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Objectives: To investigate the safety and efficacy outcomes of intravenous thrombolysis (IVT) in patients aged >80 years with acute ischaemic stroke (AIS) after IVT was approved in this patient population in several European and non-European countries during 2018-2019., Design: This is an observational registry study using prospectively collected data from the Safe Implementation of Treatment in Stroke (SITS) registry. Comparisons will be performed between patients treated post-approval (July 2018 to December 2021) period with those treated pre-approval (June 2015 to June 2018) period using propensity score matching (PSM)., Setting: This is a multicentre international study in hospitals treating AIS with IVT., Participants: Patients aged >80 years who otherwise followed the IVT Summary of Product Characteristics of European countries as part of the mutual recognition procedure., Primary and Secondary Outcomes: The main outcomes were symptomatic intracerebral haemorrhage per SITS monitoring study definition, death and functional independency as defined by a modified Rankin Scale score of 0-2 at 90 days., Results: After PSM, 614 patients remained in each group (mean age 87 years, 39% males). All baseline data were well balanced after PSM. There were no statistically significant differences in outcomes between pre- and post-approval patients for SICH (2.5% vs 2.3%, risk ratio (RR) 1.064, 95% CI 0.345-1.784), death (25.3% vs 28.4%, RR 0.889, 0.699-1.08) and functional independency at 90 days (40.3% vs 37%, RR 1.089, 0.942-1.237)., Conclusions: In this observational study of IVT treatment in patients >80 years of age with AIS before and after formal approval for this treatment, we did not find any difference in outcomes between the pre- and post-approval periods., Competing Interests: Competing interests: NA is the chairman of SITS International. MM has received financial support from SITS International. AP is a Boehringer-Ingelheim employee and TD was a Boehringer-Ingelheim employee at the time the study was initiated. The remaining authors have no relevant conflicts of interest. SITS is currently conducting studies supported by Boehringer-Ingelheim and Biogen. SITS has previously received grants from the European Union Framework 7, the European Union Public Health Authority, the Ferrer International and the EVER Pharma and conducted a study in collaboration with the Karolinska Institutet, supported by Stryker, Covidien and Phenox., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY. Published by BMJ Group.)

Background: In STREAM-1 (Strategic Reperfusion Early After Myocardial Infarction), excess intracranial hemorrhage occurred in patients aged ≥75 years receiving full-dose tenecteplase as part of a pharmaco-invasive strategy, whereas no further intracranial hemorrhage occurred after halving the tenecteplase dose. In STREAM-2 (Second Strategic Reperfusion Early After Myocardial Infarction), half-dose tenecteplase was an effective and safe pharmaco-invasive strategy in older patients with ST-segment-elevation myocardial infarction presenting within <3 hours, compared with primary percutaneous coronary intervention (PCI). We prespecified evaluating the efficacy and safety of a half-dose versus full-dose pharmaco-invasive strategy and compared the half-dose pharmaco-invasive strategy to primary PCI in patients aged ≥75 years., Methods: We pooled data sets in patients aged ≥75 years from STREAM-1 and STREAM-2 receiving a pharmaco-invasive strategy versus primary PCI. Resolution of ST-segment-elevation after fibrinolysis and angiography was assessed, as was the relative risk of the primary composite of 30-day all-cause death, myocardial infarction, heart failure, and shock, along with bleeding., Results: A total of 390 patients were included: 42 patients were randomized to full-dose pharmaco-invasive treatment, 205 patients to half-dose pharmaco-invasive treatment, and 143 patients to primary PCI. Half-dose versus full-dose pharmaco-invasive treatment resulted in similar proportions of patients achieving ≥50% ST-segment resolution posttenecteplase (63.2% versus 62.6%), with reduced intracranial hemorrhage (7.1% versus 0%, respectively). Half-dose pharmaco-invasive treatment and primary PCI also had similar proportions of patients with ≥50% ST-segment resolution postangiography (77.9% versus 72.4%; P =0.277) and comparable composite end points (23.4% versus 28.0%; relative risk, 0.90 [95% CI, 0.62-1.30]; P =0.567) without occurrence of intracranial hemorrhage., Conclusions: Comparable efficacy exists between half- and full-dose tenecteplase pharmaco-invasive treatments with improved safety in patients with ST-segment-elevation myocardial infarction aged ≥75 years. Half-dose pharmaco-invasive therapy is a legitimate therapeutic option for elderly patients with ST-segment-elevation myocardial infarction unable to access timely primary PCI., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00623623. URL: https://www.clinicaltrials.gov; Unique identifier: NCT02777580., Competing Interests: Dr Bainey reports personal fees from Bayer, AstraZeneca, Boehringer Ingelheim, and HLS Therapeutics. Dr Welsh reports research grants from AstraZeneca and personal and travel fees from AstraZeneca, Bayer, and Boehringer Ingelheim. Dr Arias-Mendoza reports grants from Merck and Novo Nordisk, as well as personal fees from Novartis, Roche, Bayer, Boehringer Ingelheim, and Asofarma. Dr Ristic reports grants from Boehringer Ingelheim and Novartis, as well as travel fees from AstraZeneca and Pfizer. Dr Kerr Saraiva reports consulting fees from Boehringer Ingelheim, AstraZeneca, Novo Nordisk, Lilly, Janssen, Daiichi-Sankyo, and Bayer and payment or honoraria for lectures, presentations, speakers bureaus, article writing, or educational events from Novartis, Nova Quimica Brazil, Boehringer Ingelheim, AstraZeneca, Novo Nordisk, Lilly, Janssen, Daiichi-Sankyo, and Bayer. Dr French reports an unrestricted educational grant to partly support STREAM-2 (Strategic Reperfusion Early After Myocardial Infarction) recruitment in Australia. Dr Musić reports a grant from Boehringer Ingelheim and travel fees from AstraZeneca and Pfizer. Dr Sinnaeve reports consulting fees from Boehringer Ingelheim to his institution (KU Leuven). Dr Westerhout reports consulting fees from Bayer Canada. Dr Danays reports consulting fees from Boehringer Ingelheim. Dr Van de Werf reports institutional grants from Boehringer Ingelheim. Dr Armstrong reports institutional and personal grants from Merck, Bayer, CLS, Ltd, Eli Lilly, and Boehringer Ingelheim, and personal fees from Merck, Boehringer Ingelheim, Bayer, and Novo Nordisk. The other authors report no conflicts.

Introduction: Symptoms and functional limitation are frequently reported by survivors of acute pulmonary embolism (PE). However, current guidelines provide no specific recommendations on which patients should be followed after acute PE, when follow-up should be performed, and which tests it should include. Definition and classification of late PE sequelae are evolving, and their predictors remain to be determined., Methods: In a post hoc analysis of the Pulmonary Embolism Thrombolysis (PEITHO) trial, we focused on 219 survivors of acute intermediate-risk PE with clinical and echocardiographic follow-up 6 months after randomisation as well as over the long term (median, 3 years after acute PE). The primary outcome was a composite of (1) confirmed chronic thromboembolic pulmonary hypertension (CTEPH) or (2) 'post-PE impairment' (PPEI), defined by echocardiographic findings indicating an intermediate or high probability of pulmonary hypertension along with New York Heart Association functional class II-IV., Results: Confirmed CTEPH or PPEI occurred in 29 (13.2%) patients, (6 with CTEPH and 23 with PPEI). A history of chronic heart failure at baseline and incomplete or absent recovery of echocardiographic parameters at 6 months predicted CTEPH or PPEI at long-term follow-up., Conclusions: CTEPH or PPEI occurs in almost one out of seven patients after acute intermediate-risk PE. Six-month echocardiographic follow-up may be useful for timely detection of late sequelae.

Aims: The STREAM study randomly assigned ST-elevation myocardial infarction (STEMI) patients to receive a pharmacoinvasive versus primary percutaneous coronary intervention reperfusion strategy. We assessed whether there was an association between outcomes based on randomisation at a community hospital versus a prehospital location., Methods/results: Community hospital patients (358/1866 (19.2%)) were compared to prehospital patients and their outcomes categorised into pharmacoinvasive according to their treatment assignment. Compared to prehospital patients, community hospital patients had more diabetes (17.8% vs. 11.5%, P=0.001), higher Killip Class >1 (9.4% vs. 5.0%, P=0.002) and thrombolysis in myocardial infarction risk scores ⩾5 (18.2% vs. 12.4%, P=0.005). The 30-day primary endpoint (death, shock, congestive heart failure and re-infarction) for community hospital patients was 14.9% versus 13.2% for prehospital patients ( P=0.403). Community hospital pharmacoinvasive patients tended to receive less rescue (35.1% vs. 42.8%, P=0.062); when deployed their rescue was delayed 43 minutes. Community hospital patients undergoing primary percutaneous coronary intervention experienced a delay of 31 minutes versus prehospital patients. Pharmacoinvasive patients receiving scheduled angiography from a community hospital and prehospital patients had comparable times to angiography (17.7 vs. 18.7 hours) and low event rates (6.2% vs. 8.0%). Although the interaction between randomisation location and treatment received on the primary endpoint was not significant ( P interaction =0.065) those pharmacoinvasive patients requiring rescue from community hospitals had worse outcomes than prehospital rescue patients (odds ratio 2.28, 95% confidence interval 1.16-4.49)., Conclusion: Within STREAM, STEMI patients randomly assigned at community hospitals had a higher baseline risk but similar outcomes compared to those studied prehospital patients irrespective of successful pharmacoinvasive therapy or primary percutaneous coronary intervention. However, worse outcomes in the pharmacoinvasive patients requiring rescue in community hospitals emphasises their need for immediate transfer to a percutaneous coronary intervention-capable hospital.

Background: The long-term effect of thrombolytic treatment of pulmonary embolism (PE) is unknown., Objectives: This study investigated the long-term prognosis of patients with intermediate-risk PE and the effect of thrombolytic treatment on the persistence of symptoms or the development of late complications., Methods: The PEITHO (Pulmonary Embolism Thrombolysis) trial was a randomized (1:1) comparison of thrombolysis with tenecteplase versus placebo in normotensive patients with acute PE, right ventricular (RV) dysfunction on imaging, and a positive cardiac troponin test result. Both treatment arms received standard anticoagulation. Long-term follow-up was included in the third protocol amendment; 28 sites randomizing 709 of the 1,006 patients participated., Results: Long-term (median 37.8 months) survival was assessed in 353 of 359 (98.3%) patients in the thrombolysis arm and in 343 of 350 (98.0%) in the placebo arm. Overall mortality rates were 20.3% and 18.0%, respectively (p = 0.43). Between day 30 and long-term follow-up, 65 deaths occurred in the thrombolysis arm and 53 occurred in the placebo arm. At follow-up examination of survivors, persistent dyspnea (mostly mild) or functional limitation was reported by 36.0% versus 30.1% of the patients (p = 0.23). Echocardiography (performed in 144 and 146 patients randomized to thrombolysis and placebo, respectively) did not reveal significant differences in residual pulmonary hypertension or RV dysfunction. Chronic thromboembolic pulmonary hypertension (CTEPH) was confirmed in 4 (2.1%) versus 6 (3.2%) cases (p = 0.79)., Conclusions: Approximately 33% of patients report some degree of persistent functional limitation after intermediate-risk PE, but CTEPH is infrequent. Thrombolytic treatment did not affect long-term mortality rates, and it did not appear to reduce residual dyspnea or RV dysfunction in these patients. (Pulmonary Embolism Thrombolysis study [PEITHO]; NCT00639743)., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Elderly patients constitute a large and growing proportion of ST-elevation myocardial infarction (STEMI) patients, yet they have been under-represented or even excluded from reperfusion trials. Despite evidence that fibrinolysis improves outcomes irrespective of age, many elderly STEMI patients still remain undertreated or subject to major delays to primary percutaneous coronary intervention (PCI). The fear of an excessive risk of intracranial hemorrhage (ICH) in these patients can lead to avoidance of potentially life-saving reperfusion treatment, despite the fact that current STEMI guidelines do not exclude the elderly from a pharmaco-invasive strategy. Age-specific dose reductions have been succesfully made to antithrombotic drugs such as clopidogrel and enoxaparin as an adjunct to fibrinolysis, but until recently no dose adjustments for elderly patients have been applied to the fibrinolytic agents. In the pharmaco-invasive STREAM trial, halving the bolus of tenecteplase for patients aged >75 years because of an unacceptably high ICH rate in the elderly was associated with a more favorable safety/efficacy profile. Whether a pharmaco-invasive strategy including half-dose tenecteplase, age- and weight-adjusted enoxaparin, and a tailored P2Y12 inhibitor followed by routine angiography represents a safe and efficacious alternative reperfusion therapy for elderly patients remains to be prospectively assessed in a clinical trial in this age group.

Background: In the Strategic Reperfusion Early After Myocardial Infarction (STREAM) trial, a pharmaco-invasive (PI) strategy was compared with primary percutaneous coronary intervention (pPCI) in ST-segment-elevation myocardial infarction patients presenting within 3 hours after symptom onset but unable to undergo pPCI within 1 hour. At 30 days, the PI approach was associated with a nominally but nonstatistically significant lower incidence of the composite primary end point of death, shock, congestive heart failure, and reinfarction when compared with pPCI. The aim of the present study was to determine the effect of these strategies on 1-year mortality., Methods and Results: Vital status at 1 year was available in 936 of 944 (99.2%) and 941 of 948 (99.3%) patients in the PI and pPCI arm, respectively. At 1 year, all-cause mortality rates (6.7% versus 5.9%) were similar for PI and pPCI-treated patients (P=0.49; risk ratio, 1.13; 95% confidence interval, 0.79-1.62). Cardiac mortality rates were similar as well (4.0% versus 4.1%, P=0.93; risk ratio, 0.98; 95% confidence interval, 0.62-1.54). Overall, only 34 patients died between day 30 and 1 year, 20 in the PI arm and 14 in the pPCI arm, of whom 20 died of noncardiac reasons (13 in the PI and 7 in the pPCI arm). There was no significant difference in 1-year all-cause mortality between the 2 groups among the prespecified key subgroups., Conclusions: At 1 year, mortality rates in the PI and pPCI arms were similar in ST-segment-elevation myocardial infarction patients presenting within 3 hours after symptom onset and unable to undergo pPCI within 1 hour., Clinical Trial Registration Url: http://www.clinicaltrials.gov. Unique identifier: NCT00623623., (© 2014 American Heart Association, Inc.)

Although a fibrinolytic pharmacoinvasive strategy is recommended for patients with ST elevation myocardial infarction (STEMI) unable to undergo timely primary percutaneous coronary intervention (PCI), there are limited data addressing outcomes specific to those with successful or unsuccessful pharmacologic reperfusions. Accordingly, we evaluated a contemporary pharmacoinvasive strategy for failed and successful reperfusions within the STrategic Reperfusion Early After Myocardial infarction study. Of 1,823 per-protocol-treated patients with STEMI, we examined clinical outcomes and angiographic and electrocardiographic metrics in 3 groups as follows: fibrinolysis requiring rescue (rescue, n = 348), fibrinolysis with scheduled angiography (scheduled, n = 516), and primary PCI (n = 927). Compared with pharmacoinvasive patients undergoing scheduled angiography, rescue patients were more likely to have anterior wall myocardial infarction, more baseline ST-segment elevation and deviation, as well as Q waves in the distribution of their ST elevation. Residual ST elevation ≥ 2 mm 30 minutes after angiography occurred in 27.9%, 7.9%, and 24.8% of patients who underwent rescue, scheduled, and primary PCI, respectively. Thirty-day composite event rates (all-cause death, cardiogenic shock, heart failure, and reinfarction) were 18.7%, 5.5%, and 13.9%; all-cause death: 6.1%, 2.1%, and 3.9%; cardiogenic shock: 7.5%, 2.0%, and 5.4%; heart failure: 11.8%, 2.3%, and 7.6%; and reinfarction: 1.5%, 1.4%, and 2.2%, for rescue, scheduled, and primary PCI, respectively. Compared with successfully reperfused patients undergoing scheduled angiography, the adjusted relative risk of the primary outcome was 2.92 (95% confidence interval 1.92 to 4.45) in rescue patients. In conclusion, pharmacoinvasive-treated patients requiring rescue angiography had greater baseline risk with more co-morbidities and worse 30-day outcomes compared with successful fibrinolytic-treated patients. Residual ST elevation after reperfusion assists in defining prognosis., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: It is not known whether prehospital fibrinolysis, coupled with timely coronary angiography, provides a clinical outcome similar to that with primary percutaneous coronary intervention (PCI) early after acute ST-segment elevation myocardial infarction (STEMI)., Methods: Among 1892 patients with STEMI who presented within 3 hours after symptom onset and who were unable to undergo primary PCI within 1 hour, patients were randomly assigned to undergo either primary PCI or fibrinolytic therapy with bolus tenecteplase (amended to half dose in patients ≥75 years of age), clopidogrel, and enoxaparin before transport to a PCI-capable hospital. Emergency coronary angiography was performed if fibrinolysis failed; otherwise, angiography was performed 6 to 24 hours after randomization. The primary end point was a composite of death, shock, congestive heart failure, or reinfarction up to 30 days., Results: The primary end point occurred in 116 of 939 patients (12.4%) in the fibrinolysis group and in 135 of 943 patients (14.3%) in the primary PCI group (relative risk in the fibrinolysis group, 0.86; 95% confidence interval, 0.68 to 1.09; P=0.21). Emergency angiography was required in 36.3% of patients in the fibrinolysis group, whereas the remainder of patients underwent angiography at a median of 17 hours after randomization. More intracranial hemorrhages occurred in the fibrinolysis group than in the primary PCI group (1.0% vs. 0.2%, P=0.04; after protocol amendment, 0.5% vs. 0.3%, P=0.45). The rates of nonintracranial bleeding were similar in the two groups., Conclusions: Prehospital fibrinolysis with timely coronary angiography resulted in effective reperfusion in patients with early STEMI who could not undergo primary PCI within 1 hour after the first medical contact. However, fibrinolysis was associated with a slightly increased risk of intracranial bleeding. (Funded by Boehringer Ingelheim; ClinicalTrials.gov number, NCT00623623.).

Background: Primary percutaneous coronary intervention (PCI) has emerged as the preferred therapy for acute ST-elevation myocardial infarction (STEMI) provided it is performed in a timely fashion at an expert 24/7 facility. Fibrinolysis is a well-accepted alternative, especially in patients presenting early after symptom onset. The STREAM study will provide novel information on whether prompt fibrinolysis at first medical contact, followed by timely catheterization or rescue coronary intervention in STEMI patients presenting within 3 hours of symptom onset, represents an appropriate alternative strategy to primary PCI., Methods: Acute STEMI patients presenting early after symptom onset are eligible if PCI is not feasible within 60 minutes of first medical contact. This is an open-label, prospective, randomized, parallel, comparative, international multicenter trial. Patients are randomized to fibrinolysis combined with enoxaparin, clopidogrel, and aspirin, and cardiac catheterization within 6 to 24 hours or rescue coronary intervention if reperfusion fails within 90 minutes of fibrinolysis versus PCI performed according to local guidelines. Composite efficacy end points at 30 days include death, shock, heart failure, and reinfarction. Safety end points include ischemic stroke, intracranial hemorrhage, and major nonintracranial bleeding. Follow-up is extended to 1 year and includes all-cause mortality., Discussion: Continuing delays in achieving timely PCI remain a difficult issue. Many patients fail to achieve the desired reperfusion times of 90 to 120 minutes after first medical contact. The STREAM results will provide useful additional data on which to base informed therapeutic decisions., (Copyright (c) 2010 Mosby, Inc. All rights reserved.)

Background: Approximately 70% of persons who have an out-of-hospital cardiac arrest have underlying acute myocardial infarction or pulmonary embolism. Therefore, thrombolysis during cardiopulmonary resuscitation may improve survival., Methods: In a double-blind, multicenter trial, we randomly assigned adult patients with witnessed out-of-hospital cardiac arrest to receive tenecteplase or placebo during cardiopulmonary resuscitation. Adjunctive heparin or aspirin was not used. The primary end point was 30-day survival; the secondary end points were hospital admission, return of spontaneous circulation, 24-hour survival, survival to hospital discharge, and neurologic outcome., Results: After blinded review of data from the first 443 patients, the data and safety monitoring board recommended discontinuation of enrollment of asystolic patients because of low survival, and the protocol was amended. Subsequently, the trial was terminated prematurely for futility after enrolling a total of 1050 patients. Tenecteplase was administered to 525 patients and placebo to 525 patients; the two treatment groups had similar clinical profiles. We did not detect any significant differences between tenecteplase and placebo in the primary end point of 30-day survival (14.7% vs. 17.0%; P=0.36; relative risk, 0.87; 95% confidence interval, 0.65 to 1.15) or in the secondary end points of hospital admission (53.5% vs. 55.0%, P=0.67), return of spontaneous circulation (55.0% vs. 54.6%, P=0.96), 24-hour survival (30.6% vs. 33.3%, P=0.39), survival to hospital discharge (15.1% vs. 17.5%, P=0.33), or neurologic outcome (P=0.69). There were more intracranial hemorrhages in the tenecteplase group., Conclusions: When tenecteplase was used without adjunctive antithrombotic therapy during advanced life support for out-of-hospital cardiac arrest, we did not detect an improvement in outcome, in comparison with placebo. (ClinicalTrials.gov number, NCT00157261.), (2008 Massachusetts Medical Society)

Background: The optimal antithrombotic therapy to accompany tenecteplase in cases of acute ST-segment elevation myocardial infarction (STEMI) remains unclear. We undertook a prespecified pooled analysis of data from the ASSENT-3 and ASSENT-3 PLUS trials., Methods: We created a combined database of the 2040 and 818 patients who received enoxaparin in ASSENT-3 and ASSENT-3 PLUS, respectively, and compared them with the 2038 and 821 patients who received unfractionated heparin., Results: The efficacy end point (a composite of 30-day mortality, reinfarction or refractory ischemia) was 12.2% with enoxaparin versus 16.0% with unfractionated heparin (p < 0.001); the combined end point of efficacy plus safety (a composite of 30-day mortality, reinfarction, refractory ischemia, intracranial hemorrhage [ICH] or major systemic bleeding) was 15.0% versus 18.0%, respectively (p = 0.003) [corrected] The 1049 patients urgently revascularized had greater benefit from enoxaparin (15.4% v. 10.1%, p = 0.013), yet the excess in major systemic bleeding evident with enoxaparin (3.3% v. 2.4%, p = 0.01) was largely confined to the 3492 patients without or before revascularization. Although ICH rates in the groups were similar (1.3% v. 0.9%, p = 0.26), an excess of ICH occurred among those administered enoxaparin during the ASSENT-3 PLUS trial (6.7% v. 0.8%, p = 0.013), especially among women over 75 years of age., Interpretation: These data demonstrated the benefit of enoxaparin used in conjunction with tenecteplase, but raised caution about its prehospital use to treat STEMI in elderly women.

We investigated the effect of smaller dose, weight-adjusted heparin with earlier monitoring of activated partial thromboplastin time on the incidence of ischemic and hemorrhagic complications in patients with ST-elevation myocardial infarction treated with full-dose tenecteplase. We compared the outcomes of patients enrolled in the Second Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT-2; n = 8,461) who received heparin stratified by weight (patients weighing >67 kg received a 5,000-U bolus plus infusion at 1,000 U/hour; those weighing < or =67 kg received a 4,000-U bolus plus infusion at 800 U/hour) with patients in ASSENT-3 who received weight-adjusted heparin (60-U/kg bolus, maximum 4,000 U/hour, followed by a 12-U/kg/hour infusion, maximum 1,000 U/hour). Compared with patients in ASSENT-2, those in ASSENT-3 had similar rates of 30-day mortality, recurrent infarction, and intracranial hemorrhage, less major bleeding (2.2% vs 4.7%, p <0.001), and less refractory ischemia (6.5% vs 8.6%, p <0.001). After adjustment for baseline characteristics, patients in ASSENT-3 had similar rates of 30-day mortality (odds ratio [OR] 0.96, 95% confidence interval [CI] 0.77 to 1.19) and intracranial hemorrhage (OR 1.02, 95% CI 0.61 to 1.69) but less major bleeding (OR 0.49, 95% CI 0.35 to 0.67) than did patients in ASSENT-2. These findings support the use of smaller dose, weight-adjusted heparin in patients with ST-elevation myocardial infarction treated with tenecteplase.

Background: The combination of a single-bolus fibrinolytic and a low-molecular-weight heparin may facilitate prehospital reperfusion and further improve clinical outcome in patients with ST-elevation myocardial infarction., Methods and Results: In the prehospital setting, 1639 patients with ST-elevation myocardial infarction were randomly assigned to treatment with tenecteplase and either (1) intravenous bolus of 30 mg enoxaparin (ENOX) followed by 1 mg/kg subcutaneously BID for a maximum of 7 days or (2) weight-adjusted unfractionated heparin (UFH) for 48 hours. The median treatment delay was 115 minutes after symptom onset (53% within 2 hours). ENOX tended to reduce the composite of 30-day mortality or in-hospital reinfarction, or in-hospital refractory ischemia to 14.2% versus 17.4% for UFH (P=0.080), although there was no difference for this composite end point plus in-hospital intracranial hemorrhage or major bleeding (18.3% versus 20.3%, P=0.30). Correspondingly, there were reductions in in-hospital reinfarction (3.5% versus 5.8%, P=0.028) and refractory ischemia (4.4% versus 6.5%, P=0.067) but increases in total stroke (2.9% versus 1.3%, P=0.026) and intracranial hemorrhage (2.20% versus 0.97%, P=0.047). The increase in intracranial hemorrhage was seen in patients >75 years of age., Conclusions: Prehospital fibrinolysis allows 53% of patients to receive reperfusion treatment within 2 hours after symptom onset. The combination of tenecteplase with ENOX reduces early ischemic events, but lower doses of ENOX need to be tested in elderly patients. At present, therefore, tenecteplase and UFH are recommended as the routine pharmacological reperfusion treatment in the prehospital setting.

Tenecteplase is a novel fibrinolytic protein bioengineered from human tissue plasminogen activator (alteplase) for the therapy of acute ST-segment elevation myocardial infarction. Specific mutations at three sites in the alteplase molecule result in 15-fold higher fibrin specificity, 80-fold reduced binding affinity to the physiological plasminogen activator inhibitor PAI-1 and 6-fold prolonged plasma half-life (22 vs 3.5 minutes). Consequently, tenecteplase can be administered as a single intravenous bolus of 30-50mg (0.53 mg/kg bodyweight) over 5-10 seconds, in contrast to the 90-minute accelerated infusion regimen of alteplase. Tenecteplase plasma concentration-time profiles have been obtained from a total of 179 patients with acute myocardial infarction. Tenecteplase exhibited biphasic disposition; the initial disposition phase was predominant with a mean half-life of 17-24 minutes, and the mean terminal half-life was 65-132 min. Over the clinically relevant dose range of 30-50mg, mean clearance (CL) was 105 ml/min. The mean initial volume of distribution V(1) was 4.2-6.3L, approximating plasma volume, and volume of distribution at steady state was 6.1-9.9L, suggesting limited extravascular distribution or binding. Bodyweight and age were found to influence significantly both CL and V(1). Total bodyweight explained 19% of the variability in CL and 11% of the variability in V(1), and a 10kg increase in total bodyweight resulted in a 9.6 ml/min increase in CL. This relationship aided the development of a rationale for the weight-adjusted dose regimen for tenecteplase. Age explained only a further 11% of the variability in CL. The percentage of patients who achieved normal coronary blood flow was clearly related to AUC. More than 75% of patients achieved normal flow at 90 minutes after administration when their partial AUC(2-90) exceeded 320 microg.min/ml, corresponding to an average plasma concentration of 3.6 microg/ml. Systemic exposure to tenecteplase at all times after bolus administration of 30-50mg was higher than for alteplase 100mg. Tenecteplase has demonstrated equivalent efficacy and improved safety compared with the current gold standard alteplase in a large mortality trial (ASSENT-2). This suggests that the reduced clearance, greater fibrin specificity and higher PAI-1 resistance of tenecteplase allow higher plasma concentrations and thus a more rapid restoration of coronary patency to be attained, while providing a reduction in major non-cerebral bleeding events.

Prehospital cardiac arrest has been associated with a very poor prognosis. Acute myocardial infarction and massive pulmonary embolism are the underlying causes of out-of-hospital cardiac arrest in 50–70% of patients. Although fibrinolysis is an effective treatment strategy for both myocardial infarction and pulmonary embolism, clinical experience for this therapy performed during resuscitation has been limited owing to the anticipated risk of severe bleeding complications. The TROICA study is planned as one of the largest randomized, double-blind, placebo-controlled trials to assess the efficacy and safety of prehospital thrombolytic therapy in cardiac arrest of presumed cardiac origin. Approximately 1000 patients with cardiac arrest will be randomized at approximately 60 international study centres to receive either a weight-adjusted dose of tenecteplase or placebo after the first dose of a vasopressor. Patients can be included if they are at least 18 years, presenting with a witnessed cardiac arrest of presumed cardiac origin, and if either basic life support had started within 10 min of onset and had been performed up to 10 min or advanced life support is started within 10 min of onset of cardiac arrest. Primary endpoint of the study is the 30-day survival rate, and the coprimary endpoint is hospital admission. Secondary endpoints are the return of spontaneous circulation (ROSC), survival after 24 h, survival to hospital discharge, and neurological performance. Safety endpoints include major bleeding complications and symptomatic intracranial haemorrhage.Eur J Clin Invest 2005; 35 (5): 315 –323 [ABSTRACT FROM AUTHOR]