis. Direct PTCA is more efficient than thrombolysis in terms of reperfusion rates, whereas thrombolysis is more readily available. Thrombolysis reduces mortality from AMI by approximately 25%. The clinical efficacy is strongly time-dependent, and treatment within the first hour of AMI improves survival by nearly 50% by preventing transmural infarction in a significant proportion of the patients. The disadvantage of thrombolysis is its limited efficacy in terms of rapid, complete and sustained patency of the infarct vessel yielding optimal results in only 50% of the patients. Direct PTCA is generally agreed to be more efficient to recanalize the infarct vessel, but its clinical advantage remains controversial. The first randomized studies of direct PTCA in AMI from highly specialized centers in selected patients reported success rates of coronary reperfusion up to 97% resulting in a trend to less death and reinfarction, but the differences were significant only in a metaanalysis of these small studies. The real world of direct PTCA has been depicted by a large registry in Germany of the Arbeitsgemeinschaft Leitender Kardiologischer Krankenhausärzte (ALKK) now including more than 4,000 direct PTCA-procedures since 1994. In this registry, the success rate of direct PTCA was 87% as defined by a final TIMI-grade 3 perfusion of the infarct vessel which is close to the data of the MITI-registry and the GUSTO IIb study. Failed PTCA was associated with an exceptionally high mortality rate of 36% confirming earlier observational reports. The non-randomized comparison of thrombolysis and direct PTCA in the MITI-registry showed no differene in survival or reinfarction rates, and the randomized GUSTO IIb substudy of direct PTCA versus front-loaded alteplase showed a small advantage in death and reinfarction rates at 30 days which dissipated over time leaving no significant clinical advantage of direct PTCA over thrombolysis at 6 months. Thus, in myocardial infarction in general the advantage of direct PTCA over thrombolysis is at best minimal. The reason is very probably the longer time lag until the procedure is started, the lower success rate as compared to the first reports of some specialized centers, and the clearly negative impact of failed PTCA on survival. Moreover, the immediate success of direct PTCA seems to be overestimated by the operator as demonstrated by comparison of central and local estimates of the TIMI flow rates in GUSTO IIb. Improvements of direct PTCA in AMI might be possible by coronary stenting which has markedly increased to more than 60% during the last year in the ALKK-registry. This was accompanied by a slight decrease in death and reinfarction rates. Further improvements can be expected from GP IIb/IIIa platelet antagonists which are under clinical investigation. It has been claimed, that in cardiogenic shock direct PTCA is more effective than thrombolysis. This hypothesis is based on comparison of failed versus successful PTCA-attempts, but this comparison is not valid since failed procedures clearly increase mortality. In the GUSTO-1 study patients with cardiogenic shock had lower mortality with than without an early coronary angiogram. This survival advantage, however, was independent of revascularization since only half of the patients with an early angiogram had PTCA. The same was observed in the International Shock Registry, reflecting significant selection bias in that patients in relatively better condition will be taken to the cathlab whereas apparently hopeless cases will not. In the ALKK-registry half of the patients in cardiogenic shock died after direct PTCA casting doubt on the presumed high clinical efficacy of this strategy. (ABST

Background: In an in vitro model, recombinant tissue-type plasminogen activator was significantly more effective than streptokinase in dissolving 24-hour-old human blood clots. Therefore there might be a difference in the effect of time to treatment on the efficacy of these fibrinolytics with different fibrin specificity in patients with acute myocardial infarction., Methods and Results: The effect of the interval between symptom onset and initiation of therapy on the efficacy of 6 different thrombolytic regimens was studied in a retrospective analysis of 6 angiographic trials with similar design. The patency of the infarct-related artery was assessed by angiography 90 minutes after initiation of thrombolysis in patients who were seen within 6 hours after symptom onset. Patency rates of patients with an interval of 3 hours between symptom onset and start of therapy were compared. There was no difference for Thrombolysis in Myocardial Infarction (TIMI) grade 3 perfusion after front-loaded alteplase (72.5% vs 76. 3%) and reteplase (63.6% vs 63.2% ) between the 2 groups. In contrast, in patients treated with streptokinase (36.8% vs 27.6%, P =.09), anisoylated plasminogen streptokinase activator complex (59. 5% vs 34.8%, P =.004), and urokinase (62.3% vs 41.7%, P =.03), TIMI 3 patency decreased with the increasing interval between symptom onset and initiation of therapy., Conclusions: We conclude from our data that the thrombolytic efficacy of recombinant tissue-type plasminogen activator and reteplase does not decrease with the increasing interval between symptom onset and initiation of therapy. In contrast, after anisoylated plasminogen streptokinase activator complex, streptokinase, and urokinase treatment, a decrease in patency, especially TIMI-3 patency in patients treated after >3 hours after symptom onset, was observed. These results may influence the choice of the thrombolytic agent in patients who are seen >3 hours after symptom onset.

Objectives: This study assessed the prognostic impact of right ventricular involvement (RVI) in streptokinase-treated patients with inferior acute myocardial infarction (AMI) stratified for small or large AMI., Background: Only scant data exist from small studies about the impact of reperfusion therapy on survival in patients with RVI during inferior AMI., Methods: Right ventricular involvement was assessed by ST-segment elevation > or =0.1 mV in lead V4R and infarct size by the extent of ST-segment deviation on the baseline electrocardiogram: small AMI=sum ST-segment elevation < or =0.8 mV and no precordial ST-segment depression (small ST); large AMI=presence of precordial ST-segment depression or sum ST-segment elevation >0.8 mV (large ST) in 522 inferior AMI patients of the Hirudin for Improvement of Thrombolysis (HIT-4) Trial. In 187 patients, 90-min coronary angiography was performed., Results: Right ventricular involvement was present in 169 patients (32%). Higher 30-day cardiac mortality rates with RVI (5.9% vs. 2.5%) were related to larger infarct size rather than to RVI. For large ST, a proximal right coronary artery lesion was observed in 52% with and in 23% without RVI. Patency rates at 90 min were similar (54% vs. 52%). In the 28% of patients who had small ST, cardiac mortality was less than 1% irrespective of the presence of RVI. Coronary artery lesions were mostly located distally. Patency rates were 27% with and 80% without RVI., Conclusions: ST-segment elevation of > or =0.1 mV in V4R in inferior AMI patients is associated with larger infarct size and higher 30-day mortality rates. Right ventricular involvement is not an independent predictor of survival. In patients with small ST, cardiac mortality is low, even if ST V4R is > or =0.1 mV.

Objective: To define an optimal dose of hirudin that would improve early coronary artery Thrombolysis in Myocardial Infarction grade 3 (TIMI 3) patency and prevent reocclusions in patients with acute myocardial infarction treated with front-loaded recombinant tissue-type plasminogen activator (rt-PA)., Methods: Recombinant hirudin (HBW 023) was tested in a sequential dose-escalating study as adjunct to front-loaded rt-PA in 143 patients with acute myocardial infarction. The sequential model was assigned two 'decision boundaries': it triggered an increase in dosage if the 60-min TIMI 3 flow rate in a dosage group was statistically not consistent with a target patency rate of 75%, or if the deterioration in coronary blood flow (of at least one TIMI grade, from TIMI 2 or 3, from one angiography to the next) exceeded 5%., Results: The decision boundary for TIMI 3 flow grade at 60 min was crossed when 18 patients were treated with 0.1/0.06 mg/kg (bolus/infusion per hour over 48 h) r-hirudin (dosage group I), 42 patients treated with 0.2/0.1 mg/kg (dosage group II), and 83 patients with 0.4/0.15 mg/kg (dosage group III). TIMI 3 flow at 60 min was 50%, 58%, and 63% in dosage groups I-III, respectively (P = 0.15). Early, complete, and sustained patency (TIMI 3 flow at 60 min, 90 min and 48 h) were 44%, 55% and 64% (P = 0.07). Reocclusion between 90-min and 48-h angiograms or reinfarction occurred in 0 to 15, two of 36, and one of 72 patients, respectively (P = 0.5). Four patients (2.8%) died in hospital and 14 patients suffered a major bleeding event, but no intracranial bleeding was encountered., Conclusions: With increasing doses of hirudin, there was a trend towards greater early and complete patency, but no clear dose--response relationship was observed. A borderline significant effect was observed with respect to early, complete, and sustained patencies. In all groups, reocclusions or reinfarctions were rare. Neither clinical nor laboratory data predicted the imbalance in haemorrhagic events observed in a subsequent, prematurely terminated, phase III trial with hirudin and rt-PA.

Our results show significant and independent influence of the GUSTO-1 trial on the use of recombinant tissue plasminogen activator in acute myocardial infarction in Germany. This influence started soon after the publication of the trial and was not restricted to subgroups who benefitted most from recombinant tissue plasminogen activator.

Aims: To describe patient characteristics, pre-hospital delay, treatment, complications and outcome in patients with acute myocardial infarction admitted to hospitals in Germany., Methods and Results: The study was of prospective observational multicentre design. Those involved were consecutive patients with acute Q-wave myocardial infarction admitted within 96 h of onset of symptoms to 136 German hospitals between July 1992 and September 1994 (n = 14980, median age 66 (quartiles 57, 74) years, 68% male, 48% anterior wall infarction). Median pre-hospital delay was 170 (90, 475) min, with 17% arriving within the first hour and 61% within 4 h of onset of symptoms. The following patient groups had a short pre-hospital delay: males, those aged less than 65 years, those admitted at night or the weekend, those with a previous myocardial infarction, those in need of cardiopulmonary resuscitation, and those with a diagnostic first ECG. The first ECG was diagnostic in 67.6% of cases. Reperfusion therapy was used in 53%, with thrombolytic therapy in 51.6%. Median time from admission to initiation of treatment was 30 (20, 55) min. Respective rates of treatment with aspirin, nitrates, and beta-blockers were 81%, 83%, and 16%. Major complications were cerebral bleeding (0.4%), bleeding requiring transfusions (0.9%), left ventricular rupture (0.6%) and anaphylactic shock (0.1%). Median hospital stay was 20 (13, 26) days. In-hospital death rate was 17.2%. Increased hospital mortality was observed with female gender, an unknown or long pre-hospital delay, a diagnostic first ECG, anterior wall infarction, trauma or major operation within the last 14 days, renal insufficiency and malignoma., Conclusions: 'Real-life' hospital mortality is much higher than previously reported in clinical trials. To reduce hospital mortality, the efficacy of thrombolysis should be increased by shortening the pre-hospital delay, and the use of concomitant therapy, especially beta-blockers, should be increased.

Objective: To evaluate the benefit to risk ratio of thrombolytic treatment in patients with small inferior acute myocardial infarction (AMI). Controlled studies relating the benefit from thrombolysis with initial electrocardiographic features are scarce and of limited sample size., Design: Retrospective study of 728 patients with a first inferior AMI of six hours' duration from the Intravenous Streptokinase in Acute Myocardial Infarction (ISAM) study comparing streptokinase with placebo stratified by the initial sum ST segment elevation (sigma ST) of 0.8 mV or less and greater than 0.8 mV, and 636 patients from the International Joint Efficacy Comparison of Thrombolytics (INJECT) trial comparing double blind streptokinase with reteplase stratified by either sigma ST or the presence of precordial ST segment depression., Results: ISAM study patients with an sigma ST of greater than 0.8 mV had a significant mortality benefit from streptokinase throughout six years, while those with an sigma ST of 0.8 mV or less showed a trend to higher mortality at six months (6.3% streptokinase v 5.1% placebo). Despite significantly smaller infarcts and fewer clinical complications in patients with an sigma ST of 0.8 mV or less (ISAM and INJECT) or the absence of precordial ST segment depression (INJECT) thrombolytic treatment was associated with higher early mortality than in those with initially larger ST segment deviations., Conclusion: Thrombolytic treatment in patients with inferior AMI presenting with larger ST segment deviations is associated with improved survival throughout six years. The risk to benefit ratio, however, in terms of early mortality in patients who have an sigma ST of 0.8 mV or less and no precordial ST segment depression may be unfavourable.

This study investigates the hypothesis if primary angioplasty is superior to intravenous thrombolysis in the treatment of acute myocardial infarction (AMI). Small prospective randomized studies did not demonstrate a significant benefit regarding total mortality. A total of 14,980 patients with AMI were registered by "The 60-Minutes Myocardial Infarction Project," a prospective multicenter observational study: 210 of these patients were treated with primary angioplasty. A matched pair analysis comparing 1 primary angioplasty patient with 3 intravenous thrombolysis patients could be performed in 156 primary angioplasty patients. Criteria for matching were age, sex, location of AMI, systolic blood pressure, previous AMI, and prehospital delay. Patients with a bundle branch block or requiring resuscitation were excluded from analysis. Because of matching, both groups showed similar baseline characteristics. Patients with primary angioplasty had more relative contraindications for thrombolysis (ulcers: 10.3% vs 2.3%, recent intramuscular injections: 6.4% vs 1.6%, recent surgical interventions: 5.1% vs 1.1%, central punctures: 9% vs 3.9%). There was a tendency toward less combined adverse events in the primary angioplasty group (3.2% vs 5.7%, odds ratio [OR] = 0.55, 95% confidence interval [CI] = 0.21 to 1.44). In-hospital mortality rates in the primary angioplasty group and thrombolysis group were 4.3% and 10.3%, respectively (OR = 0.39, 95% CI = 0.17 to 0.92). The difference in mortality could already be demonstrated within the first 48 hours with 1.9% versus 5.3% deaths (OR = 0.35, 95% CI = 0.11 to 1.14). Thus this study indicates a superiority of primary angioplasty in comparison to intravenous thrombolysis in AMI even in a clinical routine setting, with a reduction of hospital mortality of about 60%.

This retrospective analysis reviewed 183 patients with acute myocardial infarction who were given front-loaded recombinant tissue-type plasminogen activator (rt-PA) and r-hirudin (HBW 023) in 1 of 4 dose groups (bolus dose of 0.07, 0.1, 0.2, or 0.4 mg/kg, followed by an infusion of 0.05, 0.06, 0.1, or 0.15 mg/kg/hour over 48 hours). Activated partial thromboplastin time (aPTT) levels were determined at baseline and at 4, 8, 12, 16, 20, 24, 32, 40, and 48 hours. Of the 178 patients with r-hirudin treatment for > or = 12 hours, anticoagulation was optimal in 55.1% (all aPTTs > 2 x baseline), suboptimal in 33.7% (lowest aPTT > 1.5 but < 2 x baseline), and inadequate in 11.2% (> or = 1 aPTT but < 1.5 x baseline). Optimal anticoagulation was observed more frequently in the higher dose groups (dose 1, 15%; dose 2, 44.4%; dose 3, 63.4%; dose 4, 73.4%; p for trend < 0.0001). Patency (according to Thrombolysis in Myocardial Infarction trial grade 2 or 3) of the infarct artery after 36 to 48 hours was higher in the group with optimal anticoagulation compared with those with suboptimal or inadequate anticoagulation: 97.9%, 88.4%, and 85%, respectively (p = 0.03 optimal vs suboptimal or inadequate anticoagulation). In conclusion, r-hirudin in a dose of 0.1 or 0.15 mg/kg/hour achieves an optimal anticoagulation in about 63% or 74% of patients, which is associated with an enhanced patency 24 to 48 hours after rt-PA. A subsequent study revealed that this effective anticoagulation may be accompanied by an increased risk of severe bleeding complications after thrombolysis.

Early treatment with thrombolytic drugs has been shown to reduce mortality in patients with acute myocardial infarction. Thrombolytic therapy with early, complete and sustained patency of the infarct related artery is associated with a low inhospital mortality of 3 to 4% (Figure 1). Even with the most effective thrombolytic regimens this aim at present is achieved in only about 50% of the patients. The optimal thrombolytic drug should be effective (rapid, complete and sustained recanalization of the infarct related artery), safe (low incidence of severe bleedings), easy to administer (e.g. bolus application) and cost effective. Attempts to improve thrombolytic treatment include the search for better fibrinolytic agents and more effective adjunctive therapies. In the field of adjunctive therapy new more specific thrombininhibitors appear promising and are currently under investigation. In dose-finding studies recombinant hirudin reduced reocclusions and reinfarctions after t-PA thrombolysis. There are several approaches for the improvement of plasminogen activation (Table 1). While new improved dose regimens (e.g. "front-loaded" t-PA) and combination therapies are not subject of this article, it will deal with the recombinant production of naturally occurring plasminogen activators and the development of "designer drugs", which were created in the laboratory by altering the natural occurring molecules t-PA and scu-PA. t-PA contains four domains with different functional properties (Figure 3). Of a variety of mutants and variants of t-PA with altered fibrin-affinity half-life or fibrin specificity one recombinant plasminogen activator (r-PA) is under clinical investigation. r-PA, a deletion mutant of t-PA consisting of the kringle-2 and protease domains, in a dose escalation study (GRECO) showed high early patency rates (Table 2), while there was a trend to a higher incidence of very early reocclusions. In a randomised trial (RAPID), comparing three different r-PA regimens with standard t-PA (100 mg/3 h) a double bolus of 10 MU+ 10 MU r-PA was most effective with regard to early patency (Table 3). Chimeric plasminogen activators (Figure 4) consisting of parts of t-PA and the single-chain urokinase-type plasminogen activator (scu-PA) did not significantly improve at the same time fibrin specificity and thrombolytic potency of the natural occurring molecules. Complexes of plasminogen activators and monoclonal antibodies against platelets or fibrin improve the specificity and thrombolytic activity of the plasminogen activators (Figure 5). However, these molecules are potentially antigenic, costly and not in clinical use yet. Recombinant production of naturally occurring plasminogen activators seems at least as promising as the production of the above mentioned socalled designer drugs.(ABSTRACT TRUNCATED AT 400 WORDS)

Background: Adjunctive therapy for thrombolysis in acute myocardial infarction consists of platelet inhibition with aspirin and thrombin inhibition with heparin. Thrombin inhibition may be improved by the use of hirudin as indicated by experimental and phase II clinical studies. The randomized, double-blind phase III r-Hirudin for Improvement of Thrombolysis study (HIT III) compared a recombinant hirudin (HBW 023) with heparin. The primary end point was the incidence of death or reinfarction., Methods and Results: Seven thousand patients with acute myocardial infarction and a duration of symptoms of less than 6 hours were to be randomized to receive intravenous heparin (70 IU/kg body wt bolus and 15 IU.kg-1.h-1) or hirudin (0.4 mg/kg body wt bolus and 0.15 mg.kg-1.h-1) infused over 48 to 72 hours and adjusted to an activated partial thromboplastin time of 2 to 3.5 times baseline values. In a pilot phase, 1000 patients receiving front-loaded alteplase for thrombolysis were to be recruited by 93 German centers. After enrollment of 302 patients, the trial was stopped after an increased rate of intracranial bleeding was observed in the hirudin group (5 of 148, 3.4%) compared with the heparin group (0 of 154). The overall stroke rate was 3.4% in the hirudin group and 1.3% in the heparin group. Other major bleeding occurred in five versus three patients and ventricular rupture occurred in three versus one patient in the hirudin and heparin groups, respectively. There were 19 in-hospital deaths, with 13 of them from the hirudin group., Conclusions: Although the number of patients was too small for a definite benefit-risk assessment, at the dosage tested, hirudin in combination with front-loaded alteplase and aspirin may be associated with an increased rate of intracranial hemorrhage. Our findings are consistent with the observations of the GUSTO-II and TIMI-9 trials, where higher doses of another recombinant hirudin were used. Therefore, the therapeutic range of hirudin as an adjunct to thrombolysis may be smaller than previously thought, and reappraisal of dose finding should be considered.

Objectives: This study proposed to verify the prognostic power of early ST segment elevation resolution in patients with acute myocardial infarction from the Intravenous Streptokinase in Acute Myocardial Infarction study data base., Background: Data from a small prospective study suggested that use of two cutoff points for three different levels of ST segment resolution 3 h after the start of thrombolysis may be an efficient way to predict outcome in an individual patient., Methods: The three groups of ST segment resolution were defined as 1) complete resolution (> or = 70% [552 patients]) or only slight ST segment elevation (127 patients); 2) partial resolution (< 70% to 30% [475 patients]); 3) no resolution (< 30% to > 0% [362 patients]). Infarct size was measured from creatine kinase isoenzyme, MB fraction, release and from the number of Q waves. Left ventricular function was assessed in 818 patients 1 month after infarction., Results: For complete, partial and no ST segment resolution 3 h after the start of streptokinase or placebo infusion, enzyme release was 1.2, 1.8 and 2.1 IU/ml x h; number of Q waves 1.7, 2.5 and 3.0; and ejection fraction 60%, 53% and 49%, respectively (all adjusted p = 0.0000). Mortality rate at 21 days was 2.2%, 3.4% and 8.6%, respectively. No ST segment resolution was the most powerful independent predictor of early mortality (p = 0.0001). Survival rate curves at 6-year follow-up showed significant mortality differences with increasing divergence (p = 0.0003 anterior infarction; p = 0.005 inferior infarction). In subgroups with an overall higher risk of dying, mortality was strongly determined by the extent of early ST segment resolution., Conclusions: The extent of ST segment elevation resolution conveys useful early information about outcome in an individual patient after acute myocardial infarction.

Objectives: The aim of this study was to determine the appropriate dose of a novel recombinant tissue-type plasminogen activator (BM 06.022) for thrombolysis in patients with acute myocardial infarction., Background: BM 06.022 is a mutant of tissue-type plasminogen activator expressed in Escherichia coli that can be given as a single bolus because of a prolonged half-life, which might obviate the need for complicated regimens., Methods: BM 06.022 given as a single bolus was investigated in 142 patients in a multicenter sequential dose-finding study. Efficacy of the drug was assessed from infarct-related artery patency by coronary angiography., Results: With the first dose of 10 MU of BM 06.022, the predefined minimal 90-min patency of 70% was not achieved, as indicated by the sequential probability ratio test after treatment of 42 patients (group A). The second dose of 15 MU of BM 06.022 was given subsequently in the preset maximum of 100 patients (group B). Angiography 30, 60 and 90 min after the bolus injection of BM 06.022 revealed a patent infarct-related artery (Thrombolysis in Myocardial Infarction trial [TIMI] grade 2 or 3) in 65% and 66%, 73% and 74% and 66% and 75% of patients in groups A and B, respectively. Very early reocclusion up to the 90-min angiogram occurred in 17% and 13%, late reocclusion until predischarge angiography occurred in 7% and 5%, and rescue percutaneous transluminal coronary angioplasty after the 90-min angiogram was performed in 6 and 14 patients in groups A and B, respectively. Plasma fibrinogen decreased from 2.79 g/liter (range 0.94 to 4.75) to 1.69 g/liter (range 0.0 to 3.95) in group A and from 2.54 g/liter (range 0.0 to 5.02) to 0.92 g/liter (range 0.0 to 2.68) in group B. Two bleeding complications requiring transfusion or surgical intervention and one nonfatal intracranial hemorrhage were encountered. Eight patients had a reinfarction, and five patients died, all of cardiac causes., Conclusions: With BM 06.022 given as a single bolus, a high early patency rate of the infarct-related coronary artery can be achieved. The speed of thrombolysis seems to be superior to standard thrombolytic drugs. The compound warrants further evaluation with respect to safety and efficacy by clinical end points.

Patients from 4 German multicenter studies on thrombolysis in acute myocardial infarction (AMI) were retrospectively evaluated to assess the incidence of optimal reperfusion, defined as a completely perfused infarct vessel after 90 minutes, without subsequent death or reinfarction, and without reocclusion or deterioration of flow in control angiograms. Of 907 patients with a 90-minute angiogram, 75% had an open infarct vessel by conventional definition (perfusion grade 2 or 3 according to the criteria of the Thrombolysis in Myocardial Infarction [TIMI] study). However, only 62% had TIMI grade 3 complete perfusion. Of the 561 patients with such primary treatment success, 106 (19%) had secondary treatment failure by death, reinfarction, or subtotal or total reocclusion of the infarct vessel. In a subset of 668 patients with a first angiogram after 60 minutes, conventional patency was 70%, complete perfusion 51%, and an optimal perfusion result was achieved in only 42%. The efficacy of thrombolysis in AMI is substantially overestimated by conventional 90-minute patency rates.

An early, complete, and sustained patency of the infarct related artery achieved by thrombolytic therapy reduces mortality in patients with acute myocardial infarction. In the ISIS-3-study there was no difference in mortality between t-PA, APSAC, and streptokinase. In contrast, in the GUSTO-trial, a "front-loaded" regimen of t-PA (100 mg/90 min) lead to a reduced inhospital mortality compared to streptokinase. This was most likely due to the higher early patency-rate of the infarct-related artery after the front-loaded t-PA. The search for new, more effective, thrombolytic regimens lead to a double-bolus injection of t-PA (2 x 50 mg) which revealed high early patency rates (> 80% TIMI-3 after 90 min). R-PA, a new recombinant plasminogen activator with a prolonged half-life, given as double bolus (2 x 10 MU), also produced high patency rates after 90 min without an increased incidence of reocclusions. Acetylsalicylic acid should be given routinely in every thrombolytic therapy. An anticoagulation with heparin seems to improve the efficacy of the more fibrin-specific thrombolytics t-PA, r-PA, and pro-urokinase. In dose-finding studies the specific thrombin inhibitor hirudin has been shown to significantly reduce reocclusions and reinfarctions compared to heparin. An "optimal thrombolysis" most likely can only be achieved by a thrombolytic agent with a very high early patency combined with an effective adjunctive therapy with platelet aggregation- and thrombin-inhibition.

Objective: This study evaluated the impact of early patency of the infarct-related vessel on short-term mortality after thrombolysis for acute myocardial infarction., Background: Different thrombolytic regimens for acute myocardial infarction proved to be equally effective in large scale mortality trials despite significant differences in their efficacy with respect to early infarct-related vessel patency as shown in smaller angiographic trials., Methods: Patients from four German multicenter studies of thrombolysis in acute myocardial infarction were retrospectively evaluated. Of 939 patients with acute myocardial infarction (duration of symptoms < 6 h) treated with thrombolysis, 907 (96.6%) had an angiogram of the infarct-related artery 90 min after the initiation of thrombolytic therapy. The perfusion status was graded according to the Thrombolysis in Myocardial Infarction (TIMI) study criteria., Results: Complete reperfusion (TIMI grade 3) was found in 561 of 907 patients and partial reperfusion (TIMI grade 2) in 122 of 907. Overall, the in-hospital mortality rate was 4.6% (43 patients). In patients with complete reperfusion of the infarct-related vessel, the mortality rate was only 2.7% versus 7.1% in patients with an occluded vessel at the 90-min angiogram. This difference was highly significant in univariate as well as in multivariate analysis. In patients with partial perfusion of the infarct vessel, the mortality rate was 6.6%., Conclusions: The early perfusion status of the infarct-related artery is an independent predictor of short-term survival. However, only complete early reperfusion is associated with a reduced in-hospital mortality rate whereas patients with partial perfusion (TIMI grade 2) have a short-term prognosis similar to that of patients with persistently occluded infarct vessels. Therefore, when used as a surrogate end point for mortality, only TIMI grade 3 perfusion of the infarct vessel should be interpreted as a treatment success of thrombolysis in acute myocardial infarction.

The aim of thrombolytic therapy in acute myocardial infarction is the early, complete and sustained restoration of bloodflow in the infarct-related artery. In a randomized trial in 421 patients with acute myocardial infarction front-loaded rt-PA (100 mg in 90 min) showed a significantly higher 90-min patency (84.4%) in comparison with APSAC (70.3%). In-hospital mortality was significantly lower after rt-PA (2.4%) versus 8.1% after APSAC. While a single bolus injection of rt-PA produced lower patency and higher reocclusion rates, double bolus injections showed more promising results (90 min patency > 70%). A new recombinant plasminogen activator BM 06.022 (r-PA) with a longer half life can be given as a single bolus injection. In a dose-finding study r-PA produced rapid thrombolysis with a 90-min patency of 66% (10 MU) and 76% (15 MU). There was no excess in re-occlusions or bleeding complications. Although these results are quite promising, the search for the ideal thrombolytic strategy is still ongoing.

Thrombolysis with recombinant tissue-type plasminogen activator (rt-PA) and anisoylated plasminogen streptokinase activator (APSAC) in myocardial infarction has been proved to reduce mortality. A new front-loaded infusion regimen of 100 mg of rt-PA with an initial bolus dose of 15 mg followed by an infusion of 50 mg over 30 min and 35 mg over 60 min has been reported to yield higher patency rates than those achieved with standard regimens of thrombolytic treatment. The effects of this front-loaded administration of rt-PA versus those obtained with APSAC on early patency and reocclusion of infarct-related coronary arteries were investigated in a randomized multicenter trial in 421 patients with acute myocardial infarction. Coronary angiography 90 min after the start of treatment revealed a patent infarct-related artery (Thrombolysis in Myocardial Infarction [TIMI] grade 2 or 3) in 84.4% of 199 patients given rt-PA versus 70.3% of 202 patients given APSAC (p = 0.0007). Early reocclusion within 24 to 48 h was documented in 10.3% of 174 patients given rt-PA versus 2.5% of 163 patients given APSAC. Late reocclusion within 21 days was observed in 2.6% of 152 patients given rt-PA versus 6.3% of 159 patients given APSAC. There were 5 in-hospital deaths (2.4%) in the rt-PA group and 17 deaths (8.1%) in the APSAC group (p = 0.0095). The reinfarction rate was 3.8% and 4.8%, respectively. Peak serum creatine kinase and left ventricular ejection fraction at follow-up angiography were essentially identical in both treatment groups. There were more bleeding complications after APSAC (45% vs. 31%, p = 0.0019).(ABSTRACT TRUNCATED AT 250 WORDS)

To evaluate the effect of late reperfusion of an infarct-related coronary artery on left ventricular (LV) function in the month after myocardial infarction (MI), findings from 386 patients in the Intravenous Streptokinase in Acute Myocardial Infarction (ISAM) trial were studied. All patients had a late peaking in the creatine kinase-MB serum time-activity curve, suggesting absence of early reperfusion. Significantly better LV function associated with patency of the infarct artery at angiography 1 month after the acute event confirmed the beneficial effect of reperfusion even if achieved beyond the time window for myocardial salvage. Thrombolysis commenced later than 4-6 h after symptom onset will be of benefit as long at it reopens infarct arteries more often and earlier than occurs spontaneously or from anticoagulation. The value of the size of the sum of ST-segment elevation (sigma ST increases) on admission ECG was evaluated from the total ISAM study population. The relation between sigma ST increases and final infarct size as well as mortality risk was highly significant. However, weak correlations largely limit the value of sigma ST increases to predict the outcome in an individual patient. Thus, whatever the relative beneficial effect in patients with smaller or larger MI may be, it would be unwarranted to withhold thrombolytic therapy from patients with smaller sigma ST increases on admission ECG.